The 50th Annual Meeting of the European Society for Blood and Marrow Transplantation: Physicians - Oral Session (O009-O154) (2024)

Table of Contents
19: Acute Leukaemia O009 THE DISEASE RISK STRATIFICATION SYSTEM (DRSS): VALIDATION AND REFINEMENT IN A CONTEMPORARY ACUTE LEUKEMIA COHORT - AN ALWP EBMT STUDY Roni Shouval 1, Myriam Labopin2, Joshua Fein3, Jurjen Versluis4, Matthias Stelljes5, Nicolaus Kröger6, Igor Wolfgang Blau7, Thomas Schroeder8, Matthias Eder9, Didier Blaise10, Ibrahim Yakoub-Agha11, Eva Maria Wagner-Drouet12, Régis Peffault de Latour13, Johannes Schetelig14, Tobias Gedde-Dahl15, Peter Dreger16, Anne Huynh17, Fabio Ciceri18, Mohamad Mohty2, Arnon Nagler19 O01020-YEAR STEADY INCREASE IN POST-ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION OUTCOMES FOR PATIENTS WITH PHILADELPHIA-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA. A STUDY FROM THE EBMT ACUTE LEUKEMIA WORKING PARTY Ali Bazarbachi 1, Myriam Labopin2, Iman Abou Dalle1, Ibrahim Yakoub-Agha3, Régis Peffault de Latour4, Thomas Schroeder5, Didier Blaise6, Xavier Poiré7, Marie Balsat8, Urpu Salmenniemi9, Nicolaus Kröger10, Alexander Kulagin11, Eva Maria Wagner-Drouet12, Depei Wu13, Eolia Brissot14, Arnon Nagler15, Sebastian Giebel16, Fabio Ciceri17, Mohammad Mohty14 O011 PROGNOSTIC FACTORS IMPACTING POST-TRANSPLANT OUTCOMES IN ADULT T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA: A REGISTRY-BASED STUDY BY THE EBMT ACUTE LEUKEMIA WORKING PARTY Jean El Cheikh 1, Maud Ngoya2, Jacques-Emmanuel Galimard2, Péter Reményi3, Alexander Kulagin4, Mahmoud Aljurf5, Ashrafsadat Mousavi6, Depei Wu7, Mutlu Arat8, Urpu Salmenniemi9, Cristina Castilla-Llorente10, Gerard Socie11, Grzegorz Helbig12, Thomas Schroeder13, Ioanna Sakellari14, Alessandro Rambaldi15, Ben Carpenter16, Alessandro Busca17, Helene Labussiere-Wallet18, Matthias Stelljes19, Eolia Brissot20, Sebastien Giebel21, Zina Peric22, Arnon Nagler23,24, Ali Bazarbachi25, Fabio Ciceri26, Mohamad Mohty20 O012 A MULTI-CENTER RETROSPECTIVE ANALYSIS OF OUTCOMES POST-ALLO-HCT IN TET2-MUTATED AML PATIENTS: A STUDY ON BEHALF OF THE GLOBAL COMMITTEE AND THE ALWP OF THE EBMT Lin Li 1, Yishan Ye1, Jacques-Emmanuel Galimard2, Myriam Labopin2, Depei Wu3, Jia Chen3, Nicolaus Kröger4, Jakob Passweg5, Urpu Salmenniemi6, Maija Itäla-remes7, Xavier Poiré8, Matthias Eder9, Johan Maertens10, David Burns11, Henrik Sengeloev12, Gitte Olesen13, Didier Blaise14, Jürgen Finke15, Alain Gadisseur16, Ali Bazarbachi17, Eolia Brissot2, Arnon Nagler18, Yi Luo1, Jimin Shi1, Fabio Ciceri19, Mohamad Mohty2, He Huang1, Norbert Claude Gorin2 O013 RELAPSE INCIDENCE POST UNRELATED ALLOGENEIC STEM CELL TRANSPLANTATION WITH POST-TRANSPLANT CYCLOPHOSPHAMIDE FOR ACUTE MYELOID LEUKEMIA IN FIRST COMPLETE REMISSION: FROM THE ALWP OF THE EBMT Arnon Nagler 1, Maud Ngoya2, Jacques-Emmanuel Galimard2, Myriam Labopin3,4, Igor Wolfgang Blau5, Nicolaus Kröger6, Tobias Gedde-Dahl7, Thomas Schroeder8, David Burns9, Urpu Salmenniemi10, Alessandro Rambaldi11, Goda Choi12, Régis Peffault de Latour13, Jan Vydra14, Henrik Sengeloev15, Matthias Eder16, Stephan Mielke17, Edouard Forcade18, Sergey Bondarenko19, Fabio Ciceri20, Mohamad Mohty3,4 O014 COMPARATIVE STUDY FOR HAPLO, MSD AND MUD ALLO-HCTS FOR CBF AML PATIENTS IN CR2: A STUDY FROM THE GLOBAL COMMITTEE AND ALWP OF THE EBMT Yishan Ye 1, Myriam Labopin2, Socié Gérard3, Ibrahim Yakoub-Agha4, Igor Wolfgang Blau5, Mahmoud Aljurf6, Edouard Forcade7, Tobias Gedde-Dahl8, David Burns9, Jan Vydra10, Khaled Halahleh11, Rose-Marie Hamladji12, Ali Bazarbachi13, Arnon Nagler14, Eolia Brissot2, Lin Li1, Yi Luo1, Yanmin Zhao1, Fabio Ciceri15, He Huang1, Mohamad Mohty2,16, Norbert Claude Gorin2,16 O015 ALLOGENEIC TRANSPLANTATION FOR PATIENTS WITH ACUTE MYELOID LEUKEMIA WITH MYELODYSPLASIA-RELATED FEATURES AS PER THE INTERNATIONAL CONSENSUS CLASSIFICATION (ICC) 2022: FROM THE ALWP OF THE EBMT Arnon Nagler 1, Myriam Labopin2,3, Jurjen Versluis4, Jaime Sanz5, Tobias Gedde-Dahl6, David Burns7, Michel Schaap8, Hélène Labussière-Wallet9, Peter von dem Borne10, Gwendolyn Van Gorkom11, Nathalie Contentin12, Andreas Neubauer13, Eva Maria Wagner-Drouet14, Nicolaus Kröger15, Jordi Esteve16, Fabio Ciceri17, Mohamad Mohty2,3 O016 IMPACT OF MYELODYSPLASIA-RELATED GENE MUTATIONS ON OUTCOMES OF ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION WITH POST-TRANSPLANT SORAFENIB MAINTENANCE IN FLT3-ITD AML PATIENTS: A MULTI-CENTER, RETROSPECTIVE COHORT STUDY Yeqian Zhao1,2,3,4, Jimin Shi1,2,3,4, Yi Luo1,2,3,4, Guifang Ouyang5, Lieguang Chen5, Jian Yu1,2,3,4, Yamin Tan6, Xiaoyu Lai1,2,3,4, Lizhen Liu1,2,3,4, Huarui Fu1,2,3,4, Yishan Ye1,2,3,4, Luxin Yang1,2,3,4, Congxiao Zhang1,2,3,4, He Huang1,2,3,4, Xiaoxia Hu1,2,3,4, Yanmin Zhao 1,2,3,4 O01720-YEAR STEADY INCREASE IN POST-ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION OUTCOMES FOR OLDER PATIENTS WITH ACUTE MYELOID LEUKEMIA: A REPORT FROM THE EBMT ACUTE LEUKEMIA WORKING PARTY Ali Bazarbachi 1, Myriam Labopin2, Nour Moukalled1, Nicolaus Kröger3, Christina Rautenberg4, Johannes Schetelig5, Jürgen Finke6, Igor Wolfgang Blau7, Didier Blaise8, Matthias Stelljes9, Matthias Eder10, Uwe Platzbecker11, Peter Dreger12, Wolfgang Bethge13, Johanna Tischer14, David Burns15, Henrik Sengeloev16, Eolia Brissot17, Sebastian Giebel18, Arnon Nagler19, Fabio Ciceri20, Mohamad Mohty21 O018 IMPACT OF GERMLINE RUNX1 MUTATIONS ON ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT OUTCOMES IN AML: A CIBMTR ANALYSIS Kai Yu1, Jakob D. Devos2, Mei-Jie Zhang2, Kristin Page2, Nelli Bejanyan3, Partow Kebriaei4, Filippo Milano5, Rachel Cook6,7, Brian J. Druker6,7, Katrin Ericson8, Paul Liu1, Wael Saber2, Lea Cunningham 1,9 O019 ALLOGENEIC STEM CELL TRANSPLANTATION FOR ACUTE MYELOID LEUKEMIA WITH GERMLINE DDX41 MUTATIONS: A COMPARATIVE STUDY FROM THE ALFA-FILO-SFGMTC Michael Loschi 1, Jacques-Emmanuel Galimard2, Matthieu Duchmann3, Laetitia Largeaud4, Pascal Turlure5, Stéphanie Nguyen Quoc6, Flore Sicre de Fontbrune7, Marie Robin8, Ibrahim Yakoub Agha9, Etienne Daguindau10, Sylvain Chantepie11, Amandine Charbonnier12, Sebastien Maury13, Helene Labussiere-Wallet14, Anne Huynh4, Edouard Forcade15, Cristina Castilla-Llorente16, Thomas Cluzeau1, Marie-Thérèse Rubio17, Raynier Devillier18, Natacha Maillard19, Herve Dombret7, Christian Recher4, Arnaud Pigneux15, Eric Delabesse4, Nicolas Duployez20, Regis Peffault de Latour8, Marie Sébert8 O020 A CASEMIX OUTCOME STRATIFICATION MODEL FOR SCT USING MACHINE LEARNING (COSMOS) Erik G J. von Asmuth 1, Liesbeth C. de Wreede1, Constantijn J M. Halkes1, Dirk-Jan A. Eikema2, Riccardo Saccardi3, Mette D. Hazenberg4, María Paula Busto2, John A. Snowden5, Anna Sureda6, Arjan C. Lankester1, Hein Putter1 O021 DOES SIZE MATTER? CENTER-SPECIFIC CHARACTERISTICS AND SURVIVAL AFTER ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION (ALLOHCT) FOR ACUTE MYELOBLASTIC LEUKEMIA (AML): A DRST ANALYSIS Wolfgang Bethge 1, Sarah Flossdorf2, Franziska Hanke3, Christoph Schmid4, Mark Ringhoffer5, Stefan Klein6, Bernd Hertenstein7, Johannes Schetelig8, Matthias Stelljes9, Thomas Schroeder10, Igor Blau11, Francis Ayuk12, Matthias Eder13, Robert Zeiser14, Katharina Fleischhauer10, Nicolaus Kröger12, Peter Dreger15 O022 MATCHED RELATED VERSUS MATCHED UNRELATED VERSUS HAPLOIDENTICAL DONORS IN FLT3-ITD + AML PATIENTS IN CR1: A STUDY FROM THE EBMT ACUTE LEUKEMIA WORKING PARTY Eolia Brissot 1, Myriam Labopin2, Eleni Tholouli3, Tobias Gedde-Dahl4, Mahmoud Aljurf5, Gérard Socié6, David Burns7, Ibrahim Yakoub-Agha8, Matthias Stelljes9, Thomas Schroeder10, Nicolaus Kröger11, Edouard Forcade12, Claude Eric Bulabois13, Urpu Salmenniemi14, Alessandro Rambaldi15, Ali Bazarbachi16, Arnon Nagler17, Simona Piemontese18, Jaime Sanz19, Mohamad Mohty2, Fabio Ciceri18 O023 THE USE OF GANCICLOVIR OR VALGANCICLOVIR DOES NOT INCREASE RELAPSE RISK FOLLOWING ALLOGENEIC STEM CELL TRANSPLANTATION IN PATIENTS WITH ACUTE MYELOID LEUKEMIA OR MYELODYSPLASTIC SYNDROME Nihar Desai 1, Carol Chen1, Ivan Pasic1,2, Wilson Lam1,2, Arjun Law1,2, Armin Gerbitz1,2, Auro Viswabandya1,2, Fotios Michelis1,2, Rajat Kumar1,2, Jonas Mattsson1,2, Igor Novitzky-Basso1,2, Dennis Dong Hwan Kim1,2 O024 EXCELLENT OUTCOME OF PATIENTS PROCEEDING TO ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION WITH UNTREATED MOLECULAR RELAPSE OF NPM1-MUTATED AML Gesine Bug 1, Kerstin Schäfer-Eckart2, Carina Rave3, Henning Baldauf3, Fabian Lang1, Knut Wendelin2, Katja Sockel4, Christian Reicherts5, Vera Schlipfenbacher1, Julia-Annabell Georgi4, Christoph Schliemann5, Marek Werth1, Katharina Egger-Heidrich4, Julia Marx5, Simon Call5, Heike Pfeifer1, Christian Thiede6, Johannes Schetelig4, Matthias Stelljes5 O025PRE-HCT NEXT-GENERATION SEQUENCING (NGS-MRD) AND OUTCOMES OF PEDIATRIC, ADOLESCENT, AND YOUNG ADULT B-ALL PATIENTS UNDERGOING ALLOGENEIC HCT: UPDATE FROM THE OBSERVATIONAL ARM OF PTCTC ONC1701 Troy Quigg 1, Neena Kapoor2, Jemily Malvar2, Elizabeth Gourdine2, Amy Keating3,4, Leslie Lehmann3, Kris Mahadeo5,6, Sajad Khazal7,6, Jodi Skiles8, Dana Salzberg9, Rachel Phelan10, Nahal Lalefar11, Emi Caywood12, Rabi Hanna13, Shalini Shenoy14, Heather Stefanski15, Jordan Milner16, Kevin McNerney17,18, Christine Higham19, Ulrich Duffner1, Joseph Chewning20, Niketa Shah21,22, Jeffrey Huo23, Ibrahim Ahmed24, Michael Pulsipher25, Hisham Abdel-Azim7 O026 IMPAIRED CD45RO-CCR7 + NAÏVE CD8 + T CELLS IN AML ARE ASSOCIATED WITH LOWER OVERALL SURVIVAL Yongping Zhang 1, Hujun Li1, Hui Zhang1, Qi Ji1, Shaoyan Hu1 O027 USING AN ARTIFICIAL INTELLIGENCE MODEL TO QUANTIFY UNDER-UTILISATION OF ALLOGENEIC STEM CELL TRANSPLANTATION FOR ACUTE MYELOID LEUKAEMIA IN UK Thomas Coats 1, Toby Winter2, Grace Walburn2, Rob Bennett2, Pramila Krishnamurthy3, Victoria Potter3, Justin Loke4,5, Steve Knapper6, Julia Lee7, Rachel Pearce7, Ram Malladi8, Robin Adlam2, Charles Craddock9 O028 REAL-WORLD EXPERIENCE WITH CPX-351 FOR PATIENTS WITH AML – LONG-TERM FOLLOW-UP WITH FOCUS ON YOUNGER PATIENTS (<60 YEARS OLD) AND ALLOGENEIC STEM CELL TRANSPLANTATION Christina Rautenberg 1, Friedrich Stoelzel2, Christoph Roellig3, Matthias Stelljes4, Verena Gaidzik5, Oliver Kriege6, Mareike Verbeek7, Julia Unglaub8, Felicitas Thol9, Stefan Krause10, Mathias Haenel11, Charlotte Neuerburg12, Vladan Vucinic13, Christian-Friedrich Jehn14, Maxi Weiss15, Lars Fransecky2, Jens Chemnitz16, Kerstin Schäfer-Eckart17, Josephine Schröder18, Sabrina Kraus19, William Krüger20, Ulrich Kaiser21, Sebastian Scholl22, Guido Kobbe23, Paul Jäger23, Nael Alakel3, Malte von Bonin3, Katja Sockel3, Maher Hanoun1, Uwe Platzbecker13, Tobias Holderried12, Anke Morgner11, Michael Heuser9, Tim Sauer8, Katharina Götze7, Eva Wagner6, Konstanze Döhner5, Hartmut Döhner5, Christoph Schliemann4, Johannes Schetelig3, Martin Bornhäuser3, Ulrich Germing23, Thomas Schroeder1, Moritz Middeke3 O029 CELLULAR HIERARCHY FOR UNDERSTANDING HETEROGENEITY OF ACUTE MYELOID LEUKEMIA WITH T (8;21)/RUNX1-RUNX1T1 Yibo Wu 1,2,3,4, Xiaolin Yuan1,2,3,4, Xiaoyu Lai1,2,3,4, Lizhen Liu1,2,3,4, Lihong Ni5, Shanshan Hu6, Jimin Shi1,2,3,4, Weiyan Zheng1,2,3,4, Jian Yu1,2,3,4, Yanmin Zhao1,2,3,4, Jie Sun1,2,3,4, Xiujin Ye1,2,3,4, Zhen Cai1,2,3,4, He Huang1,2,3,4, Shanshan Pei1,2,3,4, Yi Luo1,2,3,4 O030 PREDICTING TRANSPLANTATION-, TRANSFUSION- AND TREATMENT-FREE SURVIVAL AFTER IMMUNE SUPPRESSIVE TREATMENT FOR ADULTS WITH ACQUIRED APLASTIC ANEMIA Cjm Halkes 1, Eas Koster1, Ejm Bogers1, Lgm Daenen2, Sk Klein3, Smc Langemeijer4, F. Moenen5, E. Nur6,7, Mhg Raaijmakers8, Tjf Snijders9, Jennifer ML Tjon1, L.C. de Wreede1 O031 UPFRONT MATCHED UNRELATED DONOR HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR SEVERE IDIOPATHIC APLASTIC ANEMIA AND REFRACTORY CYTOPENIA OF CHILDHOOD IN PEDIATRIC PATIENTS. SPANISH EXPERIENCE M.Luz Uria-Oficialdegui 1, Victor Quintero2, M.Isabel Benitez-Carabante1, Maria Travazo3, David Bueno2, Marta Gonzalez-Vicent4, Monica Lopez-Duarte5, Jaime Verdu6, Carolina Fuentes7, Graciela Gomez8, Laura Murillo-SanJuan1, Laura Alonso1, Melissa Panesso1, Crsitina Diaz-de-Heredia1 O032 UNRELATED DONOR TRANSPLANTATION IN APLASTIC ANEMIA WITH A QUADRUPLE GVHD PROPHYLAXIS Andrea Bacigalupo1, Nicola Mordini2, Francesco Zallio3, Irene Cavattoni4, Luca Castagna5, Anna Paola Iori6, Patrizia Chiusolo7, Federica Sora’7, Sabrina Giammarco 7, Elisabetta Metafuni7, Alessandro Busca8, Alessandra Carotti9, Fabio Benedetti10, Giorgia Saporiti11, Simona Sica7 O033 CLINICAL OUTCOMES OF HIGH DOSE IMMUNOSUPPRESSIVE THERAPY (HDIT) WITH AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION (AHSCT) IN MULTIPLE SCLEROSIS PATIENTS: LONG-TERM SINGLE CENTER EXPERIENCE Denis Fedorenko 1, Vladimir Melnichenko1, Anatoly Rukavitsin1, Nikolai Vasilev1, Ilya Nikolaev1, Tatiana Nikitina2, Natalia Porfirieva3, Tatiana Ionova2 O034 AUTOLOGOUS HSCT IN MULTIPLE SCLEROSIS: THE UK EXPERIENCE 2002-2023 (ON BEHALF OF THE BSBMT CTC GROUP) Majid Kazmi 1, Paolo Muraro2, Varun Mehra3, Ian Gabriel4, Eleonora De Matteis2, Gavin Brittain5, Richard Nicholas4, Eli Silber3, Julia Lee6, Rachel Pearce6, Ruth Paul6, Maria Pia Sormani7, Victoria Potter3, Eduardo Olavarria4, Ram Malladi8, Basil Sharrack5, John Snowden5 O035 AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN AGGRESSIVE MULTIPLE SCLEROSIS – A 25-YEAR MONOCENTRIC EXPERIENCE Alice Mariottini 1, Chiara Nozzoli2, Alessandro Barilaro2, Riccardo Boncompagni2, Ilaria Cutini2, Antonella Gozzini2, Chiara Innocenti2, Anna Maria Repice2, Luisa Pastò2, Maria Pia Amato1, Luca Massacesi1, Riccardo Saccardi2 O036 BEAM/ATG OR CYCLOPHOSPHAMIDE/ATG AS CONDITIONING REGIMEN IN AUTOLOGOUS TRANSPLANTATION FOR MULTIPLE SCLEROSIS: A RETROSPECTIVE ANALYSIS OF THE EBMT AUTOIMMUNE DISEASES WORKING PARTY Riccardo Saccardi 1, Marta Ponzano2, Manuela Badoglio3, Grzegorz Helbig4, Marek Smilowsky4, Alice Mariottini1, Joachim Burman5, Kristina Carlson5, Majid Kazmi6, Paolo Muraro7, Jane Apperley8, Barbara Withers9, Jennifer Massey9, Riccardo Varaldo10, Matilde Inglese2, Jaime Sanz11, Sara Garcia Gil-Perotin11, Basil Sharrack12, Tobias Alexander13, Raffaella Greco14, John Snowden12 O037 AUTOLOGOUS HSCT FOR MULTIPLE SCLEROSIS SHOULD BE DONE EARLY IN THE COURSE OF THE DISEASE María de Lourdes Pastelín-Martínez1, Moisés Manuel Gallardo-Pérez2, Andres Gómez-De-León3, Juan Carlos Olivares-Gazca2, Edgar Jared Hernández-Flores4, Daniela Sánchez-Bonilla2, Merittzel Abigail Montes-Robles1, Max Robles-Nasta2, Guillermo Ocaña-Ramm4, Silvia Soto-Olvera4, David Gómez-Almaguer3, Guillermo José Ruiz-Delgado 2,4, Guillermo José Ruiz-Arguelles2,4 O038 ENGINEERED AIR-TREG CELLS AS A NOVEL THERAPY CONCEPT FOR INFLAMMATION-DRIVEN DISEASES Sebastian Bittner 1, Thomas Hehlgans1, Markus Feuerer1 O039 DONOR-DERIVED IMMUNE RECONSTITUTION PROFILE OF AGGRESSIVE NEUROMYELITIS OPTICA IN LONG-TERM DISEASE REMISSION AFTER ALLOGENEIC TRANSPLANTATION Giorgio Orofino 1, Angela Genchi1, Maria Teresa Lupo-Stanghellini1, Matteo Doglio1, Maddalena Noviello1, Alessandra Mandelli1, Sara Mastaglio1, Simona Piemontese1, Elena Tassi1, Francesca Ferrua1, Roberto Furlan1, Gianvito Martino1,2, Massimo Filippi1,2, Massimo Bernardi1, Consuelo Corti1, Jacopo Peccatori1, Francesca Tortorelli1, Cristina Toffalori1, Luca Vago1,2, Chiara Bonini1,2, Lucia Moiola1, Fabio Ciceri1,2, Raffaella Greco1 O040 SITE-SPECIFIC RESPONSES AND EXTRANODAL INVOLVEMENT IMPLICATIONS IN LARGE B-CELL LYMPHOMAS TREATED WITH CD19-CART THERAPY Alejandro Luna de Abia 1, Sean M. Devlin1, Jessica Flynn1, Magdalena Corona de Lapuerta1, Efrat Luttwak1, Ivan Landego1, Parastoo B. Dahi1, Richard J. Lin1, Allison Parascondola1, M.Lia Palomba1, Gunjan L. Shah1, Michael Scordo1, Brandon S. Imber1, Ana Alarcón Tomás1, Gilles Salles1, Jae H. Park1, Miguel-Ángel Perales1, Roni Shouval1 O041 DONOR-DERIVED CAR-T CELLS ARE SAFELY AND EFFECTIVELY CO-INFUSED WITH THE ALLOGENIC GRAFT, DEPLETED OF AB T CELLS IN CHILDREN WITH ADVANCED B-CELL NEOPLASM Larisa Shelikhova1, Olga Molostova1, Arina Rakhteenko1, Margarita Perminova1, Maria Dunaykina1, Elena Kurnikova1, Yakov Muzalevsky1, Dmitriy Pershin1, Maria Fadeeva1, Olga Illarionova1, Alexander Popov1, Daria Kobyzeva1, Natalya Miakova1, Galina Novichkova1, Alexei Maschan 1, Michael Maschan1 O042 MACHINE-LEARNING-BASED CLUSTERING TO REFINE THE EHA/EBMT IMMUNE EFFECTOR CELL-ASSOCIATED HEMATOTOXICITY GRADING CRITERIA Emily Liang 1,2, Aya Albittar1, Andrew Portuguese1,2, Jennifer Huang1,2, Natalie Wuliji1,2, Qian Wu1, Joseph De Los Reyes1, Nikki Pin1, Aiko Torkelson1, Delaney Kirchmeier1, Abigail Chutnik1, Barbara Pender1, Joshua Hill1,2, Noam Kopmar1,2, Rahul Banerjee1,2, Andrew Cowan1,2, Damian Green1,2, Ajay Gopal1,2, Christina Poh1,2, Mazyar Shadman1,2, Alexandre Hirayama1,2, Brian Till1,2, Erik Kimble1,2, Lorenzo Iovino1,2, Aude Chapuis1,2, Folashade Otegbeye1,2, Ryan Cassaday1,2, Filippo Milano1,2, Cameron Turtle3, David Maloney1,2, Jordan Gauthier1,2 O043 SINGLE CENTRE LONG-TERM OUTCOMES OF RELAPSED/REFRACTORY PAEDIATRIC B-ALL AFTER GENOME-EDITED ‘UNIVERSAL’ CAR19 T CELL THERAPY Daniela Guardo 1,2, Vesna Pavasovic1, Avijeet Kumar Mishra1, Kimberly Gilmour1, Stuart Adams1, Giorgio Ottaviano1, Danielle Pinner1, Jan Chu1, Martin Sauer3, Ajay Vora1, Paul Veys1, Kanchan Rao1, Waseem Qasim1 O044 RATES OF RESPONSE TO SALVAGE TREATMENT AFTER POST-CAR-T PROGRESSION/RELAPSE IN LARGE B-CELL LYMPHOMA PATIENTS – A DATA METAANALYSIS Jaromir Tomasik 1, Dominik Bilicki1, Grzegorz Basak1 O045 DONOR-DERIVED CAR-T CELLS FOR THE TREATMENT OF RELAPSED ACUTE B-LYMPHOBLASTIC LEUKEMIA AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION Lei Deng1, Xiaolin Yu1, Xiaocheng Song1, Rui Guan1, Yan Shao1, Wenjun Li1, Fang Zhou 1 O046 SEVEN-DAY VEIN-TO-VEIN POINT-OF-CARE–MANUFACTURED CD19 CAR T-CELL THERAPY (GLPG5201) IN RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA INCLUDING RICHTER TRANSFORMATION: RESULTS FROM THE PHASE 1 EUPLAGIA-1 STUDY Valentín Ortiz-Maldonado 1, Nuria Martinez-Cibrian1, Julio Delgado1, Sergi Betriu1, Leticia Alserawan1, Ana Triguero1, Nadia Verbruggen2, Maike Spoon3, Marte C. Liefaard3, Anna D.D. van Muyden3, Natalia Tovar1 O047SEVEN-DAY VEIN-TO-VEIN POINT-OF-CARE–MANUFACTURED CD19 CAR T-CELL THERAPY (GLPG5101) IN RELAPSED/REFRACTORY NON-HODGKIN LYMPHOMA (NHL): RESULTS FROM THE PHASE 1 ATALANTA-1 TRIAL Marie José Kersten1, Kirsten Saevels2, Sophie Servais3, Yves Beguin 3, Joost S. P. Vermaat4, Eva Santermans5, Stavros Milatos6, Maike Spoon7, Marte C. Liefaard7, Claire Vennin7, Margot J. Pont7, Anna D.D. van Muyden7, Maria T. Kuipers1, Sébastien Anguille2 O048 IN VIVO LOWER CD4/CD8 CARCIK-CD19 CELL RATIO IS ASSOCIATED WITH EARLY TREATMENT RESPONSE IN PATIENTS WITH RELAPSE/REFRACTORY B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA Benedetta Rambaldi 1, Giulia Risca2, Stefania Galimberti2,3, Cristian Meli1, Giuliana Rizzuto1,4, Chiara Buracchi5,3, Alex Moretti5,6,4, Chiara Francesca Magnani7, Marianna Ponzo3,5, Sarah Tettamanti5, Muriel Paganessi1, Silvia Zaninelli8, Elisa Gotti8, Chiara Capelli1, Benedetta Cabiati9, Michele Francesco Quaroni9, Martino Introna1, Federico Lussana1,10, Giuseppe Gritti1, Silvia Ferrari1, Anna Grassi1, Sara Napolitano6, Adriana Balduzzi6,11, Maria Grazia Valsecchi3,2, Giuseppe Dastoli5, Alessandro Rambaldi1,10, Andrea Biondi6,11, Giuseppe Gaipa6,5,9 O049 BASELINE SBCMA PLASMA LEVEL HAS NO IMPACT ON THE EFFICACY OF EQUECABTAGENE AUTOLEUCEL,A BCMA-CAR T CELL THERAPY IN PATIENTS WITH RRMM: SUBANALYSIS OF FUMANBA-1 TRIAL Lu-Gui Qiu 1, Chunrui Li2, Di Wang2, Yongping Song3, He Huang4, Jianyong Li5, Bing Chen6, Jing Liu7, Xi Zhang8, Yujun Dong9, Kai Hu10, Peng Liu11, Jianqing Mi12, Kaiyang Ding13, Zhenyu Li14, Qie Dong15, Peng Guo15, Fuyuan Zhang15, Hong-yu Gui15, Guang Hu15, Wen Wang15 O050 DISTURBED MITOCHONDRIAL DYNAMICS REINFORCE CAR-T CELL EXHAUSTION Mi Shao 1, Xiaohui Si1, Yue Huang1, Xinyi Teng1, Pengxu Qian1, He Huang1 O051 IN VIVO TRANSFER OF CD4+ T CELLS RESHAPES CD8+ T CELL DIFFERENTIATION TRAJECTORY IN HUMANS Andrew McIntyre 1,2, Maria Cuadrado2, Joshua Hughes1, Aideen O’Neill1,2, William Wilson3, Darren Edwards3, Ka Man Mak3, Jessica Hunt3, Laura Clifton-Hadley3, Adrian Bloor4, Andrew Clark5, Anne Parker5, Maria Gilleece6, Richard Lovell7, Alexander M. Martin8, Ann Hunter8, Deborah Richardson9, John Snowden10, Stephen Robinson11, Ben Uttenthal12, Charles Crawley12, Mark Lowdell13, Karl Peggs2, Persephone Borrow14, Ronjon Chakraverty1,2 O052 A MACROPHAGES-BASED IMMUNOTHERAPY OF SOLID TUMORS MICROENVIRONMENT: PRELIMINARY RESULTS OF THE TEM-GBM_01 STUDY Francesca Farina 1, Bernhard Gentner2,3, Gaetano Finocchiaro4, Marica Eoli5, Alessia Capotondo3, Elena Anghileri5, Matteo Barcella3, Valentina Brambilla6, Matteo Carrabba1, Valeria Cuccarini7, Quintino Giorgio D’Alessandris8, Francesco DiMeco9, Valeria Ferla1, Paolo Ferroli9, Filippo Gagliardi10, Federico Legnani9, Stefania Mazzoleni6, Alessandro Olivi8, Roberto Pallini8, Marco Saini9, Luigi Naldini3, Carlo Russo11, Fabio Ciceri1 O053 MULTIVALENT-SPECIFIC T CELLS AS LIVING DRUGS FOR THE TREATMENT OF OPPORTUNISTIC INFECTIONS POST ALTERNATIVE-DONOR HEMATOPOIETIC CELL TRANSPLANTATION Ioannis Kyriakou 1, Zoi Boussiou1, Georgios Karavalakis1, Chrysa Pantazi1, Ioanna Vallianou1, Maria Giannaki1, Fani Stavridou1, Maria Liga1, Ioulia Mavrikou1, Kyriakos Koukoulias1, Apostolia Papalexandri1, Fotini Kika1, Eleftheria Sagiadinou2, Ioannis Batsis1, Alexandros Spyridonidis2, Ioanna Sakellari1, Anastasia Papadopoulou1, Evangelia Yannaki1 O054 MOCRAVIMOD FAVOURABLY AFFECTS OVERALL SURVIVAL IN PATIENTS UNDERGOING ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION Dominik Heim1, Christoph Bucher1, Michael Medinger1, Udo Holtick 2, Gérard Socié3, Christos Stylianou4, Simone Dertschnig5, Malika Souquieres5, Stephan Oehen5, Elisabeth Kueenburg5, Jakob Passweg1 O055 CLINICAL OUTCOMES OF PATIENTS WITH BLAST PHASE CHRONIC MYELOID LEUKEMIA AND UTILITY OF ALLOGENEIC STEM CELL TRANSPLANTATION IN IMPROVING LONG-TERM SURVIVAL Benjamin McCormick 1, Anthony Findley1, James Foran1, Mohamed Kharfan-Dabaja1, Madiha Iqbal1, Lisa Sproat2, Jeanne Palmer2, William Hogan3, Kebede Begna3, Mark Litzow3, Talha Badar1 O056 PHASE II STUDY OF PHARMACOKINETIC MODEL-BASED ATG DOSING TO IMPROVE SURVIVAL THROUGH ENHANCED IMMUNE RECONSTITUTION IN PATIENTS UNDERGOING EX VIVO CD34-SELECTED ALLOGENEIC HCT (PRAISE-IR) Michael Scordo 1, Miguel-Angel Perales1, Audrey Mauguen2, Andrew Lin2, Binni Kunvarjee2, Jennifer Bieler2, Linh K. Nguyen2, Maria Paes Pena3, Christina Cho4, Boglarka Gyurkocza1, Andrew C. Harris2, Ann A. Jakubowski1, Richard J. Lin1, Esperanza B. Papadopoulos1, Ioannis Politikos1, Doris M. Ponce1, Brian C. Shaffer1, Gunjan L. Shah1, Barbara Spitzer4, Roni Tamari1, Sergio A. Giralt1, Jaap Jan Boelens2, Kevin J. Curran2 O057 ASSOCIATION OF BUSULFAN EXPOSURE WITH SURVIVAL AND TOXICITY AFTER HCT FOR PRIMARY IMMUNE DEFICIENCY IN CHILDREN AND YOUNG ADULTS; A MULTI-CENTER, RETROSPECTIVE COHORT ANALYSIS Tim Bognàr 1, Moises Garcia2, Arief Lalmohamed1,3, A. C. G. Egberts1,3, Caroline A. Lindemans4,5, Geoffrey D. E. Cuvelier6, Tayfun Güngör7, Mathias Hauri-Hohl7, Christen L. Ebens8, Robbert G.M. Bredius9, Hannah Lust10, Sonali Chaudhury10, Susan Prockop11, Layne Oram11, Sun-Yung Pai11,12, Robert Chiesa13, Marc Ansari14,15, Maja Krajinovic16, Anne-Charlotte Teyssier16, Yves Théoret16, Jordan Brooks17, Rada M. Savic17, Christopher C. Dvorak17, Janel R. Long-Boyle17, Cary Martinez18, Erin Morales18, Mary Slatter19, Maria P. Cicalese20,21,22, Robert F. Wynn23, Mary Coussons23, Christa E. Nath24, Peter J. Shaw24, Steven J. Keogh24, Imke H. Bartelink25, Jaap-Jan Boelens2 O058 A PROSPECTIVE RANDOMIZED CONTROLLED TRIAL TO ADDRESS THE IMPACT OF TARGETED FLUDARABINE ON THE INCIDENCE OF VIRAL COMPLICATIONS AFTER TCRALPHABETA/CD19 DEPLETED ALLO-HCT Moniek de Witte 1,2, Klaartje Nijssen1, Tim Bognar1, Anna van Rhenen1, Lotte van der Wagen1, Laura Daenen1, Anke Janssen1, Anniek Stuut2, Peter van de Ven3, Dirk-Jan Moes4, Peter van Balen4, Stijn Halkes4, Kim van der Elst1, Jurgen Kuball1,2 O059 TOTAL MARROW AND LYMPHOID IRRADIATION (TMLI) WITH FLUDARABINE-MELPHALAN AS CONDITIONING FOR MATCHED-DONOR ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION (ALLOHCT) IN PATIENTS WITH HIGH-RISK ACUTE LEUKEMIAS OR MDS Monzr Al Malki 1, Susanta Hui1, Dongyun Yang1, Sally Mokhtari1, Kay Chanea1, Firoozeh Sahebi1, Hoda Pourhassan1, Matthew Mei1, Amanda Blackmon1, Brian Ball1, Shukaib Arslan1, Salman Otoukesh1, Haris Ali1, Guido Marcucci1, Ryotaro Nakamura1, Stephen Forman1, Anthony Stein1, Jeffrey Wong1 O060 TREOSULFAN- VERSUS BUSULFAN-BASED CONDITIONING IN ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION FOR MYELODYSPLASTIC SYNDROME: A SINGLE-CENTRE RETROSPECTIVE PROPENSITY SCORE-MATCHED COHORT STUDY Tommy Alfaro Moya 1,2, Mats Remberger3, Carol Chen1, Armin Gerbitz1,2, Dennis Dong Hwan Kim1,2, Rajat Kumar1,2, Wilson Lam1,2, Arjun Datt Law1,2, Jeffrey H. Lipton1,2, Fotios V. Michelis1,2, Igor Novitzky Basso1,2, Auro Viswabandya1,2, Jonas Mattsson1,2, Ivan Pasic1,2 O061 TREOSULFAN VERSUS BUSULFAN-BASED CONDITIONING REGIMENS FOR FIRST ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANT IN CHILDREN WITH ACUTE MYELOID LEUKEMIA IN COMPLETE REMISSION: A RETROSPECTIVE PDWP/EBMT STUDY Hemalatha G. Rangarajan 1, Antonio Pérez Martínez2, Jacques-Emmanuel Galimard3, Arnaud Dalissier4, Rose-Marie Hamladji5, Oana Mirci-Danicar6, Franco Locatelli7, Monika Mielcarek-Siedziuk8, Adriana Balduzzi9, Jan Styczynski10, Franca Fagioli11, Cécile Renard12, Jean Hugues Dalle13, Mouhab Ayas14, Jochen Buechner15, Marianne Ifversen16, Petr Sedlacek17, Kanchan Rao18, Robert Wynn19, Marc Ansari20, Katharina Kleinschmidt21, Krzysztof Kalwak8 O062 FLUDARABINE PLUS TREOSULFAN OR TBI AS A CONDITIONING THERAPY BEFORE ALLOGENEIC HSCT IN ACUTE LYMPHOBLASTIC LEUKEMIA. A MATCHED-PAIR ANALYSIS FROM THE ALWP OF THE EBMT Ryszard Swoboda 1, Myriam Labopin2, Nicolaus Kröger3, Matthias Stelljes4, Thomas Schroeder5, Peter Dreger6, Gesine Bug7, Andrew McDonald8, Tülay Özçelik9, Montserrat Rovira10, Igor Wolfgang Blau11, Desiree Kunadt12, Gerard Socié13, Werner Rabitsch14, Matthias Eder15, Marie Therese Rubio16, Alexandros Spyridonidis17, Bipin Savani18, Zinaida Peric19, Sebastian Giebel1, Mohamad Mohty2, Fabio Ciceri20 O063 TCRALPHA/BETA DEPLETED MOBILIZED PBSCS WITHOUT CALCINEURIN INHIBITORS IN PATIENTS WITH FANCONI ANEMIA Margaret MacMillan 1, Qing Cao1, David McKenna1, Meera Srikanthan1, John Wagner1 O064 REKLAIM, A NOVEL PHASE IB CLINICAL TRIAL OF FBX-101 (AAVRH10.GALC) INTRAVENOUSLY ADMINISTERED AFTER UCBT FOR THE TREATMENT OF INFANTILE AND LATE INFANTILE KRABBE DISEASE Maria Escolar 1, Michele D. Poe1, Juan Ruiz1, Mark Vander Lugt2, Raymond Wang3, David Buchbinder4, Paul Szabolcs5 O065 LONG-TERM AND REAL-WORLD SAFETY AND EFFICACY OF RETROVIRAL GENE THERAPY FOR ADENOSINE DEAMINASE DEFICIENCY Maddalena Migliavacca 1,2, Federica Barzaghi2,1, Claudia Fossati1, Paola M.V. Rancoita3, Michela Gabaldo4, Francesca Dionisio1, Stefania Giannelli1, Federica Andrea Salerio1, Francesca Ferrua2,1, Francesca Tucci1,2, Calbi Valeria2,1, Vera Gallo2,1, Salvatore Recupero2,1, Giulia Consiglieri2,1, Roberta Pajno2,1, Vittoria Garella5, Ilaria Monti1, Paolo Silvani6, Silvia Darin1, Miriam Casiraghi1, Ambra Corti1, Stefano Zancan4, Margherita Levi4, Daniela Cesana1, Anna Pituch-Noworolska7, Dalia AbdElaziz8, Ulrich Baumann9, Andrea Finocchi10,11, Caterina Cancrini10,11, Saverio Ladogana12, Andrea Meinhardt13, Isabelle Meyts14, Davide Montin15, Lucia Dora Notarangelo16, Fulvio Porta17, Marlène Pasquet18, Carsten Speckmann19,20, Polina Stepensky21, Alberto Tommasini22, Marco Rabusin22, Zeynep Karakas23, Miguel Galicchio24, Lucia Leonardi25, Marzia Duse25, Sukru Nail Guner26, Clelia Di Serio3,27, Fabio Ciceri5,28,1, Maria Ester Bernardo5,2,1, Alessandro Aiuti5,2,1, Maria Pia Cicalese5,2,1 O066 TRANSCRIPTIONAL REWIRING OF NK CELL FEATURES IMPRINTED BY DIFFERENT MODALITIES OF POST-TRANSPLANTATION LEUKEMIA RELAPSE Giorgio Orofino 1, Pier Edoardo Rovatti1, Marco Punta1, Matteo Maria Naldini1, Matteo Barcella1, Laura Zito1, Matteo Carrabba1, Massimo Bernardi1, Jacopo Peccatori1, Bernhard Gentner1, Fabio Ciceri1,2, Luca Vago1,2, Cristina Toffalori1 O067 DEVELOPING A UNIVERSAL HAEMATOPOIETIC STEM CELL GENE EDITING THERAPY FOR XIAP DEFICIENCY Anne Charlotte Adriane Mudde 1, Soraia Silva1, Emily Hu1, Giandomenico Turchiano1, Nathan White1, Claire Booth1 O068 NON-NEUROLOGICAL, NON-SKELETAL OUTCOMES AFTER HAEMATOPOIETIC STEM AND PROGENITOR CELL-GENE THERAPY IN HURLER PATIENTS: RETROSPECTIVE COMPARISON WITH ALLOGENEIC HAEMATOPOIETIC STEM CELL TRANSPLANTATION Francesca Tucci 1, Maria Luz Uria Oficialdegui2, Giulia Consiglieri1, Matilde Cossutta1, Chiara Filisetti1, Luca Galimberti1, Mariana Priviero Spiridon3, Maria Pia Manitto1, Carla Butera1, Roberto Santangelo1, Giulia Danè1, Chiara Camesasca1, Silvia Darin1, Mireia Del Toro2, Cristina Diaz de Hereida Rubio2, Rossella Parini4, Bernhard Gentner4, Alessandro Aiuti1, Maria Ester Bernardo1 O069 INTERIM ANALYSIS ON NEUROLOGICAL OUTCOMES IN HURLER SYNDROME PATIENTS TREATED WITH EX-VIVO HAEMATOPOIETIC STEM CELL GENE THERAPY Giulia Consiglieri 1, Francesca Fumagalli1, Francesca Tucci1, Chiara Filisetti1, Matilde Cossutta1, Stefano Scarparo1, Marina Sarzana1, Cristina Puricelli1, Francesca Ciotti1, Maurizio Barbera1, Silvia Darin1, Rossella Parini1, Cristina Baldoli1, Bernhard Gentner2, Alessandro Aiuti1, Maria Ester Bernardo1 O070 HAEMATOPOIETIC STEM CELL GENE THERAPY FOR HURLER SYNDROME: CLINICAL SKELETAL OUTCOME DATA AND STUDY OF THE SKELETAL CROSS-CORRECTION MECHANISMS Francesca Tucci1, Giulia Consiglieri1, Maurizio De Pellegrin2, Matilde Cossutta1, Chiara Filisetti1, Marina Sarzana1, Stefano Scarparo1, Cristina Baldoli1, Renata Mellone1, Ludovica Santi2, Stefania Crippa2, Rossella Parini2, Bernhard Gentner2, Alessandro Aiuti1, Maria Ester Bernardo 1 O071 AXATILIMAB FOR CHRONIC GRAFT-VERSUS-HOST DISEASE: RESPONSES IN FIBROSIS-DOMINANT ORGANS IN AGAVE-201 Jose A. Perez-Simon 1, Zachariah DeFilipp2, Stephanie J. Lee3, Wendy Ingram4, Jennifer White5, Helene Schoemans6,7, Laetitia Souchet8, Daniel Wolff9, Carrie L. Kitko10, Simona Sica11,12, Avichai Shimoni13, Britnie Thomas14, Vedran Radojcic15, Chuan Tian14, Amandeep Salhotra16, Corey Cutler17 O072 POOLED FECAL ALLOGENEIC MICROBIOTHERAPY FOR REFRACTORY GASTROINTESTINAL ACUTE GRAFT-VERSUS-HOST DISEASE: RESULTS FROM THE EARLY ACCESS PROGRAM IN EUROPE Florent Malard 1, Michael Loschi2, Thomas Cluzeau2, Faezeh Legrand3, Anne Huynh4, Sarah Guenounou4, Cécile Borel4, Jean-Baptiste Méar5, Faustine Lhomme5, Déborah Desmier6, Niels Moya6, Amandine Charbonnier7, Delphine Lebon7, Hélène Labussière-Wallet8, Martin Carré9, Jérôme Cornillon10, Vincent Camus11, Patrice Ceballos12, Francesco Saraceni13, Corentin Orvain14, Sylvain Chantepie15, Jakob Rudzki16, Marie-Anne Couturier17, Patrice Chevallier18, Clémence Mediavilla19, David Beauvais20, Etienne Daguindau21, Karin Bilger22, Stefan Klein23, Jaime Sanz24, Sarah Altmeyer25, Francesca Patriarca26, Marion Bruelle27, Emilie Plantamura27, Mohamad Mohty1 O073 RANDOMIZED MULTICENTER TRIAL OF CALCINEURIN-FREE GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS WITH POST-TRANSPLANTATION CYCLOPHOSPHAMIDE AND RUXOLITINIB IN UNRELATED AND HAPLOIDENTICAL TRANSPLANTATIONS: A FINAL ANALYSIS OF THE PRIMARY ENDPOINT Ivan Moiseev 1, Mikhail Drokov2, Yulia Kitaeva3, Tatyana Rudakova1, Maria Barabanshchikova1, Ksenia Afanasyeva1, Sergei Bondarenko1, Larisa Kuzmina2, Elena Morozova1, Natalia Popova2, Vera Vasilyeva2, Yulia Vlasova1, Dmitrii Zhogolev1, Tatyana Konstantinova3, Elena Parovichnikova2, Alexander Kulagin1 O074 THE IMPACT OF INDIVIDUAL COMORBIDITIES ON NRM RISK FOLLOWING PTCY BASED ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION: AN ALWP EBMT STUDY Alexandros Spyridonidis 1, Myriam Labopin2, Bipin Savani3, Alexander Kulagin4, Didier Blaise5, Jurjen Versluis6, Simona Sica7, Anna Maria Raiola8, Jan Vydra9, Goda Choi10, Montserrat Rovira11, Mi Kwon11, Jaime Sanz12, Maija Itäla-Remes13, Peter von dem Borne14, Rodrigo Martino15, Yener Koc16, Eolia Brissot17, Arnon Nagler18, Mohamad Mohty17, Fabio Ciceri19 O075 PTCY, TAC/ CSA, MMF VS ATG, TAC / CSA, MTX GVHD PROPHYLAXIS POST SIBLING AND UNRELATED TRANSPLANTATIONS FOR AML: FROM THE ALWP OF THE EBMT Arnon Nagler 1, Myriam Labopin2,3, Thomas Schroeder4, Rose-Marie Hamladji5, Laimonas Griskevicius6, Urpu Salmenniemi7, Alessandro Rambaldi8, Stephan Mielke9, Sergey Bondarenko10, Jakob Passweg11, Peter Dreger12, Tobias Gedde-Dahl13, Edouard Forcade14, Grzegorz Helbig15, Matthias Stelljes16, Cristina Castilla-Llorente1717, Alexandros Spyridonidis18, Bipin Savani19, Eolia Brissot3, Fabio Ciceri20, Mohamad Mohty2,3 O076 A PRETRANSPLANT INFLAMMATORY SIGNATURE IS ASSOCIATED WITH ACUTE GRAFT-VERSUS-HOST DISEASE AND MORTALITY IN PEDIATRIC PATIENTS Anne B. Verbeek 1, Erik G J. von Asmuth1, Erik B. van den Akker1, Anja M. Jansen-Hoogendijk1, Marco W. Schilham1, Arjan C. Lankester1, Gertjan Lugthart1, Alexander B. Mohseny1, Emilie P. Buddingh1 O077 DELAYED ADMINISTRATION OF IXAZOMIB AS PROPHYLAXIS FOR CHRONIC GRAFT-VERSUS-HOST DISEASE (CGVHD) Javier Delgado Serrano 1,2,3, Lucía López Corral4,5, David Valcárcel6,7, Jorge Sierra8, Christelle Ferra-Coll9, Teresa Caballero Velázquez1,2,3, Francisco Martín Domínguez1,2,3, Reyes Jiménez León1,2,3, Juan Luis Reguera Ortega1,2,3, Cristina Blázquez Goñi1,2,3, Estefanía Pérez López4,5, Almudena Cabero Martínez4,5, Irene García Cadenas8, José Antonio Pérez Simón1,2,3 O078 RUXOLITINIB IN ACUTE AND CHRONIC GRAFT-VERSUS-RECEPTOR DISEASE: LONG-TERM REAL-LIFE EXPERIENCE IN A MULTI-CENTRE STUDY IN PEDIATRIC POPULATION Virginia Escamilla Gómez 1, Beatriz Astibia Mahillo2, Patricia Alcalde Mellado1, Francisco Manuel Martín Domínguez1, Marta González Vicent3, Pedro Asensi Cantó4, Juan Montoro Gómez4, Inés Gómez Seguí4, María Isabel Benítez Carabante5, Cristina Díaz de Heredia Rubio5, Luisa Sisinni6, Antonio Pérez Martínez6, José María Pérez Hurtado1, José Antonio Pérez Simón1, Valentín García Gutiérrez2 O079 CLINICAL EXPERIENCE IN THE USE OF MESENCHYMAL STROMAL CELLS IN PEDIATRIC GRAFT-VERSUS-HOST DISEASE: ON BEHALF OF THE SPANISH GROUP OF STEM CELL TRANSPLANTATION (GETH) Carlos Echecopar Parente1, David Bueno Sánchez1, Blanca Molina Angulo2, María Isabel Benitez Carabante3, Iván López Torija4, María Trabazo5, Carolina Fuentes6, Mercedes Plaza7, Antonia Pascual Martínez8, Andrea Urtasun9, Susana Riesco10, Soledad González Muñíz11, Sara Vinagre2, Cristina Díaz de Heredia3, Julia Marsal 5, Marta González-Vicent2, Antonio Pérez-Martínez1,12,13 O080 POST-TRANSPLANT CYCLOPHOSPHAMIDE, ABATACEPT, AND VEDOLIZUMAB TO PREVENT GVHD AFTER HSCT FROM HAPLOIDENTICAL DONORS IN CHILDREN WITH ACUTE LEUKEMIA: RESULTS OF A PROSPECTIVE TRIAL Margarita Perminova1, Larisa Shelikhova1, Maria Klimentova1, Maria Dunaykina1, Anna Vasilieva1, Sergey Blagov1, Svetlana Kozlovskaya1, Dmitriy Balashov1, Alexander Popov1, Daria Kobyzeva1, Natalya Miakova1, Yakov Muzalevsky1, Galina Novichkova1, Alexey Maschan1, Michael Maschan1, Alexandra Laberko 1 O081 PTCY PLUS ATG COMPARED TO PTCY ALONE IN HAPLOIDENTICAL TRANSPLANTATION WITH PBSCS: A RETROSPECTIVE STUDY ON BEHALF OF THE CTIWP OF THE EBMT Antoine Capes 1, Jarl Mooyaart2, Didier Blaise3, Stefania Bramanti4, Mi Kwon5, Mohamad Mohty1, Patrice Chevallier6, Jan Vydra7, Péter Reményi8, Edouard Forcade9, Lucía López Corral10, Maija Itäla-Remes11, Ali Bazarbachi12, Enrico Derenzini13, Jorinde D. Hoogenboom14, Jürgen Kuball15, Giorgia Battipaglia16, Florent Malard1, Annalisa Ruggeri17 O082 GITMO PROSPECTIVE STUDY IN 266 CGVHD PATIENTS, RECEIVING BEST AVAILABLE TREATMENT; VALIDATION OF A SOFTWARE FOR CGVHD SCORING AND RESPONSE EVALUATION ACCORDING TO NIH 2014 Attilio Olivieri 1, Giorgia Mancini1, Francesco Saraceni1, Ilaria Scortechini1, Irene Federici1, Alessandro Busca2, Luisa Giaccone2, Alessandro Rambaldi3, Maria Caterina Micò3, Alessandra Algarotti3, Giuseppe Milone4, Salvatore Leotta4, Jacopo Peccatori5, Maria Teresa Lupo Stanghellini5, Francesca Bonifazi6, Mario Arpinati6, Maura Faraci7, Fabio Benedetti8, Simone Cesaro8, Franca Fagioli9, Francesco Saglio9, Irene Maria Cavattoni10, Vincenzo Pavone11, Anna Mele11, Riccardo Saccardi12, Chiara Nozzoli12, Domenico Russo13, Michele Malagola13, Carlo Borghero14, Daniele Vallisa15, Adriana Balduzzi16, Francesca Patriarca17, Antonella Giromin17, Edoardo Benedetti18, Nicola Mordini19, Francesco Merli20, Fabio Ciceri5, Massimo Martino21 O083 ADDITION OF RUXOLITINIB TO STANDARD GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS FOR ALLOGENEIC STEM CELL TRANSPLANTATION IN APLASTIC ANEMIA PATIENTS XiaoYu Zhang 1, Yi He1, Sizhou Feng1, Mingzhe Han1, Erlie Jiang1 O084 LIPOCALIN-2 REDUCES ACUTE GRAFT-VERSUS-HOST DISEASE SEVERITY IN MICE Marie Czech 1, Robert Zeiser2 O085 GALECTIN-9 RELEASED BY CHEMOTHERAPY-DAMAGED INTESTINAL EPITHELIUM ATTRACTS AND STIMULATES ACTIVATION OF ALLO T CELLS Suze Anne Jansen 1,2, Alessandro Cutilli1, Coco de Koning2,1, Marliek van Hoesel2,1, Leire Saiz Sierra1, Stefan Nierkens2,1, Michal Mokry1, Edward Nieuwenhuis1,3, Alan Hanash4, Enric Mocholi1, Paul Coffer1, Caroline A. Lindemans2,1 O086 VASOACTIVE INTESTINAL POLYPEPTIDE SYNTHESIS BY THE GUT ENTERIC NEURAL PLEXUS PROMOTES A DIVERSE MICROBIOME AND CONFERS RESISTANCE TO GRAFT VERSUS HOST DISEASE Edmund K. Waller 1, Yi-Wen Li1, Shuhua Wang1, Hanwen Zhang1, Yutong Liu1, Po-Chih Hsu1, Pankoj Das1, Passang Lim1, Tamas Nagy2, Zhaohui Qin1, Cynthia Giver1 O087 TARGETING PI3KDELTA FUNCTION FOR TREATMENT OF CHRONIC GRAFT‐VERSUS‐HOST DISEASE Yuxi Xu1,2, Guancui Yang1, Qing Xu1, Ya Zhou1, Rui Wang1, Xiaoqi Wang1, Shijie Yang1, Qingxiao Song 1,2, Xi Zhang1,2 O088 VLA-4 AGONIST PROMOTE ENGRAFTMENT AND CELL IMMUNE RECONSTITUTION OF ALLOGENEIC HEMATOPOIETIC STEM CELLS Qiaomei He 1, Xi Sun1, Lin Chen2, Jun Yang1, Huixian Wu1, Shixuan Tang1, Liping Wan1, Yan Zhang1, Bo O. Zhou2, Fang Zhang3, Xianmin Song1 O089 AN AI MODEL TO OPTIMIZE DONOR SELECTION USING A CONTEMPORARY DATASET Martin Maiers 1, Sapir Israeli2, Yoram Louzoun2, Stephen R. Spellman1, Heather E. Stefanski1, Jeffery J. Auletta1, Steven M. Devine1 O090 OUTCOMES OF ALLOGENEIC HAEMATOPOIETIC STEM-CELL TRANSPLANTATION IN MYELOFIBROSIS: A MULTICENTER STUDY Tatiana Fernández-Barge 1, Juan José Domínguez-García1, Miriam Sánchez Escamilla1, Jaime Sanz Caballer2, Pedro Chorão2, Juan Carlos Hernández Boluda3, Sara Redondo Velao4, Irene García Cadenas4, Rodrigo Martino Bufarull4, Rodrigo Cantera Estefanía1, Irene Francés Alexandre1, Ana Gea Peña1, Ana Tobalina García1, Raquel García Ruiz1, Sara Fernández Luis1, Enrique M. Ocio San Miguel1, Mercedes Colorado Araújo1, Sonia González de Villambrosia Pellón1, María Aranzazu Bermúdez Rodríguez1 O091 GAMMA DELTA T CELLS RECONSTITUTION IN LONG-TERM SURVIVORS AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION – HOMEOSTATIC STEADY-STATE? Faisal Alagrafi 1,2, Arwen Stikvoort1, Thomas Poiret1, Ahmed Gaballa1, Martin Solders1, Lucas Arruda1, Michael Uhlin1,3 O092 HLA-HAPLOIDENTICAL HEMATOPOIETIC STEM CELL TRANSPLANTATION WITH PTCY IN VIVO DEPLETED T-CELL FOR NON-SCID INBORN ERRORS OF IMMUNITY: A MONOCENTRIC CENTER EXPERIENCE Jean-Sebastien Diana 1, Benjamin Fournier1, Quentin Riller2, Martin Castelle1, Romain Levy1,2,3, Clotilde Aussel1,3, Elisa Margin1, Marwa Chbihi1,3, Agathe Escudier1, Paul Bastard1,2,3, Stephane Blanche1,3, Naim Bouazza1,3,2, Despina Moshous1,2,3, Benedicte Neven1,2,3 O093 UNRELATED DONOR TRANSPLANTATION OFFERS A REAL CURATIVE OPPORTUNITY FOR PATIENTS WITH TRANSFUSION-DEPENDENT THALASSAEMIA. EXPERIENCE OF THE SPANISH GROUP FOR BONE MARROW TRANSPLANTATION IN CHILDREN (GETH-TC) Maria Isabel Benitez Carabante 1, Angela Menárguez1, Cristina Beléndez Bieler2, Laura Alonso García1, María Luz Uría Oficialdegui1, Melissa Panesso1, Mercedes Plaza Fornieles3, Carolina Fuentes4, Sara Vinagre Enríquez5, Graciela Gómez Silva6, Mónica López Duarte7, José María Pérez Hurtado8, Montserrat Torrent9, Cristina Díaz de Heredia Rubio1 O094 ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION IN PATIENTS WITH SICKLE CELL DISEASE: PRELIMINARY RESULTS OF THE FIRST FOUR PATIENTS TRANSPLANTED IN TANZANIA Fabio Giglio 1,2,3, David Mashala4, Stella Malangahe4, Shakilu Jumanne4,5, Merlikiad Mhozya4, Paola Erminia Ronchi1,3, Alessia Orsini1,3, Francis Ngiliule4, Zimbwe Bakari4, Alen Patrick Magoha4, Anna Carmagnola1,3, Musa Dubali1,6, Nunzia Manna1, Pietro Pioltelli1, Fabio Ciceri3, Alphonse Chandika4, Cornelio Uderzo1 O095 NON-MYELOABLATIVE HAEMATOPOIETIC STEM CELL TRANSPLANT FROM MATCHED RELATED DONORS IN ADULT PATIENTS WITH SEVERE SICKLE CELL DISEASE: THE UK REAL-LIFE EXPERIENCE Fabio Serpenti 1, Ben Carpenter2, John Snowden3, Elisa Roldangalvan3, Rachel Kesse-Adu4, Eleni Tholouli5, Clare Samuelson3, Subarna Chakravorty1, Victora Potter1 O096 IMPACT OF ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION IN ADOLESCENTS AND ADULTS WITH SICKLE CELL DISEASE: COMPARISON OF THE OUTCOME IN TRANSPLANTED VERSUS NON-TRANSPLANTED PATIENTS Cécile Pivert 1, Loïc Vasseur1, Edouard Flammarion2, Corinne Guitton3, Maryse Etienne-Julan4, Abdourahim Chamouine5, Laurent Cimasoni6, Claire Dichamp7, Annie Kandem8, Isabelle Genty8, Marie Lagarde9, Aude Marie Fourmont10, Florian Chevillon1, Jean-Benoît Arlet2, Corrine Pondarré8, Nathalie Dhedin1 O097 HAEMATOPOIETIC STEM CELL TRANSPLANTATION FOR CTLA-4 INSUFFICIENCY: AN EBMT INBORN ERRORS WORKING PARTY STUDY Christo Tsilifis 1,2, Carsten Speckmann3, Su Han Lum1,2, Andrew R. Gennery1,2, Arjan C. Lankester4, Jennifer Tjon4, Emilie P. Buddingh4, Petr Sedlacek5, Alexandra Laberko6, Suzanne Elcombe7, Venetia Bigley7,2, Vassilios Lougaris8, Michele Malagola8, Robert Wynn9, Fabian Hauck10, Claudia Wehr3, Bodo Grimbacher3,11, Thomas Fox12,13, Emma C. Morris12,13, Adriana Margarit-Soler14, Yasmina Mozo15, Dolores Corral15, Anna-Maria Ewins16, Rosie Hague16, Christina Oikonomopoulou17, Krzysztof Kalwak18, Katarzyna Drabko19, Michael H. Albert10, Bénédicte Neven20, Mary A. Slatter1,2 O098 HAEMATOPOIETIC STEM CELL TRANSPLANTATION FOR STAT3 DOMINANT-NEGATIVE HYPER-IGE SYNDROME: INTERNATIONAL STUDY Christo Tsilifis 1,2, Christina Oikonomopoulou3, Ramya Uppuluri4, Masakatsu Yanagimachi5, Ásgeir Haraldsson6, Melanie Wong7, Steven J. Keogh7, Paul Gray8, Richard Mitchell8,9, Michael Raum10, Peter Ciznar11, Corina Gonzalez12, Dimana Dimitrova12, Jennifer Kanakry12, Venetia Bigley13,2, Mary A. Slatter1,2, Niraj Patel14, Emilie P. Buddingh15, Michael Medinger16, Joanna Renke17, Fabian Hauck10, Michael H. Albert10, Austen Worth18, Alexandra F. Freeman12, Andrew R. Gennery1,2 O099 OUTCOMES AFTER ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION IN PATIENTS WITH GATA2 DEFICIENCY Alejandra Escobar Vasco 1, Soyoung Kim2, George Georges3, Andrew Gennery4,5, Kasiani Myers6,7, Rafeek Yusuf8, Wael Saber1, Mehdi Hamadani1, Stephanie Lee9, Brian Ball10, Larisa Broglie1 O100 PRE-TRANSPLANT IMMUNE DYSREGULATION PREDICTS FOR POOR OUTCOME FOLLOWING ALLOGENEIC HAEMATOPOIETIC STEM CELL TRANSPLANTATION FOR ADOLESCENTS AND ADULTS WITH INBORN ERRORS OF IMMUNITY (IEI) Thomas A. Fox 1, Valerie Massey1, Charley Lever1, Rachel Pearce2, Arian Laurence3, Kirsty Thomson4, Sarah Grace4, Filippo Oliviero4, Sarita Workman3, Andrew Symes3, David M. Lowe3, Valeria Fiaccadori4, Rachael Hough4, Susan Tadros3, Siobhan O. Burns1, Markus G. Seidel5, Ben Carpenter4, Emma C. Morris1 O101 OUTCOMES OF SECOND CONDITIONED TRANSPLANT AFTER AN UNCONDITIONED STEM CELL INFUSION IN INFANTS AND CHILDREN WITH SEVERE COMBINED IMMUNODEFICIENCY (SCID) Purushotham Ramachandran1, Su Han Lum1,2, Zohreh Nademi 1, Terry Flood1, Stephen Owens1, Eleri Williams1, Sophie Hambleton1,2, Andrew Gennery1,2, Mary Slatter1,2 O102 HAPLOIDENTICAL STEM-CELL TRANSPLANTATION FOR CHRONIC GRANULOMATOUS DISEASE, AN EBMT-IEWP RETROSPECTIVE STUDY Quentin Riller 1, Mathias Hauri2, Jeroen Knippenberg3, Tiar Sirait3, Alexandra Laberko4, Khalid Halahleh5, Musa Karakukcu6, Henrik Sengeloev7, Fulvio Porta8, Bénédicte Bruno9, Marco Zecca10, Despina Moshous1, Andy Gennery11, Alexei Maschan4, Michael Albert12, Mary Slatter11, Tayfun Gungor2, Bénédicte Neven1 O103 OUTCOME OF PATIENTS WITH SIGNAL-TRANSDUCER AND ACTIVATOR OF OF TRANSCRIPTION 1 MUTATIONS (STAT1) GAIN-OF-FUNCTION VARIANTS AFTER HAEMATOPOIETIC STEM CELL TRANSPLANTATION – AN IEWP/PIDTC STUDY Emilie Pauline Buddingh 1, Mary Slatter2, Juan Carlos Aldave Becerra3, Laura Alonso Garcia4, Erik von Asmuth1, Safa Baris5, Oscar de la Calle-Martín6, Alice Chan7, Bianca Chan8, Shanmuganathan Chandrakasan9, Deepak Chellapandian10, Jasmeen Dara7, Hans Christian Erichsen Landsverk11, Susan Farmand12, Anders Fasth13, Lisa Forbes14, Renata Formankova15, Eyal Grunebaum16, Steven Keogh17, Ayça Kiykim18, Jörn-Sven Kühl19, Alexandra Laberko20, Arjan Lankester1, T.R. (Ronan) Leahy21, Caroline Lindemans22, Caridad Martinez14, Laura Martínez-Martínez23, William Glenn Mitchell9, Emma Morris24, Benedicte Neven25, Joe Oved26, Maria Prazenicova27, Jacques Gabriel Riviere4, Chaim Roifman16, Sara Şebnem Kiliç Gültekin28, Petr Sedlacek15, Ami Shah29, Linda Vong16, Jennifer Leiding10, Catharina Schütz27 O104 LENTIVIRAL HAEMATOPOIETIC STEM CELL GENE THERAPY (ATIDARSAGENE AUTOTEMCEL) FOR LATE JUVENILE METACHROMATIC LEUKODYSTROPHY (MLD) Vera Gallo 1,2, Valeria Calbi1,2, Fabiola De Mattia1, Alberto Zambon2, Salvatore Recupero2,1, Elena Fratini2, Francesca Ciotti2, Maddalena Fraschini2, Mara Sangalli2, Marina Sarzana2, Alessandra Clerici1, Francesco Morena3, Sabata Martino3, Jean Brooks4, Alan Richardson4, Laura Campbell4, Maria Ester Bernardo2,1,5, Alessandro Aiuti1,2,5, Francesca Fumagalli2,1 O105 VALIDATION OF COMORBIDITY INDEX FOR PATIENTS WITH INBORN ERRORS OF IMMUNITY UNDERGOING HEMATOPOIETIC STEM CELL TRANSPLANTATION Alexandra Laberko 1, Kirill Voronin1, Michael Maschan1, Alexei Maschan1, Anna Shcherbina1, Dmitry Balashov1 O106 HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR C1Q DEFICIENCY Helena Buso 1, Peter Arkwright2, Etai Adam3, Maryam Behfar4, Alice Chan5, Christopher Dvorak5, Amir Ali Hamidieh4, Risa Matsumura6, Arjan Lankester7, Satoshi Okada6, Nima Parvaneh4, Stalin Ramprakash8, Samin Sharafian9, Robert Wynn10, Eleri Williams11, Mary Slatter11,12, Andrew Gennery11,12 O107 RETROSPECTIVE STUDY ON THE INCIDENCE AND OUTCOME OF ADENOVIRUS INFECTIONS IN PATIENTS AFTER HAPLOIDENTICAL SCT. A STUDY OF INFECTIOUS DISEASE WORKING PARTY OF THE EBMT Maura Faraci 1, Gloria Tridello2, Malgorzata Mikulska3, Elio Castagnola1, Musa Karakukcu4, Lotus Wendel2, Anna Maria Raiola3, Awatif AlAnazi5, Per Ljungman6, Gergely Krivan7, Giulia Prunotto8, Melissa Gabriel9, Sophie Ducastele Lepretre10, Jose Luis Pinana11, Katia Perruccio12, Johannes Clausen13, Sabrina Kraus14, Herbert Pichler15, Ilaria Cutini16, Eva Maria Wagner-Drouet17, Andreas H. Groll18, Michael Loschi19, Nicolaus Kröger20, Giorgia Saporiti21, Katharine Patrick22, Varun Mehra23, Akif Yesilipek24, Beatriz Aguado Bueno25, Sara Lozano Cerrada26, Krzysztof Kalwak27, Bruno Lioure28, Giuseppe Milone29, Cecile Renard30, Anna Torrent31, Domenico Russo32, Thomas Schroeder33, Bernd Gruhn34, Caroline Besley35, Andrei Colita36, Federica Galaverna37, Xavier Poiré38, Arcangelo Prete39, Matthias Woelfl40, Simona Sica41, Jan Styczynski42, Francesco Paolo Tambaro43, Peter von dem Borne44, Jan Vydra45, Diana Averbuch46, Rafael de la Camara25 O108 TOXOPLASMA QPCR KINETICS TO FOLLOW TREATMENT OF TOXOPLASMOSIS AFTER HAEMATOPOIETIC STEM CELL TRANSPLANTATION Robina Aerts1, Alienor Xhaard 2, Christine Robin3, Andreas Groll4, Catherine Cordonnier3, Katrien Lagrou1, Stéphane Bretagne5 O109 ANALYSIS OF PRE-TRANSPLANTATION CMV-SPECIFIC HUMORAL IMMUNITY AS A PREDICTOR OF CMV REACTIVATION AFTER HEMATOPOIETIC CELL TRANSPLANTATION (HCT) USING VIRSCAN SEROLOGIC PROFILING AND PENTAMERIC COMPLEX-SPECIFIC NEUTRALIZATION Danniel Zamora 1, Elizabeth Krantz1, Khaleel Yahya1, Laurel Joncas-Schronce1, Rachel Blazevic1, Brad Edmison1, Elizabeth Wong1, Jocelyn Contreras1, Hu Xie1, Alicja Sadowska-Klasa1,2, Terry Stevens-Ayers1, Rachel Bender Ignacio1, Wendy Leisenring1, Joshua Hill1, Mariapia Degli-Esposti3, Geoffrey Hill1, Michael Boeckh1 O110 CMV SPECIFIC T-CELL ACTIVITY DETERMINES THE RISK OF CLINICALLY SIGNIFICANT CMV REACTIVATION FOLLOWING LETERMOVIR PROPHYLAXIS AFTER ALLO-HSCT Timothé Duplessix 1, Ben-Niklas Baermann2, Alexander Hölscher2, Inga Ursula Henrike Tometten1, Felicitas Isabel Schultz2, Stefanie Munder2, Paul Sebastian Jäger2, Kathrin Nachtkamp2, Sascha Dietrich2, Joerg Timm1, Guido Kobbe2, Nadine Lübke1 O111 INCIDENCE AND OUTCOME OF HHV-6 ENCEPHALITIS IN HLA-HAPLOIDENTICAL STEM CELL TRANSPLANT RECIPIENTS: A PROSPECTIVE ANALYSIS OF THE IDWP-EBMT Katia Perruccio 1, Gloria Tridello2, Nina Knelange3, Alessandra Carotti1, Hélène Labussiere-Wallet4, Franco Locatelli5, Federica Galaverna5, Maija Itala-Remes6, Matthew Collin7, Malgorzata Sobczyk-Kruszelnicka8, Alessandro Rambaldi9, Emanuele Angelucci10, Anna Maria Raiola10, Malgorzata Mikulska10, Khalid Halahleh11, Antonio Pérez-Martinez12, Luisa Sisinni12, Francesco Onida13, Goda Choi14, Mathilde Hunault-Berger15, Robert Zeiser16, Jakob Passweg17, Maura Faraci18, Matthias Eder19, Melissa Gabriel20, Marta Gonzalez Vicent21, Lucia Lopez Corral22, Henrik Sengeloev23, Musa Karakukcu24, Alina Tanase25, John Snowden26, Raffaella Greco27, Dina Averbuch28, Simone Cesaro29, Rafael De La Camara30 O112 ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION IN PATIENTS WITH ADVANCED MYCOSIS FUNGOIDES AND SÉZARY SYNDROME: A RETROSPECTIVE ANALYSIS INCLUDING 63 CONSECUTIVE PATIENTS WITH LONG-TERM MEDIAN FOLLOW-UP Francesco Onida 1, Francesca Cavallaro2, Silvia Alberti Violetti2, Maria Goldaniga2, Kordelia Barbullushi2, Fabio Serpenti2, Simona Iacobelli3, Giorgio Alberto Croci4, Gabriele Simontacchi5, Francesco Passamonti6, Emilio Berti2, Giorgia Saporiti2 O113 COMPARISON OF THIOTEPA-BASED CONDITIONING REGIMENS FOR OLDER ADULTS WITH PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA RECEIVING AUTOLOGOUS HEMATOPOIETIC CELL TRANSPLANTATION Othman Salim Akhtar 1, Qinghua Lian2, Kwang W. Ahn2, Anita D’Souza1, Binod Dhakal1, Meera Mohan1, Marcelo Pasquini1,2, Walter Longo1, Timothy S. Fenske1, Nirav N. Shah1, Mehdi Hamadani1,2 O114 ALLOGENEIC TRANSPLANTATION AFTER IMMUNOTHERAPY OR DRUG-CONJUGATED ANTIBODY FOR RELAPSED/REFRACTORY NON-HODGKIN LYMPHOMA: A COMPARISON WITH A HISTORICAL COHORT Jacopo Mariotti 1, Cristina Zucchinetti1, Laura Giordano2, Chiara De Philippis1, Daniele Mannina1, Barbara Sarina1, Daniela Taurino2, Rachele Carbon1, Armando Santoro1, Stefania Bramanti1 O115 OUTCOMES IN AFRICAN-AMERICAN (AA) AND WHITE PATIENTS WITH NEWLY DIAGNOSED MULTIPLE MYELOMA RECEIVING RVD-ALONE VS RVD + ASCT IN DETERMINATION: EFFICACY, SAFETY, AND SECOND PRIMARY MALIGNANCIES (SPMS) Paul G. Richardson 1, Jeffrey A. Zonder2, Abdullah M. Khan3, Susanna J. Jacobus4, Hani Hassoun5, Larry D. Anderson Jr6, Lauren E. Merz1, Rebecca L. Zon1, Yvonne Efebera7, Tondre Buck8, Racquel D. Innis-Shelton9, Monique A. Hartley-Brown1, Sagar Lonial10, Erica L. Campagnaro11, Peter M. Voorhees12, Robert Z. Orlowski13, Edward N. Libby14, David D. Hurd15, Caitlin L. Costello16, Noopur S. Raje17, Eva Medvedova18, Philip L. McCarthy19, Carter P. Milner Milner20, Cristina Gasparetto21, Mounzer E. Agha22, Krisstina Gowin23, Rammurti T. Kamble24, Sundar Jagannath25, Nitya Nathwani26, Melissa Alsina27, Sergio Giralt5, Jacob P. Laubach1, Omar Nadeem1, Irene M. Ghobrial1, Clifton C. Mo1, Mehmet K. Samur1, Nikhil C. Munshi1, Kenneth C. Anderson1 O116 POST-TRANSPLANT CYCLOPHOSPHAMIDE (PTCY) COMPARED TO ATG IN PATIENTS WITH MDS ALLOGRAFTED WITH UNRELATED DONOR: A STUDY OF THE CHRONIC MALIGNANCIES WORKING PARTY OF THE EBMT Yves Chalandon 1, Diderik-Jan Eikema2, Ivan Moiseev3, Fabio Ciceri4, Linda Koster5, Jan Vydra6, Jakob Passweg7, Montserrat Rovira8, Mutlu Arat9, Tobias Gedde-Dahl10, Nicolaus Kröger11, Victoria Potter12, Ibrahim Yakoub-Agha13, Alessandro Rambaldi14, Maija Itäla-Remes15, Alina Tanase16, Francesco Onida17, Carmelo Gurnari18, Christof Scheid19, Joanna Drozd-Sokolowska20, Kavita Raj21, Donal P. McLornan21, Marie Robin22 O117 ASSOCIATION BETWEEN STEM CELL SOURCE, CD34 + CELL DOSE AND OUTCOMES AFTER HAPLOIDENTICAL HEMATOPOIETIC CELL TRANSPLANTATION FOR MYELOFIBROSIS: AN ANALYSIS FROM THE CMWP OF THE EMBT Tomasz Czerw 1, Luuk Gras2, Laurien GA Baaij3, Emanuele Angelucci4, Didier Blaise5, Patrizia Chiusolo6, Mi Kwon7, Jakob Passweg8, Alessandro Busca9, Hélène Labussière-Wallet10, Patrice Ceballos11, Mohamad Mohty12, Fabio Ciceri13, Radovan Vrhovac14, Antonio Bianchessi15, Matteo Parma16, Hakan Ozdogu17, Johannes Clausen18, Linda Koster3, Joanna Drozd-Sokolowska19, Kavita Raj20, Giorgia Battipaglia21, Nicola Polverelli22,23, Juan Carlos Hernández-Boluda24, Donal P. McLornan20 O118 MUTATION CLEARANCE AFTER AND DISEASE BURDEN BEFORE TRANSPLANTATION PREDICT RELAPSE IN PATIENTS WITH MYELOFIBROSIS Nico Gagelmann 1, Anita Badbaran1, Christine Wolschke1, Evgeny Klyuchnikov1, Silke Heidenreich1, Kristin Rathje1, Johanna Richter1, Radwan Massoud1, Christian Niederwieser1, Boris Fehse1, Francis Ayuk1, Nicolaus Kröger1 O119 SPLENIC IRRADIATION PRIOR TO HEMATOPOIETIC CELL TRANSPLANTATION REDUCES RISK OF RELAPSE IN MYELOFIBROSIS Nico Gagelmann 1, Gabriela Hobbs2, Edoardo Campodonico3, Grzegorz Helbig4, Polona Novak5, Thomas Schroeder6, Christina Rautenberg6, Hans Christian Reinhardt6, Michael Heuser7, Victoria Panagiota7, Carmelo Gurnari8, Jaroslaw Maciejewski8, Fabio Ciceri3, Kristin Rathje1, Marie Robin9, Simona Pagliuca10, Vanderson Rocha11, Vaneuza Funke12, Nelson Hamershlak13, Rachel Salit14, Bart Scott14, Fernando Duarte15, Tomasz Czerw16, Raffaella Greco17, Nicolaus Kröger1 O120 IMPACT OF ATG/ATLG ON OUTCOMES AFTER HEMATOPOIETIC CELL TRANSPLANTATION FOR PATIENTS WITH MYELOFIBROSIS: A PROPENSITY SCORE MATCHED ANALYSIS Kristin Rathje 1, Nico Gagelmann1, Rachel B. Salit2, Thomas Schroeder3, Carmelo Gurnari4,5, Simona Pagliuca6, Victoria Panagiota7, Christina Rautenberg3, Bruno Cassinat8, Felicitas Thol7, Christine Wolschke1, Marie Robin8, Michael Heuser7, Marie-Thérèse Rubio6, Jaroslaw P. Maciejewski5, Hans Christian Reinhardt3, Bart L. Scott2, Nicolaus Kroeger1 O121 TRIPLEX VACCINE TO INDUCE PROTECTIVE AND DURABLE CYTOMEGALOVIRUS-SPECIFIC CELLULAR IMMUNITY IN PEDIATRIC HEMATOPOIETIC STEM CELL TRANSPLANT PATIENTS AT RISK FOR CYTOMEGALOVIRUS COMPLICATIONS Anna Pawlowska 1, Corinna La Rosa1, Yoonsuh Park1, Dongyun Yang1, Qiao Zhou1, Teodora Kaltcheva1, Nicole Karras1, Jerry Cheng2, Weili Sun3, Don J. Diamond1 O122 RECIRCULATING REGULATORY T CELLS MEDIATE THYMIC REGENERATION Andri Leo Lemarquis1,2, Kimon Argyropoulos1, Anastasia Kousa 1, Lorenz Jahn1, Brianna Gipson1, Jarrod Dudakov3, Susan DeWolf1, Marcel van den Brink1 O123 DARATUMUMAB FOR PURE RED CELL APLASIA AFTER HEMATOPOIETIC CELL TRANSPLANTATION: A STUDY FROM THE TRANSPLANT COMPLICATIONS WORKING PARTY OF EBMT Nico Gagelmann 1, Moniek De Witte2, Christophe Peczynski3, William Boreland3, Abboek Broers4, Edgar Jost5, Alexander Kulagin6, Albert Esquirol7, Simona Sica8, Jürgen Kuball2, Jennifer Byrne9, Wolfgang Bethge10, Johan Maertens11, Friedrich Stölzel12, Edouard Forcade13, Matthew Collin14, Matteo Parma15, Goda Choi16, Nicolaus Kröger1, Paolo Corradini17, Maria Chiara Finazzi18, Lucia Corral19, Sara Villar20, Alberto Mussetti21, Adrian Bloor22, Marco Ladetto23, Hélène Schoemans11, Olaf Penack24, Ivan Moiseev6, Zinaida Peric25 O124 EARLY POST-TRANSPLANTATION HEMOPHAGOCYTOSIS (PTHPS) IS ASSOCIATED WITH HIGH MORTALITY AFTER HAPLOIDENTICAL HCT: DECIPHERING THE RISK FACTORS AND PATHOGENESIS Sarita Rani Jaiswal 1,2,3, Mahak Agarwal1, Aakash rajendra Gupta1, Subhrajit Biswas2, Suparno Chakrabarti3,1,2 O125 SALVAGE HAPLOIDENTICAL TRANSPLANTATION FROM A DIFFERENT HAPLOIDENTICAL DONOR USING FLU/CY REGIMEN FOR GRAFT FAILURE AFTER FIRST HAPLOIDENTICAL ALLOGENEIC STEM CELL TRANSPLANTATION: AN UPDATED FOLLOW-UP Rui Ma1, Xiao-Hui Zhang1, Yu Wang1, Lan-Ping Xu1, Ying-Jun Chang1, Kai-Yan Liu1, Xiao-Jun Huang1, Yu-Qian Sun 1 O126 OUTCOMES OF DEFIBROTIDE-TREATED PATIENTS WITH VENO-OCCLUSIVE DISEASE/SINUSOIDAL OBSTRUCTION (VOD/SOS) FOLLOWING POST-TRANSPLANT CYCLOPHOSPHAMIDE (PT-CY): RESULTS FROM THE DEFIFRANCE REGISTRY Mohamad Mohty 1, Régis Peffault de Latour2, Virginie Gandemer3, Cécile Renard4, Charlotte Jubert5, Deborah Gutierrez6, Nalina Dronamraju7, Vian Amber8, Didier Blaise9 O127 HOW RISKY IS A SECOND ALLOGENEIC STEM CELL TRANSPLANTATION? AN EBMT REGISTRY ANALYSIS BY THE TRANSPLANT COMPLICATIONS WORKING PARTY Olaf Penack 1, Mouad Abouqateb2, Christophe Peczynski2, William Boreland2, Nicolaus Kröger3, Robert Zeiser4, Ciceri Fabio5, Thomas Schroeder6, Peter Dreger7, Jakob Passweg8, Johannes Schetelig9, Matthias Stelljes10, Igor Blau1, Uwe Platzbecker11, Helene Schoemans12, Ivan Moiseev13, Zinaida Peric14 O128 VENO-OCCLUSIVE DISEASE AND EARLY CARDIAC EVENTS IN CHILDREN RECEIVING ALLOGENIC STEM CELL TRANSPLANTATION WITH POST-TRANSPLANT CYCLOPHOSPHAMIDE Alice Corsia 1, Bénédicte Neven1, Charles De Marcellus1, Marina Cavazzana1, Marilyne Lévy1, Despina Moshous1 O129 EASIX SCORE AS A PREDICTIVE TOOL FOR SINUSOIDAL OBSTRUCTION SYNDROME IN PEDIATRIC PATIENTS UNDERGOING ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION Edoardo Muratore 1, Davide Leardini1, Giacomo Gambuti1, Leyna Larcinese1, Francesco Baccelli1, Francesca Gottardi1,1, Tamara Belotti1, Francesco Venturelli1, Arcangelo Prete1, Riccardo Masetti1 O130 APPLICATION OF RECENTLY PROPOSED EBMT/ ASTCT/CIBMTR/APCMT CONSENSUS RISK STRATIFICATION FOR TRANSPLANT ASSOCIATED THROMBOTIC MICROANGIOPATHY (TA-TMA) IN CHILDREN Michelle Schoettler 1,2, Elyse Bryson1,2, Kathleen Spencer1,2, Muna Qayed1,2, Satheesh Chonat1,2, Adrianna Westbrook1,2,3, Kirsten Williams1,2 O131 SALVAGE THERAPY WITH NINTEDANIB AND LOW-DOSE RUXOLITINIB LEADS TO SIGNIFICANT IMPROVEMENT IN PATIENTS WITH BRONCHIOLITIS OBLITERANS SYNDROME WHO FAILED CALCINEURIN AND GLUCOCORTICOIDS AFTER ALLOGENEIC TRANSPLANTATION Ya Luo 1, Meng Lv1, Jing Liu1, Xiao-Lu Zhu1, Xiao-Dong Mo1, Yu-Qian Sun1, Yu Wang1, Lan-Ping Xu1, Xiao-Hui Zhang1, Xiao-Jun Huang1,2 O132 SUBSEQUENT NEOPLASMS AFTER UMBILICAL CORD BLOOD TRANSPLANTATION IN THE JAPANESE AND EUROPEAN POPULATIONS Junya Kanda 1, Fernanda Volt2, Hanadi Rafii2, Hideki Nakasone3,4, Annalisa Ruggeri2,5, Nobuharu Fujii6, Chantal Kenzey2, Naoyuki Uchida7, Régis Peffault De La Tour8, Hikaru Kobayashi9, Graziana Maria Scigliuolo2,10, Koji Kato11, Barbara Cappelli10,2, Fumihiko Ishimaru12, Tatsuo Ichinohe13, Satoshi Takahashi14, Vanderson Rocha15,2, Teshima Takanori16, Yoshiko Atsuta17, Eliane Gluckman2,10 O133 FRAILTY SYNDROME IN ADULTS UNDERGOING AUTOLOGOUS HEMATOPOIETIC CELL TRANSPLANTATION. PROSPECTIVE STUDY ON BEHALF OF THE GRUPO ESPAÑOL DE TRASPLANTE HEMATOPOYÉTICO Y TERAPIA CELULAR (GETH-CT) Maria Queralt Salas 1,2, María Teresa Solano1,2, Mónica Baile-Gonzalez3,2, Marina Acera-Gómez3,2, Laura Fox4,2, María del Mar Pérez-Artigas4,2, Ana Santamaría5,2, María del Carmen Quintela-González5,2, Andrés Sánchez-Salinas6,2, Joaquina M. Salmerón-Camacho6,2, Verónica Illana-Álvaro7,2, Zahra Abdallahi-Lefdil7,2, Javier Cornago-Navascues8,2, Laura Pardo8,2, Sara Fernández-Luis9,2, Leddy Patricia Vega-Suárez9,2, Sara Villar10,2, Patricia Beorlegui-Murillo10,2, Albert Esquirol11,2, Isabel Izquierdo-García12,2, Sonia Rodríguez-González13,2, Alberto Mussetti13,2, Aitor Abuin-Blanco14,2, Javier Lopez-Marín15,2, Silvia Filarerro2,2, Leyre Bento16,2, Anna Sureda13,2 O134 MODEL-BASED DOSING OF ANTI-THYMOCYTE GLOBULIN IN PEDIATRIC ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION IMPROVES SURVIVAL CHANCES: UPDATED RESULTS FROM THE PHASE II PARACHUTE-TRIAL COMBINED WITH REAL-WORLD DATA Rick Admiraal 1, Stefan Nierkens1,2, Marc Bierings1,3, Mirjam Belderbos1, Alwin Huitema4,5, Robbert Bredius6, Yilin Jiang4, Kevin Curran7, Andrew Harris7, Andromachi Scaradavou7, Maria Cancio7, Elizabeth Klein7, Wouter Kollen1, Dorine Bresters1, Friso Calkoen1, Birgitta Versluijs1,8, Jaap Jan Boelens7, Caroline Lindemans1,3 O135 IMPACT OF MINIMAL RESIDUAL DISEASE AT HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA WITHIN THE FORUM TRIAL Adriana Balduzzi 1,2, Evgenia Glogova3, Peter Bader4,5, Jean-Hugues Dalle6,7, Franco Locatelli8,9, Rachel Staciuk10, Jacek Wachowiak11, Petr Sedlacek12,13, Jochen Buechner14, Tayfun Güngör15, Luisa Sisinni16, Marc Bierings17,18, Peter Svec19, Krzysztof Kalwak20, Ulrike Poetschger3, Christina Peters21, Marianne Ifversen22 O136 ACUTE GVHD IN PATIENTS ENROLLED IN THE PROSPECTIVE, INTERNATIONAL FORUM TRIAL: CLINICAL RESULTS Pietro Merli 1, Mattia Algeri1, Ulrike Poetschger2, Peter Bader3, Marianne Ifversen4, Jerry Stein5, Petr Sedlacek6, Jochen Buechner7, Marc Ansari8, Krzysztof Kalwak9, Jean-Hugues Dalle10, Christina Peters11, Franco Locatelli1,12, Anita Lawitschka11 O137 CLINICAL, MICROBIOLOGICAL CHARACTERISTICS AND OUTCOME OF BLOODSTREAM INFECTIONS IN PEDIATRIC HCT RECIPIENTS: RETROSPECTIVE MULTICENTER, ANALYSIS BY INFECTION WORKING GROUP OF ITALIAN PEDIATRIC HEMATOLOGY ONCOLOGY ASSOCIATION Francesco Baccelli 1, Daniele Zama1, Paola Muggeo2, Rosamaria Mura3, Maura Faraci4, Federica Barzagho5, Monica Cellini6, Antonella Colombini7, Elisabetta Calore8, Francesca Compagno9, Katia Perruccio10, Laura Luti11, Raffaella De Santis12, Manuela Spadea13, Giulia Caddeo14, Gloria Tridello14, Simone Cesaro15 O138 FACTORS INFLUENCING IMMUNE RECOVERY (IR) AFTER HAEMATOPOIETIC STEM CELL TRANSPLANT (HSCT) IN 114 PATIENTS WITH SEVERE COMBINED IMMUNODEFICIENCY (SCID) Andrea Meinhardt 1,2, Rachel Pearce3, Arnold Awuah1, Mercedes Selby1, Kimberly Gilmour1,4, Daisy Shillingford5, Emma Gravett5, Susanne Kricke5, Stuart Adams5,4, Kanchan Rao1,4, Reem Elfeky1,4 O139 HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR SICKLE CELL DISEASE IN CHILDREN USING THIOTEPA-BUSULFAN-FLUDARABINE CONDITIONING WITHOUT SEROTHERAPY IN 101 MATCHED RELATED DONOR TRANSPLANTS –A SINGLE-CENTER STUDY Mohammed Essa 1,2,3, Rodaina Abujoub1, Shahbaz Memon1, Abdulaziz AlSaud1, Nada AlShaikh1, Enas Elbashir1, Abdulrahman Alsultan4 O140 POST-TRANSPLANT RELAPSE IN PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA IN THE ERA OF CAR-T CELL THERAPY. A MULTICENTER ANALYSIS OF GRUPO ESPAÑOL DE TRASPLANTE HEMATOPOYETICO Y TERAPIA CELULAR (GETH-TC) PEDIATRIC COMMITTEE Marta Gonzalez Vicent 1, Blanca Molina1, Melissa Panesso2, David Bueno3, Antonia Pascual4, Sara Vinagre1, Yasmina Mozo3, Jose Luis Fuster5, Raquel Olivas6, Carolina Fuentes7, Monica Lopez8, Alexandra Regueiro9, Pilar Palomo10, Cristina Diaz de Heredia2 O141 COMPARISON OF EARLY IMMUNE RECONSTITUTION AFTER HAPLOIDENTICAL HSCT IN CHILDREN WITH ACUTE LEUKEMIA: PBSC WITH TCRΑΒ+/CD19+ DEPLETION VERSUS BM WITH POST-TRANSPLANT CYCLOPHOSPHAMIDE Mariia Igonina1, Dmitriy Pershin 1, Svetlana Glushkova1, Viktoria Vedmedskaya1, Oyuna Lodoeva1, Tatiana Sozonova1, Yakov Muzalevskii1, Alexei Kazachenok1, Elena Kurnikova1, Svetlana Radygina1, Maria Ilushina1, Rimma Khismatullina 1, Larisa Shelikhova 1, Alexei Maschan 1, Michael Maschan 1, Alexandra Laberko 1 O142 HAEMATOPOIETIC STEM CELL TRANSPLANTATION FOR TEENAGE AND YOUNG ADULT PATIENTS WITH ACUTE LEUKAEMIA IN THE UK AND IRELAND: COMPARISONS WITH CHILDREN AND ADULTS Graham McIlroy 1, Ben Carpenter2, Rachael Hough2, Caroline Besley3, Emma Nicholson4, Persis Amrolia5, Oana Mirci-Danicar3, Caroline Furness4, Victoria Potter6, Rachel Pearce7, Julia Lee7, Clementina Abamba7, Anna Castleton8, Ram Malladi9 O143 HAPLOIDENTICAL STEM CELL TRANSPLANTATION WITH POST-TRANSPLANT CYCLOPHOSPHAMIDE IN CHILDREN AND ADOLESCENTS WITH HEMATOLOGIC MALIGNANCIES: A RETROSPECTIVE MULTICENTRIC STUDY FROM THE SFGM-TC AND THE SFCE Charlotte Calvo*1,2, Cléo Hautefeuille* 1, Loïc Vasseur3, Charlotte Nazon4, Bénédicte Bruno5, Marc Ansari6, Arthur Sterin7, Anne Sirvent8, Audrey Grain9, Marie Angoso10, Virginie Gandemer11, Pascale Schneider12, Carine Halfon-Domenech13, Pierre-Simon Rohrlich14, Cécile Pochon15, Catherine Paillard4, Stéphanie Nguyen Quoc16, Nicole Raus17, Françoise Méchinaud1, Nathalie Dhedin3, Jean-Hugues Dalle1,2 O144 SECOND HAPLOIDENTICAL HEMATOPOIETIC CELL TRANSPLANTATION (HCT) WITH POST-TRANSPLANT CYCLOPHOSPHAMIDE (PT-CY) IN CHILDREN WITH HIGH-RISK HEMATOLOGIC MALIGNANCIES RELAPSED OR GRAFT FAILURED Francesca Gottardi1, Davide Leardini 1, Francesco Baccelli1, Tamara Belotti1, Francesca Vendemini2, Marek Ussowicz3, Simone Cesaro4, Maura Faraci5, Jean Hugues Dalle6, Adriana Balduzzi2, Francesco Saglio7, Arcangelo Prete1, Riccardo Masetti1 O145 LONG-TERM RESULTS OF RANDOMISED PHASE 2 TRIAL TO COMPARE TREOSULFAN WITH BUSULFAN BASED CONDITIONING IN CHILDREN WITH NON-MALIGNANT DISEASES Rita Beier 1, Peter Bader2, Jan Styczynski3, Ansgar Schulz4, Johann Greil5, Dirk Reinhardt6, Johannes Schulte7, Franca Fagioli8, Bernd Gruhn9, Franco Locatelli10, Simona Piras11, Manfred Hönig4, Petr Sedlacek12, Sonia Bonanomi13, Marco Zecca14, Maurizio Caniglia15, Simone Cesaro16, J. Gozdzik17, Karl-Walter Sykora1, M. Mielcarek-Siedziuk18, Krzysztof Kalwak18 O146 YOUNG MATCHED UNRELATED DONORS SHOULD BE PRIORITIZED OVER OLDER-AGED MATCHED SIBLING DONORS AND YOUNG HAPLOIDENTICAL DONORS IN ALLOGENEIC TRANSPLANTATION WITH POST-TRANSPLANT CYCLOPHOSPHAMIDE IN RECIPIENTS ≥ 50-YEARS Karthik Nath 1, Mei-Jie Zhang2, Matthew Bye2, Stephanie Lee3, Yung-Tsi Bolon4, Cara Benjamin5, Brian Betts6, Shahinaz Gadalla7, Steven GE Marsh8, Parinda Mehta9, Filippo Milano3, Stephen Spellman4, Hannah Choe10, Brian Shaffer1 O147 EVALUATING THE IMPACT OF ABO COMPATIBILITY ON ALLOGENEIC STEM CELL TRANSPLANTATION OUTCOMES A CONTEMPORARY AND COMPREHENSIVE STUDY FROM THE EBMT TRANSPLANT COMPLICATIONS WORKING PARTY Mustafa Güven 1,2, Christophe Peczynski3, William Boreland3, Didier Blaise4, Régis Peffault de Latour5, Ibrahim Yakoub-Agha6, Tobias Gedde-Dah7, Urpu Salmenniemi8, Jakob Passweg9, Patrice Chevallier10, Hélène Labussière-Wallet11, Stephan Mielke12, Annoek Broers13, Patrice Ceballos14, Jennifer Byrne15, Cristina Castilla- Llorente16, Johan Maertens17, Anne Huynh18, Raffaella Cerretti19, Claude Eric Bulabois20, Gwendolyn Van Gorkom21, Charles Crawley22, Hélène Schoemans17, Olaf Penack23, Ivan Moiseev24, Zinaida Peric25 O148 SUPERIOR DISEASE CONTROL WITH YOUNGER MATCHED UNRELATED DONOR VS OLDER-AGED MATCHED SIBLING DONOR IN RECIPIENTS ≥ 50-YEARS WITH ALL, AML, OR MDS USING CNI-BASED GVHD PROPHYLAXIS Karthik Nath 1, Mei-Jie Zhang2, Matthew Bye2, Stephanie Lee3, Yung-Tsi Bolon4, Cara Benjamin5, Brian Betts6, Shahinaz Gadalla7, Steven GE Marsh8, Parinda Mehta9, Filippo Milano3, Stephen Spellman4, Brian Shaffer1, Hannah Choe10 O149 DONOR AGE AND CMV STATUS ARE ASSOCIATED WITH T-CELL IMMUNOPHENOTYPE IN G-CSF MOBILIZED GRAFTS: AN INITIAL ANALYSIS FROM THE DKMS AND NMDP GRAFT COMPOSITION STUDY Hugh MacMillan1, Hans Minderman2, Ashley Spahn3, Orla Maguire2, Xiaojun Liu2, Huy Pham4, Elke Rucker-Braun5,6, Bose Falk5,6, Henning Baldauf5, Nicole Heymann5,6, Heike Uhlemann Uhlemann5,6, Lisa Heiduschke5,6, Kieran O’Loughlin2, Alexander Schmidt5, Steven Devine3, Jeffrey Auletta3, Falk Heidenreich5,6, Jay Feinberg7, Marcel van den Brink8, Evan Newell1, Johannes Schetelig5,6, Stephen Spellman3, Kate Markey 1,9 O150 COMPARING THE OUTCOMES OF USING NON-FIRST-DEGREE RELATED DONORS TO FIRST-DEGREE RELATED DONORS IN HAPLOIDENTICAL HSCT FOR HEMATOLOGICAL MALIGNANCIES: A CASE-CONTROL ANALYSIS Yue Lu1, Jianping Zhang1, Xingyu Cao1, Min Xiong1, Yanli Zhao1, Deyan Liu1, Ruijuan Sun1, Xu Fang 1 O151 IMPACT OF HAPLOIDENTICAL OR MISMATCHED UNRELATED DONOR AGE (<35 VS >35 YEARS) ON TRANSPLANTATION WITH PTCY OUTCOMES: ON BEHALF OF THE ALWP OF THE EBMT Arnon Nagler 1, Myriam Labopin2,3, Didier Blaise4, Emanuele Angelucci5, Jan Vydra6, Lucia Lopez Corral7, Stefania Bramanti8, Simona Sica9, Mi Kwon10, Yener Koc11, Maija Itäla-Remes12, Massimo Martino13, Alexander Kulagin14, Alessandro Busca15, Fabio Ciceri16, Mohamad Mohty2,3 O152 IMPACT OF GVHD PROPHYLAXIS ON THE OUTCOMES OF 8/10 HLA-MISMATCHED UNRELATED DONOR ALLOGRAFT: AN ANALYSIS ON BEHALF OF THE TRANSPLANT COMPLICATIONS WORKING PARTY OF EBMT Ivan Moiseev 1, Mouad Abouqateb2, Christophe Peczynski2, Alessandro Busca3, Nicolaus Kröger4, Raffaella Cerretti5, Robert Zeiser6, Thomas Schroeder7, Matteo Parma8, Régis Peffault de Latour9, Wolfgang Bethge10, Jan Vydra11, Didier Blaise12, Matthias Eder13, Franca Fagioli14, William Boreland2, Hélène Schoemans15, Olaf Penack16, Zinaida Peric17 O153 OLD MATCHED SIBLING DONOR VERSUS YOUNG HAPLO-IDENTICAL DONOR FOR ELDERLY PATIENTS WITH ACUTE MYELOID LEUKEMIA TRANSPLANTED IN FIRST REMISSION Xavier Poiré 1, Myriam Labopin2,3,4,5, Emmanuelle Polge2,3,4,5, Didier Blaise6, Patrice Chevallier7, Johan Maertens8, Nicolaus Kröger9, Caroline Besley10, Stéphanie Nguyen11, Cristina Castilla-Llorente12, Gerard Socié13, Edouard Forcade14, Anne Huynh15, Igor Wolfgang Blau16, Jaime Sanz17, Simona Piemontese18, Mohamad Mohty2,3,4,5, Fabio Ciceri2,18 O154 ALTERNATIVE DONORS IN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR ACUTE MYELOID LEUKEMIA IN ADOLESCENT AND YOUNG ADULTS: A REPORT FROM THE SFGM-TC Aude-Marie Fourmont 1,2, Ibrahim Yakoub-Agha3, Hélène Labussière-Vallet4, Johan Maertens5, Edouard Forcade6, Anne Huynh7, Xavier Poiré8, Raynier Devillier9, Cristina Castilla-Llorente10, Patrice Chevallier2, Marie-Thérèse Rubio11, Etienne Daguindau12, Philippe Lewalle13, Claude-Eric Bulabois14, Mohamad Mothy15, Nicole Raus16, Stéphanie Nguyen17, Loic Vasseur1, Nathalie Dhedin1

14 – 17 April, 2024 Hybrid Meeting

Copyright: Modified and published with permission from https://www.ebmt.org/annual-meeting

Sponsorship Statement: Publication of this supplement is sponsored by the European Society for Blood and Marrow Transplantation. All content was reviewed and approved by the EBMT Committee, which held full responsibility for the abstract selections.

19: Acute Leukaemia

O009 THE DISEASE RISK STRATIFICATION SYSTEM (DRSS): VALIDATION AND REFINEMENT IN A CONTEMPORARY ACUTE LEUKEMIA COHORT - AN ALWP EBMT STUDY

Roni Shouval 1, Myriam Labopin2, Joshua Fein3, Jurjen Versluis4, Matthias Stelljes5, Nicolaus Kröger6, Igor Wolfgang Blau7, Thomas Schroeder8, Matthias Eder9, Didier Blaise10, Ibrahim Yakoub-Agha11, Eva Maria Wagner-Drouet12, Régis Peffault de Latour13, Johannes Schetelig14, Tobias Gedde-Dahl15, Peter Dreger16, Anne Huynh17, Fabio Ciceri18, Mohamad Mohty2, Arnon Nagler19

1Memorial Sloan Kettering Cancer Center, New York, United States, 2Sorbonne University, Saint-Antoine Hospital, AP-HP, Paris, France, 3Weill Cornell Medicine, New York, United States, 4Erasmus MC, Rotterdam, Netherlands, 5University of Muenster, Muenster, Germany, 6University Hospital Eppendorf, Hamburg, Germany, 7Medizinische Klinik m. S. Hämatologie, Onkologie und Tumorimmunologie, Berlin, Germany, 8University Hospital | Essen, Essen, Germany, 9Hannover Medical School, Hannover, Germany, 10Programme de Transplantation & Therapie Cellulaire, Marseille, France, 11CHU de Lille, Lille, France, 12University Medical Center Mainz, Mainz, Germany, 13Saint-Louis Hospital, Paris, France, 14University Hospital, TU Dresden, Dresden, Germany, 15Oslo University Hospital, Rikshospitalet, Oslo, Norway, 16University of Heidelberg, Heidelberg, Germany, 17CHU - Institut Universitaire du Cancer Toulouse, Toulouse, France, 18IRCCS San Raffaele Scientific Institute, Milan, Italy, 19Chaim Sheba Medical Center, Ramat Gan, Israel

Background: The Disease Risk Stratification System (DRSS) serves as a vital prognostic tool in determining the outcomes of allogeneic hematopoietic cell transplantation (HCT) candidates. Initially developed and validated in a substantial cohort exceeding 47,000 patients transplanted between 2012 and 2016 (Shouval et al., Lancet Haem 2021), the DRSS relies on disease-related factors encompassing histological aspects, genetic profiles, and treatment responses. Recognizing the evolving landscape of transplantation practices and demographic shifts over time, this study aimed to validate and refine the DRSS within a contemporary cohort of acute leukemia patients.

Methods: We investigated 31,425 adult HCT recipients with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) transplanted between 2017 and 2021, as reported to The European Society for Blood and Marrow Transplantation (EBMT). We assessed the original DRSS’s prognostic impact and refined the risk levels based on individual disease feature combinations and their association with overall survival (OS), ultimately generating a refined version of the system (rDRSS).

Results: Patients had a median age of 54 years (interquartile range 40-63), with AML being the primary indication for HCT (76%). Most patients received myeloablative conditioning (54%) and donors were predominantly unrelated to recipients (57%). Post-transplantation cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis in 25% of patients. The original DRSS categorized patients into OS risk groups of low (26%), intermediate 1 (34%), intermediate 2 (14%), high (11%), and very high-risk (15%). Corresponding 2-year OS probability was 66%, 61%, 51%, 44%, and 34%. Subsequent multivariable Cox regression models, accounting for key patient and transplant characteristics, confirmed the association between DRSS levels and a stepwise increase in risks of mortality, leukemia-free survival (LFS), and relapse following HCT.

Refinements implemented in the rDRSS resulted in an increased proportion of patients classified as low-risk (36%) and a decreased number in the very high-risk category (6%). With the refined risk groups, the 2-year OS ranged from 33% in the very-high risk group to 73% in the low-risk group. rDRSS was consistently associated with mortality, LFS, and relapse. Furthermore, within a subset of patients with available pre-HCT measurable residual disease (MRD; n = 5148), the rDRSS maintained its prognostic impact, irrespective of MRD status.

Finally, we categorized patients based on the Disease Risk Index (Armand et al., Blood 2014). Notably, the bulk of patients (59%) were categorized as intermediate-risk and had a projected 2-year OS of 71% (95%CI 70–71). Among this group, rDRSS offered finer prognostic stratification, revealing substantial variability in survival outcomes across its risk categories, ranging from a 59% to 73% OS probability at 2 years after HCT.

Conclusions: This study successfully validated the DRSS in a large contemporary acute leukemia cohort. Additionally, we propose a refined model (rDRSS), updated to reflect recent HCT practice in acute leukemia. Both the DRSS and rDRSS can serve as benchmarks for future studies, facilitating interpretation and disease adjustment within heterogeneous cohorts, and enabling trial designs with more inclusive populations.

Disclosure: None

19: Acute Leukaemia

O01020-YEAR STEADY INCREASE IN POST-ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION OUTCOMES FOR PATIENTS WITH PHILADELPHIA-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA. A STUDY FROM THE EBMT ACUTE LEUKEMIA WORKING PARTY

Ali Bazarbachi 1, Myriam Labopin2, Iman Abou Dalle1, Ibrahim Yakoub-Agha3, Régis Peffault de Latour4, Thomas Schroeder5, Didier Blaise6, Xavier Poiré7, Marie Balsat8, Urpu Salmenniemi9, Nicolaus Kröger10, Alexander Kulagin11, Eva Maria Wagner-Drouet12, Depei Wu13, Eolia Brissot14, Arnon Nagler15, Sebastian Giebel16, Fabio Ciceri17, Mohammad Mohty14

1American University of Beirut Medical Center, Beirut, Lebanon, 2EBMT Statistical Unit, Sorbonne University, Paris, France, 3CHU de Lille, Lille, France, 4Saint-Louis Hospital, Paris, France, 5University Hospital Essen, Essen, Germany, 6Transplantation and Cellular Immunotherapy Program, Marseille, France, 7Cliniques Universitaires St. Luc, Brussels, Belgium, 8Centre Hospitalier Lyon Sud, Lyon, France, 9Comprehensive Cancer Center, Stem Cell Transplantation Unit, Helsinki University Hospital, Helsinki, Finland, 10University Medical Center, Hamburg, Germany, 11Alexander Kulagin, Saint-Petersburg, Russian Federation, 12University Medical Center Mainz, Mainz, Germany, 13First Affiliated Hospital of Soochow University, Suzhou, China, 14Sorbonne University, Paris, France, 15Chaim Sheba Medical Center, Tel-Hashomer, Israel, 16Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, Poland, 17IRCCS Ospedale San Raffaele, Milano, Italy

Background: Allogeneic hematopoietic cell transplantation (allo-HCT) remains an important curative modality for patients with Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) in first complete remission (CR1). Recent results using the combination of blinatumomab and second or third-generation tyrosine kinase inhibitors (TKI) have challenged the role of allo-HCT in CR1.

Methods: Using a large dataset from the EBMT registry, we identified 3292 adult patients (45% female; median age 45 years, range 18-76) with Ph+ ALL allografted between 2001 and 2020 in CR1 from a matched sibling (38%), unrelated (54%) or haploidentical donor (8%). At transplant, 41% of patients were measurable disease (MRD) positive (pos). Conditioning was myeloablative (MAC) in 77% of patients, and included total body irradiation (TBI) in 64% of patients. Median follow-up for live patients was 56 months (interquartile range [IQR] 28-32).

Results: We compared changes in patient and transplant characteristics over time in 245 patients transplanted in 2001-2005, 679 patients transplanted in 2006-2010, 1035 patients transplanted in 2011-2015, and 1333 patients transplanted in 2016-2020. Patients transplanted in recent years were older, were less likely to be MRDpos, and more likely to receive peripheral blood stem cells (PBSC) and in vivo T cell depletion (TCD). The 3-year cumulative incidence of relapse (CIR) gradually and significantly decreased from 41% to 32%, 27%, and 19% over the 4 time periods (p = 0.001), and non-relapse mortality (NRM) significantly decreased as well from 25% to 24%, 23% and 17% (p = 0.001). The 3-year leukemia-free survival (LFS) and overall survival (OS) gradually and significantly improved over time from 34% to 44%, 50%, and 64% (p = 0.001) and from 47% to 56%, 65%, and 75% (p = 0.001), respectively. Finally, graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) improved from 26% to 34%, 37%, and 49% (p = 0.001). In a Cox regression multivariate analysis (MVA), a progressive and significant improvement in all transplant outcomes was noted including reduced acute and chronic GVHD, reduced CIR and NRM, and increased LFS, OS, and GRFS. This improvement in post-transplant outcomes over time was observed both in MRDpos and in MRD negative (neg) patients. In MRDneg patients, 3-year CIR decreased from 34% to 30%, 24%, and 17% (p = 0.001) over the 4 time periods whereas LFS improved from 41% to 46%, 52%, and 66% (p = 0.001). Similarly, in MRD-positive patients, CIR decreased from 48% to 34%, 32%, and 23% (p = 0.001) over the 4 time periods whereas LFS improved from 27% to 42%, 47% and 60% (p = 0.001).

Conclusions: In patients with Ph+ ALL, we observed an impressive improvement over time in post-transplant outcomes with decreased CIR and NRM and improved LFS, OS, and GRFS, both in MRDpos and MRDneg patients. These large-scale, real-world data can serve as a benchmark for future studies in this setting, including those testing the combination of TKI and blinatumomab as an alternative to transplant.

Disclosure: Nothing to Disclose

19: Acute Leukaemia

O011 PROGNOSTIC FACTORS IMPACTING POST-TRANSPLANT OUTCOMES IN ADULT T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA: A REGISTRY-BASED STUDY BY THE EBMT ACUTE LEUKEMIA WORKING PARTY

Jean El Cheikh 1, Maud Ngoya2, Jacques-Emmanuel Galimard2, Péter Reményi3, Alexander Kulagin4, Mahmoud Aljurf5, Ashrafsadat Mousavi6, Depei Wu7, Mutlu Arat8, Urpu Salmenniemi9, Cristina Castilla-Llorente10, Gerard Socie11, Grzegorz Helbig12, Thomas Schroeder13, Ioanna Sakellari14, Alessandro Rambaldi15, Ben Carpenter16, Alessandro Busca17, Helene Labussiere-Wallet18, Matthias Stelljes19, Eolia Brissot20, Sebastien Giebel21, Zina Peric22, Arnon Nagler23,24, Ali Bazarbachi25, Fabio Ciceri26, Mohamad Mohty20

1AUBMC, Beyrouth, Lebanon, 2EBMT ALWP Saint Antoine Hospital Sorbonne University, Paris, France, 3Dél-Pesti Centrumkórház – Országos Hematológiai és Infektológiai Intézet, Budapest, Hungary, 4RM Gorbacheva Research Institute, Pavlov University, Saint Petersburg, Russian Federation, 5c. King Faisal Specialist Hospital & Research Centre, Oncology (Section of Adult Haematolgy/BMT), Riyadh,, Saudi Arabia, 6Shariati Hospital, Hematology-Oncology and BMT Research, Teheran, Iran, Islamic Republic of, 7First Affiliated Hospital of Soochow University, Suzhou, China, 8Demiroglu Bilim University Istanbul Florence Nightingale Hospital, Hematopoietic SCT Unit, Istanbul, Turkey, 9HUCH Comprehensive Cancer Center, Stem Cell Transplantation Unit, Helsinki, Finland, 10Gustave Roussy Cancer Campus, BMT Service Villejuif, Paris, France, 11Hopital St. Louis, Paris, France, 12Silesian Medical Academy, Katowice, Poland, 13University Hospital, Essen, Germany, 14George Papanicolaou General Hospital, Thessaloniki., Greece, 15University of Milan and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy, 16University College London Hospital, London, United Kingdom, United Kingdom, 17S.S.C.V.D Trapianto di Cellule Staminali, A.O.U Citta della Salute e della Scienza di Torino, Torino., Italy, 18Centre Hospitalier Lyon Sud, Service Hematologie, Lyon, France, 19University of Muenster, Muenster, Germany, 20Sorbonne University, Saint Antoine Hospital, INSERM UMRs 938, Paris, France, 21Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, Poland, 22School of Medicine, University Hospital Centre Zagreb, University of Zagreb, Zagreb, Croatia, 23Sheba Medical Center, Tel Aviv University, Tel Hashomer, Israel, 24Tel Aviv University, Ramat Gan, Israel, 25Bone Marrow Transplantation Program, American University of Beirut Medical Center, Beirut, Lebanon, 26Ospedale San Raffaele s.r.l. Hematology and BMT, Milano, Italy

Background: T-cell acute lymphoblastic leukemia (T-ALL) predominantly affects individuals in late childhood and young adulthood. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative modality particularly in the setting of poor risk genetics and/or persistent minimal residual disease. Limited studies have directly explored the impact of patient- and transplant-related factors on post-transplant outcomes in T-ALL.

Methods: Using a large dataset from the European Society for Blood and Marrow Transplantation registry, we identified 1907 adult T-ALL patients (70% male) who underwent their first allo-HSCT in first complete remission (CR1) from matched sibling donors (MSD; 45%), unrelated donors (UD; 43%) or haploidentical donors (12%) between 2010 and 2021.

Results: The median age at transplant was 33.4 years (18.1-75). The median follow up was 2.9 years. Most patients underwent total body irradiation (TBI)-based myeloablative conditioning (69%). The 2-year overall survival (OS) was 69.4%, and leukemia-free survival (LFS) was 62.1%. In multivariate analysis, advanced age at transplant negatively affected LFS (for each 10-year increment, HR = 1.11, p = 0.004), GVHD-free, relapse-free survival (GRFS) (HR = 1.06, p = 0.04), OS (HR = 1.12, p = 0.002), and non-relapse mortality (NRM) (HR = 1.23, p = 0.001). A later year of HSCT was associated with improved GFRS (For each 3 year increment, HR = 0.89, p = 0.001), OS (HR = 0.9, p = 0.02), and decreased NRM (HR = 0.82, p = 0.008). TBI improved LFS (HR = 0.79, p = 0.02), GRFS (HR = 0.83, p = 0.04), and relapse incidence (RI) (HR = 0.65, p = 0.001). Female-to-male transplant negatively affected GFRS (HR = 1.21, p = 0.02) and OS (HR = 1.23, p = 0.048). In vivo T-cell depletion significantly improved GFRS.

Multivariate Analysis of Prognostic Factors Influencing Patient Outcomes Following Allogeneic Hematopoietic Stem Cell Transplantation.

Outcome

Patient / Transplant Characteristics

HR (P-value)

LFS

Age at HSCT by 10 years

TBI

1.11 (0.004)

0.79 (0.02)

GRFS

Age at HSCT by 10 years

Year of HSCT by 3 years

Female to male donation

In vivo T-cell depletion

TBI

1.06 (0.04)

0.89 (0.001)

1.21 (0.02)

0.74 (0.001

0.83 (0.04)

OS

Age at HSCT by 10 years

Year of HSCT by 3 years

Female to male donation

1.12 (0.002)

0.9 (0.02)

1.23 (0.048)

RI

TBI

0.65 (0.001)

NRM

Age at HSCT by 10 years

Year of HSCT by 3 years

Delay from diagnosis to HSCT

1.23 (0.001)

0.82 (0.008)

1.06 (0.005)

aGVHD 2-4

Year of HSCT by 3 years

MUD

Haplo

MMUD

0.83 (0.001)

1.5 (0.02)

1.73 (0.001)

1.87 (0.001)

aGVHD 3-4

Year of HSCT by 3 years

In vivo T-cell depletion

MUD

Haplo

MMUD

0.81 (0.009)

0.54 (0.005)

2.04 (0.01)

1.83 (0.01)

2.41 (0.003)

cGVHD

Year of HSCT by 3 years

Female to male donation

In vivo T-cell depletion

MMUD

0.8 (0.001)

1.39 (0.002)

0.51 (0.001)

1.42 (0.04)

cGVHD (extensive)

Year of HSCT by 3 years

Female to male donation

In vivo T-cell depletion

0.8 (0.002)

1.47 (0.01)

0.36 (0.001)

Conclusions: This large study identified prognostic factors, such as age at transplant conditioning regimen, in influencing post-transplant in adult T-ALL patients undergoing allo-HSCT. Importantly, a significant improvement over time was noted. These findings hold great promise for new adapted treatment strategies and can serve as a benchmark for future studies in that setting.

Disclosure: no disclosure

19: Acute Leukaemia

O012 A MULTI-CENTER RETROSPECTIVE ANALYSIS OF OUTCOMES POST-ALLO-HCT IN TET2-MUTATED AML PATIENTS: A STUDY ON BEHALF OF THE GLOBAL COMMITTEE AND THE ALWP OF THE EBMT

Lin Li 1, Yishan Ye1, Jacques-Emmanuel Galimard2, Myriam Labopin2, Depei Wu3, Jia Chen3, Nicolaus Kröger4, Jakob Passweg5, Urpu Salmenniemi6, Maija Itäla-remes7, Xavier Poiré8, Matthias Eder9, Johan Maertens10, David Burns11, Henrik Sengeloev12, Gitte Olesen13, Didier Blaise14, Jürgen Finke15, Alain Gadisseur16, Ali Bazarbachi17, Eolia Brissot2, Arnon Nagler18, Yi Luo1, Jimin Shi1, Fabio Ciceri19, Mohamad Mohty2, He Huang1, Norbert Claude Gorin2

1The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China, 2EBMT Paris Office, Hôpital Saint Antoine 184, rue du faubourg Saint Antoine 75571 Paris cedex 12, Paris, France, 3First Affiliated Hospital of Soochow University, Suzhou, China, 4University Hospital Eppendorf, Hamburg, Germany, 5University Hospital Basel, Basel, Switzerland, 6HUCH Comprehensive Cancer Center, Helsinki, Finland, 7Turku University Hospital, Turku, Finland, 8Cliniques Universitaires St. Luc, Brussels, Belgium, 9Hannover Medical School, Hannover, Germany, 10University Hospital Gasthuisberg, Leuven, Belgium, 11University Hospital Birmingham NHS Trust, Stoke, United Kingdom, 12Rigshospitalet, Copenhagen, Denmark, 13Aarhus University Hospital Denmark, Aarhus, Denmark, 14Programme de Transplantation & Therapie Cellulaire, Marseille, France, 15University of Freiburg, Freiburg, Germany, 16Antwerp University Hospital (UZA), Antwerp E, Belgium, 17American University of Beirut, Beirut, Lebanon, 18Hematology Division, Chaim Sheba Medical Center, Tel-Hashomer, Israel, 19Unit of Hematology and Stem Cell Transplantation, Ospedale San Raffaele, University Vita-Salute San Raffaele, Milano, Italy

Background: Mutations in TET2 present in about 15% of adult AML. However the impact of allogeneic hematopoietic cell transplantation (allo-HCT) for the treatment of these patients remains unclear.

Methods: 644 adult AML patients with TET2 mutations receiving first non ex-vivo depleted allo-HCT from 2013-2022 in 127 centers were analyzed. All patients achieved first complete remission (CR1) before allo-HCT.

Results: The median age of the 644 AML patients was 59.4 (range, 18.1-86.3) years. 556 patients (86.3%) had de novo, and 88 (13.7%) had secondary AML, respectively. 367 (57.2%) patients were male. The median interval from diagnosis to allo-HCT was 4.9 (IQR, 3.8-6.2) months. Patients were categorized into favorable -(N = 23, 3.9%), intermediate-(N = 475, 79.8%) and adverse (N = 97, 16.3%) risk categories according to cytogenetic characteristics. Conditioning regimen was myeloablative (MAC) in 46.7% of patients. 149 patients (23.1%) received a matched-sibling donor, 176 (27.3%) a haploidentical donor (Haplo), 268 (41.6%) a 10/10 unrelated donor (UD) and 51 (7.9%) a 9/10 UD allo-HCT, respectively.For the entire cohort, with a median follow-up of 1.9 years, the 30-day cumulative incidence of engraftment was 97.6%. The 100-day cumulative incidence of grade II-IV aGVHD was 22.9% and the 2-year cumulative incidence of extensive cGVHD was 13.7%. In addition, the 2-year relapse incidence and NRM were 23.2% and 12.8%, respectively. Finally, the 2-year OS, LFS and GRFS were 69.8%, 63.9% and 49.8%, respectively.In multivariable analyses, a donor type 9/10 UD was associated with a higher RI (HR = 2.33, 95% CI 1.21-4.48; p = 0.01), a lower LFS (HR = 2.20, 95% CI 1.31-3.70; p < 0.01) and OS (HR = 2.29, 95% CI 1.33-3.96; p < 0.01) as compared to MSD as reference. Compared to MSD, 10/10 UD and Haplo had similar outcomes. The adverse-cytogenetic group was associated with higher RI (HR = 1.85, 95% CI 1.19-2.86; p < 0.01), and higher incidence of grade II-IV acute GVHD (HR = 1.74, 95% CI 1.14-2.64; p = 0.01) as compared to other groups combined as reference. Compared to de novo AML (reference), secondary AML was associated with lower LFS (HR = 1.49, 95% CI 1.03-2.15; p < 0.05) and OS (HR = 1.68, 95% CI 1.15-2.45; p < 0.01). When age increased, patients faced higher RI (HR for 10y increment=1.24, 95% CI 1.01-1.53; p < 0.05) and extensive chronic GVHD (HR = 1.34, 95% CI 1.02-1.77; p < 0.05), which translated into higher NRM (HR = 1.66, 95% CI 1.23-2.24; p < 0.01), lower LFS (HR = 1.36, 95% CI 1.14-1.62; p < 0.01) and OS (HR = 1.60, 95% CI 1.31-1.96; p < 0.01). Later year of transplantation was associated with lower incidence of II-IV acute GVHD (HR for 2y increment=0.76, 95% CI 0.63-0.92; p < 0.01), chronic GVHD (HR = 0.67, 95% CI 0.54-0.83; p < 0.01) and extensive chronic GVHD (HR = 0.72, 95% CI 0.52-0.99; p < 0.05). Female to male, patient CMV status and interval between diagnosis and HCT did not affect significantly the transplant outcomes in multivariable analysis.

Conclusions: No significant difference was observed in outcomes of AML patients with TET2 mutations following MSD, HAPLO and 10/10 UD allo-HCTs, while 9/10 UD was associated with higher relapse incidence and lower survival outcomes. Higher patient age, secondary AML and adverse cytogenetics predicted worse transplant outcomes. GVHD prevention improved with time for these patients.

Disclosure: Nothing to declare.

19: Acute Leukaemia

O013 RELAPSE INCIDENCE POST UNRELATED ALLOGENEIC STEM CELL TRANSPLANTATION WITH POST-TRANSPLANT CYCLOPHOSPHAMIDE FOR ACUTE MYELOID LEUKEMIA IN FIRST COMPLETE REMISSION: FROM THE ALWP OF THE EBMT

Arnon Nagler 1, Maud Ngoya2, Jacques-Emmanuel Galimard2, Myriam Labopin3,4, Igor Wolfgang Blau5, Nicolaus Kröger6, Tobias Gedde-Dahl7, Thomas Schroeder8, David Burns9, Urpu Salmenniemi10, Alessandro Rambaldi11, Goda Choi12, Régis Peffault de Latour13, Jan Vydra14, Henrik Sengeloev15, Matthias Eder16, Stephan Mielke17, Edouard Forcade18, Sergey Bondarenko19, Fabio Ciceri20, Mohamad Mohty3,4

1Sheba Medical Center, Division of Hematology, Tel Hashomer, Israel, 2EBMT Statistical Unit, Paris, France, 3EBMT Paris study office; Saint Antoine Hospital, Paris, France, 4Sorbonne University, Saint-Antoine Hospital, AP-HP, INSERM UMRs 938, Paris, France, 5Medizinische Klinik m. S. Hämatologie, Onkologie und Tumorimmunologie, Berlin, Germany, 6University Hospital Eppendorf, Eppendorf, Germany, 7Oslo University Hospital, Rikshospitalet, Norway, 8University Hospital of Essen, Essen, Germany, 9University Hospital Birmingham NHSTrust, Birmingham, United Kingdom, 10HUCH Comprehensive Cancer Center, Helsinki, Finland, 11ASST Papa Giovanni XXIII, Bergamo, Italy, 12University Medical Center Groningen (UMCG), Groningen, Netherlands, 13Saint-Louis Hospital, BMT Unit, Paris, France, 14Institute of Hematology and Blood Transfusion, Prague, Czech Republic, 15Rigshospitalet, Herlev, Denmark, 16Hannover Medical School, Hannover, Germany, 17Karolinska University Hospital, Stockholm, Sweden, 18CHU Bordeaux, Hôpital Haut-Leveque, Pessac, France, 19RM Gorbacheva Research Institute, Pavlov University, Petersburg, Russian Federation, 20IRCCS Osspedale San Raffaele, Vita-Salute San Raffaele University Hematology and BMT, Milano, Italy

Background: Post-transplant cyclophosphamide (PTCy) reduces chronic (c) graft-versus-host disease (GVHD) and thus may suppress the graft-versus-leukemia (GVL) effect leading to increased relapse (RI).

Methods: The study aim was to compare RI post 9-10/10 unrelated donor transplantations (UD-HSCT) with PTCy vs. no PTCy (in vivo T-cell depletion or calcineurin inhibitor-based) GVHD prophylaxis, in adult patients (pts) with AML in CR1 transplanted between 2014 and 2021 with peripheral blood grafts. Engraftment was a secondary endpoint. Statistical tests included a multivariate analysis (MVA) using a Cox proportional-hazards regression model for main outcomes.

Results: In total, 7049 pts were included: 707 received PTCy, and 6342 did not (no PTCy). Median follow-up was 2.8 (range, 2.6-2.9) years(y). The pts in the PTCY group were younger, median age was 52.7 (range, 18-77.5) vs. 56.6 (range, 18-80.3) y (p < 0.001). Cytogenetic risk category (ELN2017 classification) did not differ between the groups, (p = 0.54) (missing data-1196 pts). There were more HLA 9/10 donors in the PTCy group 33.8% vs. 16.4% (p < 0.001). More pts in the PTCy group received myeloablative conditioning, 61.7% vs. 50.2%, respectively (p < 0.001). In the no PTCy group, 87.7% of pts received in vivo T-cell depletion.

Day 30 neutrophil (ANC > 0.5x109/L) and platelet ( > 20x109/L) engraftment was achieved in 93.8% and 80.9% vs. 97.6% and 92.6% of the pts in the PTCy and no PTCy groups, respectively. Median days of engraftment were +17 and +20 vs. + 14 and + 18, respectively (p < 0.001). In the MVA, RI was not significantly different in the PTCy vs. the no PTCy group, with a hazard ratio (HR) of 1.11 (95% CI 0.9-1.37) (p = 0.31). Relapse was the cause of death in 58.8% vs. 54.3% of the pts that died. Myeloid and platelet engraftment were significantly lower in the PTCy vs. the no PTCy group, HR = 1.67 (95% CI 1.47-1.92, p < 0.001) and HR = 2.44 (95% CI 2.17-2.78, p < 0.001). Day 180 acute (a) GVHD (grades II-IV and severe grades III-IV) were significantly lower with PTCy compared to the no PTCy group, with HR of 0.74 (95% CI 0.59-0.92, p = 0.007) and HR = 0.56 (95% CI 0.38-0.83, p = 0.004), as were 2-y cGVHD (total and extensive) with HRs of 0.5 (95% CI 0.41-0.62, p = 0.001) and HR = 0.31 (95% CI 0.22-0.42, p = 0.001). NRM was significantly lower with PTCy compared to the no PTCy group with an HR of 0.67 (95% CI 0.5-0.91, p = 0.007). GRFS was higher in the PTCY vs the no PTCy group, with a HR = 0.69 (95% CI 0.59-0.81, p = 0.001). LFS and OS did not differ significantly between the groups, with HRs of 0.93 (95% CI 0.78-1.1, p = 0.39) and HR = 0.93 (95% CI 0.77-1.12, p = 0.45), respectively.

Conclusions: In this registry-based, retrospective analysis of UD-HSCT with PTCy vs. no PTCy in pts with AML in CR1, we observed non-significantly different RI, OS, and LFS. Incidence of GVHD and NRM were significantly lower, while GRFS was significantly higher with PTCy compared to no PTCy anti-GVHD prophylaxis. Engraftment was significantly lower with PTCy. Clinically, these results do not support PTCy negating the GVL effect in UD-HSCT.

Disclosure: Nothing to declare

19: Acute Leukaemia

O014 COMPARATIVE STUDY FOR HAPLO, MSD AND MUD ALLO-HCTS FOR CBF AML PATIENTS IN CR2: A STUDY FROM THE GLOBAL COMMITTEE AND ALWP OF THE EBMT

Yishan Ye 1, Myriam Labopin2, Socié Gérard3, Ibrahim Yakoub-Agha4, Igor Wolfgang Blau5, Mahmoud Aljurf6, Edouard Forcade7, Tobias Gedde-Dahl8, David Burns9, Jan Vydra10, Khaled Halahleh11, Rose-Marie Hamladji12, Ali Bazarbachi13, Arnon Nagler14, Eolia Brissot2, Lin Li1, Yi Luo1, Yanmin Zhao1, Fabio Ciceri15, He Huang1, Mohamad Mohty2,16, Norbert Claude Gorin2,16

1The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China, 2EBMT Paris Office, Paris, France, 3Saint-Louis Hospital, Paris, France, 4CHU de Lille, Lille, France, 5Medizinische Klinik m. S. Hämatologie, Berlin, Germany, 6King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia, 7CHU Bordeaux, Hopital Haut-Leveque, Bordeaux, France, 8Oslo University Hospital, Oslo, Norway, 9University Hospital Birmingham NHSTrust, Birmingham, United Kingdom, 10Institute of Hematology and Blood Transfusion, Prague, Czech Republic, 11King Hussein Cancer Centre Adult BMT Program, Amman, Jordan, 12Centre Pierre et Marie Curie, Alger, Algeria, 13American University of Beirut Medical Center, Beirut, Lebanon, 14Chaim Sheba Medical Center, Tel-Hashomer, Israel, 15Ospedale San Raffaele s.r.l., Haematology and BMT, Milano, Italy, 16Hospital Saint Antoine, Paris, France

Background: Although core-binding factor acute myeloid leukemia (CBF-AML) generally has a favorable prognosis, relapse occurs in ~40% of cases. Allogeneic hematopoietic cell transplantation (allo-HCT) is recommended when patients achieve second complete remission (CR2). However, transplant outcomes and donor preference for these patients remain unclear. We compared in an EBMT global multi-center registry-based analysis the outcomes following allo-HCT using either haploidentical donors (HAPLO), matched siblings donors (MSD), or 10/10 matched unrelated donors (MUD).

Methods: Data from 865 de novo adult CBF AML patients in CR2 receiving allo-HCT in 227 EBMT centers from 2010-2022 were analyzed. Transplants from mismatched UD ( < 10/10), umbilical cord blood or grafts with ex-vivo manipulation were excluded. Univariate analyses and Cox regression models were used.

Results: Results from 329 MSD, 374 MUD, and 162 HAPLO HCTs were analyzed. For the entire cohort, median age was 43y (range: 18-76). Inv(16)/CBFBMYH11 was detected in 503 patients (58%) and t(8;21)/RUNX1-RUNX1T1 was detected in 362 patients (42%). Peripheral blood was the major graft source (86.1%), and myeloablative conditioning was used for the majority (60.1%) of all allo-HCTs. 83% of patients in the HAPLO group received post transplant cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis. Engraftment rates were higher in the MSD (98.8%) and MUD (98.9%) than in the HAPLO (94.9%) group (p < 0.01). Original disease was the major cause of death for the MSD and MUD cohorts, while in the HAPLO group, it was infection.

On univariate analysis, HAPLO HCT was associated with a higher 2-year non-relapse mortality (NRM) (MSD 17.1%, MUD 15.3%, HAPLO 25.7%). The 180-day cumulative incidence of grade II-IV acute GVHD was higher in HAPLOs (14.8%) than in MSD (6.8%) or MUD (7.9%) recipients, respectively. No significant difference was observed among the three cohorts for 2-year leukemia-free survival (LFS), overall survival (OS) and GVHD-free/relapse free survival (GRFS). CBF-AML with inv(16) was associated with lower relapse incidence RI (18.1%) than with t(8;21) (28.3%), which contributed to better OS (75.7% vs 59.8% at 2 years), LFS (65.8% vs 51.2%) and GRFS (50.8% vs 38.5%).

On multivariate analysis, no significant difference was observed among HAPLO, MSD and MUD allo-HCTs on NRM. HAPLO HCT was associated with lower RI compared to MSD (hazard ratio [HR] = 0.56, 95% CI 0.32-0.97; p < 0.05) and MUD (HR = 0.57, 95% CI: 0.33-0.99, p < 0.05) while there was no significant differences between the 3 types of donors on LFS, OS and GRFS. CBF-AML with t(8;21) was associated with both higher RI (HR = 1.79, 95% CI 1.3-2.47; p < 0.01) and higher NRM (HR = 1.58, 95% CI 1.1-2.27; p < 0.01) than CBF-AML with inv(16), which led to worse LFS, OS and GRFS. Higher age (per 10 year) was associated with higher risk of NRM (HR = 1.29, 95% CI 1.11-1.5; p < 0.01) and worse OS (HR = 1.13, 95% CI 1.01-1.27; p = 0.03).

Conclusions: For CBF-AML patients in CR2, haploidentical HCTs were associated with a lower RI compared to MSD and MUD allo-HCTs. HAPLO achieved similar LFS, OS and GRFS to MSD or MUD, respectively. In addition, CBF AML with inv(16) had better outcomes than with t(8;21) after allo-HCT.

Disclosure: Nothing to declare

19: Acute Leukaemia

O015 ALLOGENEIC TRANSPLANTATION FOR PATIENTS WITH ACUTE MYELOID LEUKEMIA WITH MYELODYSPLASIA-RELATED FEATURES AS PER THE INTERNATIONAL CONSENSUS CLASSIFICATION (ICC) 2022: FROM THE ALWP OF THE EBMT

Arnon Nagler 1, Myriam Labopin2,3, Jurjen Versluis4, Jaime Sanz5, Tobias Gedde-Dahl6, David Burns7, Michel Schaap8, Hélène Labussière-Wallet9, Peter von dem Borne10, Gwendolyn Van Gorkom11, Nathalie Contentin12, Andreas Neubauer13, Eva Maria Wagner-Drouet14, Nicolaus Kröger15, Jordi Esteve16, Fabio Ciceri17, Mohamad Mohty2,3

1Sheba Medical Center, Division of Hematology, Tel Hashomer, Israel, 2EBMT Paris study office; Saint Antoine Hospital, Paris, France, 3Sorbonne University, Saint-Antoine Hospital, AP-HP, INSERM UMRs 938, Paris, France, 4Erasmus MC Cancer Institute, Rotterdam,, Netherlands, 5University Hospital La Fe, Valencia, Spain, 6Oslo University Hospital, Rikshospitalet,, Norway, 7University Hospital Birmingham NHSTrust, Birmingham, United Kingdom, 8Nijmegen Medical Centre, Nijmegen, Netherlands, 9Hopital Lyon Sud, Hospices Civils de Lyon, Pierre Bénite, France, 10Leiden University Hospital, Leiden, Netherlands, 11University Hospital Maastricht, Maastricht, Netherlands, 12Centre Henri Becquerel, Rouen, France, 13Philipps Universitaet Marburg, Marburg, Germany, 14University Medical Center Mainz, Mainz, Germany, 15University Hospital Eppendorf, Eppendorf, Germany, 16Hospital Clínic of Barcelona, IDIBAPS, Barcelona, Spain, 17IRCCS Osspedale San Raffaele, Vita-Salute San Raffaele University Hematology and BMT, Milano, Italy

Background: Patients (pts) formerly diagnosed as AML with myelodysplasia-related changes are currently recategorized according to their underlying genetic events in three different AML subgroups, namely AML with mutated TP53, AML with myelodysplasia-related gene mutations (MR-GM), and AML with myelodysplasia-related cytogenetic abnormalities (MR-CG) (International Consensus Classification 2022) (Arber AD, Blood 2022). The relevance of this new classification for transplantation (HSCT) outcome is largely unknown.

Methods: We analyzed outcomes of AML pts with TP53-mutation, pts with any of the 9 MR-GM (Arber AD, Blood 2022), and pts with MR-CG without TP53 and or MR-GM transplanted in CR1 between 2010-2022 from matched siblings, unrelated or haplo donors. Pts were hierarchically assigned to these genetic categories after excluding any pre-defined AML with recurrent genetic abnormalities (ICC 2022). The TP53 pts were subdivided into those that harbor in addition to the TP53 mutation complex karyotype (CK) (TP53 mut.CK) and those with no CK (TP53 mut. notCK).

Results: 1152 pts were included: TP53 -(n = 527: CK -328; notCK -199), MR-GM (n = 379), and MR-CG (n = 246). Median FU was 24 mos. [IQR, 21-24]. Median age was 60.3 years (range 18.4-78.2). FLT3-ITD was more prevalent in the MR-GM group at 17.1% vs.7.4 % and 10.7% in the other 2 groups (p = 0.001). A higher proportion of pts in the TP53 group had KPS < 90 32.4% vs. 23.2% and 27.7% in the MR-GM and MR-CG groups (p < 0.012). A higher proportion of pts in the MR-CG group received MAC at 46.5% vs. 37.8% and 37% in the TP53 and MR-GM groups (p = 0.036). Finally, more pts in the MR-GM group received PTCy as GVHD prophylaxis 38.8% vs. 24.7% and 29.1% of the pts in the TP-53 and MR-GM groups (p < 0.0001). On MVA, pts in the MR-GM and MR-CG groups showed a better outcome compared to. the TP53 group with lower RI: HR = 0.24 (95% CI 0.18-0.33, p < 0.0001) and HR = 0.4 (95% CI 0.29-0.54, p < 0.0001) and better LFS HR = 0.37 (95% CI 0.3-0.47, p < 0.0001) and HR = 0.52 (95% CI 0.41-0.66, p < 0.0001), OS HR = 0.37 (95% CI 0.39-0.46, p < 0.0001) and HR = 0.5 (95% CI 0.39-0.64, p < 0.0001) and GRFS HR = 0.47 (95% CI 0.38-0.57, p < 0.0001) and HR = 0.64 (95% CI 0.51-0.79, p < 0.0001), respectively. Outcome was the worse for the TP53 with CK group. NRM, acute, and chronic GVHD did not differ significantly. In addition, pts with MR-CG showed worse outcome vs. those with MR-GM with higher RI HR = 1.67 (95% CI 1.14-2.43, p = 0.008) and lower LFS HR = 1.39 (95% CI 1.05-1.84, p < 0.021), OS HR = 1.36 (95% CI 1.01-1.82, p < 0.043) and GRFS HR = 1.37 (95% CI 1.07-1.75, p < 0.012). Of note, patients with sAML did not show a worse outcome than those with de novo AML after adjustment for genetic features, on MVA.

Conclusions: Analysis of HSCT outcomes in pts with myelodysplasia-related features per ICC 2022 classification demonstrated worse outcomes in pts with TP53 compared to those with MR-GM or MR-CG. Notably, the outcomes of pts with MR-GM were better than those with MR-CG. This is to our knowledge the first validation of the ICC2022 classification in AML pts with myelodysplasia-related changes undergoing transplantation.

Disclosure: Nothing to declare

19: Acute Leukaemia

O016 IMPACT OF MYELODYSPLASIA-RELATED GENE MUTATIONS ON OUTCOMES OF ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION WITH POST-TRANSPLANT SORAFENIB MAINTENANCE IN FLT3-ITD AML PATIENTS: A MULTI-CENTER, RETROSPECTIVE COHORT STUDY

Yeqian Zhao1,2,3,4, Jimin Shi1,2,3,4, Yi Luo1,2,3,4, Guifang Ouyang5, Lieguang Chen5, Jian Yu1,2,3,4, Yamin Tan6, Xiaoyu Lai1,2,3,4, Lizhen Liu1,2,3,4, Huarui Fu1,2,3,4, Yishan Ye1,2,3,4, Luxin Yang1,2,3,4, Congxiao Zhang1,2,3,4, He Huang1,2,3,4, Xiaoxia Hu1,2,3,4, Yanmin Zhao 1,2,3,4

1Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China, 2Institute of Hematology, Zhejiang University, Hangzhou, China, 3Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China, 4Zhejiang Province Engineering Research Center for Stem Cell and Immunity Therapy, Hangzhou, China, 5Ningbo First Hospital, Ningbo, China, 6Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China

Background: Post-transplant sorafenib maintenance could reduce relapse in patients with FLT3-ITD acute myeloid leukemia (AML), however, a subset of patients still experienced relapse after allogeneic hematopoietic stem-cell transplantation (allo-HSCT) even in the era of tyrosine kinase inhibitor (TKI). This study aimed to identify specific subgroups of FLT3-ITD AML experiencing poorer outcomes after allo-HSCT in the context of sorafenib maintenance.

Methods: This multi-center retrospective cohort study included patients with AML who underwent allo-HSCT at three hospitals between January 2016 and December 2022. The study’s inclusion criteria were (1) aged from 14 to 70 years, (2) diagnosed as FLT3 -ITD AML, (3) achieving complete remission (CR) post-transplantation and subsequently receiving sorafenib as part of their post-HSCT maintenance. A comprehensive profiles of cytogenetic and concomitant gene mutation were screened to identify the genetic risk factors influencing prognosis in FLT3-ITD AML patients.

Results: A total of 171 patients diagnosed with FLT3-ITD AML receiving allo-HSCT were included in the analysis. The median age of patients was 45 (range: 14-70) years, with approximately 30% manifesting refractory/relapse (R/R) diseases (Table 1). At the time of transplantation, 88% had achieved CR/CRi. The median follow-up period after transplantation was 20 months, 20% of the cohort experienced relapse, with a median time to relapse was 18 months (IQR 10-33 months) post-transplantation. The 2-year overall survival (OS) was 85.5% (95% CI 80.0%-91.3%). The 2-year relapse-free survival (RFS) and cumulative incidence of relapse were 79.1% (95% CI 72.8%-86.0%) and 20.3% (95% CI 14.7%-27.6%), respectively. Based on the European LeukemiaNet 2022 risk stratification (ELN2022), 25% of the patients were classified into the adverse-risk group, among whom 12% harbored myelodysplasia-related (MR) gene mutations, including ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and ZRSR2. Univariate analyses have suggested that MR gene mutations, DNMT3A mutations and non-remission status at transplantation significantly correlated with poorer OS, whereas R/R disease, along with aforementioned factors, indicated significantly inferior RFS. The FLT3-ITD allelic ratio, karyotype and application of pre-transplant TKIs have no impact on OS and RFS. Among patients in CR at transplant, there were no differences in prognosis between those who had minimal residual disease (MRD) negative, and MRD positive (2-year OS: 88.70% versus 83.30%, p = 0.930). Multivariate analysis by Cox proportional hazard model revealed that MR gene mutations were independently associated with adverse outcomes (OS: HR 11.51, 95%CI 1.44 -91.80, p = 0.021, RFS: HR 2.50, 95% CI 1.09-5.80, p = 0.031). Additionally, DNMT3A mutation was also identified as an independent risk factor affecting RFS (HR 2.7, 95%CI 1.30-5.60, p = 0.008). More interestingly, among the ELN2022 adverse-risk individuals, patients with MR gene mutations exhibited a significantly inferior OS and RFS, compared with those without the mutations, while the ELN2022 adverse risk individuals without MR gene mutations yielded survival outcomes similar to their ELN2022 intermediate risk counterparts.

Table 1. Baseline characteristics of 171 AML patients with FLT3-ITD receiving sorafenib maintenance post-transplantation

Patient characteristics

All (N = 171)

Gender, male

83 (49%)

Age at HSCT

45 (34, 53)

White blood cell counts at first diagnosis, 10^9 per L

37 (13, 92)

VAF of FLT3-ITD

36 (18, 47)

MR gene mutatonsa

21 (12%)

Karyotypes

Intermediate

120 (90%)

Adverse

13 (10%)

NA

38

ELN2022

Intermediate

129 (75%)

Adverse

42 (25%)

pre-HSCT FLT3 inhibitors

59 (35%)

R/R disease

52 (30%)

NA

2

preHSCT status

pre-MRDb -

118 (72%)

pre-MRD +

25 (15%)

PR/NR

21 (13%)

NA

7

Conditioning regimens

MAC

149 (87%)

RIC

22 (13%)

Donor Type

HID

132 (77%)

MSD

19 (11%)

URD

20 (12%)

  1. Data are n (%) or median (IQR)
  2. aMR gene related alterations: myelodysplastia-related gene alterations, including ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and ZRSR2;
  3. bMRD positivity is measured by multi-parameter flow cytometry (MPFC).

Conclusions: Among FLT3-ITD AML patients undergoing sorafenib maintenance post-transplantation, patients in CR at transplant will have similar outcomes regardless of MRD status. Further, those with MR gene mutations experienced inferior outcomes after HSCT. This particular subset of FLT3-ITD AML warrants further investigation.

Disclosure: The authors declare that they have no competing interests.

19: Acute Leukaemia

O01720-YEAR STEADY INCREASE IN POST-ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION OUTCOMES FOR OLDER PATIENTS WITH ACUTE MYELOID LEUKEMIA: A REPORT FROM THE EBMT ACUTE LEUKEMIA WORKING PARTY

Ali Bazarbachi 1, Myriam Labopin2, Nour Moukalled1, Nicolaus Kröger3, Christina Rautenberg4, Johannes Schetelig5, Jürgen Finke6, Igor Wolfgang Blau7, Didier Blaise8, Matthias Stelljes9, Matthias Eder10, Uwe Platzbecker11, Peter Dreger12, Wolfgang Bethge13, Johanna Tischer14, David Burns15, Henrik Sengeloev16, Eolia Brissot17, Sebastian Giebel18, Arnon Nagler19, Fabio Ciceri20, Mohamad Mohty21

1American University of Beirut Medical Center, Beirut, Lebanon, 2EBMT Statistical Unit, Sorbonne University, Saint-Antoine Hospital, Paris, France, 3University Medical Center, Hamburg, Germany, 4University Hospital Essen, Essen, Germany, 5Universitaetsklinikum Dresden, Dresden, Germany, 6University of Freiburg, Freiburg, Switzerland, 7Medizinische Klinik m. S. Hämatologie, Onkologie und Tumorimmunologie, Berlin, Germany, 8Instititut Paoli Calmettes, MSC Lab, Aix Marseille University, Marseille, France, 9University Hospital Muenster, Muenster, Germany, 10Hannover Medical School, Hannover, Germany, 11Medical Clinic and Policinic 1, Leipzig, Germany, 12University of Heidelberg, Heidelberg, Germany, 13University Hospital Tuebingen, Tuebingen, Germany, 14LMU University Hospital, Munich, Germany, 15University Hospital Birmingham NHSTrust, Stoke, United Kingdom, 16Rigshospitalet, Herlev, Denmark, 17Sorbonne University, Paris, France, 18Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, Poland, 19Hematology Division, Chaim Sheba Medical Center, Tel-Hashomer, Israel, 20IRCCS Ospedale San Raffaele, Milano, Italy, 21Sorbonne University, Saint-Antoine Hospital, Paris, France

Background: Acute myeloid leukemia (AML) is a disease of older patients. Progress in allogeneic hematopoietic cell transplantation (allo-HCT) allowed the delivery of allo-HCT to older patients. However, little information is available about the global impact of the current standard of care for older AML patients after allo-HCT and about the predictive factors for post-transplant outcomes. To address these challenges, we assessed real-world changes over time in transplant characteristics and post-transplant outcomes in older patients with AML (>65 years), using a large dataset from the EBMT registry.

Methods: We identified 7215 adult patients (40% female; median age 68 years, range 65-80) with AML (secondary AML in 25%) allografted between 2000 and 2021 from a matched sibling donor (MSD; 23%), unrelated donor (UD; 63%) or haploidentical donor (Haplo; 14%). Karyotype risk was intermediate in 71% and adverse in 25%. At transplant, 64% of patients were in first complete remission (CR1), 14% in CR2+ and 22% had active disease. Comorbidity index was zero in 43% of patients, 1-2 in 26% and >3 in 31%, while the Karnofsky score was <90 in 35%. Conditioning was reduced intensity (RIC) in 82% of patients. Median follow up was 40 months.

Results: Patients transplanted in recent years (65%) were older, were more likely to be in CR1 and to have an adverse-risk karyotype. Patients transplanted more recently were less likely to have had an MSD but more likely to have had a Haplo, peripheral blood stem cells and in vivo T cell depletion. The 3-year cumulative relapse incidence (RI) gradually and significantly decreased from 37% to 31%, then to 30% (p = 0.001) over the 3 time periods (2000-2009; 2010-2014; 2015-2021) whereas NRM decreased from 31% and 31% to 27% (p = 0.003). The 3-year leukemia free survival (LFS) and overall survival (OS) gradually and significantly improved from 32% to 38%, and then to 44% (p = 0.001) and from 37% to 42%, and then to 49% (p = 0.001), respectively. In multivariate analysis, significant improvement in the RI, LFS and OS were noted after 2015 whereas NRM was not significantly affected. This improvement of post-transplant outcomes over time was observed for patients in CR1 with LFS and OS increasing from 39% to 44% and then to 47% (p = 0.005) and from 43% to 48%, and then to 52% (p = 0.006) as well as for patients in CR2+ with LFS and OS increasing from 29% to 40% and then to 47% (p = 0.001) and from 37% to 44% and then to 52% (p = 0.001), respectively.

Conclusions: In older AML patients, we observed an impressive improvement over time in post-transplant outcomes, mostly attributed to decreased RI rather than decreased NRM, and regardless of disease status at transplant. These large-scale, real-world data can serve as a benchmark for future studies in this setting and indicate that the opportunity for transplant for the elderly should be mandatory and no longer an option.

Disclosure: Nothing to declare

19: Acute Leukaemia

O018 IMPACT OF GERMLINE RUNX1 MUTATIONS ON ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT OUTCOMES IN AML: A CIBMTR ANALYSIS

Kai Yu1, Jakob D. Devos2, Mei-Jie Zhang2, Kristin Page2, Nelli Bejanyan3, Partow Kebriaei4, Filippo Milano5, Rachel Cook6,7, Brian J. Druker6,7, Katrin Ericson8, Paul Liu1, Wael Saber2, Lea Cunningham 1,9

1National Human Genome Research Institute/National Institutes of Health, Bethesda, United States, 2Center for International Blood and Marrow Transplant Research, Milwaukee, United States, 3Moffitt Cancer Center, Tampa, United States, 4MD Anderson Cancer Center, Houston, United States, 5Fred Hutchinson Cancer Center, Seattle, United States, 6Knight Cancer Institute, Oregon Health & Science University, Portland, United States, 7Division of Hematology & Medical Oncology, Oregon Health & Science University, Portland, United States, 8RUNX1 Research Program, Santa Barbara, United States, 9National Cancer Institute/National Institutes of Health, Bethesda, United States

Background: RUNX1 mutations have been reported in 10% of large de novo AML cohorts of which 27-30% were germline1,2 and 16% were deleterious in subsequent analysis3. RUNX1 mutations are associated with poor prognosis and patients are usually referred for HSCT. A systematic analysis comparing outcomes for patients with germline vs somatic RUNX1 mutations has not been reported. We hypothesized that germline RUNX1 mutation status may affect HSCT outcomes. The primary objectives of this retrospective study were to estimate the prevalence of germline RUNX1 mutations and describe overall survival (OS), disease-free survival (DFS), transplant-related mortality (TRM), and relapse for patients with germline RUNX1 mutations who underwent allogeneic HSCT for AML. The secondary objective was to compare post-HSCT outcomes in AML patients with germline RUNX1 mutations to those with somatic RUNX1 mutations.

Methods: The CIBMTR registry was queried for individuals with RUNX1 mutations who underwent first allogeneic HSCT during 2013-2020 with banked pre-HSCT blood samples. Extracted DNA was used for targeted sequencing to detect RUNX1 small variants in all coding exons and flanking regions of RUNX1, to the coverage of >500x, using Illumina MiSeq protocol. A variant allele frequency (VAF) threshold in the range of 0.3-0.7 was used to categorize germline variants. A subset of variants that met pathogenic or likely pathogenic classification according to ACMG guidelines were deemed RUNX1 mutations.

Results: A total 330 patients (median follow up: 60.8 months (range, 3.3-115) from 98 centers were included. Of 330 patients, 6.7% (n = 22) patients had P/LP germline RUNX1 mutations and 93.3% (n = 308) had somatic mutations per the identified criteria. Patients with germline mutations were more likely to be older, (median 61 vs 49.1 years, p < 0.02), with primary induction failure (40.9% vs 33%, p < 0.01), with AML transformed from MDS rather than de novo (40.9% vs 13.3%, p < 0.01) and detectable measurable residual disease (MRD) pre-HSCT (84.6% vs 37.6%, p < 0.01). Patients with germline RUNX1 mutations had lower 2-year OS (40.9% vs 64.1%, p < 0.033) and DFS (36.4% vs 60%, p < 0.027) compared to patients with somatic RUNX1 mutations. TRM (13.8% vs 15.4%, p = 0.884) and relapse (23.6% vs 38.5%, p = 0.308) at 2 years were not different between the 2 groups. Within the subset of patients receiving HSCT in complete remission (n = 13), no differences in OS and DFS were observed between germline and somatic RUNX1 mutations. Sex, ethnicity, PS, HCT-CI, donor type, graft source, conditioning intensity, GVHD prophylaxis, year of HSCT, engraftment, GVHD were also not different between the two groups.

Conclusions: In this study, germline RUNX1 mutations are associated with greater likelihood of AML arising from MDS rather than de novo AML, primary induction failure, and MRD positivity at time of HSCT as compared to somatic RUNX1 mutations. While germline RUNX1 mutations results in lower OS and DFS after HSCT, if transplanted in CR the survival outcomes are similar to patients with somatic RUNX1. This study is not without limitations because true germline testing from cultured skin fibroblasts for germline confirmation was not possible. These results should be validated with a larger number of participants in multivariate analysis.

Disclosure: This study was supported by the Intramural Research programs of NHGRI, NCI of NIH, and by CIBMTR. Funding for DNA extraction from whole blood samples was also provided by the RUNX1 Research Program (501c non-profit).

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19: Acute Leukaemia

O019 ALLOGENEIC STEM CELL TRANSPLANTATION FOR ACUTE MYELOID LEUKEMIA WITH GERMLINE DDX41 MUTATIONS: A COMPARATIVE STUDY FROM THE ALFA-FILO-SFGMTC

Michael Loschi 1, Jacques-Emmanuel Galimard2, Matthieu Duchmann3, Laetitia Largeaud4, Pascal Turlure5, Stéphanie Nguyen Quoc6, Flore Sicre de Fontbrune7, Marie Robin8, Ibrahim Yakoub Agha9, Etienne Daguindau10, Sylvain Chantepie11, Amandine Charbonnier12, Sebastien Maury13, Helene Labussiere-Wallet14, Anne Huynh4, Edouard Forcade15, Cristina Castilla-Llorente16, Thomas Cluzeau1, Marie-Thérèse Rubio17, Raynier Devillier18, Natacha Maillard19, Herve Dombret7, Christian Recher4, Arnaud Pigneux15, Eric Delabesse4, Nicolas Duployez20, Regis Peffault de Latour8, Marie Sébert8

1Nice University Hospital, Cote d’Azur University, Nice, France, 2EBMT, Statistical Unit, Paris, France, 3Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP); Université de Paris, INSERM and Centre National de la Recherche Scientifique (CNRS), Paris, France, 4CHU Toulouse, IUCT-Oncopole, Toulouse, France, 5CHU Dupuytren Limoges, Limoges, France, 6Pitie-Salpetriere Hospital, AP-HP, Sorbonne Université, Paris, France, 7Hôpital Saint Louis, APHP, Paris, France, 8Hôpital Saint Louis, APHP, Université Paris Cité, Paris, France, 9CHU de Lille, Univ Lille, INSERM, Lille, France, 10CHU Besançon, Besançon, France, 11Caen University Hospital, Caen, France, 12Amiens University Hospital, Amiens, France, 13Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris (AP-HP), Institut Mondor de Recherche Biomédicale, Université Paris Est, Créteil, France, 14Hopital Lyon Sud, Hospices Civils de Lyon, Pierre Bénite, France, 15CHU Bordeaux, Bordeaux, France, 16Gustave Roussy Cancer Campus, Villejuif, France, 17Nancy University Hospital, Vandoeuvre les Nancy, France, 18Institut Paoli-Calmettes; Aix-Marseille Université, Marseille, France, 19CHU de Poitiers, Poitiers, France, 20CHU de Lille, Lille, France

Background: Pathogenic germline mutations of DDX41 (DDX41mut) are the most common genetic predisposition to myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML). Even if some recent studies reported DDX41mut neoplasms as a specific entity with favourable outcomes compared to DDX41wt, there are scarce data on the outcome after allogeneic hematopoietic stem cell transplantation (aSCT) in this population. We report a pair matched analysis comparing the outcome of DDX41mut and DDX41wt AML patients after aSCT in first complete remission (CR1).

Methods: In our previous study on 1690 AML patients treated with intensive chemotherapy in ALFA and FILO prospective trials, we reported detailed germline DDX41mut identification (Duployez et al., Blood 2022). In the present work, we focused on the 304 patients who received aSCT in CR1. The primary endpoint was the leukemia free survival (LFS). In order to take into account, the differences between the DDX41mut and DDX41wt groups, a pair-match analysis have been performed. Exact matching have been applied on the donor type, source of cells, patient sex and ELN2017 classification. Propensity score matching have been applied with age at transplant, donor female to male recipient, conditioning regimen and use of ATG. We were eventually able to pair matched 32 DDX41mut with 77 DDX41wt patients.

Results: Patients characteristics are displayed in Table 1. With a median age at aSCT of 61.5 yo for DDX41mut and 58.9 yo for DDX41wt, the median follow-up in the entire pair match cohort was 6.1 years (95%CI, 5-6.9).

There was no significant difference in LFS nor Overall Survival (OS) between DDX41mut and DDX41wt (6y LFS: 47.7% (95%CI, 27.6 – 65.4) and 52.1% (95% CI, 40.1 – 60.4) HR: 1.06 (95%CI 0.59-1.91), p = 0.86; and 6y OS: : 56.8% (95%CI, 36.5 - 72.8) and 54.2 (95% CI, 42 - 64.8), HR: 1.04 (95%CI: 0.48-1.94), p = 0.92) respectively). The 6y relapse incidence (RI) was 21% (95%CI: 7-40) and 28% (95%CI: 18-38) for DDX41mut and DDX41wt respectively. The timing of the relapse however wasn’t similar between the two groups. Indeed, even if those results are not significant, there was a trend for a lower RI in the 1y post-transplant in DDX41mut (HR: 0.29 (95%CI: 0.07-1.23), p = 0.09), while the RI of DDX41mut 1y after aSCT was higher as compared to DDX41wt(HR: 6.69 (95%CI: 0.73-61.5), p = 0.09). NRM at 6y was not significantly higher in DDX41mut than DDX41wt group, (31.2% (95%CI: 16.1 - 47.6) for DDX41mut vs 20.2% (95%CI: 11.9 - 30.2) for DDX41WT, (HR: 1.63% (95%CI: 0.75-3.55), p = 0.22). Of note, aGVHD was not different regarding DDX41 status (p = 0.33) and accounted for 30% of the NRM in the DDX41mut patients.

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Conclusions: Our study revealed no significant difference in LFS, OS, and NRM between DDX41mut and DDX41wt AML patients who received an aSCT in CR1 after intensive chemotherapy. However, regarding DDX41 status, we observed specificities in the chronology of post-transplantation events, especially for the time to relapse and the cause of NRM. This suggests that DDX41mut patients may require dedicated pre and post-transplant management.

Disclosure: Authors have nothing to declare

19: Acute Leukaemia

O020 A CASEMIX OUTCOME STRATIFICATION MODEL FOR SCT USING MACHINE LEARNING (COSMOS)

Erik G J. von Asmuth 1, Liesbeth C. de Wreede1, Constantijn J M. Halkes1, Dirk-Jan A. Eikema2, Riccardo Saccardi3, Mette D. Hazenberg4, María Paula Busto2, John A. Snowden5, Anna Sureda6, Arjan C. Lankester1, Hein Putter1

1Leiden University Medical Center, Leiden, Netherlands, 2The European Society for Blood and Marrow Transplantation, Leiden, Netherlands, 3Careggi University Hospital, Firenze, Italy, 4Amsterdam UMC, Amsterdam, Netherlands, 5Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom, 6Institut Català d’Oncologia, Barcelona, Spain

Background: When investigating determinants of outcome after allogeneic HSCT (alloHSCT), such as when comparing centers in benchmarking, adjustment for patient- and transplant-specific variables (casemix variables) is needed, which can be done by using a prediction model. Existing models often do not account for non-linear effects or interactions. We aimed to create a more accurate model by using machine learning which can incorporate these aspects as well as disease-specific factors.

Methods: We included patients undergoing a first alloSCT between 2017 and 2021 using the same inclusion criteria as EBMT benchmarking (N = 54.457), and modelled overall survival (OS) based on patient, donor and transplant characteristics not freely chosen by the physician, so including matching and donor variables, but excluding conditioning-, country and hospital-related variables.

We coded complex data into categories using the following scores: DRSS for disease, stage and cytogenetics, HCT-CI for comorbidity, IPSS-R and ELN2017 for cytogenetics in MDS and AML. HLA mismatches were coded using molecular matching on 10 alleles.

We created an XGBoost model, and fitted a normal Cox model on the same dataset for comparison. Within the XGBoost model, hierarchical parameterization of disease was used, and disease-specific covariates were added. These weren’t added to the normal Cox model, as it cannot process these parameters in the same way.

Predictive performance was quantified using the AUC at 1 and 2 years, where 0.5 means no better than random and 1 means perfect predictions. We used a 70-30 train test split, and 10-fold cross-validation within the train cohort. Results are from the N = 38.103 train set, reported results including risk group assignments are based on cross-validated predictions.

Results: The XGBoost model had an AUC of 0.691 at 1 year, while the Cox model performed significantly worse as assessed using AUC (AUC 0.675, delta AUC 0.015, P < 0.001) and Brier score (delta Brier score 0.002, P < 0.001).

Disease was the main determinant of outcome, with age, HLA match, performance score and comorbidities being secondary. Donor relation was of little importance to the model, indicating that when adjusting for HLA match and donor age, donor relation does not impact outcome.

To create risk groups, we plotted each cross-validated risk percentile, which revealed good continuous ordering between percentiles from low to high risk, with two discrete groups at the low- and high end. We then created the following risk groups: very low (≤7th percentile), low (7-25th percentile), low-intermediate (25-50th percentile), high-intermediate (50-75th percentile), high (75-97th percentile), and very high (>97th percentile). The most common diagnosis in the very low risk group was a hemoglobinopathy, while the majority of the very high risk group had high-risk malignant disease. A trend of higher age, lower performance score, more HLA mismatched donors and more comorbidities can be seen according to risk groups (table 1).

Full size table

Conclusions: Using machine learning to account for nonlinear effects and interactions can improve accuracy of survival predictions compared to the standard Cox model, leading to better adjustment of casemix effects, which could be applied in benchmarking.

Disclosure: Nothing to declare

19: Acute Leukaemia

O021 DOES SIZE MATTER? CENTER-SPECIFIC CHARACTERISTICS AND SURVIVAL AFTER ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION (ALLOHCT) FOR ACUTE MYELOBLASTIC LEUKEMIA (AML): A DRST ANALYSIS

Wolfgang Bethge 1, Sarah Flossdorf2, Franziska Hanke3, Christoph Schmid4, Mark Ringhoffer5, Stefan Klein6, Bernd Hertenstein7, Johannes Schetelig8, Matthias Stelljes9, Thomas Schroeder10, Igor Blau11, Francis Ayuk12, Matthias Eder13, Robert Zeiser14, Katharina Fleischhauer10, Nicolaus Kröger12, Peter Dreger15

1University Hospital Tuebingen, Tuebingen, Germany, 2DRST and University Hospital Essen, Essen, Germany, 3DRST - Deutsches Register für Stammzelltransplantationen e. V., Ulm, Germany, 4University Hospital Augsburg, Augsburg, Germany, 5Hospital Karlsruhe, Karlsruhe, Germany, 6Universtity Hospital Mannheim, Mannheim, Germany, 7Central Hospital Bremen, Bremen, Germany, 8University Hospital Dresden, Dresden, Germany, 9University Hospital Muenster, Muenster, Germany, 10University Hospital Essen, Essen, Germany, 11University Hospital Charité Berlin, Berlin, Germany, 12University Hospital Hamburg, Hamburg, Germany, 13University Hospital Hannover, Hannover, Germany, 14University Hospital Freiburg, Freiburg, Germany, 15University Hospital Heidelberg, Heidelberg, Germany

Background: While disease- and procedure-related outcome predictors in alloHCT for AML are well characterized, the impact of center-specific variables on outcomes are still a matter of debate. A CIBMTR analysis has suggested a superior outcome for patients transplanted in high-volume centers, defined by ≥ 40 transplants/year. The purpose of the present study was to investigate the effects of numbers of alloHCT procedures per year, center experience, program duration, academic status, and JACIE accreditation along with common disease- and transplant-specific parameters on survival after alloHCT in AML using registry data provided by the DRST, the German national partner of the EBMT.

Methods: Eligible were adult patients who had received a first alloHCT for AML in any disease stage from a matched or mismatched related or unrelated donor (>= 9/10) between 2015 and 2021 and were registered with the DRST. The primary endpoint was overall survival (OS) and secondary endpoint was competing risk relapse and non-relapse mortality (NRM) in the first 12 months after HCT. Univariable and multivariable analyses of the impact of baseline characteristics on survival endpoints were performed using Cox regression and Fine & Gray modeling, respectively. Best subset selection was used to select relevant variables for multivariable analysis. In further analysis, center volume (as a non-linear covariate) was modelled using splines.

Results: Of the 5328 patients meeting all eligibility criteria, 83% had been transplanted in a high-volume center (≥40 alloHCT/year); 90% in a university hospital; 90% in a center performing alloHCT for ≥10 years; and 73% in a JACIE-accredited center. Median age was 58y (range: 18-83y). 54% of the patients were in CR1 at alloHCT; 64% and 33% had an ECOG performance status (PS) of 0 and 1, respectively; and 42% had a documented HCT-CI < 3. Of 4162 patients (78%) with ELN risk information available, risk was adverse in 37% and intermediate in 42%. Donor distribution was matched related (MRD) 29%, matched unrelated (MUD) 49%, and mismatched related (MMRD) and unrelated (MMUD) each 11%. On multivariable analysis, center-specific factors predicting adverse OS (12 month since HCT) were program duration <5-10 years (hazard ratio (HR) 1.23, 95% CI [1.02; 1.49]); center volume <40/y (HR 1.21, [1.02; 1.45]); and non-academic hospital (HR 1.21, [0.98; 1.49]), whereas JACIE accreditation did not remain in the final model. Of note, the survival effect of the center-related adverse factors was largely driven by excess non-relapse mortality rather than relapse/progression. The volume effect could be shown for any cutoff between 30 and 70 alloHCT/year. Spline modeling suggested that the volume effect becomes non-significant beyond 45 allotransplants per year. Other parameters that remained in the final models were age, sex, disease status at HCT, stem cell source, donor type, conditioning, ECOG PS, HCT-CI and ELN risk.

Conclusions: Center volume, center experience, academic status, but not JACIE accreditation have an impact of alloHCT outcomes in adult patients with AML in Germany.

Disclosure: No conflict of interests to disclose

19: Acute Leukaemia

O022 MATCHED RELATED VERSUS MATCHED UNRELATED VERSUS HAPLOIDENTICAL DONORS IN FLT3-ITD + AML PATIENTS IN CR1: A STUDY FROM THE EBMT ACUTE LEUKEMIA WORKING PARTY

Eolia Brissot 1, Myriam Labopin2, Eleni Tholouli3, Tobias Gedde-Dahl4, Mahmoud Aljurf5, Gérard Socié6, David Burns7, Ibrahim Yakoub-Agha8, Matthias Stelljes9, Thomas Schroeder10, Nicolaus Kröger11, Edouard Forcade12, Claude Eric Bulabois13, Urpu Salmenniemi14, Alessandro Rambaldi15, Ali Bazarbachi16, Arnon Nagler17, Simona Piemontese18, Jaime Sanz19, Mohamad Mohty2, Fabio Ciceri18

1Sorbonne University, Inserm U_938S, Service d’hématologie et thérapie cellulaire, Hôpital Saint-Antoine, APHP, Paris, France, 2Service d’hématologie et thérapie cellulaire, Hôpital Saint-Antoine, APHP, Paris, France, 3Manchester Royal Infirmary, Manchester, United Kingdom, 4Oslo University Hospital, Rikshospitalet, Oslo, Norway, 5King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia, 6Saint-Louis Hospital, BMT Unit, Paris, France, 7Birmingham Centre for Cellular Therapy and Transplant (BCCTT), Stoke, United Kingdom, 8CHU de Lille, Univ Lille, INSERM U1286, Infinite, Lille, France, 9University of Muenster, Muenster, Germany, 10University Hospital | Essen, Essen, Germany, 11University Hospital Eppendorf, Hamburg, Germany, 12Service d’Hématologie Clinique et Thérapie Cellulaire, CHU Bordeaux, Bordeaux, France, 13CHU Grenoble Alpes - Université Grenoble Alpes, Grenoble, France, 14HUCH Comprehensive Cancer Center, Helsinki, Finland, 15University of Milan and ASST Papa Giovanni XXIII, Bergamo, Italy, 16American University of Beirut-Medical Center, Bone Marrow Transplantation Program, Beirut, Lebanon, 17Chaim Sheba Medical Center, Tel-Hashomer, Israel, 18Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Hospital, San Raffaele, Italy, 19University Hospital La Fe, University of Valencia, Valencia, Spain

Background: In acute myeloid leukemia (AML), the presence of FLT3-ITD mutation is associated with early relapse and an overall poor prognosis. The availability of active FLT3 inhibitors has improved the survival of FLT3-mutated patients with AML. In the 2022 European LeukemiaNet (ELN) classification, patients with FLT3-ITD mutation are classified in the intermediate-risk category, regardless of NPM1 mutation, and allogeneic hematopoietic stem cell transplantation (allo-HCT) for FLT3-ITD AML patients in first complete remission (CR1) is still recommended. However, the impact of donor type has not yet been well established. Therefore, the current study aimed to compare allo-HCT from matched sibling donors (MSD) with those from matched 10/10 unrelated donors (MUD) and T-replete haploidentical (Haplo) donors in FLT3-ITD + AML in CR1.

Methods: Patients with FLT3-ITD + AML in CR1 who underwent an allo-HCT from an MSD, MUD or Haplo donor between 2017 and 2022, and were reported to the registry of the EBMT ALWP, were included. The major endpoints were overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI), non-relapse mortality (NRM), and graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS). Univariate comparisons were performed using the log-rank test for LFS, OS, and GRFS, and Gray’s test for cumulative incidences of NRM and RI. A Cox proportional-hazards model was used for multivariate regression.

Results: We identified 2113 patients: 721 patients received a transplant from an MSD, 1015 from an MUD, and 377 from a Haplo donor. The median follow-up was 24.4 months. Median age was lower in the MSD group compared to the other groups (50.8 years, p < 10-4). Time from diagnosis to transplant was higher in the MUD group. The proportion of intermediate- and adverse-risk cytogenetics was similar in the 3 groups, as well as the proportion of mutated-NPM1 versus non-mutated NPM1. Measurable residual disease at transplant was negative in 64.2% patients with no statistical difference between the 3 groups (p = 0.1). The HCT-CI was higher in the MUD group. Significantly more patients received a myeloablative conditioning regimen in the MSD group compared to the MUD and Haplo groups (62%, p < 10-4). At 2 years, for the whole population, OS was 70.6% (95% CI: 68.3-72.8), LFS was 62.7% (95% CI:60.3-64.9), RI was 25.9% (95% CI, 23.9-28), NRM was 11.4% (95% CI:9.9-12.9), and GRFS was 50.9% (95% CI: 48.5-53.3). Acute GVHD II–IV was higher in the MUD compared to MSD group. No difference in chronic GVHD was observed. RI was significantly lower in the Haplo group compared to the MSD group (hazard ratio [HR] = 0.6, 95% CI: 0.42-0.89, p = 0.01). NRM was higher in MUD and in Haplo recipients than in the MSD group. LFS, OS and GRFS did not differ significantly between donor types.

Conclusions: Our study results show that allo-HCT may rescue two thirds of patients with FLT3-ITD + AML in CR1. Importantly, the donor type did not have any impact on patients’ OS, LFS, or GRFS. Moreover, the significant decrease in RI in the Haplo group underlines the potential interest in this donor type, taking into account the need for good timing and feasibility of SCT in this patient population

Disclosure: Nothing to declare

19: Acute Leukaemia

O023 THE USE OF GANCICLOVIR OR VALGANCICLOVIR DOES NOT INCREASE RELAPSE RISK FOLLOWING ALLOGENEIC STEM CELL TRANSPLANTATION IN PATIENTS WITH ACUTE MYELOID LEUKEMIA OR MYELODYSPLASTIC SYNDROME

Nihar Desai 1, Carol Chen1, Ivan Pasic1,2, Wilson Lam1,2, Arjun Law1,2, Armin Gerbitz1,2, Auro Viswabandya1,2, Fotios Michelis1,2, Rajat Kumar1,2, Jonas Mattsson1,2, Igor Novitzky-Basso1,2, Dennis Dong Hwan Kim1,2

1Hans Messner Allogeneic Transplant Program, Division of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto, Canada, 2University of Toronto, Toronto, Canada

Background: Leukemia relapse following allogeneic hematopoietic stem cell transplantation (HCT) in acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) still remains a significant challenge. Loss of heterozygosity (LOH) in major histocompatibility complex (MHC) gene or down-expression of MHC gene have been identified as a potential mechanism leading to relapse post-HCT. A Recent work (Toffalori et al, ASH 2023 abstract 362) suggested the genotoxicity of ganciclovir as one of the mechanisms of LOH-MHC, leading to post-HCT relapse. It has never been replicated whether ganciclovir or valganciclovir are associated with an increased risk of relapse. We attempted to replicate the hypothesis that the use of (val)ganciclovir is associated with increased relapse incidence in a large single-centre cohort.

Methods: Patients with a diagnosis of AML/MDS who underwent HCT at Princess Margaret Cancer Centre between January 2015 and March 2023 were evaluated. Cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) was determined considering competing events, respectively. Overall Survival (OS) was determined using the Kaplan-Meier method. A p-value of <0.05 was considered statistically significant.

Results: A total of 727 patients with AML/MDS underwent HCT, of whom 624 (85.8%) were CMV seropositive, constituting the primary group for analysis. Baseline characteristics are summarized in Table 1. More than half of the patients were aged >60 years. The median follow-up duration was 24.9 months (range, 8-54.5) among survivors, and 146 (23.4%) patients relapsed at a median of 6 months (range, 2.8-10.2) post-HCT.

Of the 350 episodes (56.1%) of CMV viremia, 317 were treated with (Val)ganciclovir. Patients receiving (Val)ganciclovir exhibited a lower CIR at 24 months, 19.6% (95% confidence interval: 15.4-24.2) compared to controls, 25.8% (20.8–31.1, p = 0.03). Regarding specific donor types, CIR for mismatched unrelated donor (MMUD) transplants was 33% (20.5-46.1) for patients who received (Val)ganciclovir compared to 35.6% (16.1-55.7) in controls (p = 0.95); the corresponding numbers for haploidentical transplants were 21.5% (12.7-31.9) and 24.6 (11-41), respectively (p = 0.68).

The OS rate at 24 months was 56.4% (50.7-61.7) for patients who received (Val)ganciclovir and 68% (62.1-73.1) for controls (p = 0.006), whereas the NRM rate at 2 years was 28.1% (23.2-33.2) in those who received (Val)ganciclovir and 14.6% (10.8-18.9) in the control group (p < 0.001).

On univariate analysis, exposure to (Val)ganciclovir (HR: 0.60; p = 0.003), and the use of myeloablative conditioning (MAC) (HR: 0.49; p = 0.004) were associated with decreased incidence of relapse. Conversely, a high-very high disease risk index (HR: 2.52; p < 0.001) and the use of MMUD (HR: 1.72; p = 0.01) increased the likelihood of relapse. Multivariable analysis confirmed that the exposure to (Val)ganciclovir does not increase the risk of relapse, rather reducing the relapse risk (Table 1).

Table 1: Patient characteristics and multivariable analysis

All patients (624)

(Val)ganciclovir exposed (317)

Control (307)

p value

Age at allo-HCT (median, range)

58 (46 – 65)

58 (46 – 65)

58 (46 – 65)

• Age >60 years (n, %)

320

174 (54.8)

146 (47.6)

0.30

Male (n, %)

321 (51.4)

159 (50.2)

162 (52.8)

0.73

Diagnosis (n,%)

• Acute Myeloid Leukemia

491 (78.7)

252 (79.5)

239 (77.9)

0.90

• Myelodysplastic Syndrome

133 (21.3)

65 (20.5)

68 (22.1)

0.70

KPS < 90 (n, %)

117 (18.8)

62 (19.6)

55 (17.9)

0.68

Disease Risk Index (n, %)

• High - Very high

124 (19.9)

74 (23.3)

50 (16.2)

0.07

HCT-CI (median, range)

2 (1 – 3)

2 (1 – 3)

2 (1 – 3)

Donor: (n, %)

• Matched related

152 (24.4)

70 (22.1)

82 (26.7)

0.32

• Matched unrelated

240 (38.5)

126 (39.8)

114 (37.1)

0.70

• Mismatched unrelated

75 (12.1)

51 (16.1)

24 (7.8)

0.004

• Haploidentical

105 (16.8)

70 (22.1)

35 (11.4)

0.002

Conditioning intensity: (n, %)

• Myeloablative

166 (26.6)

63 (19.9)

103 (33.6)

0.003

• Reduced intensity

458 (73.4)

254 (80.1)

204 (66.4)

0.13

ATG for GVHD prophylaxis (n, %)

500 (80.1)

257 (81.1)

243 (79.2)

0.85

GVHD: (n, %)

• Acute GVHD

327 (52.4)

169 (53.3)

158 (51.4)

0.83

• Grade II-IV aGVHD

52 (8.3)

37 (11.7)

15 (4.9)

0.005

• Chronic GVHD

180 (28.9)

91 (28.7)

89 (28.9)

1.0

• Moderate-severe cGVHD

92 (14.7)

56 (17.7)

36 (11.8))

0.07

Multivariable analysis

Hazard Ratio

95% Confidence Interval

p value

Myeloablative conditioning

0.46

0.29 – 0.71

<0.0001

Mismatched Unrelated Donor

1.71

1.09 – 2.66

0.01

Exposure to Val(ganciclovir

0.65

0.46 – 0.90

0.01

  1. Abbreviations: KPS: Kanofsky Performace Status; ATG: Antithymocyte Globulin; GVHD: Graft versus host disease

Conclusions: We could not replicate that (Val)ganciclovir treatment is associated with an increased risk of relapse post HCT in patients with AML/MDS, including MMUD and haploidentical transplant recipients. Further study is warranted to define the genotoxic effects of ganciclovir, and its impact on LOH-MHC and relapse post-HCT in a larger cohort.

Disclosure: Conflict of interest: Nothing to declare

Funding: Nothing to declare

19: Acute Leukaemia

O024 EXCELLENT OUTCOME OF PATIENTS PROCEEDING TO ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION WITH UNTREATED MOLECULAR RELAPSE OF NPM1-MUTATED AML

Gesine Bug 1, Kerstin Schäfer-Eckart2, Carina Rave3, Henning Baldauf3, Fabian Lang1, Knut Wendelin2, Katja Sockel4, Christian Reicherts5, Vera Schlipfenbacher1, Julia-Annabell Georgi4, Christoph Schliemann5, Marek Werth1, Katharina Egger-Heidrich4, Julia Marx5, Simon Call5, Heike Pfeifer1, Christian Thiede6, Johannes Schetelig4, Matthias Stelljes5

1Goethe University, Frankfurt, Germany, 2Klinikum Nürnberg, Nürnberg, Germany, 3DKMS gemeinnützige GmbH, Dresden, Germany, 4TU Dresden, Dresden, Germany, 5University Hospital Münster, Münster, Germany, 6AgenDix Applied Genetic Diagnostics, Dresden, Germany

Background: Patients with NPM1-mutated AML have a good prognosis after intensive chemotherapy, but most patients with persistence or recurrence of measurable residual disease (MRD) will eventually relapse. Since molecular relapse detected by RT-qPCR of NPM1 precedes hematological relapse by 2-4 months, many centers provide allogeneic hematopoietic cell transplantation (HCT) upon detection of MRD, assuming better transplant results than with HCT after overt relapse. Aim of this retrospective study was to describe the outcome of patients with NPM1-mutated AML at different disease stages, and to identify prognostic variables.

Methods: We included 227 consecutive adult patients with NPM1-mutated AML who received a first allogeneic HCT in 2010-2020 with molecular persistence or relapse detected by NPM1-specific RT-qPCR within 60 days prior to conditioning, or primary refractory or relapsed disease. Exclusion criteria included use of post-transplant cyclophosphamide for GVHD prophylaxis outside of haploidentical HCT and in vivo T-cell depletion other than ATG. Median follow-up was 4.5 years.

Results: Patients had a median age of 56 years (range, 24-76), 67% had a Karnofsky score ≥90 and 85% an HCT-comorbidity index <3. Karyotype was normal in 69% of patients and 47% harbored an FLT-3 mutation. Transplant characteristics included myeloablative, reduced intensity, sequential and non-myeloablative conditioning in 21%, 37%, 41% and 2% of patients, respectively. Patients primarily received peripheral blood stem cells (93%). Grafts were from an HLA-identical sibling (21%), haploidentical family donor (5%), 10/10 HLA-matched unrelated donor (MUD, 54%) and 9/10 MUD (17%). GVHD prophylaxis included CSA/MTX (35%), CSA/MMF (53%) or Tacrolimus/MMF (4%), plus ATG (57%).

At four years, overall survival (OS) was 61% (95%-CI: 54%-68%), the cumulative incidence of relapse/progression was 26% (95%-CI: 21%-33%) and of non-relapse mortality (NRM) 22% (95%-CI: 17%-28%). The 4y-OS rate was most favorable and not significantly different (p = 0.7, log-rank test) in patients transplanted in MRD-positive CR1 (82%, 95%-CI: 71%-94%, n = 46), molecular relapse (84%, 95%-CI: 74%-96%, n = 45) or MRD-negative CR2 (73%, 95%-CI: 53%-100%, n = 15). Notably, 35/45 patients (78%) with molecular relapse had not been treated prior to start of conditioning. In patients transplanted with hematological relapse or refractory AML (untreated relapse, n = 40; refractory relapse (r/r AML), n = 44; primary refractory disease, n = 24) 4y-OS was 34%-45%, not significantly different (p = 0.3, log-rank test) from that of patients transplanted in MRD-positive CR2 (54%, 95%-CI: 33%-89%, n = 13). Poor outcome in patients with overt untreated or refractory relapse was attributable to high 4y-NRM (27% and 35%) and relapse/progression (33% and 36%), respectively.

In multivariable analysis, transplant outcome depended primarily on disease status, with significantly worse OS and event-free survival (EFS) in patients transplanted with overt disease. In addition, 9/10 MUD transplantation and reduced intensity conditioning negatively impacted OS and EFS, respectively. Stem cell source, age, performance status, GVHD prophylaxis and FLT-3 mutation status had no significant impact on overall and event-free survival.

Conclusions: A favorable outcome in patients experiencing molecular recurrence in CR1 depends on being transplanted before progressing to hematological relapse, with no need for additional therapy aimed at inducing MRD-negativity at HCT. In contrast, transplantation with overt disease is associated with poor outcome, warranting experimental treatment approaches.

Disclosure: Gesine Bug: Honoraria from Novartis, Jazz, BMS, Gilead. Travel grants from Jazz, Gilead and Neovii. Johannes Schetelig: Participation at Advisory Boards organized by Abbvie, AstraZeneca, BeiGene, BMS, Janssen, and MSD. Lecture Fees from Astellas, AstraZeneca, BeiGene, BMS, Novartis, Eurocept, Medac and Janssen.

19: Acute Leukaemia

O025PRE-HCT NEXT-GENERATION SEQUENCING (NGS-MRD) AND OUTCOMES OF PEDIATRIC, ADOLESCENT, AND YOUNG ADULT B-ALL PATIENTS UNDERGOING ALLOGENEIC HCT: UPDATE FROM THE OBSERVATIONAL ARM OF PTCTC ONC1701

Troy Quigg 1, Neena Kapoor2, Jemily Malvar2, Elizabeth Gourdine2, Amy Keating3,4, Leslie Lehmann3, Kris Mahadeo5,6, Sajad Khazal7,6, Jodi Skiles8, Dana Salzberg9, Rachel Phelan10, Nahal Lalefar11, Emi Caywood12, Rabi Hanna13, Shalini Shenoy14, Heather Stefanski15, Jordan Milner16, Kevin McNerney17,18, Christine Higham19, Ulrich Duffner1, Joseph Chewning20, Niketa Shah21,22, Jeffrey Huo23, Ibrahim Ahmed24, Michael Pulsipher25, Hisham Abdel-Azim7

1Section of Pediatric Blood and Marrow Transplantation and Cellular Therapy, Helen DeVos Children’s Hospital, Grand Rapids, United States, 2Children’s Hospital of Los Angeles, Los Angeles, United States, 3Dana-Farber/Boston Children’s Cancer & Blood Disorders Center, Boston, United States, 4Division of Pediatric Hematology-Oncology-BMT, University of Colorado, Aurora, United States, 5Division of Transplant and Cellular Therapy, Duke University School of Medicine, Durham, United States, 6Pediatric Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Children’s Cancer Hospital, Houston, United States, 7Loma Linda University School of Medicine, Cancer Center, Children Hospital and Medical Center, Loma Linda, United States, 8Riley Hospital for Children, Indianapolis, United States, 9Phoenix Children’s Hospital, Phoenix, United States, 10Division of Pediatric Hematology, Oncology, and Blood and Marrow Transplantation, Medical College of Wisconsin, Milwaukee, United States, 11University of California San Francisco Benioff Children’s Hospital Oakland, Oakland, United States, 12Nemours/Alfred I duPont Hospital for Children, Wilmington, United States, 13Taussig Cancer Institute, Cleveland Clinic, Cleveland, United States, 14Washington University School of Medicine, St. Louis, United States, 15CIBMTR (Center for International Blood and Marrow Transplant Research), National Marrow Donor Program/Be The Match, Minneapolis, United States, 16Division of Hematology/Oncology, University of Florida, UF Health Shands Children’s Hospital, Gainesville, United States, 17Lurie Children’s Hospital, Northwestern University School of Medicine, Chicago, United States, 18Johns Hopkins All Children’s Hospital, St. Petersburg, United States, 19Division of Pediatric Allergy, Immunology, and Bone Marrow Transplant, Benioff Children’s Hospital, University of California San Francisco, San Francisco, United States, 20Pediatric Blood and Marrow Transplant Program, University of Alabama at Birmingham, Birmingham, United States, 21Rutgers Cancer Institute, Pediatric Bone Marrow Transplant/Stem Cell Transplant and Pediatric Cellular Therapy Program, New Brunswick, United States, 22Yale New Haven Children’s Hospital, New Haven, United States, 23Pediatric Cellular Therapies, Cancer and Blood Disorders, Atrium Health Levine Children’s Hospital, Charlotte, United States, 24Pediatric Hematology, Oncology and BMT, Children’s Mercy Hospital Kansas City, Kansas City, United States, 25Division of Hematology and Oncology, Intermountain Primary Children’s Hospital, Huntsman Cancer Institute, Spencer Fox Eccles School of Medicine, University of Utah, Salt Lake City, United States

Background: Our updated analysis with extended follow up shows key insights into the predictive ability of BCR (B-cell) vs TCR (T-cell) [beta (B) and gamma (G)] receptor rearrangements for NGS-MRD analysis and excellent relapse-free (RFS) and overall (OS) survival in children with pre-HCT NGS-MRD negative B-ALL undergoing allogeneic HCT.

Methods: 86 B-ALL patients enrolled on the observational arm of PTCTC ONC1701 trial (NCT03509961) were included. All patients were in complete morphological remission (CR) at time of HCT (CR1 n = 32; CR2 n = 40; ≥CR3 n = 14). Detectable bone marrow pre-HCT NGS-MRD, regardless of detection level, was considered positive. All patients received myeloablative conditioning, including TBI and non-TBI regimens, based on center standard/preference.

Results: Median age at HCT was 12.1 (range= 0.4-25.3) years. Pre-HCT NGS-MRD by trackable BCR rearrangements, regardless of residual TCR rearrangements, best predicts relapse-free survival (RFS) for allogeneic HCT in B-ALL. RFS was significantly better for pre-HCT NGS-MRD negative patients (based on BCR) for the whole cohort (p = 0.005) and for patients in CR1/2 compared to ≥ CR3 (p = 0.045). Patients ≥ CR3 and pre-HCT NGS-MRD negative have higher RFS (>75%) than historically reported in literature. Of 14 patients with detectable pre-HCT NGS-MRD by TCRG+ alone, RFS was 100%. None of the patients in this cohort had detectable TCRB on pre-HCT NGS-MRD. More than half of pre-HCT NGS-MRD positive patients can be salvaged with HCT. Of patients who received TBI-based conditioning (n = 68; 79.1%), 16.2% (n = 11) relapsed with 77.9% (n = 53) alive at a at a median follow-up of 452 (range= 19-1465) days post-HCT. Of patients who received non-TBI conditioning (n = 18; 20.9%), 16.7% (n = 3) relapsed with 77.8% (n = 14) alive at a median follow-up of 705 (range= 73-1406) days post-HCT. RFS of pre-HCT NGS-MRD negative patients who received TBI vs non-TBI conditioning were similar, as was overall survival. RFS for patients who had pre-HCT CART to achieve negative pre-HCT NGS-MRD was lower (p = 0.036) compared to patients who achieved negative MRD without CART which may reflect the molecular biology of the disease, previous lines of treatments, later remission status, or earlier prior relapse and currently the subject of ongoing analysis.

Conclusions: Pre-HCT NGS-MRD negative B-ALL patients continue to have excellent RFS and OS with allogeneic HCT. Trackable BCR rearrangements offer the most reliable and predictive measure of relapse risk for B-ALL undergoing allogeneic HCT while isolated TCRG + , in the face of BCR-, unlikely represent residual disease. The interaction and outcomes of patients who required pre-HCT CART, to achieve MRD negativity, appear inferior, and further data analysis is needed to better understand factors impacting those outcomes. While sample size is limited, outcomes of TBI and non-TBI allogeneic HCT remain similar. Further data from the study observational and non-TBI treatment arms will help define the role of TBI for pre-HCT NGS-MRD negative patients.

Clinical Trial Registry: NCT03509961

Disclosure: Research is supported by Gateway for Cancer Research and Adaptive Biotechnologies (Hisham Abdel-Azim).

Hisham Abdel-Azim has research funding from Adaptive Biotechnologies to support this research.

Michael Pulsipher has received research funding from Adaptive Biotechnologies.

All other authors have nothing to declare related to this work.

19: Acute Leukaemia

O026 IMPAIRED CD45RO-CCR7 + NAÏVE CD8 + T CELLS IN AML ARE ASSOCIATED WITH LOWER OVERALL SURVIVAL

Yongping Zhang 1, Hujun Li1, Hui Zhang1, Qi Ji1, Shaoyan Hu1

1Children’s Hospital of Soochow University, Suzhou, China

Background: In the bone marrow micro-environment of AML, the coordinated interaction of various immune cells and immune regulatory factors results in the dysfunction of T cells. In this process, naïve CD8 + T cells, upon activation by antigen presentation from APCs such as DCs, differentiate into effector cells and memory cells. However, a considerable proportion of the remaining CD8 + T cells exhibit diminished effector functions due to exhaustion or senescence. While numerous studies have been conducted on the mechanisms and intervention strategies related to the exhaustion or senescence, the functional role of naïve CD8 + T cells in AML remains unclear. Therefore, our aim is to identify the correlation between the functional status of naïve CD8 + T cells in AML and to investigate its impact on the survival prognosis of AML patients.

Methods: Collecting fresh bone marrow samples from pediatric AML patients below the age of 14 at the time of diagnosis. Flow-cytometry, transcriptome sequencing and in vitro culture models were adapted to identify the quantity, activation, and differentiation of CD45RO-CCR7+ naïve CD8 + T cells(CD8+Tnaïve). Single-cell RNA sequencing was utilized to reveal the key genes and transcription factors and CRISPR-Cas9 technology was employed to perform gene editing on naïve CD8 + T cells to study the impact on exhaustion. Conducting correlation analysis with chemotherapy assessment and survival data, the role of naïve CD8 + T cells in AML treatment and prognosis was elucidated.

Results: Compared to 21 age-matched healthy donors (HDs) of HSCT candidates, 56 pediatric AML patients showed a significantly lower proportion of CD45RO-CCR7 + CD8+Tnaïve cells in BM (mean: HDs, 60%; AML, 45%; p < 0.05). CD45RO-CCR7 + CD8+Tnaïve cells in AML exhibited significantly higher expression of inhibitory molecules VISTA and CTLA-4 (HDs, < 5%; AML, 10% to 20%; p < 0.05). After sorting and in vitro culture, the CD69-CD25- non-activated fraction of CD45RO-CCR7 + CD8+Tnaïve cells was significantly higher in AML compared to HDs (HDs, 20%; AML, 60%; p < 0.05). RNA-seq and GSEA revealed significantly activated bile-acid metabolism pathway but down-regulated MTORC1 signaling in CD45RO-CCR7 + CD8+Tnaïve cells in AML. Single-cell RNA-seq demonstrated significantly higher expression of FCER1G, ID2 in CD8+Tnaïve cells which highly expressed CCR7, SELL, LTB and TCF1 in AML. Over-expression of FCER1G in CD45RO-CCR7 + CD8+Tnaïve cells using CRISPR-Cas9 led to significant decrease in memory T cells but increase in effector T cells with elevated expressions of PD-1 and GZMB. Paired analysis of CD45RO-CCR7 + CD8+Tnaïve cells’ proportion before and after the first induction chemotherapy showed an increasing trend in 11 complete remission (CR) patients, but a decreasing trend in 4 non-CR patients among 15 pediatric AML patients. Using the mean proportion (60%) of CD45RO-CCR7 + CD8+Tnaïve cells in HDs as the cutoff point, the 47 AML patients were divided into high and low expression groups (high : 10 cases; low : 37 cases). The 2-year overall survival was significantly lower in the high group (about 70%) compared to the low group (95%) (p = 0.026, log-rank test).

Conclusions: In pediatric AML patients, CD45RO-CCR7+ naïve CD8 + T cells exhibited impaired activation and memory-formation, and serve as a risk factor for 2-year overall survival.

Disclosure: Nothing to declare

19: Acute Leukaemia

O027 USING AN ARTIFICIAL INTELLIGENCE MODEL TO QUANTIFY UNDER-UTILISATION OF ALLOGENEIC STEM CELL TRANSPLANTATION FOR ACUTE MYELOID LEUKAEMIA IN UK

Thomas Coats 1, Toby Winter2, Grace Walburn2, Rob Bennett2, Pramila Krishnamurthy3, Victoria Potter3, Justin Loke4,5, Steve Knapper6, Julia Lee7, Rachel Pearce7, Ram Malladi8, Robin Adlam2, Charles Craddock9

1Royal Devon University Hospital Foundation Trust, Exeter, United Kingdom, 2Lone Star Analysis UK, Lincoln, United Kingdom, 3King’s College Hospital NHS Foundation Trust, London, United Kingdom, 4University of Birmingham, Birmingham, United Kingdom, 5Dana Farber Cancer Institute, Boston, United States, 6Cardiff University, Cardiff, United Kingdom, 7British Society of Blood and Marrow Transplantation and Cellular Therapy (BSBMTCT), London, United Kingdom, 8Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom, 9Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom

Background: Allogeneic stem cell transplant (allo-SCT) is a centrally important treatment in adults with acute myeloid leukaemia (AML) in first complete remission (CR1). Despite advances in transplant technology and increased donor availability, concerns remain that this potentially curative modality is under-utilised. We have developed an explainable AI model to estimate the under-referral of patients with AML in CR1 who could gain an overall survival (OS) advantage from allo-SCT.

Methods: We modelled a typical annual UK cohort of newly diagnosed patients. Five senior AML clinicians independently estimated relevant patient variables, including age, performance status, co-morbidities (HCT-CI), disease biology and response rates.

For each variable, the experts supplied five data points, representing 0th, 10th, 50th, 90th, and 100th percentiles. Aggregated distributions were fed through a Bayesian Inference Network (built with Lone Star Analysis), representing each individual patient pathway. Running Monte-Carlo simulations, 50,000 cases were derived from the experts’ answers to identify an expected range of patients in CR.

The clinicians provided a threshold of HCT-CI score for recommending transplants (based on: ELN risk group, MRD status, age [</>40] and performance status [ECOG < 2/2/ > 2)]). Allo-SCT is rarely performed in patients >75yr old so this demographic was excluded from transplant eligibility analysis. These thresholds were applied to the simulated patients to identify patients with potential OS benefit from CR1 allo-SCT, this being compared to the number of AML CR1 allografts actually performed (data obtained from the British Society of Blood and Marrow Transplantation and Cellular Therapy (BSBMTCT), 2016-2020). Given that BSBMTCT data do not differentiate whether patients had intensive chemotherapy (IC) or non-intensive chemotherapy (N-IC) to achieve CR1, we asked our experts what proportion of N-IC-treated patients treated achieving CR would be predicted to gain OS benefit from allo-SCT.

Sensitivity analyses were performed to determine the impact of uncertainty of each variable on the model output.

Results: Sensitivity analyses identified highest variability in clinicians’ estimates of i) number of AML cases/year and ii) age distribution at diagnosis. To improve accuracy of the model, clinician estimates were replaced with published incidence data (Cancer UK) and age distribution from National Cancer Registry and Analysis Service data (Hanhua et al, Blood 2023). All other variables had less than or equal to 10% variation above or below the model prediction.

Our updated model predicts a median of 569 UK adult patients/year should derive improved OS from allo-SCT in CR1 (95% CI range 477-669), 443 following induction with IC and 126 following N-IC. This is significantly higher than the UK allo-SCT rate of 318/year.

The proportion of patients predicted to be transplant-eligible who did not have allo-SCT in CR1 was highest in the older age groups; 36% aged 18-54, 33% aged 55-64, 44% aged 65-69, 75% aged 70-74.

Conclusions: Our innovative AI model suggests that the annual transplant rate in the UK should be almost 80% higher than observed. There is substantial inter-expert agreement on the size of the transplant eligible population to support these findings. These data provide the basis for further work to examine why there is ongoing under-transplantation.

Disclosure: Nothing to declare.

19: Acute Leukaemia

O028 REAL-WORLD EXPERIENCE WITH CPX-351 FOR PATIENTS WITH AML – LONG-TERM FOLLOW-UP WITH FOCUS ON YOUNGER PATIENTS (<60 YEARS OLD) AND ALLOGENEIC STEM CELL TRANSPLANTATION

Christina Rautenberg 1, Friedrich Stoelzel2, Christoph Roellig3, Matthias Stelljes4, Verena Gaidzik5, Oliver Kriege6, Mareike Verbeek7, Julia Unglaub8, Felicitas Thol9, Stefan Krause10, Mathias Haenel11, Charlotte Neuerburg12, Vladan Vucinic13, Christian-Friedrich Jehn14, Maxi Weiss15, Lars Fransecky2, Jens Chemnitz16, Kerstin Schäfer-Eckart17, Josephine Schröder18, Sabrina Kraus19, William Krüger20, Ulrich Kaiser21, Sebastian Scholl22, Guido Kobbe23, Paul Jäger23, Nael Alakel3, Malte von Bonin3, Katja Sockel3, Maher Hanoun1, Uwe Platzbecker13, Tobias Holderried12, Anke Morgner11, Michael Heuser9, Tim Sauer8, Katharina Götze7, Eva Wagner6, Konstanze Döhner5, Hartmut Döhner5, Christoph Schliemann4, Johannes Schetelig3, Martin Bornhäuser3, Ulrich Germing23, Thomas Schroeder1, Moritz Middeke3

1University Hospital Essen, Essen, Germany, 2UK Kiel, Kiel, Germany, 3University Hospital Dresden, Dresden, Germany, 4University Hospital Muenster, Muenster, Germany, 5UK Ulm, Ulm, Germany, 6UK Mainz, Mainz, Germany, 7Klinikum rechts der Isar, Muenchen, Germany, 8University Hospital Heidelberg, Heidelberg, Germany, 9MHH Hannover, Hannover, Germany, 10UK Erlangen, Erlangen, Germany, 11Städtische Kliniken Chemnitz, Chemnitz, Germany, 12UK Bonn, Bonn, Germany, 13UK Leipzig, Leipzig, Germany, 14Asklepios St. Georg Hamburg, Hamburg, Germany, 15Klinik St. Georg, Leipzih, Germany, 16Klinikum Koblenz, Koblenz, Germany, 17Klinikum Nürnberg, Nuernberg, Germany, 18Helios Berlin buch, Berlin, Germany, 19UK Würzburg, Würzburg, Germany, 20UK Greifswald, Greifswald, Germany, 21Krankenhaus Bernward, Bernward, Germany, 22UK Jena, Jena, Germany, 23UK Düsseldorf, Düsseldorf, Germany

Background: CPX-351, the liposomal formulation of AraC and daunorubicin, has been approved for the treatment of therapy-related AML (tAML) and AML myelodysplasia-related (AML-MR) without age-specific limiitations based on the results from a phase-3 trial performed in patients aged 60 to 75 years. Three European real-world analyses including one from our group (Rautenberg et al., 2021) generally confirmed the results following CPX-351 first-line treatment, but all with short median follow-up <1 year. Furthermore, although all reports included patients below the age of 60 years, a detailed analysis focusing specifically on younger patients (<60 years) is still lacking.

Methods: To address this age aspect as well as the outcome after subsequent allo-SCT and to provide longer follow-up, we updated and reanalyzed the data of the initially published 188 patients, of which 122 (67%) received allo-SCT after in-label CPX-351 induction. Focusing on the age issue, results were compared between patients aged <60 years and >60 years for the purpose of this analysis.

Results: Overall, we were able to update the data of 182 (97%) of the 188 patients with AML-MR (70%) or t-AML (29%) thereby providing a median follow-up of 35.6 months in all patients from CPX-351 start. Median overall survival (OS) in the entire cohort was 32.3 months and 2-year OS rate was 52%. In univariate analysis, OS was significantly longer in younger patients (<60 years; hazard ratio 0.48 [0.31-0.75], p = 0.008), although baseline characteristics were comparable between the two age groups. This survival benefit was not related to a higher likelihood of response (CR/CRi/MLFS) to CPX-351 based induction (<60 years 67% vs ≥60 years 71%, n. s.), but rather to a higher frequency of subsequent allo-SCT (<60 years 85% vs ≥60 years 61%, p = 0.003) in younger patients. Accordingly, allo-SCT (<0.001) but not younger age was associated with longer OS in multivariate analysis, while prior use of hypomethylating agents (p = 0.09) and adverse European LeukemiaNet 2017 genetic risk (p < 0.002) were associated with lower OS. In line with this 2-year OS rate, relapse incidence and non-relapse mortality in those 122 patients (67%) undergoing allo-SCT were 64%, 20% and 20%, respectively, with no significant difference between younger and older patients.

Conclusions: These updated real-world data with extended follow-up of almost 3 years confirm that CPX-351 is an efficient treatment for high-risk AML patients, facilitating allo-HCT in many patients with promising post-transplantation outcome. Our results suggest that this also applies to younger patients (<60 years), which were initially not included in the phase-III trial, but this requires confirmation in a prospective trial.

Disclosure: CR: travel support and lecture fees from JAZZ

TS: travel support and lecture fees and research funding from JAZZ

19: Acute Leukaemia

O029 CELLULAR HIERARCHY FOR UNDERSTANDING HETEROGENEITY OF ACUTE MYELOID LEUKEMIA WITH T (8;21)/RUNX1-RUNX1T1

Yibo Wu 1,2,3,4, Xiaolin Yuan1,2,3,4, Xiaoyu Lai1,2,3,4, Lizhen Liu1,2,3,4, Lihong Ni5, Shanshan Hu6, Jimin Shi1,2,3,4, Weiyan Zheng1,2,3,4, Jian Yu1,2,3,4, Yanmin Zhao1,2,3,4, Jie Sun1,2,3,4, Xiujin Ye1,2,3,4, Zhen Cai1,2,3,4, He Huang1,2,3,4, Shanshan Pei1,2,3,4, Yi Luo1,2,3,4

1Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China, 2Liangzhu Laboratory, Hangzhou, China, 3Institute of Hematology, Zhejiang University, Hangzhou, China, 4Zhejiang Province Engineering Research Center for Stem Cell and Immunity Therapy, Hangzhou, China, 5Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China, 6Jinhua Hospital of Wenzhou Medical University, Jinhua, China

Background: AML was a disease remains challenging with a dismal prognosis. Recent advance in the single-cell transcriptomics reveals the polyclonal and evolving heterogeneity of AML. The differentiation hierarchies of myeloid malignancies may directly impact the drug responses, clinical predictions. AML with t (8;21) contributes one of the most recurring genetic subtypes of AML, consisting 4%-8% of whole AML patients. It was a unique entity in AML with similar characteristics classified as favorable group. However, only 45%-70% of patients achieve long-term disease-free survival. Approximately 30-40% of patients relapse after achieving complete remission. As we know the potential impact of leukemia cell differentiation status on drug responses, clinical predictions. AML with t (8;21) was an ideal model to find whether phenotypically-defined stages of leukemia may impact mutations and outcomes in AML. Here, we did a phenotypic, cytogenetic, molecular and therapeutic response correlative analysis of a large cohort of AML with t (8;21) patients to capture the stage of leukemia arrest, specific genomic features and clinical outcomes.

Methods: We enrolled the AML patients diagnosed with recurring genetic subtypes of t (8;21) treated at three centers of hematology in China. We classify AML blasts into two stages of AML differentiation-arrest categories primitive cells (Prim) and Monocyte (Mon) group based on CD34, CD117, CD13, CD33, CD38, MPO, CD11b, CD15, CD64 expression.

Results: A of total of 338 AML with t (8;21) patients were enrolled. 170(50.30%) patients accepted chemotherapy only and 141(41.72%) patients bridge to allo-HSCT treatment. There were 68(24.46%), 49(17.63%), 43(15.47%), 83(29.86%), 35(12.59%) patients classified as MPP, LMPP, CMP, GMP, GP/MP. Thus, 160(57.55%) patients were classified as Prim group and 118(42.45%) patients were classified as Mono group. The most gene mutations were KIT(42.4%), FLT3(17.0%), NRAS(12.2%) in whole cohort.

Mono group was associated with lower 2-year OS and higher 2-year cumulative incidence of relapse (CIR) than Prim group based immunophenotypic stratification. Patients with KIT mutation had worse 2-year OS and higher 2-year CIR than patients without KIT mutation. Mono and Prim group with KIT mutation had lower 2-year OS than Mono and Prim group without KIT mutation respectively (P < 0.001). Mono group with or without KIT mutation had higher 2-year CIR than Prim group with or without KIT mutation respectively (P < 0.001).

In allo-HSCT cohort, Mono group was associated with lower 2-year OS and higher 2-year CIR than Prim group. Gene mutations and loss of chromosome didn’t significantly impact both OS and CIR. Differentiation stage of leukemia cells itself significantly impact the outcomes after transplantation. Mono group with or without KIT mutation had higher 2-year CIR than Prim group with or without KIT mutation respectively. GO enrichment analysis of RNA-seq of patients’primary samples showed lower expression of antigen associate genes in Mono group than Prim group. It indicates that immune escape of GVL effect may mediate relapse after allo-HSCT in Mono group.

Conclusions: We demonstrate that AML with t (8;21) arrested at specific stages of myeloid differentiation that significantly correlate with AML genetic lesions, clinical presentation, response to therapy, and outcomes.

Clinical Trial Registry: none

Disclosure: There are no conflicts of interest to report.

20: Aplastic Anaemia

O030 PREDICTING TRANSPLANTATION-, TRANSFUSION- AND TREATMENT-FREE SURVIVAL AFTER IMMUNE SUPPRESSIVE TREATMENT FOR ADULTS WITH ACQUIRED APLASTIC ANEMIA

Cjm Halkes 1, Eas Koster1, Ejm Bogers1, Lgm Daenen2, Sk Klein3, Smc Langemeijer4, F. Moenen5, E. Nur6,7, Mhg Raaijmakers8, Tjf Snijders9, Jennifer ML Tjon1, L.C. de Wreede1

1Leiden University Medical Centre, Leiden, Netherlands, 2Utrecht UMC, Utrecht, Netherlands, 3UMC Groningen, Groningen, Netherlands, 4Radboudumc, Nijmegen, Netherlands, 5Maastricht UMC, Maastricht, Netherlands, 6Amsterdam UMC, Amterdam, Netherlands, 7Sanquin Research, Amsterdam, Netherlands, 8EramsusMC, Rotterdam, Netherlands, 9Medical Spectrum Twente, Enschede, Netherlands

Background: The preferred first-line treatment options for adult severe aplastic anemia (AA) patients are allogeneic stem cell transplantation (alloSCT) and anti-thymocyte globulin (ATG)-based intensive immune suppressive treatment (IST). Analysis of long-term and detailed real-world results of these treatment modalities can guide personalized treatment decisions. Long-term favorable outcome of IST can be hampered by relapse AA, development of PNH disease or AML/MDS and the need for long-term treatment with immunosuppressive drugs. We developed a new endpoint to define treatment success after IST in AA: Transplantation-, Transfusion- and Treatment- (for AA, PNH disease or AML/MDS) free survival (TTT-free survival) and analyzed which baseline characteristics are associated with the probability of reaching this endpoint.

Methods: We analyzed data from a real-world prospective multi-center cohort study of 127 adult AA patients in the Netherlands who all received IST with ATGAM and Cyclosporine within a standardized treatment protocol as first-line therapy. We used a multi-state model to model the disease-recovery process after start of IST, taking into account the individual start and stop dates of different transfusion and treatment episodes. The impact of risk factors on becoming transfusion-free and becoming non-transplant therapy-free was modelled by means of two Cox proportional hazards models. The probability of TTT-free survival over time was estimated by adding up the (time-dependent) probabilities to be in any of the relevant states

Results: Median age was 54 years (range 18-79; 40% >60, 32% <41) and 64% was male. Disease severity was non-severe, severe and very severe in 33%, 43% and 24%, respectively. PNH clone at diagnosis was present (>1%) in 45% of patients. In the total cohort, overall survival (OS) at 5 years was 79% (95%-CI 70-87), while the 5-year TTT-free survival was only 42% (95%-CI 33-54). Patients aged <41 years had a 5-year OS of 94% (CI 87-100) and a 5-years TTT-free survival of 58% (95%-CI 43-80), in patients older than 60 years this was only 66% (95%-CI 49-83) and 33% (95%-CI 20-54), respectively. The presence of a PNH-clone at diagnosis was associated with a higher chance of response to IST (HR 2.2, 95%-CI 1.4-3.4). In contrast, higher age and higher severity of AA were associated with lower chance of becoming transfusion independent after IST. Patients aged 41 to 60 and with an age above 60 were less likely to become transfusion-independent after IST compared to younger patients (HR for both age groups 0.4, 95%-CI 0.2-0.7 and 0.3-0.7, respectively). The same was observed for patients with (very) severe AA compared to patients with non-severe AA (HR for severe and very severe AA both 0.4, 95%-CI 0.3-0.7 and 0.3-0.8, respectively). We used these three distinguishing baseline characteristics to calculate model-based predictions of treatment success for reference patients. The Figure shows an example for 2 reference patients with severe AA but different baseline characteristics.

The 50th Annual Meeting of the European Society for Blood and Marrow Transplantation: Physicians - Oral Session (O009-O154) (1)

Conclusions: TTT-free survival can be used as a treatment goal for IST in AA patients. Higher age, (very-)severe AA and the absence of a PNH clone at diagnosis are all associated with a lower probability to reach this positive endpoint.

Clinical Trial Registry: Not applicable

Disclosure: No potential conflicts of interest

20: Aplastic Anaemia

O031 UPFRONT MATCHED UNRELATED DONOR HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR SEVERE IDIOPATHIC APLASTIC ANEMIA AND REFRACTORY CYTOPENIA OF CHILDHOOD IN PEDIATRIC PATIENTS. SPANISH EXPERIENCE

M.Luz Uria-Oficialdegui 1, Victor Quintero2, M.Isabel Benitez-Carabante1, Maria Travazo3, David Bueno2, Marta Gonzalez-Vicent4, Monica Lopez-Duarte5, Jaime Verdu6, Carolina Fuentes7, Graciela Gomez8, Laura Murillo-SanJuan1, Laura Alonso1, Melissa Panesso1, Crsitina Diaz-de-Heredia1

1Hospital Universitari Vall d´Hebron, Barcelona, Spain, 2Hospital Universitario La Paz, Madrid, Spain, 3Hospital Sant Joan de Deù, Barcelona, Spain, 4Hospital Universitario Niño Jesus, Madrid, Spain, 5Hospital Universitario Marqués de Valdecilla, Santander, Spain, 6Hospital Clinico Universitario, Valencia, Spain, 7Hospital Universitario La Fe, Valencia, Spain, 8Hospital Clinico de Santiago, Santiago, Spain

Background: The recommended treatment in pediatric patients with Severe Idiopathic Aplastic Anemia (SAA) and Refractory Cytopenia of Childhood (RCC) in first-line is hematopoietic stem cell transplantation (HSCT) from a matched sibling/family donor (MSD). When MSD is unavailable, immunosuppressive therapy (IST) with horse antithymocyte globulin (ATG) plus cyclosporin is indicated. Nevertheless, IST has a high failure rate attributed to lack of response, relapse, and clonal evolution. The outcomes of matched unrelated donor (MUD) HSCT following IST are favorable but inferior when compared to MSD. Front-line MUD-HSCT may improve outcomes compared to IST and rescue MUD-HSCT after IST failure. The aim of this study is to assess the role of upfront MUD-HSCT for pediatrics patients with SAA/RCC who lack a MSD.

Methods: We performed a retrospective multicenter observational study of pediatric patients diagnosed with either SAA or RCC and treated with MUD-HSCT as first line in the absence of MSD. All patients were treated in six hospitals in Spain affiliated to the Spanish Group for HSCT in children.

Results: 19 patients (16 males/3 females) with SAA (17) and RCC (2) underwent an upfront MUD-HSCT (10/10). Median age at diagnosis was 11 years (1-17). No one had cytogenetic anomalies. Median time from diagnosis to HSCT was 102 days (61-258). Most patients had a good performance status (Lansky >70). Two had fungal infections before HSCT. Conditioning regimen consisted of fludarabine plus cyclophosphamide in SAA-patients (n = 17), and busulfan/treosulfan, fludarabine +/- thiotepa in RCC-patients (n = 2). All received lymphodepletion with thymoglobulin. GVHD prophylaxis was cyclosporine/methotrexate in most cases. Bone marrow (BM) was the prevalent source. Median cell dose for BM was 4x108 CNT/kg (1.72-8.8) and for peripheral blood 13.5x106 CD34 + /kg (7.3-12.3). All patients engrafted. Fifteen had complete donor chimerism, four SAA-patients had mixed chimerism, and one experienced secondary graft failure 11 months after-HSCT. The remaining three maintained stable mixed chimerism. Four developed poor graft function (PGF) and eight immune cytopenias post-HSCT. Eleven experienced bacterial infections, two with severe septic shock requiring Pediatric Intensive Care Unit admission. No cases of post –HSCT fungal infection occurred, and while viral reactivations were common, no patient developed viral disease. Endothelial complications included veno-occlusive disease (n = 3) and transplant-associated microangiopathy (n = 2). Five presented grade 2 acute GVHD and two developed chronic GVHD (one mild, one moderate), none developed severe chronic GVHD. No transplant-related mortality was registered. Median duration of post-transplant immunosuppressive treatment was 15 months (2-23). After a median follow up of 20 months (6-105), the overall survival (OS) for the entire cohort was 100% and the event-free survival (EFS) was 94.7% (CI 84-100).

Conclusions: In our experience, upfront MUD-HSCT yields outstanding outcomes in terms of OS, EFS, chronic GVHD, and transplant-related complications. The main complications were bacterial infections, viral reactivation, and immune cytopenias. Managing mixed chimerism and PGF is a critical aspect. A more extended follow-up is required to assess late sequelae and substantiate these findings. Our data strongly support the preference for upfront MUD-HSCT in pediatric patients newly diagnosed with SAA and RCC.

Disclosure: none

20: Aplastic Anaemia

O032 UNRELATED DONOR TRANSPLANTATION IN APLASTIC ANEMIA WITH A QUADRUPLE GVHD PROPHYLAXIS

Andrea Bacigalupo1, Nicola Mordini2, Francesco Zallio3, Irene Cavattoni4, Luca Castagna5, Anna Paola Iori6, Patrizia Chiusolo7, Federica Sora’7, Sabrina Giammarco 7, Elisabetta Metafuni7, Alessandro Busca8, Alessandra Carotti9, Fabio Benedetti10, Giorgia Saporiti11, Simona Sica7

1Fondazione Policlinico Universitario Gemelli IRCCS, Roma, Italy, 2Ospedale Santa Croce, Cuneo, Italy, 3Ospedale Civile, Alessandria, Italy, 4Ospedale di Bolzano, Bolzano, Italy, 5Ospedale Cervello, Palermo, Italy, 6Policlinico Umberto1, Roma, Italy, 7Policlinico Gemelli, Roma, Italy, 8Ospedale Le Molinette, Torino, Italy, 9Ospedale Perugia, Perugia, Italy, 10Ospedale Borgo Roma, Verona, Italy, 11Policlinico Ca Granda, Milano, Italy

Background: The Baltimore group has introduced a new transplant platform for patients with aplastic anemia (AA) undergoing a haploidentical transplantation (HAPLO) (De Zern et al 2020); the conditioning regimen is based on fludarabine cyclophosphamide (FLU-CY) TBI ; GvHD prophylaxis is based on 4 drugs : ATG on day -9-8-7, post transplant CY (PTCY) 50 mg/kg on days +3 + 4 and tacrolimus mycophenolate. The Baltimore group reports 37 patients, with 35 surviving without GvHD. The Brasilian group has confirmed these results in a multicenter study on 87 AA patients, with survival in excess of 90%, especially for those receiving an intensified TBI dose of 4Gy (instead of 2 Gy) and an increased dose of CY pre transplant (50 instead of 30 mg/kg) (BBMT, 2020; e222-e226). If this platform allows the engraftment of an HLA HAPLO mismatched marrow, with little or no GvHD, then the same platform should be successful in patients with AA undergoing an unrelated donor (UD) transplant, or in elderly patients grafted from matched siblings.

Methods: We have grafted 25 patients with AA with this platform. The conditioning was as follows: CY 14.5 mg/kg days -6-5, Fludarabine 30 mg/m^2 days -6-5-4-3-2, TBI 2 Gy day -1 and unmanipulated bone marrow on day 0 (8 patients were grafted with PB cells). GvHD prophylaxis was ATG 0.5, 2 and 2 mg/kg days -9-8-7, PTCY 50 mg/kg day +3 + 4, cyclosporine (CSA) on day +5 onward and mycophenolated (MMMF) day 5 day 35. The median age was 40 years (range 19-70). The donor was unrelated, matched (8/8, n = 16), or mismatched (7/8, n = 6), HAPLO (n = 2), or a matched sibling (n = 1). In the latter this transplant platform was chosen because of the patients age (60 years).

Results: All patients had 100% donor chimerism within 30 days from transplant. There were 4 early deaths within day +100 (2 infections, 1 cardiac failure, 1 brain hemorrhage). One patient (UD 7/8 matched donor) (4%) experienced a rejection on day +88; underwent a second transplant from the same UD with peripheral blood as a stem cell source, on day +154 from the first transplant; the patient is currently alive and well with trilineage recovery on day +901. The median time to a neutrophil count of 0.5x10^9/L was 19 days (15-27) and for 20x10^9/L platelets, it was 22 days (13-38). Acute GvHD grade I was recorded in 3 patient (11%), minimal chronic GvHD was reported in 2 patients (7%); moderate severe chronic GvHD was not reported. EBV reactivation was seen in 5 patients and was treated in 2 patients with rituximab. CMV reactivation was seen in 3 patients. With a median follow up for surviving patients of 490 days (30-1400), the one year actuarial survival is 85% (92% vs 75% for patients younger or older than 40 years).

Conclusions: This initial experience with the Baltimore quadruple GvHD prophylaxis, in patients undergoing unrelated donor transplants for AA, confirms a very high degree of engraftment, low early mortality, low rate of rejection, and little or no GvHD.

Clinical Trial Registry: NA

Disclosure: The AUthors declare no conflict of interest

21: Autoimmune Diseases

O033 CLINICAL OUTCOMES OF HIGH DOSE IMMUNOSUPPRESSIVE THERAPY (HDIT) WITH AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION (AHSCT) IN MULTIPLE SCLEROSIS PATIENTS: LONG-TERM SINGLE CENTER EXPERIENCE

Denis Fedorenko 1, Vladimir Melnichenko1, Anatoly Rukavitsin1, Nikolai Vasilev1, Ilya Nikolaev1, Tatiana Nikitina2, Natalia Porfirieva3, Tatiana Ionova2

1Pirogov National Medical Surgical Center, Moscow, Russian Federation, 2Saint-Petersburg State University Hospital, Saint-Petersburg, Russian Federation, 3Multinational Center for Quality of Life Research, Saint-Petersburg, Russian Federation

Background: Multiple sclerosis (MS) is a major inflammatory and demyelinating autoimmune disease of the central nervous system, which affects mainly young people and can lead to severe and irreversible clinical disability. Modern disease-modifying treatment does not provide satisfactory control of MS. At present HDIT + AHSCT may be considered as an optimistic therapeutic option for patients with MS. We aimed to evaluate outcomes of HDIT + AHSCT in patients with various types of MS at long-term follow-up.

Methods: Patients with various types of MS who underwent HDIT + AHSCT from October 2006 to January 2022 were enrolled in a single-center study. Three low intensity conditioning regimens were used – BEAM-like, Cyclophosphamide, and Fludarabine+Cyclophosphamide. Transplantation-related mortality (TRM) definition included every death occurring within 100 days of transplantation. For clinical outcomes neurological assessment and MRI scans were performed. Neurological assessment using EDSS was performed at baseline, at discharge, at 3, 6, and 12 months after transplantation, every 6 months thereafter up to 48 months, and then at yearly intervals. Study end-points were disability defined by the EDSS score and event-free survival (EFS). EDSS decrease of 1.0 or greater was considered significant improvement and an increase of 1.0 or greater is considered significant worsening. For comparisons paired t-test, Wilcoxon test and ANOVA were used. EFS in terms of relapse-free survival (RFS) and progression-free survival (PFS) after AHSCT were evaluated using Kaplan-Meyer method. For comparison of survival log-rank and Tarone-Ware criterions were applied.

Results: In total, 730 patients with relapsing-remitting (RRMS, n = 387, 53%), primary progressive MS (PPMS, n = 120, 16%), and secondary progressive MS (SPMS, n = 223, 31%) were enrolled. Median age – 40 years (Q1;Q3 – 32;48), 39% were males. Mean (SD) disease duration was 6.8 (5.9) yrs. BEAM-like regimen was used in 31%, Cyclophosphamide – 60%, and Fludarabine+Cyclophosphamide - 9%. There were 6 cases of TRM (RRMS - 3, SPMS - 2, PPMS - 1; median EDSS 4.5). In all cases Cyclophosphamide was used. TRM in whole group was 0.82%. Median follow-up after AHSCT was 21.5 months (Q1;Q3 – 12;47). The vast majority of patients responded to treatment and exhibited EDSS improvement or were stable during the entire period of follow-up. Significant improvement in EDSS for the entire group at all-time intervals after transplantation as compared with baseline was observed (p < 0.001). At 12 months after AHSCT the decrease of EDSS in RRMS took place from median 2.0 to 1.5, in SPMS – from median 6.0 to 5.0, and in PPMS – from 5.5 to 4.0. At 5-years the estimated EFS probability for the entire group was 82.8% (95%CI 78.2-87.3), RFS for RRMS – 87.8% (95%CI 81.5-94.2), PFS for SPMS – 83.6% (95%CI 76.5-90.8), and for PPMS – 85.6% (95%CI 75.9-95.1). No differences in EFS were found depending on conditioning regimen (log-rank, p = 0.128, Tarone-Ware, p = 0.129).

Conclusions: The results of our study demonstrate that HDIT + AHSCT with low-intensity conditioning regimens is safe and effective in patients with different types of MS. The vast majority of patients improved and clinical improvement was persistent at long-term follow-up. The outcomes were similar across patients who received different low intensity conditioning regimens.

Clinical Trial Registry: No

Disclosure: Nothing to declare

21: Autoimmune Diseases

O034 AUTOLOGOUS HSCT IN MULTIPLE SCLEROSIS: THE UK EXPERIENCE 2002-2023 (ON BEHALF OF THE BSBMT CTC GROUP)

Majid Kazmi 1, Paolo Muraro2, Varun Mehra3, Ian Gabriel4, Eleonora De Matteis2, Gavin Brittain5, Richard Nicholas4, Eli Silber3, Julia Lee6, Rachel Pearce6, Ruth Paul6, Maria Pia Sormani7, Victoria Potter3, Eduardo Olavarria4, Ram Malladi8, Basil Sharrack5, John Snowden5

1Guys & St Thomas’ NHS Trust, London, United Kingdom, 2Imperial College London, London, United Kingdom, 3Kings College Hospital NHS Trust, London, United Kingdom, 4Imperial College Healthcare Trust, London, United Kingdom, 5Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom, 6British Society of Blood and Marrow Transplantation and Cellular Therapy, London, United Kingdom, 7University of Genova, Genova, Italy, 8Cambridge University Hospitals NHS Trust, Cambridge, United Kingdom

Background: Autologous Haematopoietic Stem Cell Transplant (HSCT) has been used as a treatment for Multiple Sclerosis (MS) since 1995 with over 2000 procedures now reported to the EBMT registry, making it the most common indication for any autoimmune disease. The UK activity has increased significantly since 2016 and it is now one of the most active countries performing HSCT for MS in the EBMT registry. We report on the UK experience of HSCT in MS in terms of UK activity (2002 to 2023), transplant related mortality (TRM) and efficacy of HSCT for MS as defined by expanded disability status scale (EDSS) Progression Free Survival (PFS) at 2 years and 4 years (EDSS-PFS).

Methods: Retrospective cohort study on patients with MS (pwMS) treated with HSCT at 14 transplant centres across the UK, between 2002 and 2023. Patients in active trials were excluded. EDSS-PFS was defined as 6 months confirmed EDSS progression compared to pre-treatment baseline (0.5 point increase if the baseline score was ≥6.0 and 1.0 for baseline scores <6.0). TRM was defined as all patients who had started conditioning therapy for HSCT regardless of whether they received stem cell re-infusion.

Results: 363 pwMS from 14 UK transplant centres were identified; 129 patients (38%) had progressive MS (primary (PPMS) or secondary (SPMS)) and 209 (62%) had relapsing-remitting MS (RRMS). By cohort analysis 22 % of patients were transplanted prior to 2016 and 88% post 01/2016. 97% of patients had cyclophosphamide/ATG based conditioning. Overall median EDSS at time of HSCT was 6.0 (range 0-9) and duration of disease 10 years (range 4-34) [table 1].TRM was 1.1%. Median EDSS for those that died was 6.5 at time of HSCT. EBV reactivation occurred in 76.8 % of patients where EBV results were reported (239/311). EDSS-PFS was 86% at 2 years post HSCT and 71% at 4 years (Fig.1). At 4 years patients with PPMS had lower EDSS-PFS (56%) compared to SPMS (71%) and RRMS (75%). When split by EDSS at time of HSCT; 4 year EDSS-PFS was 80% for those with EDSS 4.5 or less and 66 % for those with EDSS above 4.5.

Table 1.

Factor

Overall

Type of multiple sclerosis

Secondary

Primary

Relapsing

Progressive

Progressive

Remitting

Total

363

83

46

209

Patient sex, N (%)

Male

153, (42)

38 (46)

33 (72)

70 (33)

Female

210 (58)

45 (54)

13 (28)

139 (67)

Age at transplant, years median (range, IQR) - Mean (±SD)

40 (range 19-66, IQR 33-47)

40 (±9.4)

43 (range 25-62, IQR 38-49)

44 (±7.9)

47 (range 31-64, IQR 39-50)

46 (±8)

38 (range 19-66,

IQR 31-45)

38 (±9.4)

Duration of MS at HSCT

(since 1st symptoms), years median (range, IQR) - mean (±SD)

10 (range 4-34,

IQR 5-14)

10 (±6)

12 (range 3-29, IQR 9-17)

13 (±5)

7 (range 1-31,

IQR 4-11)

8 (±5)

9 (range 4-34,

IQR 5-13)

10 (±6)

Year of transplant N (%)

2002-2012

13 (4)

5 (6)

8 (4)

2013-2015

29 (8)

8 (10)

21 (10)

2016-2023

321 (88)

70 (84)

46 (100)

180 (86)

Baseline EDSS, years median (range, IQR) -

mean (±SD)

6 (range 0-9,

IQR 4-6.5)

5.2 (±1.6)

6.125 (range 0-8, IQR 6-6.5)

6 (±1)

6 (range 2-7,

IQR 4.5-6.5)

5.4 (±1.3)

5.5 (range 1.5-9,

IQR 3.5-6)

4.9 (±1.7)

  1. Abbreviations: EDSS-Expanded Disability Status Scale, IQR -interquartile range, N-number, SD-standard deviation.

Fig 1.

The 50th Annual Meeting of the European Society for Blood and Marrow Transplantation: Physicians - Oral Session (O009-O154) (2)

Conclusions: This is the largest UK report on HSCT for pwMS. Most activity occurred since Jan 2016 in line with published evidence and commissioning approval. This study included 38% progressive MS patients historically excluded from randomised studies of HSCT and many patients had advanced disability at time of HSCT (median EDSS 6.0). Despite that, in this real-world cohort, 71% of patients remain free of progression at 4 years post HSCT. Higher disability at time of HSCT and primary progressive MS is associated with worse EDSS-PFS. TRM was 1.1% with all those patients having advanced disability. EBV reactivation remains a significant issue and routine monitoring is mandatory. Careful patient selection is important to minimise risk and maximise benefit. The STAR MS trial is currently examining the efficacy of HSCT vs high efficacy Disease modifying therapy in relapsing-remitting MS.

Clinical Trial Registry: BSBMT CTCR 18-01.

Disclosure: Nothing to declare

21: Autoimmune Diseases

O035 AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN AGGRESSIVE MULTIPLE SCLEROSIS – A 25-YEAR MONOCENTRIC EXPERIENCE

Alice Mariottini 1, Chiara Nozzoli2, Alessandro Barilaro2, Riccardo Boncompagni2, Ilaria Cutini2, Antonella Gozzini2, Chiara Innocenti2, Anna Maria Repice2, Luisa Pastò2, Maria Pia Amato1, Luca Massacesi1, Riccardo Saccardi2

1University of Florence and Careggi University Hospital, Florence, Italy, 2Azienda Ospedaliero Universitaria Careggi, Florence, Italy

Background: Autologous haematopoietic stem-cell transplantation (AHSCT) is a treatment option in aggressive relapsing-remitting (RR-) multiple sclerosis (MS) refractory to conventional disease-modifying treatments (DMTs). Here we report the long-term outcomes from our 25-year experience at the Careggi University Hospital in Florence.

Methods: We performed a monocentric retrospective study including relapsing (R-)MS patients (primary-progressive MS excluded) treated with AHSCT in Florence between 1998 and 2023. Peripheral blood hematopoietic stem cells were mobilized with chemotherapy (Cyclophosphamide [Cy] 4 g/sqm) followed by G-CSF; the conditioning protocol used was BEAM + ATG in all the patients. Variables are reported as median (range) and number (frequency), as appropriate. Efficacy outcomes include survival free from relapses (RFS), EDSS worsening (progression-free survival, PFS) and No Evidence of Disease Activity (NEDA-3), defined as the absence of all the following: relapses, EDSS worsening, and new inflammatory activity at brain magnetic resonance imaging (MRI). Primary safety endpoints explored were 100-days transplant-related mortality (TRM) and hospital readmission for any cause.

Results: One hundred and ten R-MS patients were included. TRM at 100 days was 1% and 4 (3%) patients required hospital readmission, mainly for infective episodes. Efficacy outcomes are currently available for 93 cases (Table 1). Follow-up duration was 57 months (1 – 262). PFS at 3, 5 and 10 years was 71%, 69% and 62%, respectively, being higher in RR-MS than in secondary-progressive (SP-)MS (at year 5: 88% vs 48%, respectively; p < 0.0001). RFS was 98% at 5 years, due to 3 relapsed patients in the RR-MS group and 1 in the SP-MS group. NEDA-3 survival at 3, 5 and 10 years was 70%, 68%, and 52%, respectively, being higher in RR-MS than in SP-MS (at year 5: 86% vs 48%, respectively; p < 0.0001). NEDA-3 failure was mostly caused by EDSS progression, with sparse events of new focal inflammatory activity, being 6 events (4 relapses + 2 new asymptomatic brain lesions) observed over 575 patient-years of follow-up.

Table 1: Baseline clinical-demographic characteristics of the R-MS patients included in the efficacy analyses

MS overall (n = 93)

RR-MS (n = 50)

SP-MS (n = 43)

median

(range)

median

(range)

median

(range)

Age, y

36

(20 – 57)

36

(20 – 53)

40

(27 – 57)

Disease duration (onset), y

11

(1 – 33)

9.5

(1 – 29)

13

(6 – 33)

Number of previous DMTs

3

(0 – 7)

3

(0 – 7)

3

(1 – 6)

ARR in the prior 2 y

1

(0 – 4.5)

1.25

(0 – 4.5)

0.5

(0 – 2)

EDSS

5.0

(1.0 – 7.5)

3.0

(1.0 – 7.0)

6.0

(3.5 – 7.5)

n

(%)

n

(%)

Gender, female

70

(75%)

37

(74%)

33

(77%)

Conclusions: Our data firmly support that AHSCT is a safe and effective treatment for patients with aggressive R-MS, likely offering better long-term efficacy outcomes compared to high-efficacy DMTs. However, limitations arise from the lack of prospective comparative data with DMTs and of comparison between different intensity conditioning regimens.

Disclosure: Nothing to declare.

21: Autoimmune Diseases

O036 BEAM/ATG OR CYCLOPHOSPHAMIDE/ATG AS CONDITIONING REGIMEN IN AUTOLOGOUS TRANSPLANTATION FOR MULTIPLE SCLEROSIS: A RETROSPECTIVE ANALYSIS OF THE EBMT AUTOIMMUNE DISEASES WORKING PARTY

Riccardo Saccardi 1, Marta Ponzano2, Manuela Badoglio3, Grzegorz Helbig4, Marek Smilowsky4, Alice Mariottini1, Joachim Burman5, Kristina Carlson5, Majid Kazmi6, Paolo Muraro7, Jane Apperley8, Barbara Withers9, Jennifer Massey9, Riccardo Varaldo10, Matilde Inglese2, Jaime Sanz11, Sara Garcia Gil-Perotin11, Basil Sharrack12, Tobias Alexander13, Raffaella Greco14, John Snowden12

1Azienda Ospedaliero Universitaria Careggi, Florence, Italy, 2University of Genoa, Genoa, Italy, 3EBMT Paris Study Unit, Paris, France, 4Silesian Medical Academy, Katowice, Poland, 5University Hospital | Uppsala, Uppsala, Sweden, 6Kings College Hospital, London, United Kingdom, 7Imperial College London and Imperial College Healthcare Trust, London, United Kingdom, 8Imperial College Hammersmith London, London, United Kingdom, 9St. Vincent’s Hospital, Sydney, Australia, 10IRCCS Ospedale Policlinico San Martino, Genoa, Italy, 11University Hospital La Fe, Valencia, Spain, 12Sheffield Teaching Hospitals, Sheffield, United Kingdom, 13Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany, 14IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy

Background: Multiple Sclerosis (MS) is the most frequent Autoimmune Disease (AD) treated with Autologous HSCT. Starting from 1985 more than 2000 patients underwent the procedure and were reported to the EBMT Registry, with a constant increasing trend in the last 10 years. BEAM/ATG was the most frequent conditioning regimen up to 2013, whilst Cyclophosphamide (CYC)/ATG predominated in the following years. Both regimens are included in the guidelines and recommendations from the EBMT Autoimmune Diseases Working Party (Sharrack et al 2020). Intensity of conditioning regimen results in different toxicity and, at least in the oncological setting, in different efficacy. There are no prospective trials comparing these two regimens: we report here a retrospective analysis of the EBMT database aimed to assess the risk/benefit ratio of the two regimens.

Methods: We selected 1114 MS patients from the EBMT database who were conditioned with either BEAM/ATG or CYC/ATG between 1985 and 2023. Primary endpoint was time to fail NEDA (Non-Evidence of Disease Activity), which is lack of relapses, no progression of the disability and lack of new lesions at MRI scan. Kaplan Meier estimates, log rank test and multivariable Cox regression models were used to study time to events (engraftment, death and NEDA).

Results: Data about engraftment and 100-days mortality were available in 1114 patients (442 BEAM/ATG, 672 CYC/ATG). PMN engraftment in BEAM/ATG- and CYC/ATG-treated patients occurred at a median time of 11 (95% CI: 11; 11) and 10 (95%CI: 10; 11) days after HSCT, respectively, p = 0.079. Nine out 442 (2.0%) patients conditioned with BEAM/ATG and 7 out 672 (1.04%) with CYC/ATG died within 100 days from HSCT (p = 0.191).

Exhaustive data MS about the primary endpoint (time to fail NEDA) were available from 616 patients (295 received BEAM/ATG, 321 CYC/ATG). Details about this patient subset are reported in table 1. Overall incidence of NEDA failure in BEAM/ATG and CYC/ATG at 5 years was 42.3% (95% CI: 36.3%-48.8%) and 44.2% (95% CI: 31.0%-60.2%), respectively (p = 0.145). No statistically significant differences between the two treatments (HR = 0.95, p-value = 0.809, 95% CI = 0.65; 1.41) were confirmed, when adjusting for disease type (progressive vs relapsing), EDSS at baseline and year of transplant. KM curves reporting time to NEDA failure are reported in graph 1.

Table 1

BEAM/ATG

CYC/ATG

p-value

Age at Tx (years)

36.4 (8.7)

38.0 (10.0)

0.036

Gender % (M/F)

36.9/63.1

41,7/58.3

0.22

Interval Mobilization-HSCT (months)

1.5 (1.1-2.1)

1.9 (1.3-2.6)

<0.001

Relapse-Remitting/Progressive (%)

59.3/ 40.7

77.9/22.1

<0.001

EDSS at transplant

5.5 (4.0-6.5)

4.5 (3.0-6.0)

<0.001

Number of previous DMTs

3.0 (2.0-4.0)

2.0 (1.0-2.0)

<0.001

Graph 1

The 50th Annual Meeting of the European Society for Blood and Marrow Transplantation: Physicians - Oral Session (O009-O154) (3)

Conclusions: Despite the relevant number of patients included in the analysis, a clear difference between the regimens is lacking, both in terms of toxicity and efficacy, possibly due also to the different median follow-up interval in the two groups. Type of disease (relapsing/remitting vs progressive) is still the major determinant of neurological outcome. A prospective comparative trial is likely necessary to assess the risk/benefit ratio of the two regimens. However, a tailored approach according to patients and disease characteristics might be considered.

Disclosure: Nothing to declare.

21: Autoimmune Diseases

O037 AUTOLOGOUS HSCT FOR MULTIPLE SCLEROSIS SHOULD BE DONE EARLY IN THE COURSE OF THE DISEASE

María de Lourdes Pastelín-Martínez1, Moisés Manuel Gallardo-Pérez2, Andres Gómez-De-León3, Juan Carlos Olivares-Gazca2, Edgar Jared Hernández-Flores4, Daniela Sánchez-Bonilla2, Merittzel Abigail Montes-Robles1, Max Robles-Nasta2, Guillermo Ocaña-Ramm4, Silvia Soto-Olvera4, David Gómez-Almaguer3, Guillermo José Ruiz-Delgado 2,4, Guillermo José Ruiz-Arguelles2,4

1Universidad Anáhuac Puebla, Puebla, Mexico, 2Centro de Hematología y Medicina Interna, Clínica Ruiz, Puebla, Mexico, 3Servicio de Hematología del Hospital Universitario “Dr. José Eleuterio González”, Monterrey, Mexico, 4Universidad Popular Autónoma del Estado de Puebla, Puebla, Mexico

Background: Multiple sclerosis (MS) is a disabling disease that affects young adults. Treatments for MS have increased exponentially in number, efficacy and risk. Autologous hematopoietic stem cell transplantation (aHSCT) can change the natural history of the disease. To analyze if aHSCT should be done early in the course of the disease or after failing of other therapies, we have studied the long-term results of aHSCT in a cohort of persons with MS.

Methods: Patients with MS referred to our center for aHSCT between June 2015 and July 2023 were prospectively entered in the study. All phenotypes of MS were included. The follow up was assessed with the patient reported EDSS score in an online form; only patients followed by three or more years were included in the analysis. The progression of MS was assessed by changes in the expanded disability status scale (EDSS).The response rate was analyzed for four variables: Disease-modyfing treatment (DMT) given or not before the HSCT and delay in the diagnosis and treatment: More (delayed diagnosis DD), or less (non-delayed diagnosis NDD) than 8 months after the onset of symptoms.

Results: 1518 subjects were prospectively enrolled. In a subset of 103 patients, detailed pre- and post-transplant evolution could be recorded. Two groups of patients were analyzed according to the time of evolution between the onset of symptoms and the definite diagnosis of MS: More than 8 months, (delayed diagnosis, DD) or less than 8 months (non-delayed diagnosis, NDD). The time elapsed between the onset of symptoms and the correct diagnosis was lower for the NDD group (1.55 vs 35.87 months, p < 0.05). The EDSS at the time of the transplant was higher in the DD group (4.5 vs 3.0, p = 0.3) and the response of the EDSS score to the transplant was significantly better for the NDD group, the last censored values for the EDSS being 2.5 vs 4.25 (p = 0.03). The two groups of patients responded to aHSCT by diminishing the EDSS, but the response was significantly better in the NDD group. 74 patients were followed for more than 36 months, the response rate (RR = improvement + stabilization) at 12, 24 and 36 mo was 84%, 84% and 58% respectively for patients not receiving prior disease modifying treatments (DMT) and 72%, 90% and 67% for patients receiving DMT. The EDSS score was on average worsening in patients before the aHSCT, but the transplant stabilized the EDSS score at 3 years in patients with prior exposure to DMT, whereas in persons not given DMT, the transplant resulted in a significant decrease (p = .01) of the EDSS score.

Conclusions: These data indicate that both the pre-transplant progression of the disease and the response to aHSCT were significantly worse in persons with a delayed diagnosis. The response to aHSCT was better for persons not exposed to immunosuppressive DMT before the transplant. Additional studies are needed to further analyze the impact of the use of DMT before aHSCT in MS, as well as the timing of the procedure.

Disclosure: Nothing to declare

21: Autoimmune Diseases

O038 ENGINEERED AIR-TREG CELLS AS A NOVEL THERAPY CONCEPT FOR INFLAMMATION-DRIVEN DISEASES

Sebastian Bittner 1, Thomas Hehlgans1, Markus Feuerer1

1Leibniz Institute for Immunotherapy, Regensburg, Germany

Background: Engineered regulatory T cell (Treg cell) therapy is a promising strategy to treat patients suffering from inflammatory diseases, autoimmunity and transplant rejection. However, in human autoimmune diseases, the implicated autoantigens, which could serve as potential targets for TCR- or CAR-engineered Treg cells, are often unknown or vary strongly between individual patients. In order to circumvent this problem, we invented a new class of artificial receptors for Treg cells that sense and respond mediators of inflammation instead of tissue-specific antigens.

Methods: We genetically modify Treg cells with new synthetic receptors, named artificial immune receptors (AIRs), that recognize inflammatory ligands and trigger Treg activation resulting in improved Treg-mediated protection in a major MHC mismatch model of graft versus host disease (GvHD).

Results: In many autoimmune and inflammatory diseases there is a lack of knowledge about relevant disease-driving antigens and often also multiple organs and tissues are affected in individual patients. Therefore, potential uniform target antigens that could be selected for TCR- or CAR–Treg cell therapy are unknown. In contrast to this, mediators of inflammation show a high redundancy as well as functional importance for the development of various inflammatory diseases, including autoimmunity and alloreactivity. Especially, cytokines of the tumor necrosis factor (TNF) superfamily are involved in different inflammatory and autoimmune diseases. For example, therapeutic intervention with TNF-inhibitors is an important treatment option for several inflammatory diseases. These considerations led us to develop a concept for engineered Treg cell therapy by generating artificial immune receptors (AIRs) that target these inflammatory mediators instead of tissue-specific antigens.

In our work, we introduce a new class of synthetic biosensors, named AIRs, for murine and human Treg cells. AIRs consist of three domains and have an extracellular binding domain of a tumor necrosis factor (TNF)-receptor superfamily member, an intracellular costimulatory signaling domain of CD28, and T cell receptor signaling domain of CD3-ζ chain. AIR receptors equip Treg cells with an inflammation-sensing machinery and translate this environmental information into a CD3-ζ chain–dependent TCR-activation program. Different AIRs were generated, recognizing the inflammatory ligands of the TNF-receptor superfamily, including LIGHT, TNFα, CD40L/ CD154 and TNF-like ligand 1A (TL1A), leading to activation, differentiation, and proliferation of AIR–Treg cells. In preclinical GvHD models, AIR-expressing Treg cells, which can be activated by the ligands LIGHT or CD40L, protect significantly better than control Treg cells. Expression and signaling of the corresponding human AIR in human Treg cells prove that this concept can be translated. AIRs as a synthetic tool for cellular therapy allow Treg cells to sense and target these environmental inflammatory signals and translate them into a CD3-ζ chain–dependent TCR program, enabling Treg cells to fulfill their suppressive and tissue-protective functions, independent of a CAR- or TCR-specific antigen.

Conclusions: Engineering AIR-Treg cells that target inflammatory ligands leading to TCR signaling and activation might be used as a Treg cell–based therapy approach for a broad range of inflammation-driven diseases.

Disclosure: S.B., T.H., and M.F. are inventors on patent application (patent application no. WO/2023/227521) based on the presented technology.

21: Autoimmune Diseases

O039 DONOR-DERIVED IMMUNE RECONSTITUTION PROFILE OF AGGRESSIVE NEUROMYELITIS OPTICA IN LONG-TERM DISEASE REMISSION AFTER ALLOGENEIC TRANSPLANTATION

Giorgio Orofino 1, Angela Genchi1, Maria Teresa Lupo-Stanghellini1, Matteo Doglio1, Maddalena Noviello1, Alessandra Mandelli1, Sara Mastaglio1, Simona Piemontese1, Elena Tassi1, Francesca Ferrua1, Roberto Furlan1, Gianvito Martino1,2, Massimo Filippi1,2, Massimo Bernardi1, Consuelo Corti1, Jacopo Peccatori1, Francesca Tortorelli1, Cristina Toffalori1, Luca Vago1,2, Chiara Bonini1,2, Lucia Moiola1, Fabio Ciceri1,2, Raffaella Greco1

1IRCCS Ospedale San Raffaele Scientific Institute, Milan, Italy, 2San Raffaele Vita-Salute University, Milan, Italy

Background: Here we report the long-term follow-up analysis of the first 2 patients treated with allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for refractory neuromyelitis optica (NMO), an aggressive neurological autoimmune disease with poor prognosis, respectively 14 and 13 years ago, with a sustained disease remission.

Methods: Both patients exhibited serum positivity for pathogenic anti-aquaporin 4 antibodies (AQP4-Ab). They had a severe disease course with disability accumulation, despite several lines of immunosuppressive treatment, including autologous HSCT. UPN#1 underwent allogeneic HSCT from his HLA-identical sibling, while UPN#2 from Matched Unrelated Donor (MUD). Conditioning regimen consisted of treosulfan-fludarabine. GvHD prophylaxis combined anti-T lymphocyte globulin (ATLG) with cyclosporine-methotrexate (Upn#1) or mycophenolate-sirolimus (Upn#2); B cell depletion was obtained by rituximab. We performed sequential clinical follow-up visits, with laboratory and neuroradiological analyses. Immune-reconstitution was assessed at 3, 4, 6 and 13 years after HSCT.

Results: Hematopoietic recovery occurred within day 30, accompanied by full donor chimerism. None of the patients experienced Graft-versus-Host-Disease (GvHD). Both patients demonstrated a marked and sustained improvement of neurological functions (Expanded Disability Status Scale dropped from 6 to 2.5 in UPN#1, and from 8.5 to 7.5 in UPN#2). At the latest follow-up both patients are alive; clinical and neuroradiological assessments showed disease remission, along with the persistent disappearance of pathogenetic AQP4-Ab.

Immune-reconstitution analyses showed a normal recovery of circulating lymphocytes, except for a mild impairment of B-Cell Immune Reconstitution in #UPN1. This patient developed a post-transplant Immunoglobuline (Ig)-deficiency, with recurrent upper-tract respiratory symptoms, requiring Ig supplementation. To investigate this immunodeficiency, we performed exome sequencing on the patient’s Peripheral Blood Mononuclear Cells (PBMC), finding a mutation on the NFkB gene with a variant of uncertain significancy (VUS), and performed lineage specific microchimerism analysis, demonstrating full donor chimerism in B, T and myeloid cells.

In both patients, circulating B cells were predominantly naïve.

All the main differentiation subsets for CD4 + T-cells were present, including early differentiated ones (naive, stem-memory and central-memory T-cells). The expression of the CD31 marker on naive CD4 + T-cells, identifying bona fide recent thymic emigrants, indicates a robust thymic output.

Moreover, we observed a resting phenotype of CD4 + T-Cells (HLA-DR-), with only a minority of them expressing checkpoints inhibitors on their surface.

Upon activation with polyclonal stimuli T-cells proved to be polyfunctional with sustained cytokine production at all time-points.

Similar findings were confirmed among the CD8 + T-cell compartment.

We documented the presence and the changes of the T-Reg compartment and it’s subsets across time, potentially contributing to long-term beneficial effects.

Conclusions: The effectiveness of allogeneic HSCT in achieving sustained remission in NMO patients is noteworthy. Our immunological results suggest that allogeneic HSCT can provide long-term disease control in refractory NMO through several concurring mechanisms: the eradication of autoreactive cell clones by high-dose chemotherapy and by in vivo T and B cell depletion, elimination of long-lived plasma cells producing AQP4-Ab, the re-establishment of thymic central tolerance and renewal of the immune repertoire.

Disclosure: I declare no disclosures

4: CAR-based Cellular Therapy – Clinical

O040 SITE-SPECIFIC RESPONSES AND EXTRANODAL INVOLVEMENT IMPLICATIONS IN LARGE B-CELL LYMPHOMAS TREATED WITH CD19-CART THERAPY

Alejandro Luna de Abia 1, Sean M. Devlin1, Jessica Flynn1, Magdalena Corona de Lapuerta1, Efrat Luttwak1, Ivan Landego1, Parastoo B. Dahi1, Richard J. Lin1, Allison Parascondola1, M.Lia Palomba1, Gunjan L. Shah1, Michael Scordo1, Brandon S. Imber1, Ana Alarcón Tomás1, Gilles Salles1, Jae H. Park1, Miguel-Ángel Perales1, Roni Shouval1

1Memorial Sloan Kettering Cancer Center, New York, United States

Background: Extranodal (EN) disease is an established poor prognostic factor in large B-cell lymphoma (LBCL). Whether EN sites serve as potential sanctuaries fostering resistance against CD19-directed chimeric antigen T-cell (CAR-T) activity remains unclear. This study aims to elucidate disease dynamics before and after CD19-CAR-T therapy across anatomical sites of LBCL involvement.

Methods: In this single-center retrospective study, adults with LBCL treated with CD19-CAR-T were included; primary central nervous system (CNS) disease was an exclusion criterion. We retrospectively reviewed 921 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET) scans performed before apheresis, after apheresis, at the time of best response, and relapse; CNS and bone marrow involvements were evaluated when available.

Results: Among 274 patients with LBCL receiving CD19-CAR-T cells (axi-cel 54%, tisa-cel 26%, liso-cel 20%), 38% had transformed lymphoma, and the majority received bridging therapy (78%). EN involvement, with or without nodal (ND) disease, before apheresis was observed in 68% of cases, with 32% having ND disease exclusively. In the last disease assessment before CAR-T, the most common EN sites involved were bone/soft tissue (41%) and gastrointestinal/peritoneum (22%); 8% had CNS/orbital involvement. Poor prognostic factors, including lower performance status (p = 0.015) and higher metabolic tumor volume (p < 0.001) were enriched in the EN group.

Patients with EN disease pre-CAR-T exhibited higher grade ≥ 2 cytokine release syndrome (CRS) (45% vs. 32%, p = 0.046), grade ≥ 2 immune effector cell-associated neurotoxicity syndrome (ICANS) (27% vs. 6%, p < 0.001), and lower complete response rates (55% vs. 78%, p < 0.001) than those with exclusive ND disease. ND disease pre-CAR-T correlated with improved progression-free survival (PFS) (HR 0.51 [95%CI: 0.34-0.77]) and overall survival (OS) (HR 0.49 [0.29-0.83]), in multivariable Cox-regression models adjusting for relevant factors.

EN site-specific response rates to CAR-T were lowest for adrenal/genitourinary (12/32, 38%), gastrointestinal/peritoneum (23/68, 34%), lungs/pleura/pericardium (19/56, 34%) and CNS/orbital (8/25, 32%). In a multivariable Cox-regression model, pre-CAR-T involvement of adrenal/genitourinary (HR 2.45 [1.59-3.77]) and hepatobiliary/pancreas (HR 1.9 [95%CI 1.23-2.94]) was associated with greater risk of relapse or progression at any site after CAR-T.

Finally, the 1 year-OS rate landmarked from the time of relapse post-CAR-T was worse in EN involvement (32% [95%CI: 24-43]) than in exclusive ND involvement (63% [95%CI: 46-86]).

Conclusions: This extensive analysis highlights the significant impact of EN disease on CAR-T therapy outcomes in LBCL. It emphasizes the necessity for tailored management strategies specific to EN involvement, advocating for organ-specific approaches in future studies. Additionally, further investigations should delve into the underlying biology driving sanctuary sites to enhance our understanding and refine therapeutic interventions.

Disclosure: Palomba: Garuda Therapeutics: Honoraria; Smart Immune: Honoraria; Thymofox: Honoraria; Novartis: Honoraria; Ceramedix: Honoraria; Seres Therapeutics: Honoraria, Patents & Royalties; Rheos: Honoraria; Juno: Honoraria, Patents & Royalties; Cellectar: Honoraria; BMS: Honoraria; MustangBio: Honoraria; Kite: Honoraria; Pluto Immunotherapeutics: Honoraria; Synthekine: Honoraria. Park: Intella: Consultancy; Servier: Consultancy, Research Funding; Allogene: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Minerva Bio: Consultancy; BeiGene: Consultancy; Incyte: Research Funding; Bright Pharmacetuicals: Consultancy; Pfizer: Consultancy; Be Biopharma: Consultancy; Sobi: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy; Fate Therapeutics: Research Funding; Autolus Therapeutics: Research Funding; Genentech, Inc.: Research Funding; Kite: Consultancy; Curocell: Consultancy; Artiva Biotherapeutics: Consultancy, Current holder of stock options in a privately-held company, Membership on an entity’s Board of Directors or advisory committees; Affyimmune: Consultancy; GC Cell: Membership on an entity’s Board of Directors or advisory committees. Salles: Ipsen: Consultancy, Research Funding; Loxo/Lilly: Consultancy; Genmab: Consultancy; Merck: Consultancy, Honoraria; Nordic Nanovector: Consultancy; Kite/Gilead: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Orna: Consultancy; AbbVie: Consultancy, Honoraria; ATB Therapeutics: Consultancy; Molecular Partners: Consultancy; Incyte: Consultancy; Janssen: Consultancy, Research Funding; EPIZYME: Consultancy; Owkin: Current holder of stock options in a privately-held company; Debiopharm: Consultancy; BMS/Celgene: Consultancy; BeiGene: Consultancy; Novartis: Consultancy; Nurix: Consultancy. Scordo: Medscape, LLC: Honoraria; CancertNetwork (Intellisphere LLC): Honoraria; Omeros Corporation: Consultancy, Research Funding; Amgen, Inc.: Research Funding; Angiocrine Bioscience, Inc.: Research Funding. Shah: ArcellX: Other: DSMB; Janssen: Research Funding; Beyond Spring: Research Funding; BMS: Research Funding; Amgen: Research Funding. Perales: Allogene: Research Funding; Omeros: Consultancy, Current equity holder in publicly-traded company, Honoraria; MorphoSys: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Orcabio: Consultancy, Current equity holder in publicly-traded company, Honoraria; AbbVie: Consultancy, Honoraria; Caribou: Consultancy, Honoraria; Syncopation: Honoraria; Cidara Therapeutics: Consultancy, Other; NexImmune: Consultancy, Current equity holder in publicly-traded company; Medigene: Consultancy, Other; Equillium: Consultancy, Honoraria; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Vor Biopharma: Consultancy, Honoraria; Allovir: Consultancy; Kite: Consultancy, Honoraria, Research Funding; Servier: Other; Miltenyi Biotec: Honoraria; DSMB: Other; Incyte: Consultancy, Honoraria, Research Funding; Nektar Therapeutics: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria; Adicet: Honoraria; Celgene: Honoraria; Karyopharm: Consultancy, Honoraria; Exevir: Consultancy, Honoraria; Sellas Life Sciences: Consultancy; VectivBio AG: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Imber: research funding (to institution) from Novartis, Bayer, Kazia, GT Medical Technologies, received honorarium from GT Medical Technologies.

4: CAR-based Cellular Therapy – Clinical

O041 DONOR-DERIVED CAR-T CELLS ARE SAFELY AND EFFECTIVELY CO-INFUSED WITH THE ALLOGENIC GRAFT, DEPLETED OF AB T CELLS IN CHILDREN WITH ADVANCED B-CELL NEOPLASM

Larisa Shelikhova1, Olga Molostova1, Arina Rakhteenko1, Margarita Perminova1, Maria Dunaykina1, Elena Kurnikova1, Yakov Muzalevsky1, Dmitriy Pershin1, Maria Fadeeva1, Olga Illarionova1, Alexander Popov1, Daria Kobyzeva1, Natalya Miakova1, Galina Novichkova1, Alexei Maschan 1, Michael Maschan1

1Dmitry Rogachev Federal Research Centre of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation

Background: High disease burden is associated with CAR-T cells toxicity and high relapse rate among children with r/r BCP-ALL. In many cases long-term remission is achieved only with HSCT as post-CAR-T consolidation. We reported on the new approach with simultaneous infusion of the allogenic αβ-T cells depleted grafts and CAR-T cells, derived from the donor memory T-cells fraction. Experience suggested that this approach can be a safe treatment.

Methods: A total of 20 pts with r/r BCP-ALL (n = 16), B-NHL (n = 3) and MPAL (n = 1) (9 female, 11 male, median age 7,6 y) were enrolled. All patients had relapse after multiple lines of treatment including previous HSCT(n = 10), blinatumomab (n = 12), inotuzumab (n = 1) and CAR-T cell infusion(n = 8). At the time of HSCT application the disease burden was MRD (n = 6), AD(n = 12) and two pts had MRD negative CR2. PBMS used to produce CAR T cells were provided by the patient’s transplant donor.

The CliniMACS Prodigy T cell transduction (TCT) process was used to produce CD19 and СD19/22CAR-T cells, CD3/CD28 stimulation with MACS GMP T Cell TransAct, transduction with lentiviral (second generation CD19.4-1BB zeta, vector (Lentigen, Miltenyi Biotec company) and expansion over 7 days.

Nine (45%) pts received treosulfan-based myeloablative preparative regimen, while TBI-based regimen was used in 11(55%) pts. GvHD prophylaxis included tocilizumab at 8 mg/kg on day -1 and abatacept at 10 mg/kg on day -1, +7, +14, +28.

Final product was administered without cryopreservation to the patients: 19 pts received allogeneic CAR T cell with haplo and one with MR TCRαβ+ depletion graft (CD19 n = 3 and CD19/22 n = 17. The cell products were administered at a dose of 0,1*106/kg of CAR-T cells in haploidentical donors and 0,5 *106/kg in MRD. The median dose of CD34+ cells was 8.5 x106/kg, αβ T cells - 56x103/kg.

Results: Primary engraftment was achieved in 19 of 20 pts, the median time to neutrophil and platelet recovery was 13 and 14 days, respectively, all engrafted patients achieved CR at day +28 after CAR-T cell therapy. The median time to CAR-T cell peak expansion was 14 days. The median time of CAR-T persistence was 100 days and B cell aplasia was 150 days.

CRS occurred in 10 (50%) patients and only one had grade 3. Ten patients had neurologic events (ICANS grade 1 n = 5, grade 2 n = 4 and grade 3 n = 1). 5 patients had the signs of aGvHD, grade 2 (n = 4), grade 3(n = 1), 2 patients had mild chGvHD.

Eleven (55%) patients are alive in CR with a median follow-up of 3 years, 9 patients died (5 due to relapse (CD19 pos (n = 4), CD19 neg(n = 1), the median time of relapse was day 131; 4 in CR due to VOD, viral (ADV + COVID19) and fungal infection.

Conclusions: Our early experience suggests that allogenic CAR-T cells can be safely infused simultaneously with the HST graft on the platform of ab T cell depletion. The infusions did not compromise engraftment and GvHD control, while specific CAR-T toxicity was mild and manageable. We have documented CAR-T expansion and persistence. Prospective testing of the approach is warranted.

Disclosure: M. Maschan - Myltenyi Biotec - Honoraria

4: CAR-based Cellular Therapy – Clinical

O042 MACHINE-LEARNING-BASED CLUSTERING TO REFINE THE EHA/EBMT IMMUNE EFFECTOR CELL-ASSOCIATED HEMATOTOXICITY GRADING CRITERIA

Emily Liang 1,2, Aya Albittar1, Andrew Portuguese1,2, Jennifer Huang1,2, Natalie Wuliji1,2, Qian Wu1, Joseph De Los Reyes1, Nikki Pin1, Aiko Torkelson1, Delaney Kirchmeier1, Abigail Chutnik1, Barbara Pender1, Joshua Hill1,2, Noam Kopmar1,2, Rahul Banerjee1,2, Andrew Cowan1,2, Damian Green1,2, Ajay Gopal1,2, Christina Poh1,2, Mazyar Shadman1,2, Alexandre Hirayama1,2, Brian Till1,2, Erik Kimble1,2, Lorenzo Iovino1,2, Aude Chapuis1,2, Folashade Otegbeye1,2, Ryan Cassaday1,2, Filippo Milano1,2, Cameron Turtle3, David Maloney1,2, Jordan Gauthier1,2

1Fred Hutchinson Cancer Center, Seattle, United States, 2University of Washington, Seattle, United States, 3University of Sydney, Sydney, Australia

Background: The EHA/EBMT immune effector cell-associated hematotoxicity (ICAHT) grading system was recently developed for hematologic toxicity after CAR T-cell therapy. We assessed the application of unsupervised time-series clustering to longitudinal ANC data, relative to the ICAHT grading system.

Methods: Adults who underwent CAR T-cell therapy for hematologic malignancies with commercial or investigational products at our center between 2013 and 2023 were included (n = 454). Log10-transformed ANC trajectories were clustered using non-supervised longitudinal k-means based on Euclidean distances (latrend and kml packages in R). Overall survival (OS) was modeled using Cox regression.

Results: The most common disease types were aggressive NHL (n = 216; 48%), ALL (n = 82; 18%), and MM/PCL (n = 61; 13%) (Table). The most common CAR T-cell products were investigational CD19 CAR T-cell products (n = 180; 40%), axi-cel (n = 114; 25%), and liso-cel (n = 58; 13%). The median follow-up was 17 months (IQR, 1-18).

The longitudinal ANC data clustered into 4 distinct trajectories (“clusters”): 1) very good (high nadir followed by rapid recovery), n = 335 (74%); 2) good (low nadir followed by rapid recovery), n = 92 (20%); 3) poor (low nadir followed by intermittent recovery), n = 18 (4%); 4) very poor (aplastic phenotype), n = 9 (2%). Grade 1, 2, 3, and 4 ICAHT occurred in 141 (31%), 177 (39%), 47 (10%), and 30 (7%), respectively. Sixty-five percent of grade 3-4 ICAHT patients were in the very good or good clusters.

Clusters were strongly associated with OS (poor vs. very good, HR = 3.5, 95% CI, 1.8-6.9, p = 0.0003; very poor vs. very good, HR = 6.6, 95% CI, 3.4-12.7, p = <0.0001), as were ICAHT categories (grade 3 vs. 0, HR = 2.7 = 9, 95% CI, 1.5-5.8, p = 0.006; grade 4 vs. 0, HR = 6.8, 95% CI, 3.3-14.0, p < 0.0001) with comparable discrimination (C-index: 0.59 vs. 0.62 for the 4-cluster solution and ICAHT grades, respectively). However, clusters demonstrated less intra-cluster variability and greater inter-cluster distinction compared to ICAHT grades (Dunn index: 0.11 vs. 0.03; average silhouette width: 0.29 vs. -0.04). The 3- and 18-month OS in patients in the poor/very poor clusters was 42% and 9%, respectively, compared to 69% and 24% in patients with grade 3-4 ICAHT.

We next evaluated non-concordant trajectories within each ICAHT grade relative to the identified clusters. We found that 14% and 51% of grade 3 patients were in the very good and good clusters, respectively; these patients exhibited distinct and more favorable patterns of ANC recovery (e.g., stable ANC recovery by day 15 after CAR T-cell infusion) compared to poor/very poor clusters.

Table. Demographic, disease, and treatment characteristics (N = 454)

Age at infusion, median (range)

60 (50, 68)

Male sex

286 (63%)

Prior HCT

186 (41%)

Disease

Aggressive NHL

216 (48%)

ALL

82 (18%)

MM/PCL

61 (13%)

Indolent NHL

53 (12%)

CLL

42 (9%)

CAR T-cell product

Investigational CD19 CAR T-cell product

180 (40%)

Commercial CD19 CAR T-cell product with CD28 costimulatory domain (axi-cel, brexu-cel)

143 (31%)

Commercial CD19 CAR T-cell product with 4-1BB costimulatory domain (liso-cel, tisa-cel)

70 (15%)

Commercial BCMA CAR T-cell product (cilta-cel, ide-cel)

61 (13%)

Conclusions: Unsupervised time-series clustering identified distinct patterns of hematotoxicity that are strongly associated with OS in keeping with ICAHT grades. Our approach further stratified grade 3 ICAHT patients into clusters with distinct trajectories of ANC recovery. Our findings suggest opportunities to refine the EHA/EBMT ICAHT grading system to better capture patterns of intermittent ANC recovery.

Clinical Trial Registry: Unsupervised time-series clustering identified distinct patterns of hematotoxicity that are strongly associated with OS in keeping with ICAHT grades. Our approach further stratified grade 3 ICAHT patients into clusters with distinct trajectories of ANC recovery. Our findings suggest opportunities to refine the EHA/EBMT ICAHT grading system to better capture patterns of intermittent ANC recovery.

Disclosure: Joshua Hill: allovir: Consultancy, Research Funding; moderna: Consultancy; deverra: Research Funding. Rahul Banerjee: BMS: Consultancy; Janssen: Consultancy; Genentech: Consultancy; SparkCures: Consultancy; Sanofi: Consultancy; Caribou: Consultancy; Pfizer: Consultancy; Pack Health: Research Funding. Andrew Cowan: BMS, Adaptive: Consultancy; Adaptive Biotechnologies, Harpoon, Nektar, BMS, Janssen, Sanofi, Abbvie: Research Funding. Damian Green: Cellectar Biosciences: Research Funding; SpringWorks Therapeutics: Research Funding; Celgene: Consultancy; GlaxoSmithKline: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Research Funding; Janssen Biotech: Consultancy, Research Funding; Ensoma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Juno Therapeutics A BMS Company: Patents & Royalties, Research Funding. Ajay Gopal: Compliment Corporation: Current holder of stock options in a privately-held company; Incyte, Kite, Morphosys/Incyte, ADCT, Acrotech, Merck, Karyopharm, Servier, Beigene, Cellectar, Janssen, SeaGen, Epizyme, I-Mab bio, Gilead, Genentech, Lilly, Caribou, Fresenius-Kabi: Consultancy; Merck, I-Mab bio, IgM Bio, Takeda, Gilead, Astra-Zeneca, Agios, Janssen, BMS, SeaGen, Teva, Genmab: Research Funding. Christina Poh: BeiGene: Consultancy; Seattle Genetics: Consultancy; Incyte: Research Funding; Acrotech: Consultancy. Mazyar Shadman: Fate Therapeutics: Consultancy; Genmab: Consultancy, Research Funding; Vincerx: Research Funding; MorphoSys/Incyte: Consultancy, Research Funding; Eli Lilly: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy; AbbVie: Consultancy, Research Funding; Mustang Bio: Consultancy, Research Funding; ADC therapeutics: Consultancy; BeiGene: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; MEI Pharma: Consultancy; Regeneron: Consultancy; TG Therapeutics: Research Funding. Alexandre Hirayama: Novartis: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Nektar Therapeutics: Honoraria, Research Funding; Juno Therapeutics, a Bristol Myers Squibb Company: Research Funding. Till: Mustang Bio: Consultancy, Patents & Royalties, Research Funding; BMS/Juno Therapeutics: Research Funding; Proteios Technology: Consultancy, Current holder of stock options in a privately-held company. Kimble: Juno/BMS: Research Funding. Lorenzo Iovino: Mustang Bio: Current equity holder in publicly-traded company. Aude Chapuis: Juno Therapeutics: Research Funding. Ryan Cassaday: Amgen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Incyte: Research Funding; Autolus: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Research Funding; Servier: Research Funding; Vanda Pharmaceuticals: Research Funding; Jazz: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria, Research Funding; PeproMene Bio: Membership on an entity’s Board of Directors or advisory committees; Seagen: Other: Spouse was employed by and owned stock in Seagen within the last 24 months. Filippo Milano: ExCellThera Inc.: Research Funding. David Maloney: A2 Biotherapeutics: Consultancy, Current holder of stock options in a privately-held company, Honoraria, Other: Member of the Scientific Advisory Board; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties: Rights to royalties from Fred Hutch for patents licensed to Juno Therapeutics/BMS, Research Funding; Janssen: Consultancy, Honoraria; Legend Biotech: Consultancy, Honoraria, Research Funding; Mustang Bio: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Lyell Immunopharma: Other: Member, CAR T Steering Committee; Incyte: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria, Other: Member, Scientific Review Committee, Research Scholars Program in Hematologic Malignancies; Kite, a Gilead Sciences: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; Umoja: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: Participation on a Data Safety Monitory Board, Research Funding; Genentech: Consultancy, Honoraria, Other: Chair and Member of the Lymphoma Steering Committee; MorphoSys: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Other: Member of the JCAR017 EAP-001 Safety Review Committee and Member, CLL Strategic Council, Member of the JCAR017-BCM-03 Scientific Steering Committee under BMS, Research Funding; Amgen: Consultancy, Honoraria; Navan Technologies: Consultancy, Honoraria, Other: Member of the Scientific Advisory Board; Bioline Rx: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Other: Participation on a Data Safety Monitory Board ; Fred Hutch: Other: rights to royalties for patents licensed to Juno; Navan Technologies: Current holder of stock options in a privately-held company; Chimeric Therapeutics: Other: Member of the Scientific Advisory Board; ImmPACT Bio: Other: Member, Clinical Advisory Board, CD19/CD20 bi-specific CAR-T Cell Therapy Program; Interius: Other: Member, Clinical Advisory Board. Jordan Gauthier: Kite Pharma: Consultancy, Honoraria; MorphoSys: Consultancy, Research Funding; Angiocrine Bioscience: Research Funding; Century Therapeutics: Other: Independent data review committee; Celgene (a Bristol Myers Squibb company): Research Funding; Legend Biotech: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Juno Therapeutics (a Bristol Myers Squibb company): Research Funding; Sobi: Consultancy, Honoraria, Research Funding.

4: CAR-based Cellular Therapy – Clinical

O043 SINGLE CENTRE LONG-TERM OUTCOMES OF RELAPSED/REFRACTORY PAEDIATRIC B-ALL AFTER GENOME-EDITED ‘UNIVERSAL’ CAR19 T CELL THERAPY

Daniela Guardo 1,2, Vesna Pavasovic1, Avijeet Kumar Mishra1, Kimberly Gilmour1, Stuart Adams1, Giorgio Ottaviano1, Danielle Pinner1, Jan Chu1, Martin Sauer3, Ajay Vora1, Paul Veys1, Kanchan Rao1, Waseem Qasim1

1Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom, 2IRCCS Istituto Giannina Gaslini, Genoa, Italy, 3Hannover Medical School, Hannover, Germany

Background: Genome-edited allogeneic chimeric antigen receptor (CAR) T cells offer “off-the-shelf” alternatives to autologous CAR T cells. Great Ormond Street Hospital (GOS) has investigated editing strategies to disrupt T cell receptor (TCRαβ) and CD52 expression in early stage human applications. Editing was designed to simultaneously prevent HLA mis-matched donor T cells from mediating graft versus host disease (GVHD) and allowed their persistence in the presence of Alemtuzumab. Initial compassionate experience with TALEN-edited CAR19 T cells in two B-ALL infants was followed by treatment of six children part of a phase 1 clinical trial of UCAR19 (NCT02808442) and a further seven children received CRISPR/Cas9 genome edited TT52CAR19 T cells (NCT04557436). Here we surveyed longer term outcomes of patients who had achieved remission after universal cell therapy and had been bridged to allogeneic haematopoietic stem cell transplantation (HSCT).

Methods: Outcomes of paediatric patients (aged 0.8-16 years) treated at GOS between 2015 and 2022 with either UCART19 (1.1-4.6 x 106) or TT52CAR19 (0.8-2.0 x 106) CAR19 T cells/kg cells were surveyed. Information collected included overall (OS) and disease-free survival (DFS), graft-versus-host-disease (GVHD), chimerism, detection of vector copy number and immune reconstitution. Our GOS augmented lymphodepletion (ALD) protocol comprising (total doses) fludarabine 150 mg/m2, cyclophosphamide 120 mg/kg, and alemtuzumab 1 mg/kg was used in 12/15 children.

Results: Overall, 11/15 patients (73%) achieved complete remission (CR/CRi) with undetectable disease on bone marrow flow cytometry 28 days after cell therapy, with 8/15 (53%) also confirmed as MRD negative by PCR (MRD < 10-4). Allogenic HSCT was undertaken within the next four weeks, and the majority (64%) received reduced intensity conditionings (RIC) with ATG and low dose (2-4 Gy) TBI. Seven out of eleven transplants were second procedures and 6 of these were from the previous donor.

Sustained molecular remission was obtained in 7/8 (88%) of children who had been transplanted with PCR MRD < 10-4. Although one subject died from post-transplant complications whilst in remission, 6 subjects have maintained ongoing remission, comprising 40% (6/15) long term survival. OS and DFS are shown in Figure 1. All survivors exhibited evidence of normal immune recovery (CD4 T cells > 300/mm3) within 12 months from SCT and any receiving intra-venous immunoglobulins (IVIG) stopped replacement. Non-persistence of allo-CAR T cells was confirmed in all patients after preparative conditioning and allo-SCT.

The 50th Annual Meeting of the European Society for Blood and Marrow Transplantation: Physicians - Oral Session (O009-O154) (4)

Figure 1. OS and DFS. OS, overall survival; DFS, disease-free survival

Conclusions: Longer term data for children treated at a single centre with genome-edited allogeneic CAR19 T cells indicate sustained remission in patients transplanted in molecular (PCR) MRD remission. Overall survival at our centre has been comparable to the wider autologous CAR19 setting, despite multiple lines of previous therapy, including CARs, Bi-specific T-cell engagers (BiTEs) and previous transplant. Notably, surviving subjects had all received augmented lymphodepletion ahead of CAR19 T cells, highlighting the importance of addressing host mediated barriers to mismatched cells for deep and rapid leukemic clearance. The success of subsequent RIC transplantation was consistent with consolidation of donor derived reconstitution rather than additional anti-leukemic chemotherapy effects.

Disclosure: Nothing to declare.

4: CAR-based Cellular Therapy – Clinical

O044 RATES OF RESPONSE TO SALVAGE TREATMENT AFTER POST-CAR-T PROGRESSION/RELAPSE IN LARGE B-CELL LYMPHOMA PATIENTS – A DATA METAANALYSIS

Jaromir Tomasik 1, Dominik Bilicki1, Grzegorz Basak1

1Medical University of Warsaw, Warsaw, Poland

Background: Large B-cell lymphoma (LBCL) patients who progressed or relapsed after chimeric antigen receptor (CAR)-T therapy have a dismal prognosis with median overall survival (OS) estimated at below six months from the time of progressive disease. Various regimens are administered in a first line salvage therapy after post-CAR-T progression/relapse, however, no consensus regarding the most effective intervention has been established yet.

Methods: The aim of the study was to perform a meta-analysis of response rates to first line treatments after post-CAR-T progression/relapse (P/R) to provide pooled estimates and suggest the most efficient regimens. The population of interest were patients aged 18 or older, treated for LBCL, who experienced post-CAR-T P/R. Any treatment regimen administered as the first line after P/R was considered the intervention. Complete response (CR) rate and overall response rate (ORR) were study endpoints. The meta-analysis was performed using a random-effects model to obtain pooled CR and ORR with 95% confidence intervals (CI) for each intervention group separately. The study was conducted according to the PRISMA statement, the protocol was registered at the PROSPERO register (CRD42023473854).

Results: In the search process, we identified 39 studies meeting the inclusion criteria and providing sufficient data for the meta-analysis. Some studies included several intervention cohorts. The following interventions have been analyzed: bispecific antibodies (BiTEs) – administered in 13 studies, immune checkpoint inhibitors -12, lenalidomide-based regimens – 11, polatuzumab-based regimens – 10, radiotherapy – 9, Bruton’s Tyrosine Kinase inhibitors (BTKi) – 5, non-CD19 CAR-T – 5, CD19 CAR-T retreatment - 2 studies. Infusion of CAR-T cells other than anti-CD19 (e.g., anti-CD22, CD20) yielded the best response rates among all analyzed interventions, with pooled CR rate of 56% (95% CI: 40-71%) and pooled ORR of 80% (95% CI: 66-92%). Repeated, salvage administration of anti-CD19 CAR-T cells gave pooled CR of 30% (95% CI: 7-58%). Only two studies reported this type of intervention, with only one providing ORR. Administration of immune checkpoint inhibitors and BTKi regimens was associated with the lowest pooled CR rates of 11% (95% CI: 4-19%) and 8% (95% CI: 0-23%), respectively. Among other interventions, pooled CR rates were similar and varied from 19% in lenalidomide-treated groups to 28% in BiTEs-treated groups. Distributions of ORR estimates among the intervention groups were comparable with the distribution of CR. BiTEs presented the highest ORR of 48,5% (similar values were achieved in polatuzumab and radiotherapy groups), whereas checkpoint inhibitors and BTKi yielded 29% and 27% respectively.

Conclusions: The response rates vary depending on the intervention used as first line salvage treatment for LBCL patients after post-CAR-T progression/relapse. Infusion of CAR-T cells targeting molecules other than CD19 is the most efficient in achieving complete and overall responses. Regimens such as BiTEs also appear promising. On the contrary, BTK inhibitors and immune checkpoint inhibitors present disappointing performance. Considering the poor prognosis for the patients, the choice of the most efficient regimen is of the utmost importance.

Clinical Trial Registry: PROSPERO register (CRD42023473854)

Disclosure: Novartis and Gilead: honoraria for lectures and advisory boards.

4: CAR-based Cellular Therapy – Clinical

O045 DONOR-DERIVED CAR-T CELLS FOR THE TREATMENT OF RELAPSED ACUTE B-LYMPHOBLASTIC LEUKEMIA AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION

Lei Deng1, Xiaolin Yu1, Xiaocheng Song1, Rui Guan1, Yan Shao1, Wenjun Li1, Fang Zhou 1

1The 960th Hospital of The People’s Liberation Army Joint Logistics Support Force, Jinan, China

Background: Autologous chimeric antigen receptor T cells (CAR-T) have exhibited notable effectiveness in cases of relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). Nevertheless, patients experiencing relapse subsequent to allogeneic hematopoietic stem cell transplantation (allo-HSCT) frequently encounter difficulties in acquiring autologous CAR-T products due to diminished lymphocyte counts and accelerated disease progression. To surmount these challenges, CAR-T cells can be sourced from the hematopoietic stem cell donor.

Methods: Peripheral blood mononuclear cells (PBMCs) were obtained from the patient’s hematopoietic stem cell donor for second generation CAR-T culture. As planned, the patient received pretreatment with the FC regimen (Fludarabine and cyclophosphamide) and then received transfusion of donor-derived CAR-T cells.

Results: A total of 14 patients relapsed after allo-HSCT from August 2019 to May 2023. The relapse cases included donor-derived CD19 CAR-T (10 cases), CD22 CAR-T (2 cases), and dual-target CD19-CD22 CAR-T (2 cases). The median age was 22 years (11-43 years), with 9 males and 5 females. Eight patients had bone marrow recurrence, four patients had extramedullary recurrence, and two patients had both bone marrow and extramedullary recurrence. The median follow-up time was 311 days (11-908 days), and the minimum follow-up time excluding death was 221 days. After treatment, 10 (71.4%) cases achieved remission, 2 (14.3%) cases had a partial response, and 2 (14.3%) cases had no response.

Cytokine release syndrome (CRS) occurred in all 14 patients, with grade 1 in 7 (50%) patients, grade 2 in 5 (35.7%) patients, grade 3 in 1 (7.1%) patient, and grade 4 in 1 (7.1%) patient. Of the 14 cases, 4 (28.6%) had severe GVHD (grade III-IV), which improved after treatment. In 13 patients with granulocyte deficiency, the median recovery time (>0.5×109/L) was 10 days (2-107 days), and 1 patient did not recover until death. In 7 patients with severe thrombocytopenia (<20×109/L), the median platelet recovery time was 40 days (4-334 days), and 2 patients did not recover until death. Of the 10 patients in remission, 2 relapsed at 236 days and 495 days after CAR-T treatment. One patient relapsed and died, and 1 achieved remission again after changing the CAR-T target. The 1-year survival rate of 14 patients was 50%. 4 of the 10 patients in remission died, 3 from severe infection and 1 from disease recurrence. Of the 2 patients with a partial response, 1 achieved remission after changing the CAR-T target and 1 died of disease progression. 2 unresponsive patients died from disease progression. (Table 1)

Full size table

Conclusions: Donor-derived CAR-T cells are an effective method for relapsed acute B-lymphoblastic leukemia after HSCT, improving the remission rate and survival rate of patients. However, the main causes of death are relapse and severe infection after CAR-T therapy. This may be related to GVHD and poor recovery of blood cells after CAR-T therapy. Large-scale studies are needed to confirm.

Disclosure: Nothing to declare.

4: CAR-based Cellular Therapy – Clinical

O046 SEVEN-DAY VEIN-TO-VEIN POINT-OF-CARE–MANUFACTURED CD19 CAR T-CELL THERAPY (GLPG5201) IN RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA INCLUDING RICHTER TRANSFORMATION: RESULTS FROM THE PHASE 1 EUPLAGIA-1 STUDY

Valentín Ortiz-Maldonado 1, Nuria Martinez-Cibrian1, Julio Delgado1, Sergi Betriu1, Leticia Alserawan1, Ana Triguero1, Nadia Verbruggen2, Maike Spoon3, Marte C. Liefaard3, Anna D.D. van Muyden3, Natalia Tovar1

1Hospital Clínic de Barcelona, Barcelona, Spain, 2Galapagos NV, Mechelen, Belgium, 3Galapagos BV, Oegstgeest, Netherlands

Background: An innovative decentralized and automated point-of-care (PoC) manufacturing model was developed to administer fresh, autologous chimeric antigen receptor T-cell (CAR-T) treatments within 7 days of apheresis to patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), including Richter transformation (RT).

Methods: Euplagia-1 (CTIS:2022-501686-47-00) is an ongoing Phase (Ph)1/2 study of PoC-manufactured anti-CD19/4-1BB CAR-T therapy (GLPG5201) administered as a fresh product following lymphodepleting chemotherapy. Patients with CD19 + R/R CLL/SLL with ≥2 prior therapy lines (including BTKi) are eligible; RT patients are eligible regardless of prior lines. Primary objectives are safety and establishment of a recommended Ph2 dose (RP2D; Ph1), and objective response rate (ORR; Ph2).

Results: As of 06 September 2023, all 15 patients planned for Ph1 were enrolled at dose level (DL)1 (35×106 CAR + T cells, n = 6) or DL2 (100×106 CAR + T cells, n = 9). All enrolled patients received a fresh product after successful PoC-manufacturing. Thirteen of 15 patients (80%) were infused with a median vein-to-vein time of 7 days (range 7–14). All patients were diagnosed with R/R CLL, 9/15 with concurrent RT. The median (range) number of prior treatment lines was 3 (2–10); 14/15 patients received prior BTKi and/or venetoclax. High-risk features were common in this population; at screening: 17p deletion, (n = 3, 23%), TP53 mutation (n = 6, 46%), complex karyotype (n = 3, 50%), unmutated immunoglobulin heavy-chain variable region gene (n = 13, 100%).

Most treatment emergent adverse events were Grade 1–2; most Grade ≥3 events were hematological (Table). Seven (47%) patients had Grade 1–2 cytokine release syndrome (CRS); no CRS Grade ≥3 and no ICANS were reported. One dose limiting toxicity occurred (Grade 4 neutropenia) which was manageable. No unexpected GLPG5201-related toxicities were observed; no deaths occurred while patients were on study.

In efficacy-evaluable patients (n = 14), 13 responded (objective response rate [ORR] 93%). Complete response (CR) confirmed by imaging was observed for eight patients (CR rate [CRR] 57%). ORR and CRR were 83% and 50% at DL1, and 100% and 63% at DL2, respectively. All but one patient with RT responded (ORR 89%); CR was achieved by 6/9 RT patients (CRR 67%). One patient with RT was refractory with CD19-negative disease. All RT patients treated at DL2 (n = 6) responded (ORR 100%, CRR 67%). DL2 was selected as the RP2D. At the time of analysis, 10/13 (77%) patients had ongoing responses. The median duration of response was not reached (median follow-up on study was 6 months, range 1–15). Three patients progressed after an initial response.

Conclusions: Data from 15 patients enrolled in Ph1 of Euplagia-1 show that PoC CAR-T manufacturing with a vein-to-vein time of only 7 days is feasible and effective. There were no unexpected safety signals, and no CRS Grade ≥3 or ICANS occurred. Efficacy data were encouraging, with a best ORR of 93% and CRR of 57%; all patients at RP2D responded (100% ORR). Follow-up is ongoing and Ph2 expansion cohorts will be opened.

Table. TEAEs occurring in ≥3 patients (worst grade per patient)*

TEAE, n (%)

Total (N = 15)

Grade 1/2

Grade 3

Grade 4

Anemia

14 (93)

10 (67)

4 (27)

0 (0)

Neutropenia

13 (87)

0 (0)

2 (13)

11 (73)

Pyrexia

9 (60)

9 (60)

0 (0)

0 (0)

Thrombocytopenia

9 (60)

5 (33)

1 (7)

3 (20)

Hypocalcemia

8 (53)

7 (47)

1 (7)

0 (0)

Nausea

4 (27)

4 (27)

0 (0)

0 (0)

Asthenia

3 (20)

3 (20)

0 (0)

0 (0)

Constipation

3 (20)

3 (20)

0 (0)

0 (0)

Hypotension

3 (20)

3 (20)

0 (0)

0 (0)

Hypoxia

3 (20)

3 (20)

0 (0)

0 (0)

Upper respiratory tract infection

3 (20)

3 (20)

0 (0)

0 (0)

  1. *Listed in order of decreasing incidence. Adverse events were coded using MedDRA version 25.0 preferred terms. No cases of cytokine release syndrome Grade ≥3 or immune effector cell-associated neurotoxicity syndrome were reported. No deaths occurred while patients were on study.
  2. TEAE, treatment-emergent adverse event

Clinical Trial Registry: CTIS:2022-501686-47-00

Disclosure: Valentin Ortiz-Maldonado: Consultancy or Advisory fees: Celgene-BMS, Janssen, Kite, a Gilead company, Miltenyi and Novartis; Honoraria from Celgene-BMS, Janssen and Kite, a Gilead company

Nuria Martinez-Cibrian: Nothing to declare

Julio Delgado: Nothing to declare

Sergi Betriu: Nothing to declare

Leticia Alserawan: Nothing to declare

Ana Triguero: Nothing to declare

Nadia Verbruggen: Employee of, and shareholder in, Galapagos NV, Belgium

Maike Spoon: Employee of Galapagos BV, Netherlands; Shareholder in Galapagos NV, Belgium

Marte C. Liefaard: Employee of Galapagos BV, Netherlands

Anna D. D. van Muyden: Employee of Galapagos BV, Netherlands

Natalia Tovar: Nothing to declare

This study was funded by Galapagos NV (Mechelen, Belgium). Medical writing support was provided by Iain Haslam, PhD, CMPP (Aspire Scientific, Bollington, UK), and funded by Galapagos NV. Publication coordination was provided by John Gonzalez and Slávka Baróniková (Galapagos NV).

4: CAR-based Cellular Therapy – Clinical

O047SEVEN-DAY VEIN-TO-VEIN POINT-OF-CARE–MANUFACTURED CD19 CAR T-CELL THERAPY (GLPG5101) IN RELAPSED/REFRACTORY NON-HODGKIN LYMPHOMA (NHL): RESULTS FROM THE PHASE 1 ATALANTA-1 TRIAL

Marie José Kersten1, Kirsten Saevels2, Sophie Servais3, Yves Beguin 3, Joost S. P. Vermaat4, Eva Santermans5, Stavros Milatos6, Maike Spoon7, Marte C. Liefaard7, Claire Vennin7, Margot J. Pont7, Anna D.D. van Muyden7, Maria T. Kuipers1, Sébastien Anguille2

1University of Amsterdam, Amsterdam, Netherlands, 2Antwerp University Hospital, Antwerp, Belgium, 3Centre Hospitalier Universitaire de Liège, Liège, Belgium, 4Leiden University Medical Center, Leiden, Netherlands, 5Galapagos NV, Mechelen, Belgium, 6Galapagos GmbH, Basel, Switzerland, 7Galapagos BV, Oegstgeest, Netherlands

Background: An innovative decentralized and automated point-of-care (PoC) manufacturing model was developed to administer fresh autologous chimeric antigen receptor T-cell (CAR-T) treatments within 7 days of apheresis. Here we provide an update on the Phase (Ph)1/2 Atalanta-1 trial of GLPG5101 in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL).

Methods: Atalanta-1 (CTIS: 2022-502661-23-00) is an ongoing Phase (Ph)1/2, multicenter trial of PoC-manufactured anti-CD19 CAR-T therapy. GLPG5101 is administered as a fresh product in patients with R/R diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), Burkitt lymphoma or primary central nervous system lymphoma. Primary Ph1 objectives are safety and establishment of a recommended Ph2 dose. The primary Ph2 objective is efficacy (objective response rate [ORR]). Secondary objectives include PoC manufacturing feasibility, safety, GLPG5101 pharmacokinetics, and additional efficacy endpoints.

Results: As of 01 September 2023, 23 patients (R/R MCL [n = 5], DLBCL [n = 7], FL [n = 9], or MZL [n = 2]) were infused with a fresh product with a median vein-to-vein time of 7 days (range 7–8); one patient received a cryopreserved product with a vein-to-vein time of 13 days. In Ph1, three patients received DL1 instead of intended DL2 due to lower CAR + T-cell yield.

Twenty-three patients were included in the safety set. Most treatment-emergent adverse events were Grade 1–2; the majority of Grade ≥3 events were hematological (Table). In Ph1 and 2, respectively, seven (50%) and three (33%) patients experienced cytokine release syndrome (CRS); immune effector cell-associated neurotoxicity syndrome was seen in six (43%; all Grade 1) and one (11%; Grade 3) patient (s). In Ph1, Grade ≥3 infections occurred in two patients and dose-limiting toxicities were reported for four patients (DL1, n = 1; DL2, n = 3). The latter consisted of three cases of Grade 4 neutropenia, manageable with granulocyte colony-stimulating factor that did not limit dose escalation, and one Grade 5 intra-abdominal hemorrhage which occurred 12 days post-infusion (DL2), caused by Grade 4 disseminated intravascular coagulation in a patient with multiple comorbidities. One Grade 5 urosepsis was recorded >6 months post-infusion in a patient in ongoing complete response (CR). No Grade ≥3 infections occurred in Ph2.

In Ph1, among 14 efficacy-evaluable patients, 12 responded to treatment (ORR 86%) with 11 achieving a CR (CR rate [CRR] 79%). Four patients progressed after an initial response: two CD19-positive relapses, one CD19−negative relapse, one unconfirmed. ORR and CRR were 86% and 71% at DL1, and 86% and 86% at DL2, respectively. In Ph2, with 7 efficacy-evaluable patients, six responded to treatment (ORR 86%), including four CRs (CRR 57%). PoC manufacturing increased early T-cell phenotype in the final product compared to apheresis starting material, as assessed by exploratory flow cytometry. Lastly, GLPG5101 showed robust expansion in vivo across doses.

Conclusions: The ongoing Atalanta-1 study shows that PoC CAR-T manufacturing with a short vein-to-vein time (median 7 days) is feasible with administration of a fresh product. The safety profile of GLPG5101 is comparable to that of other CD19-targeted CAR-T therapies. CRRs were high in Ph1 and Ph2 in a heavily pretreated patient population.

Full size table

Clinical Trial Registry: CTIS: 2022-502661-23-00

Disclosure: Marie José Kersten: Research/clinical trial funding from Galapagos and Kite, a Gilead company; honoraria from Adicet Bio, Beigene, BMS/Celgene, Galapagos, Kite, a Gilead company, Miltenyi Biotech, Novartis and Roche

Kirsten Saevels: Research/clinical trial funding from Galapagos

Sophie Servais: Nothing to declare

Yves Beguin: Research/clinical trial funding from Galapagos

Joost S. P. Vermaat: Nothing to declare

Eva Santermans: Employee of, and shareholder in, Galapagos

Stavros Milatos: Employee of Galapagos GmbH, Basel, Switzerland

Maike Spoon: Employee of Galapagos BV, Netherlands; Shareholder in Galapagos NV, Belgium

Marte C. Liefaard: Employee of Galapagos BV, Netherlands

Claire Vennin: Employee of Galapagos BV, Netherlands

Margot J. Pont: Employee of Galapagos BV, Netherlands

Anna D. D. van Muyden: Employee of Galapagos BV, Netherlands

Maria T. Kuipers: Research/clinical trial funding from Galapagos

Sébastien Anguille: Nothing to declare

This study was funded by Galapagos NV (Mechelen, Belgium). Medical writing support was provided by Iain Haslam, PhD, CMPP (Aspire Scientific, Bollington, UK), and funded by Galapagos NV. Publication coordination was provided by John Gonzalez and Slávka Baróniková (Galapagos NV).

4: CAR-based Cellular Therapy – Clinical

O048 IN VIVO LOWER CD4/CD8 CARCIK-CD19 CELL RATIO IS ASSOCIATED WITH EARLY TREATMENT RESPONSE IN PATIENTS WITH RELAPSE/REFRACTORY B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA

Benedetta Rambaldi 1, Giulia Risca2, Stefania Galimberti2,3, Cristian Meli1, Giuliana Rizzuto1,4, Chiara Buracchi5,3, Alex Moretti5,6,4, Chiara Francesca Magnani7, Marianna Ponzo3,5, Sarah Tettamanti5, Muriel Paganessi1, Silvia Zaninelli8, Elisa Gotti8, Chiara Capelli1, Benedetta Cabiati9, Michele Francesco Quaroni9, Martino Introna1, Federico Lussana1,10, Giuseppe Gritti1, Silvia Ferrari1, Anna Grassi1, Sara Napolitano6, Adriana Balduzzi6,11, Maria Grazia Valsecchi3,2, Giuseppe Dastoli5, Alessandro Rambaldi1,10, Andrea Biondi6,11, Giuseppe Gaipa6,5,9

1Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy, 2Fondazione IRCCS San Gerardo dei Tintori Biostatistics and Clinical Epidemiology, Monza, Italy, 3School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy, 4Ph.D. Program in Translational and Molecular Medicine (DIMET), University of Milano-Bicocca, Monza, Italy, 5Fondazione IRCCS San Gerardo dei Tintori Tettamanti Center, Monza, Italy, 6Fondazione IRCCS San Gerardo dei Tintori Pediatrics, Monza, Italy, 7University Hospital Zurich and University of Zurich, Zurich, Switzerland, 8SS Centro di Terapia Cellulare “G. Lanzani”, Bergamo, Italy, 9Fondazione IRCCS San Gerardo dei Tintori Laboratorio di Terapia Cellulare e Genica Stefano Verri, Monza, Italy, 10University of Milan, Milan, Italy, 11University of Milano-Bicocca School of Medicine and Surgery, Monza, Italy

Background: Biomarkers associated to treatment response after Chimeric Antigen Receptor (CAR) T cell therapy are needed to understand which patients are likely to benefit from consolidative therapies. We conducted trials in patients with B-cell acute lymphoblastic leukemia (BCP-ALL) relapsed after allogeneic hematopoietic cell transplantation (HCT), receiving donor-derived, CD19-targeted CAR cytokine-induced killer (CARCIK-CD19) cells engineered with the non-viral Sleeping Beauty transposon vector.1 (Magnani et al. JCI, 2020). The aims of this study were to evaluate the impact of proliferation, differentiation, and expansion of infused CARCIK-CD19 cells on patient’s clinical outcome.

Methods: Data were prospectively collected from consecutive patients enrolled in the FT01CARCIK, phase I/IIb study (NCT03389035) (N = 15), in the compassionate use study (PUC-CARCIK-CD19) (N = 6) and in the FT03CARCIK phase II study (NCT05252403) (N = 12). CARCIK-CD19 cells were counted by flow cytometry (FC) in the peripheral blood (PB) at predefined time points until month 12. We assessed the distribution of T cell maturation subsets in infused CARCIK-CD19 cells, identified as: naïve (CD45RA + CD62L + ), central memory (CM, CD45RA-CD62L + ), effector memory (EM, CD45RA- CD62L-) T cells, and terminal differentiated T cells (TEMRA, CD45RA + CD62L-). We also measured the expression of PD1 as exhaustion marker. CR was defined as absence of leukemia in the BM at day 28. CARCIK-CD19 peak was defined as the maximum amount of CAR+ cells/mL measured in PB.

Results: The analysis included 33 patients, 4 of whom were pediatric patients. Circulating CARCIK-CD19 cells peaked in median at day 10 (range, 7-150 days). Median CARCIK-CD19 cell peak was 44.16/μL (range, 1.35-2282.31). In some cases, CARCIK-CD19 cells were still detectable at the last follow up at month 12 with a median of 1.26/μL (range 0-5.86). The majority of CARCIK-CD19 cells in the product bag were CD8+ T cells (median 83.86%, range 24.34-93.59) and the same trend persisted in vivo after the CARCIK-CD19 infusion. Responder patients (N = 28) showed lower CD4/CD8 CARCIK-CD19 mean values in time, especially at day 28 after infusion (p = 0.0004, contrast from a longitudinal mixed model) compared to non-responder patients (N = 5), suggesting that an enrichment in CD8+ CARCIK-CD19 cells correlates with treatment response at day 28.

In the product bag, the majority of CARCIK-CD19 cells were EM (median 48.5%, range, 11.44-79.02), followed by TEMRA (median 32.34%, range 4.1-79.42). At day 10 of expansion, the majority of CARCIK-CD19 cells were EM (median 46.75%, range 6.6-83.75) and CM (median 40.51%, range 6.3-93.23), followed by TEMRA (median 1.31%, range 0-29.3), and naïve cells (median 4.93%, range 0.16-18.28). The median level of PD1 expression on CARCIK-CD19 cells in the product bag was 7.1%, range 0.55-33.5, and increased soon after infusion (median 76.91%, range 33.17-98.78 at day 10).

Conclusions: CARCIK-CD19 cells efficiently expanded in vivo, reaching the peak at day 10, and persisting in some cases up to 12 months after infusions. The majority of CARCIK-CD19 cells detected in patients were CD8+ with a memory phenotype confirming the capability of these cells to persist long-term. A lower CD4/CD8 CARCIK-CD19 ratio at day 28 was associated with early treatment response.

Clinical Trial Registry: Patients included in this study were enrolled in the FT01CARCIK, phase I/IIb study (NCT03389035) (N = 15), in the compassionate use study (PUC-CARCIK-CD19) (N = 6) and in the FT03CARCIK phase II study (NCT05252403)

Disclosure: Nothing to declare:

Benedetta Rambaldi, Giulia Risca, Stefania Galimberti,

Cristian Meli, Giuliana Rizzuto, Chiara Buracchi, Alex Moretti, Chiara Francesca Magnani,

Marianna Ponzo, Muriel Paganessi, Silvia Zaninelli, Elisa Gotti, Chiara Capelli, Benedetta Cabiati, Michele Francesco Quaroni, Martino Introna, Silvia Ferrari, Anna Grassi, Sara Napolitano, Maria Grazia Valsecchi, Giuseppe Dastoli, Giuseppe Gaipa

Sarah Tettamanti, CoImmune (Research Funding)

Federico Lussana Yes: Amgen (Speakers Bureau), Pfizer (Membership on an entity’s Board of Directors or advisory committees and Speakers Bureau), Incyte (Speakers Bureau), Bristol Myers Squibb (Membership on an entity’s Board of Directors or advisory committees and Speakers Bureau), AbbVie (Membership on an entity’s Board of Directors or advisory committees), Clinigen (Membership on an entity’s Board of Directors or advisory committees)

Giuseppe Gritti:

Consultancy: Takeda

Membership on an entity’s Board of Directors or advisory committees: F. Hoffmann-La Roche Ltd, Takeda, Kite-Gilead, Ideogen, Genmab, Italfarmaco

Advisory Board: Roche, Takeda, Kite-Gilead, Italfarmaco, Ideogen, Genmab

Training activity: Takeda, Clinigen, Ideogen, Beigene, Incyte, Novartis

Support for attending meetings: Roche, Sandoz, Beigene, Janssen

Adriana Balduzzi: Novartis, Amgen, Medac, Neovii (Speakers Bureau)

Alessandro Rambaldi

Honoraria: ABBVIE, Celgene-BMS, Janssen, Roche, Incyte, Novartis, Kite-Gilead, Jazz, Astellas, Pfizer, Agmen, Omeros

Andrea Biondi: Colmmune (Membership on an entity’s Board of Directors or advisory committees and Research Funding), Galapagos (Membership on an entity’s Board of Directors or advisory committees), Agmen (Speakers Bureau), Novartis (Speakers Bureau), BMS (Membership on an entity’s Board of Directors or advisory committees)

4: CAR-based Cellular Therapy – Clinical

O049 BASELINE SBCMA PLASMA LEVEL HAS NO IMPACT ON THE EFFICACY OF EQUECABTAGENE AUTOLEUCEL,A BCMA-CAR T CELL THERAPY IN PATIENTS WITH RRMM: SUBANALYSIS OF FUMANBA-1 TRIAL

Lu-Gui Qiu 1, Chunrui Li2, Di Wang2, Yongping Song3, He Huang4, Jianyong Li5, Bing Chen6, Jing Liu7, Xi Zhang8, Yujun Dong9, Kai Hu10, Peng Liu11, Jianqing Mi12, Kaiyang Ding13, Zhenyu Li14, Qie Dong15, Peng Guo15, Fuyuan Zhang15, Hong-yu Gui15, Guang Hu15, Wen Wang15

1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China, 2Institute of Hematology; Tongji Hospital,Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, 3The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China, 4The First Affiliated Hospital, Zhejiang University, Hangzhou, China, 5The First Affiliated Hospital of Nanjing Medical University, Nanjing, China, 6Nanjing Drum Tower Hospital,Affiliated Hospital of Nanjing University Medical School, Nanjing, China, 7Third Xiangya Hospital of Central South University, Changsha, China, 8Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Army Medical University, Chongqing, China, 9Peking University First Hospital, Beijing, China, 10Beijing Boren Hospital, Beijing, China, 11Zhongshan Hospital, Fudan University, Shanghai, China, 12State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China, 13The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China, 14Affiliated Hospital of Xuzhou Medical University, Xuzhou, China, 15Nanjing IASO Biotechnology Co., Ltd., Nanjing, China

Background: B-cell maturation antigen (BCMA) is a promising therapeutic target for multiple myeloma (MM) and soluble BCMA (sBCMA) is derived from the ectodomain shedding of the BCMA. The serum sBCMA level predicts patients’ survival and can be used to monitor the course of the disease. On other hand, it was reported that sBCMA fragment was capable of inhibiting CAR T-cell function. Sufficient sBCMA can accumulate in the bone marrow of MM patients to inhibit CAR T-cell recognition of tumor cells, and potentially limit efficacy of BCMA-directed T-cell therapy. So during the design and development of equecabtagene autoleucel (eque-cel, CT103A), the competitive inhibition of sBCMA to cell-surface BCMA binding was minimized via selection of proper scFv. The pivotal phase 2 FUMANBA-1 study (NCT05066646) demonstrated deep and durable responses with eque-cel in heavily pretreated patients with RRMM. However, the correlation between baseline sBCMA plasma level and clinical outcome after CAR-T therapy is still elusive. This study aimed to investigate the potential impact of baseline serum sBCMA levels in MM after eque-cel infusion.

Methods: The level of sBCMA was analyzed by enzyme-linked immunosorbent assay (ELISA). CAR transgene copies in the patient PBMCs were monitored by digital droplet polymerase chain reaction (ddPCR). In this subanalysis, univariate and multivariate logistic regression models were used to assess baseline serum sBCMA level and other characteristics that correlate with the likelihood of achieving CR/sCR.

Results: The median baseline sBCMA level in serum of 89 RRMM patients is 225.1 ng/mL. Baseline sBCMA level was not correlated with age, gender, except patients with high tumor burden (defined as ≥50% bone marrow plasma cells) (median 605.9 ng/mL in high tumor burden, median 206.2 ng/mL in low tumor burden; P = 0.0033) and R-ISS III (median 880.7.9 ng/ml in R-ISS III, median 213.2 ng/mL in R-ISS I-II; P = 0.012). The median peak copy number (Cmax) of eque-cel was comparable between patients with high baseline serum sBCMA level (≥225.1 ng/mL) (104237.00 copies /μg DNA) and those with low baseline serum sBCMA level (<225.1 ng/mL) (86591.75copies /μg DNA). Descriptive analysis demonstrated comparable baseline sBCMA in patients with CR/sCR (median 228.06 ng/mL) versus non-CR/sCR (median 185.13 ng/mL). The ORRs and ≥CR rates were 100% and 80% patients with high baseline serum sBCMA level vs. 97.7% and 77.3% patients with low baseline serum sBCMA level. Univariate analysis of CR/sCR by baseline characteristics including gender, age, extramedullary disease, high risk cytogenetics, tumor burden, R-ISS disease stage, received bridging therapy, baseline sBCMA, showed that none of them were significantly associated with CR/sCR. And all the subgroups showed a sharp sBCMA decrease with the response to CT103. sBCMA decreased to LLOQ (lower limit of quantification) at a median of 2 months post-infusion and remained below LLOQ at month 12 in patients remaining in response.

Conclusions: These results demonstrate that eque-cel represents a promising treatment option for RRMM patients, including those with higher baseline serum sBCMA level and higher tumor burden. And the relatively long persistence of eque-cel is another demonstration that eque-cel is not inhibited or exhausted by sBCMA.

Disclosure: Nothing to declare. Professor Lu-Gui Qiu is also the corresponding author of this study.

3: CAR-based Cellular Therapy – Preclinical

O050 DISTURBED MITOCHONDRIAL DYNAMICS REINFORCE CAR-T CELL EXHAUSTION

Mi Shao 1, Xiaohui Si1, Yue Huang1, Xinyi Teng1, Pengxu Qian1, He Huang1

1Zhejiang University, Hangzhou, China

Background: In recent years, CAR-T therapy has achieved remarkable success in the treatment of R/R B-cell malignancies. Despite its success, CAR-T therapy faces several obstacles that limit its long-term efficacy and application to broader cancer types. In addition to antigen escape, poor tumor infiltration, and treatment-related adverse effects, CAR-T cell exhaustion and short-term persistence pose major challenges. The in vivo environment employs complicated immunosuppressive mechanisms to suppress the antitumor function of endogenous or adoptively transferred T cells. Metabolic intervention thus represents a promising approach for enhancing CAR-T cell function and improving clinical performance in difficult-to-treat cancers. Mitochondria play crucial roles in the adaptive immune system, mediating the development, metabolism, and activation of T cells, as reported before. In this study, we will investigate the relationship between mitochondrial dynamics and CAR-T cell exhaustion by analyzing the characteristics and transcriptomic changes in an in vitro model of exhausted CAR-T cells.

Methods: CAR-T cells were manufactured and expanded in vitro, followed by tumor antigen exposure. Expression of inhibitory receptors, differentiation markers, and activation markers was detected by flow cytometry. Whole genomic RNA sequencing (RNA-seq) was applied to detect gene expression levels in each group. The mitochondrial morphology of CAR-T cells was observed using cryoelectronic microscopy. The cellular oxygen consumption rate was detected using a cellular energy metabolism analyzer. Mitochondrial profiles, including MitoTracker, TMRM, MPTP, MitoSox, ROS and ATP, were detected by live cell staining and colorimetric methods.

Results: Tumor antigen exposure drove CAR-T cells into an exhaustion state, as evidenced by decreased proliferative capacity, increased apoptosis, decreased cytokine production, increased expression levels of multiple inhibitory receptors, increased mRNA expression levels of exhaustion-related genes, and increased terminally differentiated subsets, along with decreased activation levels. Analysis of RNA-seq revealed the downregulation of mitochondria-related pathways in the exhausted group. The mitochondria in exhausted CAR-T cells showed abnormal morphology, specifically characterized by swollen and enlarged mitochondria with few and short cristae. Exhausted CAR-T cells showed decreased oxidative phosphorylation, decreased mitochondrial mass, decreased membrane potential, increased membrane permeability, increased MitoSox and ROS levels, decreased intracellular ATP content, and decreased mRNA expression of mitochondria-related genes.

Conclusions: Multiple rounds of tumor cell exposure in vitro successfully establish a tumor antigen-induced exhaustion CAR-T cell model. Exhausted CAR-T cells display abnormal mitochondrial morphology and function.

Disclosure: Nothing to declare

5: Cellular Therapies other than CARs

O051 IN VIVO TRANSFER OF CD4+ T CELLS RESHAPES CD8+ T CELL DIFFERENTIATION TRAJECTORY IN HUMANS

Andrew McIntyre 1,2, Maria Cuadrado2, Joshua Hughes1, Aideen O’Neill1,2, William Wilson3, Darren Edwards3, Ka Man Mak3, Jessica Hunt3, Laura Clifton-Hadley3, Adrian Bloor4, Andrew Clark5, Anne Parker5, Maria Gilleece6, Richard Lovell7, Alexander M. Martin8, Ann Hunter8, Deborah Richardson9, John Snowden10, Stephen Robinson11, Ben Uttenthal12, Charles Crawley12, Mark Lowdell13, Karl Peggs2, Persephone Borrow14, Ronjon Chakraverty1,2

1Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom, 2UCL Cancer Institute, London, United Kingdom, 3CRUK and UCL Cancer Trials Centre, London, United Kingdom, 4Christie Hospital, Manchester, United Kingdom, 5Beatson West of Scotland Transplant Centre, Glasgow, United Kingdom, 6St. James’s University Hospital, Leeds, United Kingdom, 7University Hospitals Birmingham, Birmingham, United Kingdom, 8Leicester Royal Infirmary, Leicester, United Kingdom, 9University Hospitals Southampton, Southampton, United Kingdom, 10Royal Hallamshire Hospital, Sheffield, United Kingdom, 11Bristol Royal Hospital for Children, Bristol, United Kingdom, 12Addenbrooke’s Hospital, Cambridge, United Kingdom, 13Centre for Cell, Gene and Tissue Therapeutics, Royal Free Hospital, London, United Kingdom, 14Centre for Immuno-Oncology, University of Oxford, Oxford, United Kingdom

Background: Relative to donor CD8+ T cells, the recovery of CD4+ T cell populations is severely delayed following allo-SCT. We reasoned CD8+ T cell differentiation would therefore take place under ‘helpless’ conditions and impair anti-tumour immunity. To test whether accelerating CD4+ T cell recovery would improve CD8+ T cell fitness and improve anti-tumour immunity, we conducted a randomized phase II, multicentre trial to evaluate the efficacy of prophylactic transfer of CD4+ T lymphocytes after alemtuzumab-based, reduced intensity HLA-matched related donor transplant for haematological cancers (PROT4; NCT01240525). The randomised intervention permitted unbiased measurement of the effects of CD4+ T cell infusion upon T cell population architecture and function, which we report here.

Methods: 106 patients were registered for the trial and tapered cyclosporine from day 40-day 70. 54 patients without GVHD, disease progression and normal graft function were randomised at a 2:1 ratio to receive 1 x 106 CD4+ T cells/kg between day 100-120. Blood samples were taken at day 90 (pre-infusion) and at 12-week intervals over the next 12 months. Immune population architecture and function were analysed using a combination of high-parameter flow cytometry, effector molecule expression, bulk/ single cell (sc) RNAseq and TCRseq.

Results: Compared to controls, CD4+ T cell infusion significantly delayed CD8+ T cell reconstitution both in terms of frequency and absolute numbers. Although per-cell cytokine generation was similar upon ex vivo stimulation, gene expression profiling showed that CD4+ T cell infusion induced signatures of CD8+ T cellular ‘fitness’ (increased DNA replication, TCR activation and ATP generation). These qualitative changes following CD4+ T cell infusion were matched by a dramatic shift in population architecture towards less differentiated CD8+ T cells as evaluated by unbiased clustering of flow cytometry and scRNAseq data. By pairing trajectory analysis and TCRseq, we found that CD4+ T cell addback diverted CD8+ T cell clonal expansion and differentiation away from terminal effector-like cellular states. In parallel, CD4+ T cell addback remodelled the CD4+ T cell compartment by enriching for circulating PD-1+CXCR5+ T follicular helper (Tfh)-like cells with features of central memory cells, but antagonized clonal expansion of cytotoxic CD4+ T cells. To test whether Tfh cells could provide direct help to CD8+ T cells, we cultured human volunteer CD8+ T cells in vitro under conditions of repetitive anti-CD3/CD28 stimulation with or without addition of Tfh cells. Whereas helpless CD8+ T cells underwent terminal differentiation, co-incubation with Tfh cells promoted early differentiation-like cellular states and proliferative fitness, a process that required the prototypic Tfh cytokine, IL-21.

The 50th Annual Meeting of the European Society for Blood and Marrow Transplantation: Physicians - Oral Session (O009-O154) (5)

Conclusions: CD4+ T cell infusion after allo-SCT in human patients shifts CD8+ T cell clonal expansion and differentiation trajectory to less differentiated cellular states. Our finding that human Tfh cells use IL-21 to directly promote fitness in human CD8+ T cells provides a potential mechanism involved and is consistent with recent data from pre-clinical models demonstrating Tfh-mediated help for anti-tumour and anti-pathogen CD8+ T cells. These data provide further impetus to explore how the properties of CD4+ T cells can be best exploited in immunotherapeutic targeting of cancer.

Clinical Trial Registry: NCT01240525

Disclosure: Nothing to declare

5: Cellular Therapies other than CARs

O052 A MACROPHAGES-BASED IMMUNOTHERAPY OF SOLID TUMORS MICROENVIRONMENT: PRELIMINARY RESULTS OF THE TEM-GBM_01 STUDY

Francesca Farina 1, Bernhard Gentner2,3, Gaetano Finocchiaro4, Marica Eoli5, Alessia Capotondo3, Elena Anghileri5, Matteo Barcella3, Valentina Brambilla6, Matteo Carrabba1, Valeria Cuccarini7, Quintino Giorgio D’Alessandris8, Francesco DiMeco9, Valeria Ferla1, Paolo Ferroli9, Filippo Gagliardi10, Federico Legnani9, Stefania Mazzoleni6, Alessandro Olivi8, Roberto Pallini8, Marco Saini9, Luigi Naldini3, Carlo Russo11, Fabio Ciceri1

1Hematology and Bone Marrow Transplant Unit - San Raffaele Hospital – Milano, Milano, Italy, 2Centre Hospitalier Universitaire Vaudois and Université de Lausanne, Lausanne, Switzerland, 3San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Milano, Italy, 4Neuro-Oncology Unit - San Raffaele Hospital, Milano, Italy, 5Neuro-Oncology Unit - Istituto Neurologico Carlo Besta, Milano, Italy, 6Genenta Science Spa, Milano, Italy, 7Neuroradiology Unit - Istituto Neurologico Carlo Besta, Milano, Italy, 8Neurosurgery Unit - Policlinico Gemelli, Roma, Italy, 9Neurosurgery Unit - Istituto Neurologico Carlo Besta, Milano, Italy, 10Neurosurgery Unit - San Raffaele Hospital, Milano, Italy, 11Genenta Science Spa, New York, United States

Background: Glioblastoma (GBM) multiforme is an incurable glial tumor affecting the central nervous system. The reported median survival in the unfavorable patients’ subgroup with unmethylated MGMT promoter is 12.7 months with less than the 15% of patient surviving up to 2-years. Despite immunotherapies being able to slow or eradicate numerous tumors, even those metastasized to the brain, none so far have extended survival in GBM.

Methods: We are conducting a Phase 1/2a dose-escalating non-randomized open label study in newly diagnosed GBM multiforme with unmethylated MGMT gene promoter, involving an i.v. injection of autologous CD34+ HSPCs genetically modified with a lentiviral vector encoding for human interferon-a2 (Temferon). Temferon has been designed to deliver IFN-α2 within the TME by Tie-2 expressing macrophages (TEMs). The study aims to evaluate the short-term (up to 90 days) and long-term (up to 2 years) tolerability and safety of five escalating doses of Temferon in up to 27 GBM patients. Autologous CD34 + HSPC are mobilized with lenograstim and plerixafor, collected by apheresis, purified and ex vivo modified with a lentiviral vector. Following a sub-myeloablative conditioning regimen (Thiotepa + BCNU or Thiotepa + Busulfan or Busulfan alone), up to 3 million Temferon cells/kg are administered following a fixed dose of non-manipulated CD34+ supporter cells

Results: As of 27th July 2023, 21 GBM patients in 7 cohorts received incremental doses of Temferon up to 3 million cells/kg and 5 patients were still alive with a median OS of 17 months and a median PFS of 8.3 months following initial surgery. To date, no DLTs have been identified. In all patients, rapid engraftment of modified progenitors and fast hematological recovery have been observed within two weeks from the transplantation. Grade 4 or 5 serious adverse events (n = 7 patients), including graft failure, febrile neutropenia, pneumonia, steroid restart, and disease progression, were mostly attributed to the conditioning chemotherapy, but steroid usage or disease progression were also listed. 1 SUSAR (persistent GGT elevation) occurred. The higher transduced cells proportion in the BM was observed 30 days after Temefron administration with a chimerism for the highest dose tested up to 40%, still detectable in the long-term. Very low concentrations of IFNa were detected in the plasma, indicating a tight regulation of vector expression. Seven patients underwent second surgery and genetically engineered cells (6 out of 7 patients assessed) were detected within the bulk tumor lesion (>3% in 3 patients). Moreover, IFN-responsive genes were up-regulated, suggesting a local IFNα release by TEMs. In one patient, a stable lesion had a higher proportion of T cells & TEMs, an increased IFN-response signature and myeloid re-programming revealed by scRNAseq, as compared to a synchronous, progressing tumor. TCR sequencing of blood and tumor samples showed a post-treatment increase of peripherally expanded clones frequency in the tumor samples, as evidence of a crosstalk between peripheral and tumor repertoires of T cells.

Conclusions: These data corroborate the initial evidence on safety and tolerability of Temferon. They also suggest that Temferon has potential to counteract disease progression in patients affected by unmethylated MGMT GBM.

Clinical Trial Registry: NCT03866109

Disclosure: Nothing to declare

5: Cellular Therapies other than CARs

O053 MULTIVALENT-SPECIFIC T CELLS AS LIVING DRUGS FOR THE TREATMENT OF OPPORTUNISTIC INFECTIONS POST ALTERNATIVE-DONOR HEMATOPOIETIC CELL TRANSPLANTATION

Ioannis Kyriakou 1, Zoi Boussiou1, Georgios Karavalakis1, Chrysa Pantazi1, Ioanna Vallianou1, Maria Giannaki1, Fani Stavridou1, Maria Liga1, Ioulia Mavrikou1, Kyriakos Koukoulias1, Apostolia Papalexandri1, Fotini Kika1, Eleftheria Sagiadinou2, Ioannis Batsis1, Alexandros Spyridonidis2, Ioanna Sakellari1, Anastasia Papadopoulou1, Evangelia Yannaki1

1George Papanikolaou Hospital, Thessaloniki, Greece, 2University of Patras, Patra, Greece

Background: Increasing use of alternative-donor hematopoietic cell transplantation (HCT) has given prominence to morbidity and mortality that stems from opportunistic infections in this setting. Conventional drug treatment is often suboptimal or/and associated with toxicity and resistance growth, whereas adoptive transfer of pathogen-specific T-cells (pSTs) has emerged as an alternative therapeutic option. We present combined results of two phase I/II studies, evaluating the safety and efficacy of multivalent-specific T-cells targeting CMV, EBV and BKV (trivalent-STs), or in addition, adenovirus-AdV and Aspergillus fumigatus-AF (pentavalent-STs).

Methods: GMP-grade, multivalent-STs were generated by pulsing blood mononuclear cells(PBMCs) from the graft donors with peptides spanning immunogenic antigens of EBV:LMP2/EBNA1/BZLF1, AdV:Hexon/Penton, CMV:pp65/IE1, BKV:Large-T/VP1 and AF:Gel1/SHMT/Crf1 and expanding them for 10days in culture. Specificity was assessed by Elispot in the products and patient PBMCs post-infusion. pSTs (2x107 cells/m2) were administered as single infusion when infection from one or more of the targeted pathogens occurred. Patients with GvHD at infusion, requiring >0.5mg/kg methylprednisolone, were excluded. Participants were followed for up to 6 months post-infusion.

Results: So far, 29 patients post haplo- (n = 27) or volunteer unrelated-donor (n = 2) HCT, received pSTs for CMV, EBV and BKV infections. pST products reached a median 7x(2-31) expansion over baseline and mean 222±30x106cells in total. The products were enriched in CD3+cells (93.2 ± 1%) and comprised of both CD4+ (50.9 ± 3%) and CD8+cells (41.7 ± 3%) while also expressed central- (40.4 ± 4%) and effector-memory markers (43.5 ± 4%). Twenty, six and three patients received pSTs for single (CMV = 8/EBV = 6/BKV = 6), double (BKV + EBV = 3/BKV + CMV = 2/EBV + CMV = 1) or triple infection (CMV + EBV + BKV = 3), at median 70days(32-1289) post-transplant. pST administration was safe, with no infusion-related toxicity or GVHD occurrence/exacerbation. From a total 41 infections at infusion, 21 were viral diseases (BKV cystitis/nephropathy n = 14, CMV gastritis/colitis/pneumonia n = 4, EBV colitis/encephalitis/PTLD n = 3) and 20 viremias/virurias. We observed 35 (85.4%) complete responses (CMV = 13, EBV = 11, BKV = 11), 5 (12.2%) partial responses (BKV = 2, EBV = 2, CMV = 1) and 1 (2.4%) no response (CMV = 1). The latter was not unexpected as the non-responding to CMV patient with a triple infection at infusion, had received a dual specificity (EBV&BKV) product from a CMV-seronegative donor. Clinical and viral load responses occurred at a median 3(1-14) weeks post-infusion and corresponded to circulating pST expansion. Importantly, 9/41 and 7/41 infections (including one EBV-PTLD) resolved without or with short-courses of anti-viral medication respectively, and 3BKV/41 infections, previously refractory to full-course cidofovir treatment, were resolved post-infusion. During follow-up, 17/29 patients experienced 22 new viral reactivations, 11 of which resolved without or with only short antiviral treatment, due to efficient in vivo expansion of specific-T-cells. Importantly, the rest 11 reactivations which required drug treatment, occurred in 9 patients, the majority of whom (7/9), either had relapsed or were under increased immunosuppression at reactivation and 5/9 underwent a 2nd infusion. 9 of these 11 reactivations, including one EBV-PTLD, were fully resolved, 1/11 responded partially and one CMV reactivation was refractory due to continuing immunosuppression.

Conclusions: We show that pSTs can serve as potent, long-lasting and safe therapeutic alternative for opportunistic infections after allo-HCT, minimizing or even abolishing the need for drug therapy via efficient self-control of current and future reactivations.

Clinical Trial Registry: EudraCT2020-004725-23, NCT05471661

Disclosure: none

5: Cellular Therapies other than CARs

O054 MOCRAVIMOD FAVOURABLY AFFECTS OVERALL SURVIVAL IN PATIENTS UNDERGOING ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION

Dominik Heim1, Christoph Bucher1, Michael Medinger1, Udo Holtick 2, Gérard Socié3, Christos Stylianou4, Simone Dertschnig5, Malika Souquieres5, Stephan Oehen5, Elisabeth Kueenburg5, Jakob Passweg1

1University Hospital Basel, Basel, Switzerland, 2University Hospital of Cologne, Cologne, Germany, 3APHP Hospital Saint Louis and University of Paris, Paris, France, 4ClinBAY, Limassol, Cyprus, 5Priothera, St. Louis, France

Background: In allogeneic stem cell transplantation (allo-HCT), relapse is one of the major causes of mortality. There is an unmet need to mitigate this risk and thus increase the overall survival (OS) of patients (pts) undergoing allo-HCT. Mocravimod (MOC), a sphingosine-1-phosphate receptor modulator, has demonstrated a dual effect, enhanced graft-versus-leukemia (GvL) and reduced graft-versus-host disease (GvHD), by sequestering T cells in lymphoid organs. Study CKRP203A2105 (NCT01830010) was a Phase I/II trial investigating MOC in pts with hematologic diseases undergoing allo-HCT.

Methods: In this multicenter, open label trial 23 patients comprising different hematologic diseases were included across three treatment arms to receive a daily oral dose of either 3mg MOC+cyclosporine A (CsA), 1mg MOC+CsA or 3mg MOC+tacrolimus (Tac). Pts were treated for 111 days or until relapse or unacceptable toxicity and then entered an OS-follow-up (FU) period of up to 1 or 2 years. We performed a post-hoc analysis of OS. Survival estimates were compared to matched pts from a real-world cohort, the CIBMTR data base (n = 5191). In addition, OS data of a subgroup of pts receiving allo-HCT for treatment of AML (n = 7) were compared to a matched cohort of CIBMTR (n = 303). Bayesian comparison of OS of MOC-treated pts to controls from the CIBMTR database was performed.

Results: Pts characteristics were similar in both groups with a mean age of 48.9 vs 51 years in the MOC patients and CIBMTR controls, respectively. Hematologic diseases were equally distributed with the majority being treated for either AML or ALL: 30% and 39 % AML, 17% and 21% ALL of MOC pts and CIBMTR controls, respectively. Most pts received stem cells from matched donors (78% vs 85%). Survival estimates of all pts demonstrated OS rates of 83% in MOC treated pts vs 58% in the control group at 1a post allo-HCT. A prolonged OS could be shown at 2a FU time after allo-HCT with 69% in the MOC treated pts and 45% in the control group (Fig.1). The median age was 51 years for both, MOC-treated AML and CIBMTR AML pts. While all CIBMTR AML pts were in CR, only 57.1% of MOC AML pts were in CR at time of transplant. Survival estimates for AML pts demonstrated OS rates of 91% vs 73% and 84% vs 66% for MOC pts vs CIBMTR pts at 1- and 2-years post-transplant, respectively. The probability that MOC treated AML patients have higher survival rates compared to controls was 99% and 94% at 1- and 2-years post-transplant, respectively. Primary disease was main cause of death in both groups.

The 50th Annual Meeting of the European Society for Blood and Marrow Transplantation: Physicians - Oral Session (O009-O154) (6)

Conclusions: This post hoc analysis demonstrated an OS benefit for pts with hematologic diseases receiving MOC as add-on treatment to allo-HCT in comparison to a matched real-world cohort undergoing allo-HCT without MOC. These data support the development of MOC as an adjunctive and maintenance treatment to allo-HCT, which is currently evaluated in the Phase III MO-TRANS trial, a worldwide double-blind trial investigating the GvL effect of MOC translating into prolonged relapse-free-survival and OS in AML pts undergoing allo-HCT (NCT05429632).

Clinical Trial Registry: ClinicalTrials.gov: NCT01830010

Disclosure: Simone Dertschnig, Malika Souquieres, Stephan Oehen and Elisabeth Kueenburg are employees of Priothera SAS

29: Chronic Leukaemia and Other Myeloproliferative Disorders

O055 CLINICAL OUTCOMES OF PATIENTS WITH BLAST PHASE CHRONIC MYELOID LEUKEMIA AND UTILITY OF ALLOGENEIC STEM CELL TRANSPLANTATION IN IMPROVING LONG-TERM SURVIVAL

Benjamin McCormick 1, Anthony Findley1, James Foran1, Mohamed Kharfan-Dabaja1, Madiha Iqbal1, Lisa Sproat2, Jeanne Palmer2, William Hogan3, Kebede Begna3, Mark Litzow3, Talha Badar1

1Mayo Clinic, Jacksonville, United States, 2Mayo Clinic, Phoenix, United States, 3Mayo Clinic, Rochester, United States

Background: Despite significant improvements in outcomes of chronic myeloid leukemia (CML-CP) following tyrosine kinase inhibitor (TKI) implementation, CML in chronic/advanced phases (CP/AP) with TKI resistance and CML in blast phase (CML-BP) continue to have suboptimal outcomes. Allogeneic hematopoietic stem cell transplantation (alloHCT) remains the most viable treatment option for CML-BP or CML-CP/AP with TKI resistance. We aimed to evaluate clinical outcomes among patients with CML who underwent alloHCT at Mayo Clinic.

Methods: We retrospective analyzed the clinical outcomes of 59 adult patients with CML who underwent alloHCT at Mayo Clinic between 2004-2023 (n = 20 CML-myeloid BP [MBP], n = 24 lymphoid BP [LBP], n = 15 CML-CP/AP). We used statistical methods including Kaplan-Meier (KM) survival analysis, cumulative incidence estimation, and Cox proportional hazards regression to analyze patient and transplant factors associated with post-transplant outcomes.

Results: The baseline characteristics and clinical outcomes are summarized in Table 1. The median age of the patient was 46 years (range, 20.5-70). ABL1 kinase mutations (mainly T315I) were present in 44% patients with 17% receiving a 3rd generation TKI prior to alloHCT (22 [37%] received ≥ 3 TKI prior to allo-HCT). At the time of blast phase progression, 70% MBP and 28.5% LBP exhibited somatic mutations with clonal cytogenetic progression observed in 66% and 18%, respectively.

Ninety five percent of patients received myeloablative conditioning, 54% of patients had acute graft versus host disease (GVHD; ≥ 3 [10%]), and 42% had chronic GVHD (all grades). At the time of review, 39 patients were alive with 3-year and 5-year overall survival of 70% and 50%, respectively. The median OS (mOS) following alloHCT was 46.6 months. In MBP, LBP, and CML-CP/AP, the mOS in months was 46.5, 37.7 and not reached (NR) (p = 0.039) with 5-year survival of 33.3%, 45.5% and 75%, respectively. The median time from diagnosis to transplant was 51.7 and 12.5 months in CML-CP/AP and CML-BP (p < 0.001), respectively. Patients who progressed from CML-CP/AP to MBP had significantly worse mOS (15.3 months) compared to those with de novo MBP (p = 0.025). In multivariate analysis adjusting for MBP at diagnosis, 7/7q- mutation at blast phase portended significantly worse survival with hazard ratio 6.88 (95% CI, 1.1-42.8; p = 0.039). TKI maintenance therapy post-transplant was utilized in 62% patients (74% CML-BP vs 33% CML-CP/AP) without significant survival benefit amongst this cohort, including multivariate analysis accounting for ABL1 mutations.

Conclusions: We evaluated clinical outcomes of 59 patients with CML at various disease stages who underwent alloHCT at Mayo Clinic. MBP was associated with the worst outcomes followed by LBP and CML-CP/AP. MBP outcomes were worse when progressing from chronic to blast phase while on TKI before alloHCT; however, there was no significant difference in LFS or post-transplant relapse between disease groups, suggesting the difference in survival between groups relates to the disease severity prior to alloHCT rather than transplant complications. TKI maintenance therapy following alloHCT did not appear to affect survival in any group irrespective of BCR-ABL1 mutations. Further studies are warranted to explore the utility of TKI maintenance post allo-HCT and timing of allo-HCT in CML-CP/AP with T315I mutations.

Disclosure: Nothing to declare

16: Conditioning Regimens

O056 PHASE II STUDY OF PHARMACOKINETIC MODEL-BASED ATG DOSING TO IMPROVE SURVIVAL THROUGH ENHANCED IMMUNE RECONSTITUTION IN PATIENTS UNDERGOING EX VIVO CD34-SELECTED ALLOGENEIC HCT (PRAISE-IR)

Michael Scordo 1, Miguel-Angel Perales1, Audrey Mauguen2, Andrew Lin2, Binni Kunvarjee2, Jennifer Bieler2, Linh K. Nguyen2, Maria Paes Pena3, Christina Cho4, Boglarka Gyurkocza1, Andrew C. Harris2, Ann A. Jakubowski1, Richard J. Lin1, Esperanza B. Papadopoulos1, Ioannis Politikos1, Doris M. Ponce1, Brian C. Shaffer1, Gunjan L. Shah1, Barbara Spitzer4, Roni Tamari1, Sergio A. Giralt1, Jaap Jan Boelens2, Kevin J. Curran2

1Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, United States, 2Memorial Sloan Kettering Cancer Center, New York, United States, 3Sloan Kettering Institute - Pediatrics, Memorial Sloan Kettering Cancer Center, New York, United States, 4John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, United States

Background: Ex vivo CD34-selected allogeneic hematopoietic cell transplantation (allo-HCT) is associated with favorable chronic graft-versus-host disease relapse-free survival but limited by delayed immune reconstitution (IR) and in some studies higher non-relapse mortality (NRM) (BMT CTN 1301; Luznik et al., JCO 2023). We recently reported that the use of traditional weight-based ATG dosing in ex vivo CD34-selected allo-HCT led to high post-HCT ATG pharmacokinetic (PK) exposure that was associated with delayed CD4 + T cell IR (CD4 + IR) and increased NRM risk (Lakkaraja et al., Blood Advances 2022).

Methods: Between 5/2021-12/2023, we conducted an investigator-initiated, single-center, phase II study of population PK model-based ATG dosing targeting a low post-HCT exposure with the aim of improving CD4 + IR (NCT04872595). Pediatric and adult patients with hematologic malignancies undergoing their first allo-HCT received model-based ATG to target a post-HCT exposure of <20 AU*d/mL beginning on day -12 followed by one of two myeloablative conditioning regimens (Table 1) and a peripheral blood mobilized, ex vivo CD34-selected allograft (CliniMACS CD34 Reagent System [Miltenyi Biotec, Gladbach, GER]) from a HLA 7-8/8 matched donor.

The primary endpoint was the proportion of patients who reached CD4 + IR, defined as CD4 + T cell values > 50/µL at 2 consecutive timepoints by day +100. The trial size of 56 patients was based on an optimal Simon 2-stage design that had 90% power to detect a 20% increase from a historical control rate of 32% to ≥52%, with 5% 1-sided α. Successful CD4 + IR was required in ≥24 of 56 evaluable patients to reject the null hypothesis. We defined time-to-CD4 + IR as the time from HCT to CD4 + IR. For this endpoint, we censored patients without CD4 + IR at day +100 and considered death before CD4 + IR by day +100 a competing risk. Additional endpoints included the cumulative incidences of NRM and relapse, and rates of relapse-free (RFS) and overall survival (OS).

Results: To date, data were available for 59 patients: 3 were not evaluable and 2 are still within the 100-day period, leaving 54 for the current analysis. Among evaluable patients, the median age was 55 (range, 4-70), 32 (59%) were male, most (N = 30; 56%) were treated for AML, and most (N = 42; 78%) received regimen B. Median estimated pre- and post-ATG exposures were 52 (35.3-73.8) and 9.9 (4.3-16.1) AU*d/mL, respectively (Table 1).

The median follow-up was 17 months (range, 1-28). A total of 37 patients reached CD4 + IR by day +100. The cumulative incidence of CD4 + IR was 69% (95% CI, 56-81%). The 2-year incidences of NRM and relapse were 9% (0-17%) and 13% (3-24%), respectively. The 2-year RFS and OS rates were 78% (66-91%) and 86% (76-97%), respectively.

Table 1. Patient and HCT Characteristics

Characteristic

Overall N = 541

Regimen A N = 121

Regimen B N = 421

Age at HCT (years)

55 (4 – 70)

26 (4 – 57)

59 (4 – 70)

Sex

Female

22 (41%)

3 (25%)

19 (45%)

Male

32 (59%)

9 (75%)

23 (55%)

Disease

Acute Leukemias of Ambiguous Lineage (ALAL)

1 (2%)

0 (0%)

1 (2%)

Acute Lymphocytic Leukemia (ALL)

11 (20%)

11 (92%)

0 (0%)

Acute Myeloid Leukemia (AML)

30 (56%)

1 (8%)

29 (69%)

Myelodysplastic Syndrome (MDS)

12 (22%)

0 (0%)

12 (29%)

Conditioning Regimen

A (High-dose TBI/Thiotepa/Cyclophosphamide)

12 (22%)

12 (100%)

0 (0%)

B (Busulfan/Melphalan/Fludarabine)

42 (78%)

0 (0%)

42 (100%)

ATG Exposure, AU*d/mL

Pre-HCT

52 (35.0-74.0)

--

--

Post-HCT

9.9 (4.3-16.0)

--

--

  1. 1Median (Range); n (%)

Conclusions: In patients undergoing ex vivo CD34-selected allo-HCT, the use of model-based ATG dosing to achieve optimal post-HCT exposure led to high rates of CD4 + IR, thereby exceeding our study’s primary objective. These CD4 + IR rates came with low NRM resulting in highly favorable survival, suggesting that the NRM rate observed in trials involving ex vivo CD34-selected allo-HCT such as BMT CTN 1301 were driven by high ATG exposure and may be offset by model-based dosing.

Clinical Trial Registry: NCT04872595

https://clinicaltrials.gov/study/NCT04872595

Disclosure: Michael Scordo: Consultancy - McKinsey & Company, Angiocrine Bioscience, Inc., and Omeros Corporation; Research funding - Angiocrine Bioscience, Inc., Omeros Corporation, Amgen, Inc.; Ad hoc advisory boards for Kite – A Gilead Company; Honoraria - i3Health, Medscape, and CancerNetwork for CME activity.

Miguel-Angel Perales: Honoraria - Adicet, Allogene, Allovir, Caribou Biosciences, Celgene, Bristol-Myers Squibb, Equilium, Exevir, ImmPACT Bio, Incyte, Karyopharm, Kite/Gilead, Merck, Miltenyi Biotec, MorphoSys, Nektar Therapeutics, Novartis, Omeros, OrcaBio, Sanofi, Syncopation, VectivBio AG, and Vor Biopharma. He serves on DSMBs for Cidara Therapeutics and Sellas Life Sciences, and scientific advisory board - NexImmune. Ownership interests: NexImmune, Omeros and OrcaBio. Institutional research support: Allogene, Incyte, Kite/Gilead, Miltenyi Biotec, Nektar Therapeutics, and Novartis.

Boglarka Gyurkocza: Research funding - Actinium Pharmaceuticals, Inc.

Andrew C. Harris: Horizon Pharma PLC: Consultancy; Incyte Corporation: Consultancy, Research Funding; Janssen Scientific Affairs, LLC: Consultancy.

Ioannis Politikos: ExcellThera: Other: Membership on DSMB; Merck: Research Funding.

Doris M. Ponce: Kadmon/Sanofi Pharmaceuticals: Membership on a Board of Directors or advisory committees - Kadmon/Sanofi Pharmaceuticals, Ceramedix, Incyte Corporation, Evive Biotechnology; Research Funding - Incyte Corporation.

Brian C. Shaffer: Gamida Cell: Consultancy, Research Funding; Hansa Biopharma: Consultancy. Attia: Anumana: Patents & Royalties.

Gunjan L. Shah: Amgen: Research Funding; Beyond Spring: Research Funding; Janssen: Research Funding; BMS: Research Funding; ArcellX: Other: DSMB.

Sergio A. Giralt: Amgen, Actinuum, Celgene/BMS, Omeros, Johnson & Johnson, Miltenyi, Takeda: Research Funding; Amgen, Actinuum, Celgene/BMS, Kite Pharma, Janssen, Jazz Pharmaceuticals, Johnson & Johnson, Novartis, Spectrum Pharma, Takeda: Membership on a Board of Directors or advisory committees.

Jaap Jan Boelens: Bluerock: Consultancy, Honoraria; Omeros: Consultancy, Honoraria; Sobi: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Immusoft: Consultancy, Honoraria; Advanced Clinical: Honoraria; Bluebird Bio: Honoraria; SmartImmune: Consultancy, Honoraria.

Kevin J. Curran: Kevin J. Curran Consultancy and Research funding – Cellectis, Celgene, Novartis, Atara; Consultancy – Turn Bio.

The remaining authors report no conflicts of interest.

16: Conditioning Regimens

O057 ASSOCIATION OF BUSULFAN EXPOSURE WITH SURVIVAL AND TOXICITY AFTER HCT FOR PRIMARY IMMUNE DEFICIENCY IN CHILDREN AND YOUNG ADULTS; A MULTI-CENTER, RETROSPECTIVE COHORT ANALYSIS

Tim Bognàr 1, Moises Garcia2, Arief Lalmohamed1,3, A. C. G. Egberts1,3, Caroline A. Lindemans4,5, Geoffrey D. E. Cuvelier6, Tayfun Güngör7, Mathias Hauri-Hohl7, Christen L. Ebens8, Robbert G.M. Bredius9, Hannah Lust10, Sonali Chaudhury10, Susan Prockop11, Layne Oram11, Sun-Yung Pai11,12, Robert Chiesa13, Marc Ansari14,15, Maja Krajinovic16, Anne-Charlotte Teyssier16, Yves Théoret16, Jordan Brooks17, Rada M. Savic17, Christopher C. Dvorak17, Janel R. Long-Boyle17, Cary Martinez18, Erin Morales18, Mary Slatter19, Maria P. Cicalese20,21,22, Robert F. Wynn23, Mary Coussons23, Christa E. Nath24, Peter J. Shaw24, Steven J. Keogh24, Imke H. Bartelink25, Jaap-Jan Boelens2

1University Medical Center Utrecht/Wilhelmina Children’s Hospital, Utrecht, Netherlands, 2Cell Transplantation and Cellular Therapies, Memorial Sloan-Kettering Cancer Center, New York, United States, 3Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands, 4Princess Máxima Center Utrecht, Utrecht, Netherlands, 5UMC Utrecht, Utrecht, Netherlands, 6Pediatric Blood and Marrow Transplantation, CancerCare Manitoba, University of Manitoba, Manitoba, Canada, 7Division of Stem Cell Transplantation and Children’s Research Center, University Children’s Hospital Zurich, University of Zürich, Zürich, Switzerland, 8Division of Pediatric Blood and Marrow Transplant & Cellular Therapy, MHealth Fairview Masonic Children’s Hospital, University of Minnesota, Minneapolis, United States, 9Willem Alexander Children’s Hospital, Leiden University Medical Center, Leiden, Netherlands, 10Stem Cell Transplant Program, Ann & Robert Lurie Children’s Hospital/Northwestern University, Chicago, United States, 11Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, United States, 12Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), United States, 13Great Ormond Street, Hospital for Children & Stem Cell Program, London, United Kingdom, 14Cansearch Research Platform for Pediatric Oncology and Hematology, Faculty of Medicine, University of Geneva, Geneva, Switzerland, 15University Geneva Hospitals, Geneva, Switzerland, 16Centre de Cancérologie Charles-Bruneau Centre de recherche - Hôspital Sainte-Justine Montréal, Québec, Canada, 17University of California San Francisco (UCSF), San Francisco, United States, 18Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital, Texas, United States, 19Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, United Kingdom, 20San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy, 21Faculty of Medicine and Surgery, Vita-Salute S. Raffaele University, 20132, Milan, Italy, 22Pediatric Immunohematology Unit and BMT Program, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy, 23Royal Manchester Children’s Hospital, Manchester, United Kingdom, 24Children’s Hospital at Westmead, Sydney, Australia, 25Amsterdam University Medical Center, Location VUmc, Amsterdam, Netherlands

Background: Previously, a clear relation between cumulative busulfan exposure (AUC) and clinical outcomes after pediatric and young adult allogeneic hematopoietic cell transplantation (HCT) was shown. As these studies involved only a small number of primary immune deficiency (PID) patients, the optimal target for this group remains unclear. The objective of this study was to assess the optimal busulfan exposure in pediatric and young adult PID patients.

Methods: Patients who received a busulfan-based conditioning regimen between 2000 and 2023 from 17 centers in the Netherlands, USA, Canada, Switzerland, UK, Italy, Germany, and Australia, were included. Main outcome of interest was event-free survival (EFS); events considered were graft-failure (GF) and mortality. Other outcomes of interest were the most recent (myeloid or whole blood) donor chimerism, acute and chronic graft-versus-host disease, veno-occlusive disease and transplant-related mortality (TRM). Patients were categorized into 4 PID subgroups: combined immunodeficiency (CID), severe combined immunodeficiency (SCID), neutrophil disorders and hemophagocytic lymphohistiocytosis (HLH)-related disorders (including primary immune regulatory disorders; PIRD). Busulfan exposure was calculated by individual centers (AUCCENTER) and was re-estimated using all raw concentration-time profiles with nonlinear mixed-effects modeling (AUCNONMEM) by applying an externally validated busulfan pharmacokinetic (PK) model (Bartelink, 2012). To assess the validity of the AUC prediction among centers, we compared the AUCCENTER with AUCNONMEM. To evaluate the busulfan AUCNONMEM in relation with the outcomes of interest, we used propensity score adjusted Weibull survival functions and Fine-Gray competing risk regression.

Results: Overall, 562 patients were included: 154 (27.4%) SCID, 173 (30.8%) CID, 101 (18.0%) HLH (14 PIRD) and 134 (23.8%) neutrophil disorders. Median age was 1.7 years (range 0.08-27.0). Median busulfan AUCNONMEM was 69.0 mg×h/L and correlated poorly with AUCCENTER (r2 = 0.51). CID disease subtype was an effect modifier (p = 0.03), therefore, patients with SCID, HLH-related, and neutrophil disorders were analyzed together (n = 389). Estimated 2-year EFS was 79.6%. In patients with the found optimal busulfan AUCNONMEM of 70-90 mg×h/L, 2-year EFS was 87.9% (95% CI 80.3-92.6%), superior to <70 mg×h/L (adj-HR 1.97, 95% CI 1.11-3.49, p = 0.02), and >90 mg×h/L (adj-HR 5.05, 95% CI 2.43-10.49, p < 0.0001). In patients with AUCNONMEM < 70 mg×h/L, events were primarily due to GF, whereas those with AUCNONMEM > 90 mg×h/L predominantly experienced TRM. In patients with AUCNONMEM < 50 mg×h/L, the incidence of GF is considerably increased. Donor chimerism increased with higher busulfan AUCNONMEM, plateauing at 90 mg×h/L. For CID patients, optimal AUCNONMEM for donor chimerism was found to be >70 mg×h/L, while no optimal AUCNONMEM for EFS > 50 mg×h/L was found.

Conclusions: Improved EFS and higher donor chimerism may be achieved by targeting a cumulative busulfan AUCNONMEM of 80 mg×h/L (range 70-90). The data stresses the importance to uniformly use a validated population PK-model to estimate the AUCNONMEM. For patients with a higher co-morbidity index, targeting a busulfan AUCNONMEM of 60 mg×h/L (range 50-70) may reduce toxicity, at the risk of increased mixed chimerism and GF.

Clinical Trial Registry: N/A

Disclosure: Declaration of Interest: Christopher Dvorak has disclosed affiliations with Jazz Pharmaceuticals and Alexion Pharmaceuticals, Inc. The other authors report no relevant conflicts of interest

16: Conditioning Regimens

O058 A PROSPECTIVE RANDOMIZED CONTROLLED TRIAL TO ADDRESS THE IMPACT OF TARGETED FLUDARABINE ON THE INCIDENCE OF VIRAL COMPLICATIONS AFTER TCRALPHABETA/CD19 DEPLETED ALLO-HCT

Moniek de Witte 1,2, Klaartje Nijssen1, Tim Bognar1, Anna van Rhenen1, Lotte van der Wagen1, Laura Daenen1, Anke Janssen1, Anniek Stuut2, Peter van de Ven3, Dirk-Jan Moes4, Peter van Balen4, Stijn Halkes4, Kim van der Elst1, Jurgen Kuball1,2

1University Medical Center, Utrecht, Netherlands, 2Center of Translational Immunology, University Medical Center, Utrecht, Netherlands, 3UMC Utrecht, Julius Centrum, Utrecht, Netherlands, 4Leiden University Medical Center, Leiden, Netherlands

Background: We have shown in a retrospective study that in adult patients receiving fludarabine (FLU) during conditioning for allo-HCT, 57% of patients were overdosed and 1% were underdosed, and that a high exposure of FLU increased non-relapse mortality (NRM), whereas low exposure was associated with graft failure. We therefore proposed that optimizing FLU exposure by therapeutic drug monitoring (TDM) would decrease complications. Here we present the primary analyses of a prospective randomized clinical trial, comparing TDM-guided FLU dosing with conventional dosing in adults with hematological malignancies who received a TCRalphabeta/CD19 depleted allograft.

Methods: The TARGET study (NL64877.041.18) enrolled adult patients with hematological malignancies. Patients with a creatinine clearance < 40 ml/min were excluded. Allografts were derived from peripheral blood derived stem cells of matched related donors or matched unrelated donors (10/10 or 9/10). Conditioning consisted of Thymoglobulin®, fludarabine and busulfan (AUC 90 mg*h/L). TCRalphabeta/CD19-depletion was performed as previously described. Patients received FLU from day -5 to -2. Conventional FLU (FLU-C) dosing was 40 mg/m2/day and FLU-TDM targeted a cumulative area under the curve (AUC) of 20 mg*h/L (range 15-25 mg*h/L). Primary endpoint was the cumulative incidence of CTC-AE grade 3 viral infections at day 100. Secondary endpoints were NRM, acute graft-versus-host disease (GVHD), chronic GVHD, engraftment, overall survival (OS), event free survival (EFS), GVHD-relapse free survival (GRFS), immune reconstitution of CD8, CD4, γδT, NK and B cells, and FLU exposure.

Results: 48 patients were randomized to the FLU-C arm and 50 patients to the FLU-TDM arm. Patients were well balanced for age, creatinine clearance, disease and donor type. Median follow up was 18 (IQR 3-32) months. Primary endpoint analyses showed that the incidence at day 100 of severe viral infections was not different when FLU-C was compared to FLU-TDM, with a cumulative incidence of CMV in CMV seropositive patients of 67% (95% CI 50-89) vs 60% (95% CI 41-87) and of 2% (95% CI 0.3-18) vs 6% (95% CI 2-18) for EBV. There was no difference in immune reconstitution of CD8, CD4, γδT, NK and B cells between both arms. To assess the lack of difference between both study arms, we measured the FLU AUC for all patients. In the FLU-TDM arm all patients achieved the target dose (median 19.6 mg*h/L, 18.1–24.3) and in the FLU-C arm, 75.5% reached the target range and only 22.5% was overexposed. OS and EFS at 2Y were 62% (95% CI 52-73) and 54% (95% CI 44-65) for the complete cohort and no significant differences where observed between FLU-C and FLU-TDM in multivariable analyses adjusted for potential disbalanced confounders. We also compared the primary and secondary endpoints as well as immune reconstitution between patients with target exposure (n = 86) and those with overexposure (n = 12) and found no difference in outcomes.

Conclusions: This is the first prospective study comparing TDM of FLU to conventional dosing of FLU within the context of allo-HCT. Within this cohort of patients with a creatinine clearance of >40 ml/min, only a fraction of patients are overexposed and TDM does not have substantial addition.

Clinical Trial Registry: NL64877.041.18

www.clinicaltrialsregister.eu/ctr-search/trial/2018-000356-18/NL

Disclosure: J.K. reports grants Novartis, and Miltenyi Biotech and is inventor on patents dealing with γδ T-cell–related aspects as well as cofounder and shareholder of Gadeta. The remaining authors declare no competing financial interests.

16: Conditioning Regimens

O059 TOTAL MARROW AND LYMPHOID IRRADIATION (TMLI) WITH FLUDARABINE-MELPHALAN AS CONDITIONING FOR MATCHED-DONOR ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION (ALLOHCT) IN PATIENTS WITH HIGH-RISK ACUTE LEUKEMIAS OR MDS

Monzr Al Malki 1, Susanta Hui1, Dongyun Yang1, Sally Mokhtari1, Kay Chanea1, Firoozeh Sahebi1, Hoda Pourhassan1, Matthew Mei1, Amanda Blackmon1, Brian Ball1, Shukaib Arslan1, Salman Otoukesh1, Haris Ali1, Guido Marcucci1, Ryotaro Nakamura1, Stephen Forman1, Anthony Stein1, Jeffrey Wong1

1City of Hope, Duarte, United States

Background: TMLI-based conditioning, developed at City of Hope, has shown to be safe and effective at 20 Gy dose in younger patients with active disease undergoing HCT. Here, we are reporting outcomes of our phase 1 clinical trial of TMLI and Fludarabine-Melphalan for matched donor HCT in older patients with refractory and relapsed (r/r) leukemia and MDS. (NCT03494569)

Methods: Patients ≥55-years-old with r/r acute leukemia or MDS (morphologically or by MRD flow) who had a matched donor available were enrolled. Conditioning regimen included TMLI (days -8 to -5), fludarabine (30 mg/m2/day; days -4 to -2), and melphalan (100 mg/m2; day -2). Radiation dose was escalated in increments of 2 Gy (12 to 18 Gy). All patients received peripheral blood stem cells followed by Tacrolimus and Sirolimus for GvHD prophylaxis. Toxicity was recorded by Bearman and CTCEA-v5.0.

Results: We accrued a total of 30 patients: 24 patients for dose finding portion with 4 dose-levels (DLs) and 6 patients per dose level and 6 more patients at the recommended phase-2 dose (P2RD). Table 1 summarizes patient and HCT characteristics. Median off-target organ dose for lungs, upper GI, heart, testes, parotids, and thyroid was 6-7 Gy. Lower GI, liver, bladder, and brain received 7-8 Gy dose. Oral cavity dose was kept at 3.5 Gy. Almost all patients had one or more Grade-3 GI toxicities by CTCEA, including abdominal pain, diarrhea, nausea, ileus, and colitis (DL1 n = 5; DL2 n = 6; DL3 n = 10; DL4 n = 3), and only one had Grade-4 diarrhea at DL3. Mucositis including mouth, throat or esophagitis was common at lower grades (DL1 n = 1; DL2 = 3; DL4 n = 8; DL4 n = 5). Other common Grade-3 non-hematological AEs were fatigue (DL3 n = 2; DL4 n = 1) and bone pain (DL2 n = 1; DL3 n = 5; and DL4 n = 2). Grade-3 febrile neutropenia was common (DL1 n = 3; DL2 = 3; DL3 n = 9; DL4 n = 6). Three patients had dose limiting toxicities (DLTs) mostly renal, GI, and pulmonary (DL3 n = 2; and DL4 n = 1), all deemed not to be related to TMLI.

All patients achieved engraftment with full donor chimerism, with a median time to neutrophil engraftment of 14 days (range: 13-17) and platelet engraftment of 18 days (range: 16-29). All evaluable patients achieved complete remission with negative MRD by multicolor flowcytometry on day 30. With a median follow-up duration of 23.3 months, 2-year overall survival and progression-free survival were 64% (95% CI: 0.41-0.80) and 62% (95% CI: 0.40-0.78), respectively. One-year GVHD-free Relapse-free survival was at 60% (95% CI: 0.40-0.76). Two-year cumulative incidence (CI) of relapse and non-relapse mortality (NRM) were 23% (95% CI: 0.09-0.41) and 15% (95% CI: 0.05-0.32), respectively. Day-100 CI of grade 2-4 and 3-4 acute-GvHD were 27% (95% CI: 0.12-0.48),13% (95% CI: 0.04-0.28), respectively. CI of chronic-GvHD at 2-years was 36% (95% CI: 0.16-0.56).

Conclusions: TMLI combined with FM was feasible and safe in older patients with high-risk r/r acute leukemia and MDS with acceptable NRM. Disease control was promising in this advanced and high-risk population. Due to increased infections, mucositis, and GI toxicities seen at 18 Gy (DL4), 16 Gy (DL3) was deemed as P2RD.

Table 1. Patient and HCT characteristics

Total (N = 30)

Total (N = 30)

Age At consent

ELN 2017

Median (Range)

62 (53-73)

Adverse

21 (70%)

Gender

EB-1/IPSS very high

3 (10%)

Female

7 (23.3%)

Intermediate

5 (16.7%)

Male

23 (76.7%)

Unfavorable -ALL

1 (3.3%)

Ethnicity

PRIOR # THERAPY

Hispanic or Latino

4 (13.3%)

1

15 (50%)

Non-Hispanic or Latino

26 (86.7%)

2

10 (33.3%)

Primary Disease

3 or 4

5 (16.6%)

ALL

1 (3.3%)

Donor Type

AML

23 (76.7%)

Unrelated

24 (80%)

MDS

3 (10%)

Sibling

6 (20%)

MDS/AML

3 (10%)

Dose Level

Disease Status at HCT

1200 cGy Dose level 1

6 (20%)

Active disease

12 (40%)

1400 cGy Dose level 2

6 (20%)

CR1 or CR2 with MRD Positive

15 (50%)

1600 cGy Dose level 3

12 (40%)

MDS

3 (10%)

1800 cGy Dose level 4

6 (20%)

Clinical Trial Registry: NCT03494569

Disclosure: Authors have no COI to disclose.

16: Conditioning Regimens

O060 TREOSULFAN- VERSUS BUSULFAN-BASED CONDITIONING IN ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION FOR MYELODYSPLASTIC SYNDROME: A SINGLE-CENTRE RETROSPECTIVE PROPENSITY SCORE-MATCHED COHORT STUDY

Tommy Alfaro Moya 1,2, Mats Remberger3, Carol Chen1, Armin Gerbitz1,2, Dennis Dong Hwan Kim1,2, Rajat Kumar1,2, Wilson Lam1,2, Arjun Datt Law1,2, Jeffrey H. Lipton1,2, Fotios V. Michelis1,2, Igor Novitzky Basso1,2, Auro Viswabandya1,2, Jonas Mattsson1,2, Ivan Pasic1,2

1Princess Margaret Cancer Centre, Toronto, Canada, 2University of Toronto, Toronto, Canada, 3Uppsala University Hospital, Uppsala, Sweden

Background: Treosulfan has shown promise in allogeneic hematopoietic cell transplantation (HCT) for its myeloablative properties and low toxicity. However, existing retrospective studies lack data from well-matched cohorts whereas phase III data failed to define optimal treosulfan dosing. In this single-centre retrospective propensity score-matched cohort study we compared treosulfan- and busulfan-based conditioning in allogeneic HCT for myeloablative conditioning-ineligible patients with myelodysplastic syndrome (MDS).

Methods: This study included 138 adults who underwent allogeneic HCT for MDS or chronic myelomonocytic leukemia (CMML) at Princess Margaret Hospital, Toronto 2015-2022. Using propensity score matching, we compared transplant outcomes between two well-matched cohorts who received conditioning with either fludarabine-treosulfan (FT) (n = 46) or fludarabine-busulfan with total body irradiation (FBT200) (n = 92).

Results: Patient characteristics are shown in Table 1. A scoring system based on patient age, Karnofsky performance score and hematopoietic cell transplant comorbidity index was used to assign patients based on fitness to low-dose (30 g/m2) or high-dose (42 g/m2) treosulfan: 32 (69.6%) received high-dose treosulfan. Primary outcomes were analyzed at a median follow-up of 747 days.

Patients who received FT had a superior 2-y overall survival (OS) compared to those who received FBT200: 66.9% (95% confidence interval (CI): 46.1-81.2) vs. 44.5% (95% CI: 34-54.4), hazards ratio (HR): 0.43, 95% CI: 0.22-0.84 (P = 0.013). In multivariate analysis (MVA), only the use of fresh grafts (P = 0.02) and FT (P = 0.01) were associated with improved OS.

FT was associated with superior 2-y relapse-free survival (RFS) compared FBT200: 63.1% (95% CI: 42.6-77.9) vs. 39.1% (95% CI: 29.1-49.1), HR: 0.44 (95% CI: 0.24-0.81), P = 0.008. In MVA, the use of fresh grafts (P = 0.03) and FT (P = 0.009) were associated with improved RFS.

Recipients of FT demonstrated superior 2-y graft versus host disease relapse-free survival (GRFS) compared to those who received FBT200: 57.4% (95% CI: 37.8-72.8) vs. 35.1% (95% CI: 25.5-45). In MVA, only FT was associated with superior GRFS (P = 0.02).

FT was associated with lower 1-y non-relapse mortality (NRM) compared to FBT200 in univariate analysis (9.9% (95% CI: 3.0-21.8) vs. 29.7% (95% CI: 20.6-39.3), HR: 0.41 (95% CI: 0.17-0.96), P = 0.04) and MVA (P = 0.04).

FT recipients exhibited markedly superior 1-y event-free survival (EFS) compared to recipients of FBT200 in univariate analysis (40.3% (95% CI: 25.9-54.2) vs. 9.2% (95% CI: 4.4-16.3), HR: 0.47 (95%CI: 0.30-0.72), P < 0.001) and MVA (P = 0.004).

Variable

FT (N = 46)

FBT200 (N = 92)

P-value

Age (median, range)

66 (55-74)

65 (50-74)

0.15

≥65 (N, %)

25 (54.3)

45 (48.9)

0.59

Female gender (N, %)

13 (28.2)

38 (41.3)

0.19

Diagnosis (N, %)

0.82

CMML

10 (21.7)

18 (19.6)

MDS

36 (78.3)

74 (80.4)

therapy-related

10 (21.7)

9 (9.8)

0.07

Donor

MSD

9 (19.6)

20 (21.7)

0.90

MUD

27 (58.7)

50 (54.3)

MMUD

7 (15.2)

10 (10.9)

HID

3 (6.5)

12 (13.0)

Donor age (median, range)

34 (18-69)

32 (18-67)

0.26

Female -> male (N, %)

10 (21.7)

16 (17.4)

0.64

GVHD-P (N, %)

0.22

Dual TCD (ATG+PTCy)

36 (78.3)

80 (87.0)

Other

10 (21.7)

12 (13.0)

DRI (N, %)

0.92

Low-intermediate

31 (67.4)

63 (68.5)

High

15 (32.6)

29 (31.5)

IPSS (N, %)

0.85

Low

2 (2.2)

Intermediate

13 (28.3)

26 (28.3)

High

7 (15.2)

19 (20.7)

Missing

26 (56.5)

45 (48.9)

HCT-CI (N, %)

0.86

<3

22 (47.8)

46 (50.0)

≥3

24 (52.2)

45 (48.9)

Missing

1 (1.1)

KPS (N, %)

0.83

<90

12 (26.1)

21 (22.8)

≥90

34 (73.9)

70 (76.1)

Missing

1 (1.1)

CD34 dose (median, range)

6.2 (1.7-8.3)

8.2 (3.5-48.1)

<0.001

Stem cell source

1.00

PBSC

46 (100.0)

91 (98.9)

BMSC

1 (1.1)

Graft manipulation

0.55

Fresh

35 (76.1)

64 (69.6)

Frozen

11 (23.9)

28 (30.4)

Follow-up in days (median, range)

365 (100-959)

1106 (169-2734)

<0.001

Treosulfan dose

30 g/m2

14 (30.4)

42 g/m2

32 (69.6)

  1. Abbreviations: M (male), F (female), MDS (myelodysplastic syndrome), CMML (chronic myelomonocytic leukemia), MSD (matched sibling donor), MUD (matched unrelated donor), haplo (haploidentical donor), MMURD (mismatched unrelated donor), FtM (female donor to male recipient), GVHD (graft versus host disease), PTCy (post transplantation cyclophosphamide), ATG (antithymocyte globulin), DRI (disease risk index), HCT CI (hematopoietic cell transplantation specific comorbidity index), KPS (Karnofsky performance status), F-U (follow up), IPSS (international prognostic scoring system), SC (stem cell), BM (bone marrow), PBSC (peripheral blood stem cell).

Conclusions: This study is the first to utilize propensity score matching in assessing the role of treosulfan in stem cell transplantation of MAC ineligible patients with MDS and contributes to the increasing body of evidence supporting the antileukemic properties of the drug while underscoring its safety, even at the dose of 42 g/m2. Randomized controlled trials comparing treosulfan given at 30 g/m2 and 42 g/m2 are warranted.

Disclosure: Nothing to declare

16: Conditioning Regimens

O061 TREOSULFAN VERSUS BUSULFAN-BASED CONDITIONING REGIMENS FOR FIRST ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANT IN CHILDREN WITH ACUTE MYELOID LEUKEMIA IN COMPLETE REMISSION: A RETROSPECTIVE PDWP/EBMT STUDY

Hemalatha G. Rangarajan 1, Antonio Pérez Martínez2, Jacques-Emmanuel Galimard3, Arnaud Dalissier4, Rose-Marie Hamladji5, Oana Mirci-Danicar6, Franco Locatelli7, Monika Mielcarek-Siedziuk8, Adriana Balduzzi9, Jan Styczynski10, Franca Fagioli11, Cécile Renard12, Jean Hugues Dalle13, Mouhab Ayas14, Jochen Buechner15, Marianne Ifversen16, Petr Sedlacek17, Kanchan Rao18, Robert Wynn19, Marc Ansari20, Katharina Kleinschmidt21, Krzysztof Kalwak8

1Nationwide Children’s Hospital, Columbus, United States, 2University Hospital La Paz, Madrid, Spain, 3EBMT Statistical Unit, Paris, France, 4EBMT Paris Study Unit, Paris, France, 5Centre Pierre et Marie Curie, Alger, Algeria, Algeria, 6Bristol Royal Hospital for Children, Pediatric BMT, Bristol, United Kingdom, 7IRRCS Ospedale Pediatrico Bambino Gesù, Catholic University of the Sacred Heart, Rome, Italy, 8Wroclaw Medical University, Wroclaw, Poland, 9Centro Trapianti di Midollo Osseo Clinica Pediatrica Università di Milano Bicocca Ospedale San Gerardo, Monza, Italy, 10University Hospital, Collegium Medicum UMK Pediatric Hematology and Oncology Bydgoszcz, Bydgoszcz, Poland, 11Onco-Ematologia Pediatrica Centro Trapianti Cellule Staminali, Torino, Italy, 12Institut dOncologie Pediatrique, Lyon, France, 13Hôpital Robert Debre, Paris, France, 14King Faisal Specialist Hospital & Research Centre (Paeds), Riyadh, Saudi Arabia, 15Oslo University Hospital, Olso, Norway, 16Copenhagen University Hospital,Rigshospitalet, Copenhagen, Denmark, 17University Hospital Motol, Prague, Czech Republic, 18Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom, 19Royal Manchester Children’s Hospital, Machester, United Kingdom, 20University Hospital of Geneva, University of Geneva, Geneva, Switzerland, 21University of Regensburg, Regensburg, Germany

Background: Treosulfan, with its favorable toxicity profile, is increasingly being considered for conditioning in pediatric patients with acute myeloid leukemia (AML) in need of an allogeneic hematopoietic cell transplantation (HCT). Published studies comparing outcomes following Treosulfan vs. Busulfan-based conditioning mainly include recipients of ≥ 2nd HCT. Therefore, we conducted a study comparing outcomes of pediatric AML patients undergoing first allogeneic HCT following either a Treosulfan or Busulfan-based conditioning.

Methods: This retrospective EBMT study included all children ( < 18 years) with de novo AML in CR1 or CR2 who underwent first allogeneic HCT between 2014-2022 and received any of the following myeloablative regimens: Busulfan/Cyclophosphamide (BuCy), Busulfan/Cyclophosphamide/Melphalan (BuCyMel) and Treosulfan/Fludarabine/Thiotepa (TreoFluThio). We excluded recipients of cord blood, haploidentical and < 9/10 mismatched HCT due to low number of patients within at least one of the regimens of interest. We compared the following outcomes between the three groups: leukemia-free survival (LFS), overall survival (OS), non-relapse mortality (NRM), incidence of acute and chronic graft versus host disease (aGVHD, cGVHD), relapse incidence (RI), and GVHD relapse-free survival (GRFS).

Results: 988 (575 males) patients with a median age of 9.3 years [IQR: 3.8-13.7] met the study inclusion criteria, of whom 492 received BuCy, 371 BuCyMel, and 125 TreoFluThio. Baseline characteristics of the three groups (BuCy vs. BuCyMel vs TreoFluThio) were comparable except that a significant proportion of BuCyMel recipients were younger [median age in years: 10.2 vs 7.8 vs 9.5; p < 0.001], received more often bone marrow graft (64.2% vs 74.7% vs 57.6%; p < 0.001), more TreoFluThio recipients had a performance score (PS) < 90 (10.2% vs. 15.1% vs. 28.8%; p < 0.001) and BuCy recipients less often received in-vivo T cell depletion (37.6% vs 66.7% vs 61.3%; p < 0.0001) and more often sibling donors (57.9% vs. 32.9% vs 33.6%; p < 0.001). At a median follow-up of 3.1 years, the 2-year LFS, OS, GRFS, RI, and NRM of the entire cohort were 72.1% (95% CI: 68.8-75), 79.3% (95% CI: 76.4-82), 61.9% (58.4-65.1%), 21.8% (95% CI: 19-24.7) and 6.2% (95% 4.7-7.9) respectively. The cumulative incidence of grade II-IV aGVHD by day+100 was 26.4% (95% CI: 23.6-29.2), and cGVHD at 2 years was 15.1% (95% CI: 12.7-17.6). In multivariable analysis, as shown in Table 1 below, TreoFluThio was not significantly different from BuCy or BuCyMel in terms of LFS, OS, NRM, and GRFS. The incidence of relapse was, however, greater following TreoFluThio compared to BuCyMel but not to BuCy. There were no differences in the incidence of aGVHD and cGVHD. Increasing age (5-year increments) was associated with higher NRM (HR 1.66; p < 0.001), cGVHD (HR 1.35; p = 0.002), and PS of ≥ 90 with better LFS (HR: 0.66; p = 0.03) and OS (HR:0.67; p = 0.048).

Full size table

Conclusions: In our study, RI was significantly lower following BuCyMel-based conditioning, with other outcomes being not significantly different among the three groups. Data collection on veno-occlusive disease post-HCT is ongoing. The prospective randomized trial comparing BuCyMel vs TreoFluThio in pediatric AML patients will provide more definitive answers on the differences in outcomes between these two regimens.

Clinical Trial Registry: Not Applicable, Retrospective Registry Based Study

Disclosure: Jan Styczynski: Medac (Congress Fee)

All other authors have no conflicts of interest relevant to this abstract.

16: Conditioning Regimens

O062 FLUDARABINE PLUS TREOSULFAN OR TBI AS A CONDITIONING THERAPY BEFORE ALLOGENEIC HSCT IN ACUTE LYMPHOBLASTIC LEUKEMIA. A MATCHED-PAIR ANALYSIS FROM THE ALWP OF THE EBMT

Ryszard Swoboda 1, Myriam Labopin2, Nicolaus Kröger3, Matthias Stelljes4, Thomas Schroeder5, Peter Dreger6, Gesine Bug7, Andrew McDonald8, Tülay Özçelik9, Montserrat Rovira10, Igor Wolfgang Blau11, Desiree Kunadt12, Gerard Socié13, Werner Rabitsch14, Matthias Eder15, Marie Therese Rubio16, Alexandros Spyridonidis17, Bipin Savani18, Zinaida Peric19, Sebastian Giebel1, Mohamad Mohty2, Fabio Ciceri20

1Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland, 2EBMT Unit, Sorbonne University, Saint-Antoine Hospital, AP-HP, INSERM UMRs 938, Paris, France, 3University Hospital Eppendorf, Hamburg, Germany, 4University of Muenster, Muenster, Germany, 5University Hospital, Essen, Germany, 6University of Heidelberg, Heidelberg, Germany, 7Goethe-Universitaet, Frankfurt Main, Germany, 8Alberts Cellular Therapy, Pretoria, South Africa, 9Demiroglu Bilim University Istanbul Florence Nightingale Hospital, Istanbul, Turkey, 10Institute of Haematology and Oncology, IDIBAPS, Hospital clinic, University of Barcelona. Josep Carreras Leukaemia Research Foundation, Barcelona, Spain, 11Medizinische Klinik m. S. Hämatologie, Onkologie und Tumorimmunologie, Berlin, Germany, 12University Hospital TU Dresden, Dresden, Germany, 13Saint-Louis Hospital, Paris, France, 14Medizinische Universitaet Wien, Vienna, Austria, 15Hannover Medical School, Hannover, Germany, 16CHRU NANCY, Vandoeuvre les Nancy, Nancy, France, 17University of Patras, Patras, Greece, 18Vanderbilt University Medical Center, Nashville, United States, 19University of Zagreb and University Hospital Centre Zagreb, Zagreb, Croatia, 20IRCCS Ospedale San Raffaele s.r.l., Haematology and BMT, Milano, Italy

Background: Total body irradiation (TBI)-based conditioning is considered as a standard therapy before allogeneic hematopoietic stem cell transplantation (alloHSCT) in patients with acute lymphoblastic leukemia (ALL). Although treosulfan (Treo) is a frequently used component of TBI-free conditioning in patients with acute myeloid leukemia, there are very limited data on Treo-based conditioning before alloHSCT in ALL patients. As Treo is commonly used in combination with fludarabine (Flu), we aimed to compare Flu/Treo with Flu/TBI as a conditioning therapy before alloHSCT in ALL patients.

Methods: Based on EBMT registry we retrospectively analyzed data of 2055 adult patients with ALL who met inclusion criteria: 1) first alloHSCT in first or second complete remission (CR1, CR2) between years 2006 and 2022; 2) matched sibling (MS), unrelated (UD) or haploidentical donor; 3) Flu/Treo (30-42g/m2) or Flu/TBI (8-12 Gy) as a conditioning therapy. 153 patients in Flu/Treo group and 431 patients in Flu/TBI group were included in a final matched-pair analysis.

Results: The median patients age was 54.1 and 56.5 years in Flu/TBI and Flu/Treo group, respectively. Male to female proportion was 52%/48% in both groups. Philadelphia negative (Ph-), Ph positive (Ph + ) B-ALL and T-ALL were diagnosed in 61 (39.9%), 42 (27.5%), 22 (14.4%) patients in Flu/Treo group and in 168 (39%), 111 (25.8%), 70 (16.2%) patients in Flu/TBI group. CR1/CR2 proportion was 75%/25% in both groups. The allograft was derived from UD (54.2% in Flu/Treo and 52% Flu/TBI group), MS (30.7% and 32.5%) and haploidentical donor (15% and 15.5%).

Graft failure was diagnosed in 5 (3.5%) and 7 (1.7%) patients in Flu/Treo and Flu/TBI group, respectively. The incidence of acute graft versus host disease (GVHD) grade II-IV and III-IV was 26.6% and 13.7% in Flu/Treo and 30% and 9.3% in Flu/TBI group (HR 0.87 (95% CI 0.6-1.24), p = 0.43, and HR 1.5 (0.89-2.54), p = 0.13, respectively). The 2-year incidence of overall and extensive chronic GVHD was 33.5% and 18.8% in Flu/Treo while 40.7% and 20.2% in Flu/TBI group (HR 0.81 (0.57-1.14), p = 0.23, and HR 1.04 (0.65-1.68), p = 0.87). The 2-year incidence of relapse and non-relapse mortality was 28.1% and 25.6% in Flu/Treo and 25.1% and 20.4% in Flu/TBI group (HR 1.31 (0.91-1.88), p = 0.15 and HR 1.19 (0.8-1.77), p = 0.38, respectively). Leukemia-free survival and overall survival was 46.2% and 55% in Flu/Treo and 54.5 and 61.3 in Flu/TBI group (HR 1.25 (0.96-1.63), p = 0.1 and HR 1.19 (0.9-1.59), p = 0.22, respectively). GVHD and relapse-free survival was 33.7% and 40.8%, respectively in Flu/Treo and Flu/TBI group (HR 1.25 (0.99-1.57), p = 0.06).

Conclusions: The combination of Flu with Treo as a conditioning therapy before alloHSCT in ALL patients results in comparable transplant outcomes as Flu combined with TBI. Therefore Flu/Treo appears a valuable alternative for ALL patients with contraindications for irradiation. Our findings require confirmation in prospective trials.

Disclosure: Gesine Bug has received honoraria from Novartis, Jazz, BMS and Gilead and travel grants from Jazz, Gilead and Neovii.

Other authors have no conflict of interest to declare.

16: Conditioning Regimens

O063 TCRALPHA/BETA DEPLETED MOBILIZED PBSCS WITHOUT CALCINEURIN INHIBITORS IN PATIENTS WITH FANCONI ANEMIA

Margaret MacMillan 1, Qing Cao1, David McKenna1, Meera Srikanthan1, John Wagner1

1University of Minnesota, Minneapolis, United States

Background: We hypothesized that TCRalpha/beta depletion would sufficiently deplete graft-versus-host disease (GVHD) causing a/b T cells to eliminate the need for prolonged immunosuppression (IS) after related or unrelated donor peripheral blood stem cell (PBSC) transplantation in patients with Fanconi anemia (FA).

Methods: Patients were conditioned with fludarabine, cyclophosphamide and methylprednisolone alone if the patient had marrow failure only and an HLA matched sibling donor (n = 1), or in combination with busulfan (n = 14) or total body irradiation (n = 12) if there was clonal disease, or the donor was a haploidentical related (n = 2) or HLA matched or mismatched unrelated donor (n = 22). All but the first patient received one dose of rituximab the day before transplant. PBSCs collected after Neupogen mobilization were depleted of TCRa/b cells prior to transplant. Mycophenolate mofetil was given after transplant if the TCRa/b dose ≥2 x 105 TCR α/β T cells/kg recipient weight (n = 4).

Results: To date, 27 patients with FA (14 FANCA, 3 FANCC, 6 BRCA2, and one each with FANCB, FANCF, FANCG and FANCJ) received TCRa/b depleted PBSCs for marrow failure (n = 13), early MDS (n = 7), late MDS (n = 2), relapsed AML (n = 1), ALL (n = 1) or pre-emptively for BRCA2 (n = 3), with 2 patients having had a prior transplant. Median age was 9.4 years (6 > 18 years). Median CD34+ cells/kg was 1.11 x 107/kg and median TCRa/b dose was 7.0 x 104/kg. Neutrophil engraftment occurred in all patients at a median of 9 days. Platelet recovery ≥20,000/uL occurred in 96% at a median of 15 days. Complete donor myeloid engraftment was achieved by day 21 in all patients with sustained neutrophil engraftment who did not relapse. Donor lymphoid engraftment was slower with complete CD3+ chimerism achieved in only 15 patients at 1 year after PBSCT. To date, 3 patients developed grade II-IV acute GVHD. No patient has developed chronic GVHD requiring systemic therapy.With a median follow-up of 22 months, probability of survival at 2 years is 93%, including 5 of 6 BRCA2 patients and all 6 adult patients (Figure). Secondary graft failure occurred in two patients; aplasia after a febrile illness in one FANCF patient; and autologous recovery in one BRCA2 patient. Both patients were successfully retransplanted. Relapse was observed in 3 patients: two BRCA2 patients with AML or MDS, and one FANCC patient with relapsed MDS after a prior transplant. The two BRCA2 patients were successfully retransplanted and remain in remission. 2 patients developed PTLD, treated successfully with rituximab. 5 patients reactivated viral infections (3 CMV, 1 adenovirus,1 BK virus).

The 50th Annual Meeting of the European Society for Blood and Marrow Transplantation: Physicians - Oral Session (O009-O154) (7)

Conclusions: TCRa/b depleted PBSC without CNI results in excellent primary engraftment, minimal GVHD and excellent survival in FA patients including BRCA2 and older patients. Patients with biallelic BRCA2 require a TBI based regimen to achieve sustained engraftment using this approach. The absence of IS after HCT provides an opportunity for future cell therapy interventions to optimize recovery after HCT.

Clinical Trial Registry: Clinical Trials.gov NCT03579875

Disclosure: Nothing to declare

6: Experimental Transplantation and Gene Therapy

O064 REKLAIM, A NOVEL PHASE IB CLINICAL TRIAL OF FBX-101 (AAVRH10.GALC) INTRAVENOUSLY ADMINISTERED AFTER UCBT FOR THE TREATMENT OF INFANTILE AND LATE INFANTILE KRABBE DISEASE

Maria Escolar 1, Michele D. Poe1, Juan Ruiz1, Mark Vander Lugt2, Raymond Wang3, David Buchbinder4, Paul Szabolcs5

1Forge Biologics, Grove City, United States, 2University of Michigan, Ann Harbor, United States, 3Children’s Hopital of Orange County, Orange, United States, 4Children’s Hospital of Orange County, Orange, United States, 5University of Pittsburgh, Pittsburgh, United States

Background: REKLAIM is a novel intravenous AAVrh10.GALC gene therapy administered during the period of myeloablation or immune suppression after umbilical cord blood transplantation (UCBT) for the treatment of Infantile and Late Infantile Krabbe disease (IKD, LIKD). We report the results of the first 5 subjects with IKD treated with a low dose intravenous FBX-101 (1.6 x1013 gc/kg). IKD is a fatal neurodegenerative disorder due to galactocerebrosidase (GALC) deficiency that results in psychosine toxicity to myelinating cells in the brain and peripheral nervous system. If untreated death occurs in average by 2 years. Currently, pre-symptomatic neonates are treated with UCBT in the first 30-45 days of life, halting brain disease. However, follow up studies demonstrate that motor function slowly declines due to progressive peripheral neuropathy. One of the most challenging problems when administering AAV intravenously is the production of antibodies against the transgene and the capsid. UCBT is immunological naive and the healthy graft should not recognize the over expression of GALC as an antibody. Therefore, we hypothesized that FBX-101 administered during myeloablation or later during immunesuppression, will override the antibody response to the vector’s capsid and transgene, improving transduction and increasing the levels of GALC.

Methods: REKLAIM is a Phase 1b dose-escalating intravenous gene therapy to evaluate safety and efficacy of FBX-101 administered intravenously >21 days after UCBT for the treatment of Infantile and Late Infantile Krabbe disease while the subject is myeloablated, or later when the subject is immune-suppressed. Each subject at the time of gene therapy administration may be at different levels of immune suppression. Therefore, an independent committee reviews the immune status and suggest adjustments as needed in order to minimize an immune response to AAV. A Rituximab, Serolimus and Prednisolone based regime is used to adjust immune suppression. After gene therapy administration the subjects are followed for 2 years and enrolled in 3 additional years of long term follow up.

Results: FBX-101 was well tolerated, with no treatment-related serious adverse events with follow up ranging from 4 to 24 months. In the two subjects treated during myeloablation, there were no antibodies to AAV. Plasma and CSF GALC increased to supraphysiological levels with psychosine dropping below detection levels. The white mater integrity of the corticospinal tracts that rapidly myelinate in the first year, followed a normal trajectory and subjects achieved normal gross motor skills above those seen after UCBT only. The three subjects treated during immune suppression developed minimal total antibodies to AAV with no signs of humoral or cellular toxicity and improved in gross motor skills.

Conclusions: In summary, FBX-101 after UCBT leverages the myeloablation and immune suppression after UCBT, resulting in efficient AAV transduction providing increased GALC enzyme that supports normal brain myelination and gross motor development.

Clinical Trial Registry: NCT05739643

Disclosure: Escolar is an inventor on the patent application describing FBX-101(WO2018/136710)licensed to Forge Biologics by the University of Pittsburgh where she is an Adjunct Professor of Pediatrics.

6: Experimental Transplantation and Gene Therapy

O065 LONG-TERM AND REAL-WORLD SAFETY AND EFFICACY OF RETROVIRAL GENE THERAPY FOR ADENOSINE DEAMINASE DEFICIENCY

Maddalena Migliavacca 1,2, Federica Barzaghi2,1, Claudia Fossati1, Paola M.V. Rancoita3, Michela Gabaldo4, Francesca Dionisio1, Stefania Giannelli1, Federica Andrea Salerio1, Francesca Ferrua2,1, Francesca Tucci1,2, Calbi Valeria2,1, Vera Gallo2,1, Salvatore Recupero2,1, Giulia Consiglieri2,1, Roberta Pajno2,1, Vittoria Garella5, Ilaria Monti1, Paolo Silvani6, Silvia Darin1, Miriam Casiraghi1, Ambra Corti1, Stefano Zancan4, Margherita Levi4, Daniela Cesana1, Anna Pituch-Noworolska7, Dalia AbdElaziz8, Ulrich Baumann9, Andrea Finocchi10,11, Caterina Cancrini10,11, Saverio Ladogana12, Andrea Meinhardt13, Isabelle Meyts14, Davide Montin15, Lucia Dora Notarangelo16, Fulvio Porta17, Marlène Pasquet18, Carsten Speckmann19,20, Polina Stepensky21, Alberto Tommasini22, Marco Rabusin22, Zeynep Karakas23, Miguel Galicchio24, Lucia Leonardi25, Marzia Duse25, Sukru Nail Guner26, Clelia Di Serio3,27, Fabio Ciceri5,28,1, Maria Ester Bernardo5,2,1, Alessandro Aiuti5,2,1, Maria Pia Cicalese5,2,1

1San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milano, Italy, 2Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy, 3University Centre for Statistics in the Biomedical Sciences (CUSSB), Vita-Salute San Raffaele University, Milan, Italy, 4Fondazione Telethon, Milano, Italy, 5Università Vita-Salute San Raffaele, Milano, Italy, 6IRCCS San Raffaele Scientific Institute, Milano, Italy, 7University Children’s Hospital of Cracow, Cracow, Poland, 8Cairo University, Cairo, Egypt, Cairo, Egypt, 9Hannover Medical School, Hannover, Germany, 10Bambino Gesù Children’s Hospital, Scientific Institute for Research and Healthcare (IRCCS), Rome, Italy, 11University of Rome Tor Vergata, Rome, Italy, 12Paediatric Onco-haematology Unit, “Casa Sollievo della Sofferenza” Hospital, IRCCS, San Giovanni Rotondo, Italy, 13Medical Center, University Hospital Giessen, Giessen, Germany, 14Immunology and Transplantation, KU Leuven; Childhood Immunology, UZ Leuven, Leuven, Belgium, 15University of Torino, Regina Margherita Children’s Hospital, AOU Città della Salute e della Scienza di Torino, Turin, Italy, 16Medical Direction, Children’s Hospital, ASST-Spedali Civili, Brescia, Italy, 17Pediatric Oncology-Hematology and BMT Unit, Spedali Civili di Brescia, Brescia, Italy, 18Pediatric Hematology and Immunology, Children’s Hospital, Toulouse, France, 19Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany, 20University Medical Center Freiburg, University of Freiburg, Freiburg, Germany, 21Hadassah-Hebrew University Medical Center, Jerusalem, Israel, 22IRCCS Burlo Garofolo, Trieste, Italy, 23Istanbul University, Istanbul School of Medicine, Istambul, Turkey, 24Allergy and Immnunology Service, Hospital de Niños VJ Vilela, Rosario, Argentina, 25La Sapienza University of Rome, Rome, Italy, 26Division of Pediatric Allergy and Immunology, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey, 27Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland, 28Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy

Background: Autosomal recessive adenosine-deaminase (ADA) deficiency leading to severe combined immunodeficiency (SCID) is a life‐threatening immunodeficiency, characterized by lymphopenia in B/T/NK subpopulations, failure to thrive, severe infections and autoimmunity. Allogeneic hematopoietic stem cell transplant (HSCT) and Strimvelis, an ex-vivo retroviral hematopoietic stem cell gene therapy (GT) approved in the EU in 2016, are standard of care treatments for ADA-SCID.

Methods: Here we describe the post-marketing experience of 19 patients (STRIM cohort) up to 5 years of follow up, the largest cohort of patients treated worldwide with an approved product based on ex vivo transduced CD34+ cells. We also provide an extended follow-up data on 22 subjects treated in the clinical development/named patient program (CDP + NPP cohort) and report on two patients treated with mobilized peripheral blood CD34+ cells under hospital exemption (mPB-HE). Age at diagnosis and at GT, CD34+ cell dose and vector copy number (VCN) per genome in the drug product were similar in the CDP + NPP and STRIM cohorts.

Results: Nineteen patients initially referred for Strimvelis did not receive treatment due to lack of funding, other treatment choice or ineligibility due to different reasons. At data cut-off (March 2023), all 43 patients were alive, with a median follow-up of 5 years (interquartile range 2.4-15.4) and 2 year intervention-free survival (no need for long-term ERT or rescue HSCT) of 88% (95% CI: 78.7%-98.4%). Long-term persistence of multilineage gene-corrected cells was associated with immune-reconstitution. At the last available observation, 16/17 CDP + NPP patients and all STRIM patients who reached 5 years post GT, discontinued IVIg supplementation and responded to most vaccinations. Response to anti aCD3i and PHA were normal at last follow up in all STRIM and CDP + NPP patients who did not fail GT. Native pathogens’ infections had a regular evolution and resolved without sequelae. Estimated mixed-effects models showed that higher dose of CD34+ cells infused affected positively the plateau of CD15+ and CD3+ gene corrected cells. In addition, younger age at GT affected positively the plateau of CD3+ gene corrected T cells as well as lymphocytes, CD3 and CD4 + CD45RA+ naïve T cell counts. We also observed a significantly higher plateau of transduced CD15+ and CD3+ cells and better dAXP detoxification in STRIM vs CDP + NPP, but no differences in the lymphocyte or T cell reconstitution.

Most adverse events/reactions were related to disease background, busulfan conditioning or immune reconstitution. A lymphoid T cell leukemia with retroviral insertion near LMO2 emerged 4.7 years post-GT in a patient from the CDP + NPP group, who is currently in clinical remission 2.5 years after haploidentical HSCT.

Conclusions: In the post-marketing population, the safety profile was in line with the clinical development program and we did not find evidence of clonal proliferation, nor new treatment-related events. Due to the risk of insertional oncogenesis, long-term safety monitoring remains important.

Following disinvestment from the industrial holder, the marketing authorization of the retroviral GT for ADA-SCID was transferred to Fondazione Telethon which established a nonprofit model of distributing for ultrarare-diseases, allowing this gene therapy still available to eligible patients.

Clinical Trial Registry: NCT00598481[https://clinicaltrials.gov/study/NCT00598481];NCT03478670[https://clinicaltrials.gov/study/NCT03478670].

Disclosure: Gene therapy for ADA-SCID was developed at SR-Tiget and licensed to GlaxoSmithKline (GSK) in 2010. Strimvelis Marketing Authorization in Europe occurred in 2016 (under GSK holding) and then transferred to Orchard Therapeutics (Netherlands) B.V. in 2018, which divested the program and transferred the authorization to Fondazione Telethon that became the holder in July 2023.

A. Aiuti was the PI of pilot, pivotal and long-term follow up study of SR-Tiget clinical trial of gene therapy for ADA SCID. M.P. Cicalese and M. Migliavacca are PI and deputy PI, respectively, of the Strimvelis Registry, RIS and RMMs studies. All other authors declare no competing interests.

The work was partially supported by Fondazione Telethon and grants from the European Commission (ERARE-3-JTC 2015 EUROCID, A.A.), Ministero della Salute, Ricerca Finalizzata NET-2011-02350069 (to AA, CC). AA is the recipient of Else Kröner-Fresenius-Stiftung (EKFS) prize.

6: Experimental Transplantation and Gene Therapy

O066 TRANSCRIPTIONAL REWIRING OF NK CELL FEATURES IMPRINTED BY DIFFERENT MODALITIES OF POST-TRANSPLANTATION LEUKEMIA RELAPSE

Giorgio Orofino 1, Pier Edoardo Rovatti1, Marco Punta1, Matteo Maria Naldini1, Matteo Barcella1, Laura Zito1, Matteo Carrabba1, Massimo Bernardi1, Jacopo Peccatori1, Bernhard Gentner1, Fabio Ciceri1,2, Luca Vago1,2, Cristina Toffalori1

1IRCCS Ospedale San Raffaele Scientific Institute, Milan, Italy, 2San Raffaele Vita-Salute University, Milan, Italy

Background: Allogeneic Hematopoietic Cell Transplantation (allo-HCT) represents a potentially curative treatment for high-risk Acute Myeloid Leukemia (AML) patients. However, leukemia relapses are frequent and characterized by poor prognosis. Three major alternative mechanisms by which AML cells modify their features and escape immune control have been described: genetic loss of the mismatched HLA haplotype (HLA loss), downregulation of HLA-II molecules and upregulation of inhibitory ligands, all negatively impacting on T cell-mediated leukemia recognition. Increasing evidence suggests that leukemic cells weave a broader net of interactions, involving several immune cell types. Leveraging on single-cell RNA-sequencing (scRNA-seq), we profiled NK cells in the bone marrow (BM) microenvironment to understand whether and how they are affected by the emergence of immune-escape variants and why they are unable to prevent clinical relapse.

Methods: We performed scRNA-seq throught the 10x Genomics platform on BM aspirates from 25 acute AML patients at the time of relapse after allo-HCT (relapse modalities included genomic HLA loss, downregulation of MHC-II molecules, upregulation of inhibitory ligands), from 5 post-transplant patients in complete remission (CR), each tested at two timepoints ( + 90 and +365 days) and from 6 healthy controls (HC).

Results: Based on the expression of canonical NK cell transcripts we identified a total of 26,264 NK cells from the original dataset. We annotated three major subsets (CD56bright, CD56dim and transitional NK cells) and a small cluster of CD56bright NK cells, characterized by high expression of IFN-related genes and of NK exhaustion markers, identified by previous studies as “inflamed-NK”. Interestingly, inflamed-NK were more represented in patients with upregulation of T-cell inhibitory ligands compared to other relapsed patients (5.97% vs 0.91%, respectively, p.value = 0.03), suggesting a shared mechanism of dysfunction between T and NK cells in this relapse modality. Next, we specifically focused on NK cells in HLA loss relapses. In this relapse modality, the loss of some HLA alleles might in fact mean losing ligands for inhibitory KIRs, and thus trigger NK-cell alloreactivity. Using recently published gene signatures of NK cell activation, we generated a module score for CD56dim NK cells. As expected, HC exhibited the lower score, while CR samples showed a higher activation profile, similar to that of upregulation on inhibitory ligands relapses, suggesting that in most patients upon transplant NK cell immunosurveillance is activated. Interestingly, HLA loss relapses showed a very low activation score, regardless of potential alloreactivity, indicating that they might be functionally impaired by a mechanism currently under investigation.

Conclusions: Our observations support the hypothesis that, as T cells, also NK cells are differentially affected by the features of relapse, and inflammation within BM plays a central role on NK cell transcriptional features. Understanding the drivers of NK cell dysfunction in relapses may have important implications for rewiring their cytotoxic functions and developing innovative salvage strategies.

Disclosure: No disclosures

6: Experimental Transplantation and Gene Therapy

O067 DEVELOPING A UNIVERSAL HAEMATOPOIETIC STEM CELL GENE EDITING THERAPY FOR XIAP DEFICIENCY

Anne Charlotte Adriane Mudde 1, Soraia Silva1, Emily Hu1, Giandomenico Turchiano1, Nathan White1, Claire Booth1

1UCL, London, United Kingdom

Background: X-linked inhibitor of apoptosis (XIAP) deficiency is a rare, life-threatening inborn error of immunity, caused by mutations in the XIAP/BIRC4 gene. It is characterised by immune dysregulation that is associated with a spectrum of manifestations, including haemophagocytic lymphohistiocytosis (HLH) and severe inflammatory bowel disease. Elevated serum IL-18 levels are typical of the disease, irrespective of clinical status. Allogeneic haematopoietic stem cell (HSC) transplantation can be curative, but outcome post-HSCT is worse compared to other forms of HLH and graft versus host disease is associated with high mortality rates in these patients. An autologous HSC gene editing approach may offer a suitable alternative treatment, removing any risk of alloreactivity and permitting the use of less toxic preparative chemotherapy regimens. We previously demonstrated proof of concept for a lentiviral gene addition approach in a murine model and patient cells. However, we are now investigating a gene editing approach, in which the endogenous regulation of protein expression is maintained which may offer safety and efficacy advantages.

Methods: A CRISPR/Cas9 based gene editing strategy was used to achieve precise correction at the XIAP locus in human CD34+ cells, targeting early in the gene to allow correction of most described mutations. After initial experiments in T-lymphocytes, healthy donor CD34+ cells were electroporated with ribonucleoprotein (RNP) using a guide RNA targeting the first intron, followed by AAV6 transduction of a donor cassette containing codon optimised XIAP cDNA and GFP reporter. Cells were differentiated into monocytes and stimulated with MDP or LPS to assess XIAP dependent function. In vitro colony forming unit (CFU) assay and an in vivo engraftment study in NSG mice were used to assess differentiation and engraftment potential of edited CD34+ cells.

Results: As a first step, successful editing in T-lymphocytes was demonstrated with targeted integration rates of 25%. Following optimisation for HSCs, editing rates of up to 60% were achieved as measured by GFP expression, without impacting cell viability. Correction levels of up to 44% were achieved in XIAP patient HSCs derived from peripheral blood, resulting in restoration of XIAP protein expression and partial reconstitution of TNFα secretion after differentiation into monocytes and stimulation with MDP. Edited HSCs from healthy donors generated similar number of colonies compared to untreated cells in CFU assay, indicating preservation of clonogenic and differentiation potential in vitro. Engraftment potential is being further investigated in vivo; edited healthy donor CD34+ cells have been successfully engrafted into an immunodeficient NSG mouse model and analysis of engraftment specifically of gene edited cells is underway. Analyses to assess off-target endonuclease activity are currently being undertaken by sequencing of the in silico predicted top 10 off-target sites and karyotype analysis.

Conclusions: This study confirms proof-of-principle for an HSC gene editing approach as a potential durable treatment for XIAP deficiency. High editing rates in CD34+ cells were achieved at the XIAP locus, with good viability and in vitro differentiation potential. High levels of targeted integration were also observed in XIAP patient HSCs resulting in partial restoration of XIAP protein dependent immune function in differentiated, corrected cells.

Disclosure: Nothing to declare

6: Experimental Transplantation and Gene Therapy

O068 NON-NEUROLOGICAL, NON-SKELETAL OUTCOMES AFTER HAEMATOPOIETIC STEM AND PROGENITOR CELL-GENE THERAPY IN HURLER PATIENTS: RETROSPECTIVE COMPARISON WITH ALLOGENEIC HAEMATOPOIETIC STEM CELL TRANSPLANTATION

Francesca Tucci 1, Maria Luz Uria Oficialdegui2, Giulia Consiglieri1, Matilde Cossutta1, Chiara Filisetti1, Luca Galimberti1, Mariana Priviero Spiridon3, Maria Pia Manitto1, Carla Butera1, Roberto Santangelo1, Giulia Danè1, Chiara Camesasca1, Silvia Darin1, Mireia Del Toro2, Cristina Diaz de Hereida Rubio2, Rossella Parini4, Bernhard Gentner4, Alessandro Aiuti1, Maria Ester Bernardo1

1IRCCS San Raffaele Scientific Institute, Milano, Italy, 2Hospital Universitari Vall d’Hebron, Barcelona, Spain, 3Vita-Salute San Raffaele University, Milan, Italy, 4San Raffaele Telethon Institute for Gene Therapy, Milano, Italy

Background: Preliminary results of a phase I/II study (NCT03488394) of ex-vivo haematopoietic stem and progenitor cells gene therapy (HSC-GT, also known as OTL-203) in 8 Mucopolysaccharidosis type I Hurler syndrome (MPSIH) patients have demonstrated superior metabolic correction compared to allogeneic haematopoietic stem cell transplantation (HSCT). Nevertheless, HSPC-GT effects on non-neurological, non-skeletal manifestations such as corneal clouding (CC), hearing loss (HL), carpal tunnel syndrome (CTS) and cardiac involvement have not been extensively reported. Here we analysed for the first time these latter outcomes after HSPC-GT and performed a retrospective comparison with an external cohort of MPSIH patients undergoing HSCT.

Methods: MPSIH patients undergoing HSPC-GT (N. 8; NCT03488394) were retrospectively compared with MPSIH patients receiving HSCT (N. 9) in Vall d’Hebron Hospital, Barcelona. Patient and transplant characteristics of the HSC-GT and HSCT cohorts are reported in Table 1. Two of nine patients who received HSCT experienced primary graft failure and required a second HSCT.

CC was assessed using clinical grading scores (Fahnehjelm et al. Acta Opthalmol 2012 for HSC-GT patients), HL was evaluated using brainstem auditory evoked responses using dBnHL threshold. Cardiac function was studied clinically and by echocardiography. CTS was evaluated by electroneurography of the median nerve. Baseline results were compared with those obtained after treatment. HSC-GT patients were followed for up to a median of 4 years (range: 4-5) after treatment, while HSCT patients were followed-up for a median of 15 years (range: 4-21). However, to enable appropriate comparison between the two cohorts, this was performed within the same time window (4-5 years after treatment).

Table 1

HSPC-GT

HSCT

Number of patients (M/F)

8 (6/2)

9 (5/4)

Median age at treatment, months (range)

23.5 (14-34)

13 (9-29)

Median IDUA level (range)

101.3 (40.7-145.1) μmol/L/h at 4 years after HSC-GT [normal values:6 months to <6 years of age: 3.81-35.04 µmol/L/h; 6 years to 18 years of age: 2.27-22.56 µmol/L/h]

5.4 (4.6-11.3) nmol/h/mg proteins at 5 years after HSCT* [normal values 1.6-8.7 nmol/hour/mg protein]

Median follow-up, years (range)

4 (4-5)

15 (4-21)

Results: At baseline, all subjects had evidence of mild to moderate CC. Of the HSC-GT patients, 3/8 achieved CC resolution and 5/8 had mild CC at last follow-up. In the HSCT cohort, no patient experienced CC resolution with all patients showing moderate CC at 5 years after HSCT.

In the HSPC-GT cohort at baseline, 50% of the patients had mild to severe HL. An improvement in most of the patients was observed with 4/7 showing normal hearing function at last follow-up. In the HSCT cohort, 7/9 had mild or moderate HL at baseline with an improvement at the last follow-up as 4/9 showed normal hearing function. ENT surgery incidence and timing after treatment was comparable in the 2 cohorts.

In the HSC-GT-cohort none of the patients developed severe cardiomyopathy or valvular disease, while in the HSCT-cohort 2/9 patients experienced progression of valvular insufficiency but did not require valve replacement.

One HSC-GT patient underwent CT surgery before treatment, while another one 6 months after HSC-GT due to pre-existing severe damage before treatment. The remaining patients did not develop CTS. In the HSCT-cohort 7/9 patients developed CTS, requiring surgery at a median of 3.7 years post-HSCT.

Conclusions: Our results indicate stability or improvement of CC, HL, cardiac manifestations and CTS in MPSIH patients after HSC-GT up to 4 years after treatment. A longer follow-up and a prospective comparison with HSCT patients are required to draw definitive conclusions on the efficacy of HSC-GT in addressing these disease burdens.

Clinical Trial Registry: NCT03488394 (https://www.clinicaltrials.gov/study/NCT03488394)

Disclosure: The study is sponsored by IRCCS San Raffaele Scientific Institute. Fondazione Telethon was the initial financial sponsor; since May 2019 Orchard Therapeutics Ltd (OTL) is the financial sponsor when MPSIH gene therapy was licensed to OTL. Fondazione Telethon and OSR are entitled to receive milestone payments and royalties for such a therapy from OTL. AA was the study PI between May 2018 and July 2020, MEB is the PI since July 2020. BG, RP and MEB have acted as ad hoc consultant for an Orchard Therapeutic advisory board in 2020.

6: Experimental Transplantation and Gene Therapy

O069 INTERIM ANALYSIS ON NEUROLOGICAL OUTCOMES IN HURLER SYNDROME PATIENTS TREATED WITH EX-VIVO HAEMATOPOIETIC STEM CELL GENE THERAPY

Giulia Consiglieri 1, Francesca Fumagalli1, Francesca Tucci1, Chiara Filisetti1, Matilde Cossutta1, Stefano Scarparo1, Marina Sarzana1, Cristina Puricelli1, Francesca Ciotti1, Maurizio Barbera1, Silvia Darin1, Rossella Parini1, Cristina Baldoli1, Bernhard Gentner2, Alessandro Aiuti1, Maria Ester Bernardo1

1IRCCS San Raffaele Scientific Institute, Milano, Italy, 2San Raffaele Telethon Institute for Gene Therapy, Milano, Italy

Background: Early treatment with allogeneic haematopoietic stem cell transplantation (HSCT) was demonstrated in many cases to prevent deterioration of cognitive functions in Mucopolysaccharidosis type I Hurler (MPSIH) patients. Nevertheless, HSCT is not able to fully address central nervous system (CNS) manifestations, leaving patients with residual disease burden. The neurological outcomes of 8 MPSIH patients enrolled in a phase I/II study (NCT03488394) of autologous ex-vivo haematopoietic stem cell gene therapy (HSC-GT, also known as OTL-203) were evaluated up to 4 years after treatment.

Methods: IDUA activity, dermatan (DS) and heparan sulphate (HS) levels were measured in cerebral spinal fluid (CSF) at baseline and at different timepoints after HSC-GT. Ages of achievement of motor and language milestones were compared with the window of achievement defined by the World Health Organization (WHO) in healthy children. Gross and fine motor skills were analyzed using the Peabody Developmental Motor Scales, while measurement of cognitive functions was evaluated by the Bayley Scales of Infant and Toddler Development and the Wechsler Preschool and Primary Scale of Intelligence. Typical MRI brain abnormalities were assessed by a specific neuroradiologic scoring system previously developed for MPSIH patients treated with HSCT.

Results: From 3 months after GT, IDUA activity became detectable in CSF and persisted over time, accompanied by local reduction of both DS and HS with undetectable DS in 7/8 patients at +4 year-follow-up. Motor and language milestones were accomplished in all patients at the latest follow up, either at a normal or delayed time for age, except for one patient who suffers from cognitive and language delay accompanied by a behavioural disturbance, determined to be unrelated to treatment. Regarding motor abilities, we observed a stability of normality or a gain of normality in 5/8 patients in terms of total motor quotient (TMQ) and gross motor quotient (GMQ) at last follow-up, while fine motor quotients (FMQ) remained or became normal after treatment in 7/8 patients. After HSC-GT 7/8 patients continued to gain cognitive skills in line with typically developing children. All patients experienced an improvement or stabilization of the brain MRI scores with a significant reduction of the typical brain abnormalities. Compared to baseline, brain MRI images at last follow-up showed a meaningful reduction of multiple enlarged perivascular space and of subarachnoid space enlargement, regression of faint white matter alterations and normal progression of myelination.

Conclusions: This preliminary neurological analysis suggests biochemical detoxification in the CSF and initial clinical response in terms of motor and cognitive abilities up to 4 years after treatment, except for one patient with cognitive delay and behavioural disturbance determined to be unrelated to treatment. CSF detoxification suggests migration of gene-modified cells across the blood brain barrier and local engraftment in the CNS. Neuroradiological modifications correspond well with biochemical and clinical outcomes. A longer follow-up and a prospective comparison with HSCT are needed to draw definitive conclusions on the effect of HSC-GT on the typical neurological manifestations of MPSIH.

Clinical Trial Registry: NCT03488394 (https://www.clinicaltrials.gov/study/NCT03488394)

Disclosure: The study is sponsored by IRCCS San Raffaele Scientific Institute. Fondazione Telethon was the initial financial sponsor; since May 2019 Orchard Therapeutics Ltd (OTL) is the financial sponsor when MPSIH gene therapy was licensed to OTL. Fondazione Telethon and OSR are entitled to receive milestone payments and royalties for such a therapy from OTL. AA was the study PI between May 2018 and July 2020, MEB is the PI since July 2020. BG, RP and MEB have acted as ad hoc consultant for an Orchard Therapeutic advisory board in 2020.

6: Experimental Transplantation and Gene Therapy

O070 HAEMATOPOIETIC STEM CELL GENE THERAPY FOR HURLER SYNDROME: CLINICAL SKELETAL OUTCOME DATA AND STUDY OF THE SKELETAL CROSS-CORRECTION MECHANISMS

Francesca Tucci1, Giulia Consiglieri1, Maurizio De Pellegrin2, Matilde Cossutta1, Chiara Filisetti1, Marina Sarzana1, Stefano Scarparo1, Cristina Baldoli1, Renata Mellone1, Ludovica Santi2, Stefania Crippa2, Rossella Parini2, Bernhard Gentner2, Alessandro Aiuti1, Maria Ester Bernardo 1

1IRCCS San Raffaele Scientific Institute, Milano, Italy, 2San Raffaele Telethon Institute for Gene Therapy, Milano, Italy

Background: Skeletal dysplasia is a prominent feature of Mucopolysaccharidosis type I Hurler syndrome (MPSIH) which is not fully addressed by allogeneic haematopoietic stem cell transplantation (HSCT). Autologous ex vivo haematopoietic stem cell gene therapy (HSC-GT) is a promising therapeutic strategy for MPSIH since it is capable of producing supraphysiologic IDUA levels, leading to extensive metabolic correction. Here we report the interim results from a Phase I/II clinical trial (NCT03488394) on the skeletal outcome of 8 MPSIH patients treated with HSC-GT (OTL-203) up to a median follow-up of 4 years. As there is limited knowledge of the pathogenesis of skeletal defects and skeletal correction mechanisms in MPSIH after HSC-GT, we have characterized in vitro the key players of skeletal remodelling before and after HSC-GT in patients and mice.

Methods: Skeletal outcome of the 8 MPSIH patients was assessed at baseline and specific timepoints after treatment by clinical (growth), functional (motor performance and joint range of motion) and radiological parameters (X-Rays and MRIs of the hip and spine) up to a median of 4 years after HSC-GT. Specific skeletal measures were retrospectively compared with an external cohort of HSCT patients transplanted in Monza. Patient-derived osteoclasts (OCs), mesenchymal stromal cells (MSCs) and osteoblasts (OBs) were isolated and characterized before and at several timepoints after HSC-GT.

Results: IDUA activity reached supraphysiologic levels in all patients after HSC-GT resulting in extensive substrate depletion, maintained at last follow-up. All patients exhibited longitudinal growth within expected reference ranges according to age and gender, with a median height gain greater than the one observed in Monza HSCT patients. All children progressively acquired motor skills (stability of Total Motor Quotient score over time) and experienced a complete and earlier normalization of joint mobility as compared with HSCT patients. Both hip X-ray and hip MRI parameters improved after HSC-GT, representing an amelioration of hip dysplasia up to the latest follow-up. A specific spine MRI score showed stabilization of typical spine MRI features (i.e. dorsolumbar kyphosis, foramen magnum, spinal stenosis) in all patients at last follow-up.

In the HSC-GT scenario, we hypothesized that OCs, deriving from genetically corrected haematopoietic precursors, could deliver the missing enzyme in the skeletal microenvironment as mediators of cross-correction of non-haematopoietic cells. We demonstrated that patient-derived OCs after HSC-GT and their supernatant show supraphysiologic IDUA activity which can be up-taken by patient MSCs and OBs, thus rescuing GAGs engulfment in MPSIH-OBs. Osteomedullary biopsies of MPSHI patients obtained at baseline showed foamy appearance of cytoplasm of the soft tissue cells adjacent to bone cells (i.e., entheses) which fully resolved after HSC-GT. Moreover, HSPC-GT ameliorated the skeletal disease of the growth plate in terms of organization and morphology in MPSI mice.

Conclusions: Clinical, functional and radiological parameters indicate an early beneficial effect of HSC-GT on MPSIH-typical skeletal features. A longer follow-up and direct comparison with HSCT are needed to draw definitive conclusions on HSC-GT impact on skeletal dysplasia. Biological studies aimed at unveiling skeletal correction mechanisms after HSC-GT will be key to advance the treatment of MPSIH patients.

Clinical Trial Registry: NCT03488394 (https://www.clinicaltrials.gov/study/NCT03488394)

Disclosure: The study is sponsored by IRCCS San Raffaele Scientific Institute. Fondazione Telethon was the initial financial sponsor; since May 2019 Orchard Therapeutics Ltd (OTL) is the financial sponsor when MPSIH gene therapy was licensed to OTL. Fondazione Telethon and OSR are entitled to receive milestone payments and royalties for such a therapy from OTL. AA was the study PI between May 2018 and July 2020, MEB is the PI since July 2020. BG, RP and MEB have acted as ad hoc consultant for an Orchard Therapeutic advisory board in 2020.

12: Graft-versus-host Disease – Clinical

O071 AXATILIMAB FOR CHRONIC GRAFT-VERSUS-HOST DISEASE: RESPONSES IN FIBROSIS-DOMINANT ORGANS IN AGAVE-201

Jose A. Perez-Simon 1, Zachariah DeFilipp2, Stephanie J. Lee3, Wendy Ingram4, Jennifer White5, Helene Schoemans6,7, Laetitia Souchet8, Daniel Wolff9, Carrie L. Kitko10, Simona Sica11,12, Avichai Shimoni13, Britnie Thomas14, Vedran Radojcic15, Chuan Tian14, Amandeep Salhotra16, Corey Cutler17

1Hospital Universitario Virgen del Rocío Instituto de Biomedicina de Sevilla (IBIS), CSIC, University of Sevilla, Seville, Spain, 2Massachusetts General Hospital, Boston, United States, 3Fred Hutchinson Cancer Center, Seattle, United States, 4University Hospital of Wales, Cardiff, United Kingdom, 5The University of British Columbia, Vancouver General Hospital, Vancouver, Canada, 6University Hospitals Leuven, Leuven, Belgium, 7KU Leuven - University of Leuven, Leuven, Belgium, 8Clinical Hematology Unit, Groupe Hospitalier Pitié-Salpêtrière, AP-HP Sorbonne Université, Paris, France, 9University Hospital of Regensburg, Regensburg, Germany, 10Vanderbilt University Medical Center, Nashville, United States, 11Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy, 12Università Cattolica Sacro Cuore, Rome, Italy, 13Chaim Sheba Medical Center, Tel-Hashomer and Sackler Medical School Tel-Aviv University, Tel-Aviv, Israel, 14Incyte Corporation, Wilmington, United States, 15Syndax Pharmaceuticals, Inc, Waltham, United States, 16City of Hope Medical Center, Duarte, United States, 17Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States

Background: Chronic graft-versus-host disease (cGVHD) is a major cause of morbidity after allogeneic hematopoietic stem cell transplantation. Colony-stimulating factor 1 receptor (CSF-1R)-dependent monocytes and macrophages potentiate inflammation and fibrosis, which are key processes leading to multiorgan damage in cGVHD. Axatilimab, an investigational, high-affinity anti–CSF-1R monoclonal antibody, was evaluated in a pivotal, phase 2, open-label, randomized, multicenter study (AGAVE-201; NCT04710576), and primary results have been reported (Wolff D, et al. Blood. 2023;142(suppl_1):1). This analysis focuses on fibrosis-dominant organ-specific responses and related changes in patient-reported symptom burden. Safety is also examined, with an emphasis on infections.

Methods: Study design details have been reported previously. Organ-specific responses were measured using the 2014 National Institutes of Health cGVHD consensus guidelines. Modified Lee Symptom Scale organ subdomain analyses were performed to identify changes in symptom burden associated with fibrosis.

Results: Across all cohorts (n = 241), 193 patients (80%) had skin involvement (93% of whom had sclerotic skin), 162 (67%) had joints/fascia involvement, 108 (45%) had lung involvement, and 61 (25%) had esophageal involvement. Responses were seen in all involved organs, including complete responses (CRs). Notable efficacy was documented in the fibrosis-dominant organs across all doses with highest responses in the 0.3 mg/kg every 2 weeks (Q2W) cohort (Table). Median (range) time to response for fibrosis-dominant organs was concordant with the previously reported time to overall response, except for skin (0.3-mg/kg cohort, 3.7 [1.0–8.4] months) and lungs (0.3-mg/kg cohort, 2.9 [1.0–7.2] months), where a slight prolongation was observed; median (range) time to response for joints/fascia and esophagus in the 0.3-mg/kg cohort were 1.9 (1.0–9.5) and 1.9 (0.9–10.5) months, respectively. Lung responses (47% in the 0.3-mg/kg cohort), including CR, were based on both forced expiratory volume in 1 second and symptom score improvement criteria. Skin responses were accompanied by reductions in the percentage of sclerotic body surface area in almost half of patients (46% overall), and clinician-reported skin and joint tightening improvement was documented in the majority of patients (61% overall). A ≥ 2-point improvement in photographic range of motion score was recorded in all cohorts and was highest with the 0.3-mg/kg dose (55%), consistent with overall response results. The majority of patients with symptoms related to thickened skin reported improvement (72% overall). Adverse events in the overall population were mostly low grade, reversible, and increased with higher doses, with no unexpected safety signals. No cytomegalovirus or Epstein–Barr virus infections (including reactivations) and no invasive fungal infections occurred in the 0.3-mg/kg cohort; these events were infrequent in the higher-dose cohorts (1–4 patients in each cohort). COVID-19 infections occurred in 44 patients overall (18%); none were fatal.

Table. Responses to Axatilimab in Fibrosis-Dominant Organs.

% (n/N)

0.3 mg/kg Q2W (n = 80)

1 mg/kg Q2W (n = 81)

3 mg/kg Q4W (n = 80)

Overall (N = 241)

Esophagus response*

78 (18/23)

61 (11/18)

60 (12/20)

67 (41/61)

Joints/fascia response*

76 (42/55)

63 (35/56)

57 (29/51)

65 (106/162)

P-ROM

55 (27/49)

36 (18/50)

42 (18/43)

44 (63/142)

Lung response*

47 (15/32)

34 (14/41)

37 (13/35)

39 (42/108)

Skin response*

27 (17/64)

11 (7/63)

23 (15/66)

20 (39/193)

Skin/joint tightening 1-point improvement

66 (35/53)

56 (31/55)

60 (34/57)

61 (100/165)

Skin/joint tightening 2-point improvement

47 (25/53)

35 (19/55)

37 (21/57)

39 (65/165)

Sclerotic skin BSA reduction§

44 (19/43)

34 (15/44)

60 (28/47)

46 (62/134)

Thickened skin (mLSS) reported improvement

73 (33/45)

77 (33/43)

68 (36/53)

72 (102/141)

  1. BSA, body surface area; cGVHD, chronic graft-versus-host disease; mLSS, modified Lee Symptom Score; P-ROM, photographic range of motion; Q2W, every 2 weeks; Q4W, every 4 weeks.
  2. Denominator is the number of patients with an assessment at baseline.
  3. * Per 2014 National Institutes of Health cGVHD consensus guidelines.
  4. Defined as ≥2-point improvement in P-ROM score (range, 0–25).
  5. Improvement in severity of skin and/or joint tightening (clinician assessment; range, 0–10).
  6. § Reduction in BSA involvement by sclerotic skin (any amount, regardless of skin response).
  7. Defined as ≥1-point improvement in mLSS thickened skin subdomain (range, 0–4).

Conclusions: In AGAVE-201, clinical activity in fibrosis-dominant organs is supported by clinician-reported changes in the majority of patients and patient-reported reductions in organ-specific symptom burden. Axatilimab had a generally well-tolerated safety profile; opportunistic infections, which are typically common in patients with cGVHD under heavy immunosuppression, were infrequent with axatilimab.

Clinical Trial Registry: NCT04710576

Disclosure: JAP-S served as a consultant for Incyte Corporation and Sanofi.

ZD served as a consultant for Incyte Corporation, Inhibrx, MorphoSys, Ono Pharmaceuticals, PharmaBiome AG, and Sanofi; received honoraria from Incyte Corporation and MorphoSys; and received research funding from Incyte Corporation, Regimmune, and Taiho Oncology.

SJL received research funding from Amgen, AstraZeneca, Incyte Corporation, Kadmon, Pfizer, and Syndax Pharmaceuticals; served as a consultant for Equillium, Incyte Corporation, Kadmon, Mallinckrodt, and Novartis; received study medication from Janssen; and served as a steering committee member for Novartis and Sanofi.

WI received honoraria from Medac Pharma and served as an advisory board member for Gilead, Novartis, Roche, Sobi, and Synairgen.

JW received honoraria from Novartis and Sanofi.

HS received personal fees from Incyte Corporation, Janssen, Novartis, Sanofi, and the Belgian Hematological Society (BHS) and research grants from Novartis and BHS, all paid to her institution. She also received nonfinancial support (travel grants) from Gilead, Pfizer, EBMT, and CIBMTR.

LS, SS, and A. Shimoni have no disclosures to report.

DW received honoraria from Behring, Gilead, Incyte Corporation, Mallickrodt, Novartis, Sanofi, and Takeda and received research funding from Novartis.

CLK served as an advisory committee member for Horizon Therapeutics and Incyte Corporation.

BT and CT are employees and shareholders of Incyte Corporation.

VR is an employee and shareholder of Syndax Pharmaceuticals.

A. Salhotra received research funding from Bristol Myers Squibb, Gilead, Jazz Pharmaceuticals, Kura Oncology, Orca Bio, and Rigel Pharmaceuticals; served as a speakers bureau member for Sanofi; and served as a board of directors/advisory committee member for Swedish Orphan Biovitrum.

CC served as a consultant for Astellas, Incyte Corporation, Inhibrx, Rigel Pharmaceuticals, Sanofi, and Syndax Pharmaceuticals; served as a data safety monitoring board member for AlloVir and Pluristem Therapeutics; and served as a board of directors/advisory committee member for Cimeio Therapeutics and Oxford Immune Algorithmics.

12: Graft-versus-host Disease – Clinical

O072 POOLED FECAL ALLOGENEIC MICROBIOTHERAPY FOR REFRACTORY GASTROINTESTINAL ACUTE GRAFT-VERSUS-HOST DISEASE: RESULTS FROM THE EARLY ACCESS PROGRAM IN EUROPE

Florent Malard 1, Michael Loschi2, Thomas Cluzeau2, Faezeh Legrand3, Anne Huynh4, Sarah Guenounou4, Cécile Borel4, Jean-Baptiste Méar5, Faustine Lhomme5, Déborah Desmier6, Niels Moya6, Amandine Charbonnier7, Delphine Lebon7, Hélène Labussière-Wallet8, Martin Carré9, Jérôme Cornillon10, Vincent Camus11, Patrice Ceballos12, Francesco Saraceni13, Corentin Orvain14, Sylvain Chantepie15, Jakob Rudzki16, Marie-Anne Couturier17, Patrice Chevallier18, Clémence Mediavilla19, David Beauvais20, Etienne Daguindau21, Karin Bilger22, Stefan Klein23, Jaime Sanz24, Sarah Altmeyer25, Francesca Patriarca26, Marion Bruelle27, Emilie Plantamura27, Mohamad Mohty1

1Saint-Antoine Hospital, Paris, France, 2CHU Nice, Nice, France, 3Institut Paoli Calmettes, Marseille, France, 4IUCT Oncopole, Toulouse, France, 5University Hospital of Rennes, Rennes, France, 6University Hospital of Poitiers, Poitiers, France, 7CHU Amiens-Picardie, Amiens, France, 8Hôpital Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France, 9CHU Grenoble Alpes, Grenoble, France, 10CHU de St-Etienne, Saint Priest en Jarrez, France, 11Centre Henri Becquerel, Rouen, France, 12Hôpital Saint Eloi, Montpellier, France, 13Ospedali Riuniti Torrette di Ancona, Ancona, Italy, 14CHU Angers, Angers, France, 15CHU Caen Normandie, Caen, France, 16Medizinische Universität Innsbruck, Innsbruck, Austria, 17CHRU Brest, Brest, France, 18Nantes University Hospital, Nantes, France, 19CHU Bordeaux, Bordeaux, France, 20CHRU Lille, Lille, France, 21Hôpital Jean Minjoz, Besançon, France, 22Institut de Cancérologie de Strasbourg, Strasbourg, France, 23Medizinische Klinik Hämatologie und Onkologie Universitätsmedizin, Mannheim, Germany, 24Hospital Universitario y Politécnico La Fe, Valencia, Spain, 25Universitätsklinikum des Saarlandes, Homburg, Germany, 26Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy, 27MaaT Pharma, Lyon, France

Background: Fecal microbiotherapy has shown promising results in several pilot studies in aGvHD patients. Here we report clinical outcomes from 140 steroid-refractory (SR) or steroid-dependent (SD) GI-aGvHD patients treated with the pooled allogeneic microbiotherapy MaaT013 as part of the Early Access Program (EAP) in Europe.

Methods: 140 patients (including 2 pediatric patients aged 12 and 15) with SR/SD GI-aGvHD were treated with MaaT013 therapy as part of the EAP in Europe. These patients had previously failed 1 to 6 systemic lines. For each patient, a total of 3 MaaT013 administrations were planned every 7+/-2 days. Each dose is composed of 30 g of feces in 150 mL suspension from 4 to 8 healthy donors, administered by enema (except 1).Treatment response was calculated among all treated patients based on aGvHD staging and grading at D28 at the time of the EAP request.

Results: D28 GI-ORR was 52%: 39 complete response (CR,28%), 26 very good partial response (VGPR,19%), 8 partial response (PR,6%).

Administration of MaaT013 in the two pediatric patients was well tolerated. For one, treatment with MaaT013 led to CR of GI and skin symptoms for up to M12. Liver symptoms improved from M6 without additional therapy. For the other, VGPR was achieved for GI symptoms.

OS was 54% at M6, 47% at M12 and 42% at M18. OS was significantly higher in patients achieving at least GI-PR at D28 (Responder, R; n = 73) compared to patients in treatment failure (Non-responder, NR; n = 67): 74% versus 33% at M6, 68% versus 24% at M12, 58% versus 24% at M18 (p < 0.0001).

In 49 patients previously treated with ruxolitinib (2nd line) and MaaT013 (3rd line), D28 GI-ORR was 63%, with 49% CR. OS was 52% (M6), 49% (M12) and 42% (M18). OS was significantly higher in R, when compared to NR (76% versus 11% at M6,76% versus 6% at M12 and 64% versus 6% at M18 for R and NR respectively, p < 0.0001).

MaaT013 displays a good safety profile in the EAP population: 35 pharmacovigilance cases were reported in 33 patients, including 22 cases that could possibly be considered related to MaaT013 either by the physician or the company: sepsis in 6, bacteremia in 10, rectal bleeding/anorectal disorder in 3, C. difficile colitis in 1, E. coli osteoarthritis in 1, G. silvicola in stools in 1. No pathogen transmission was reported. In 2 patients, non-pathogenic commensal bacteria isolated following infectious events were detected in the administered MaaT013. Causality could not be formally excluded in these cases.

70 deaths were reported: GvHD in 28, severe infection in 24, relapse in 11, hemorrhage in 2, neurological complications post allo-HCT in 1, respiratory distress in 1, cardiac arrest in 2 and unknown for 1 patient. No causality link with MaaT013 administration has been identified.

Conclusions: Clinical data showed that MaaT013 was safe and effective for the treatment of SR/SD-GI-aGvHD, especially in patients having failed ruxolitinib. GI-response correlates with increased OS, suggesting a favorable benefit-risk profile for MaaT013. A Phase 3 trial is currently ongoing to confirm these results in ruxolitinib-refractory patients (NCT04769895).

Disclosure: MBR and EPL are MaaT Pharma’s employees.

12: Graft-versus-host Disease – Clinical

O073 RANDOMIZED MULTICENTER TRIAL OF CALCINEURIN-FREE GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS WITH POST-TRANSPLANTATION CYCLOPHOSPHAMIDE AND RUXOLITINIB IN UNRELATED AND HAPLOIDENTICAL TRANSPLANTATIONS: A FINAL ANALYSIS OF THE PRIMARY ENDPOINT

Ivan Moiseev 1, Mikhail Drokov2, Yulia Kitaeva3, Tatyana Rudakova1, Maria Barabanshchikova1, Ksenia Afanasyeva1, Sergei Bondarenko1, Larisa Kuzmina2, Elena Morozova1, Natalia Popova2, Vera Vasilyeva2, Yulia Vlasova1, Dmitrii Zhogolev1, Tatyana Konstantinova3, Elena Parovichnikova2, Alexander Kulagin1

1RM Gorbacheva Research Institute, Pavlov University, Saint Petersburg, Russian Federation, 2National Research Center for Hematology, Moscow, Russian Federation, 3Regional Hospital #1, Ekaterinburg, Russian Federation

Background: Post-transplant cyclophosphamide (PTCy) is a widely used graft-versus-host disease (GVHD) prophylaxis in haploidentical and unrelated hematopoietic cell transplantation (HCT). Based on the results of a phase I/II study in myelofibrosis (Morozova et al., Acta Hematologica, 2021), it is hypothesized that the combination of PTCy and ruxolitinib may have comparable efficacy in controlling GVHD and better safety profile.

Methods: This multicenter randomized trial (PTCyRuxo, CINC424ARU01T, clinicaltrials.gov NCT04669210) enrolled 128 adult HCT recipients from Nov 2020 to Feb 2023. Inclusion and exclusion criteria defined study group as acute leukemia patients in complete remission without major co-morbidities or complications. Patients were randomized 1:1 with type of donor and Disease Risk Index as strata. Study procedures included FB2-FB4 conditioning according to centers’ standard operating procedures and GVHD prophylaxis with PTCY 50 mg/kg on days +3, + 4. Control group received tacrolimus from day 5 to 100, MMF 30 mg/kg/day from day 5 to 35 and PTCyRuxo group received ruxolitinib 15 mg/day on days 5-21, and 10 mg/day on days 22-150 (PTCyRuxo). Groups were balanced by major patient and HCT characteristics (Table).

Characteristic

Control (N = 66)

PTCyRuxo (N = 62)

Р-value

Age, median (range)

37 (19-66)

34 (18-61)

0.44

Acute myeloid leukemia

67%

66%

Acute lymphoblastic leukemia

33%

34%

0.95

Unrelated donor

56%

60%

Haploidentical donor

44%

40%

0.68

Famales

48%

53%

Males

52%

47%

0.59

DRI 1

9%

6%

DRI 2

85%

84%

DRI 3

6%

10%

0.66

Complete remission 1

70%

73%

0.24

Complete remission 2

26%

27%

Complete remission 3

4%

0%

HTC-CI 0

55%

47%

0.73

HTC-CI 1

31%

36%

HTC-CI 2

10%

13%

HTC-CI 3

4%

2%

HTC-CI 4

0%

2%

Graft source: PBSC

94%

92%

0.66

Graft source: BM

6%

8%

FB2 conditioning

15%

20%

0.81

FB3 conditioning

65%

65%

FB4 conditioning

20%

15%

Results: Median follow up was 16 months. There was no differences in the incidence of engraftment: 89% vs 98%, median day of engraftment - 19 in both groups (р=0.56). The study met its primary endpoint of acute GVHD grade II-IV non-inferiority: acute GVHD incidence 11.4% (95%CI 5.0-20.8%) in PTCyRuxo vs 19.7% (95%CI 11.1-30.1%) in Control group, non-inferiority p = 0.0031, superiority p = 0.1932. Also non-inferiority was demonstrated for PTCyRuxo prophylaxis of moderate and severe chronic GVHD: 24.8% (95%CI 14.7-36.3%) vs 42.0% (95%CI 28.6-54.9%), non-inferiority p = 0.0020, superiority p = 0.1220. Cumulative incidence of non-relapse mortality in PTCyRuxo and Control groups was 8.2% (95%CI 3.0-16.7%) vs 23.5% (95%CI 11.6-37.7%), р=0.0964, cumulative incidence of relapse – 18.3% (95%CI 9.3-29.8%) vs 21.5% (95%CI 6.7-41.8%), р=0.3633, respectively. Overall survival was 91.8% (95%CI 81.4-96.5%) vs 72.4% (95%CI 55.6-83.7%), р=0.0451, event-free survival - 73.5% (95%CI 59.8-83.2%) vs 62.8% (95%CI 44.9-76.4%), р=0.6922, GVHD-relapse-free survival – 63.4% (95%CI 49.2-74.6%) vs 46.1% (95%CI 29.1-61.6%), p = 0.2142, in PTCyRuxo and Control groups respectively. Reduced incidence of cytomegalovirus reactivation (45% vs 63%, р= 0.0439), grade ≥2 kidney toxicity (0% vs 8%, р= 0.0296) and reduced incidence of transplant-associated microangiopathy (0% vs 8%, р=0.0319) was observed in PTCyRuxo arm, while the incidence of other complications was comparable. The incidence of severe adverse events was 27% vs 42%, р= 0.0756. The pattern of immunologic recovery was different in PTCyRuxo group with more pronounced naïve T-cell depletion and higher prevalence of memory and effector CD8+ cells.

Conclusions: PTCyRuxo trial has met its primary endpoint of comparable GVHD control and secondary endpoint of improved safety profile. The final analysis of survival outcomes is planned after the end of follow up.

Clinical Trial Registry: NCT04669210, clinicaltrials.gov

Disclosure: The study was supported through Investigator Initiated Trial program by Novartis. The exploratory laboratory studies were supported by RSF grant №23-15-00327. COI: I.M.: recieved honoraria from Novartis, Sanofi, Takeda, J&J.

12: Graft-versus-host Disease – Clinical

O074 THE IMPACT OF INDIVIDUAL COMORBIDITIES ON NRM RISK FOLLOWING PTCY BASED ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION: AN ALWP EBMT STUDY

Alexandros Spyridonidis 1, Myriam Labopin2, Bipin Savani3, Alexander Kulagin4, Didier Blaise5, Jurjen Versluis6, Simona Sica7, Anna Maria Raiola8, Jan Vydra9, Goda Choi10, Montserrat Rovira11, Mi Kwon11, Jaime Sanz12, Maija Itäla-Remes13, Peter von dem Borne14, Rodrigo Martino15, Yener Koc16, Eolia Brissot17, Arnon Nagler18, Mohamad Mohty17, Fabio Ciceri19

1University of Patras, Patras, Greece, 2Sorbonne University, Saint-Antoine Hospital, Paris, France, 3Vanderbilt University Medical Center, Nashville, United States, 4RM Gorbacheva Research Institute, Pavlov University, St. Petersburg, Russian Federation, 5Programme de Transplantation & Therapie Cellulaire, Marseille, France, 6Erasmus MC Cancer Institute, Rotterdam, Netherlands, 7Universita Cattolica S. Cuore, Rome, Italy, 8IRCCS Ospedale Policlinico San Martino, Genova, Italy, 9Institute of Hematology and Blood Transfusion, Prague, Czech Republic, 10University Medical Center Groningen, Groningen, Netherlands, 11Hospital General Universitario Gregorio Marañon, Madrid, Spain, 12IRCCS Ospedale Policlinico San Martino, Valencia, Spain, 13Turku University Hospital, Turku, Finland, 14Leiden University Hospital, Leiden, Netherlands, 15Hospital Santa Creu i Sant Pau, Barcelona, Spain, 16Medicana International Hospital Istanbul, Istanbul, Turkey, 17Hospital Saint Antoine, Paris, France, 18Chaim Sheba Medical Center, Tel-Hashomer, Israel, 19IRCCS Ospedale San Raffaele s.r.l., Milano, Italy

Background: Post-transplant cyclophosphamide (PTCY) is increasingly used as an effective GvHD prophylaxis in allogenic HCT. However, PTCY is associated with specific organ toxicities. Whether patients with specific comorbidities are more vulnerable to cyclophosphamide-induced toxicity is unclear.

Methods: We evaluated the impact of individual comorbidities for NRM risk in an ALWP-EBMT registry cohort of adult AML patients who underwent between 2010 and 2023 an allogenic HCT (cord blood excluded) with PTCY (in vivo and ex vivo TCD excluded). Comorbidities were defined per standard definitions in the HCT-CI, whereas cardiac comorbidity included also valvular disease and arrhythmia. Outcomes were analyzed using Cox-proportional hazard models.

Results: A total of 5883 AML patients (CR-1 64%, CR2 + 17%, advanced 20%) median age of 58 years (interquartile range, 43-64) received PTCY as GVHD prophylaxis after haploidentical/UD/MSD (61%/28%/11%), RIC/MAC (49%/51%), PBSC/BM (81%/19%) transplantation. 75% patients (n = 4390) had no comorbidities, while 21% (n = 1229) of them had 1 and 4.5% (n = 269) had 2 comorbidities. The most frequently comorbidities were moderate or severe pulmonary dysfunction (15%, n = 870 and 10% n = 578), cardiac disease (9.4%, n = 555), active infection (9%, n = 519), prior malignancy (8%, n = 466) and mild or severe hepatic dysfunction (4.7%, n = 275 and 1.4%, n = 80). NRM incidence was 18.2% (17.2-19.3) and the most frequently NRM causes were multiorgan failure (28%, n = 308), infection (27%, n = 294) and GvHD (11%, n = 122). Cardiac toxicity was identified as primary cause of NRM in 17 cases (1.5%). In a multivariate analysis which included 7 individual comorbidities selected in a stepwise model using the lower Akaike criteria, 5 of them (cardiac, kidney, severe hepatic, severe pulmonary, infection) were independently associated with adverse transplant outcomes (NRM and OS) without influencing the REL rate. Besides individual organ dysfunction, NRM was also significantly influenced by incremental age (per 10years), KPS < = 80%, active disease or infection at transplant and use of an haploidentical donor. Regarding specific organs, cardiac disease was associated with an increased NRM risk in univariate and multivariate analysis (hazard ratio [HR], 1.47; 95% confidence interval [CI], 1.22-1.77, p < 0.0001) and reduced OS (HR, 1.3; 1.3-1.5, p = 0.0002). Severe hepatic or severe pulmonary were also independently associated with NRM (HR 1.64; 1.02-2.62 and 1.22; 1-1.49, respectively) and OS (HR 1.6; 95% CI, 1.13-2.26 and 1.22; 95% CI, 1.06-1.4, respectively). Renal disease, albeit rare (0.9%, n = 54), remained significant for NRM (HR, 2.27; 95% CI, 1.45-3.56, p = 0.0004) and OS (HR, 1.69; 95% CI, 1.16-2.46, p = 0.006). Diabetes and obesity, though prevalent (5% and 4.5%, respectively), were not associated with increased NRM. A simplified model using the absence (n = 4390), presence of 1 (n = 1229) or presence of 2 or 3 (n = 269) of the 5 comorbidities which were determined individually to contribute to NRM, could stratify patients into 3 NRM risk (16.2%, 21.6%, 36%, respectively, p = 0.001) and OS categories (64%, 56%, 36.4%. respectively, p = 0.001).

Conclusions: Individual dysfunction of key organs (cardiac, pulmonary, kidney) confers significant additional NRM risk in PTCY treated patients. In contrast, diabetes or obesity should not preclude for using PTCY. Programs of PTCY dose modulation should be promoted in patients with selected comorbidities.

Clinical Trial Registry: EBMT Registry study, approved by the ALWP of EBMT

Disclosure: Nothing to declare related to this study. Mi Kwon decalred following COIs: speaker for Gilead, Jazz, Pfizer.

12: Graft-versus-host Disease – Clinical

O075 PTCY, TAC/ CSA, MMF VS ATG, TAC / CSA, MTX GVHD PROPHYLAXIS POST SIBLING AND UNRELATED TRANSPLANTATIONS FOR AML: FROM THE ALWP OF THE EBMT

Arnon Nagler 1, Myriam Labopin2,3, Thomas Schroeder4, Rose-Marie Hamladji5, Laimonas Griskevicius6, Urpu Salmenniemi7, Alessandro Rambaldi8, Stephan Mielke9, Sergey Bondarenko10, Jakob Passweg11, Peter Dreger12, Tobias Gedde-Dahl13, Edouard Forcade14, Grzegorz Helbig15, Matthias Stelljes16, Cristina Castilla-Llorente1717, Alexandros Spyridonidis18, Bipin Savani19, Eolia Brissot3, Fabio Ciceri20, Mohamad Mohty2,3

1Sheba Medical Center, Division of Hematology, Tel Hashomer, Israel, 2EBMT Paris study office; Saint Antoine Hospital, Paris, France, 3Sorbonne University, Saint-Antoine Hospital, AP-HP, INSERM UMRs 938, Paris, France, 4University Hospital of Essen, Essen, Germany, 5Centre Pierre et Marie Curie, Alger, Algeria, 6Vilnius University, Hospital Santaros Klinikos, Vilnius, Lithuania, 7HUCH Comprehensive Cancer Center, Helsinki, Finland, 8University of Milan and Azienda Socio-Sanitaria Territoriale, Papa Giovanni XXIII, Bergamo, Italy, 9Karolinska University Hospital, Stockholm, Sweden, 10RM Gorbacheva Research Institute, Pavlov University, Petersburg, Russian Federation, 11University Hospital of Basel, Basel, Switzerland, 12University of Heidelberg, Heidelberg, Germany, 13Oslo University Hospital, Rikshospitalet,, Norway, 14CHU Bordeaux, Hôpital Haut-Leveque, Pessac, France, 15Silesian Medical Academy, Katowice, Poland, 16University of Muenster, Muenster, Germany, 17Gustave Roussy Cancer Campus, Villejuif, France, 18University Hospital of Patras, Patras, Greece, 19Vanderbilt University, Medical Center, TN, United States, 20IRCCS Osspedale San Raffaele, Vita-Salute San Raffaele University Hematology and BMT, Milano, Italy

Background: The BMT CTN 1703 phase III randomized study compared post-transplant cyclophosphamide with tacrolimus with mycophenolate mofetil (PTCy/TAC/MMF) to TAC /methotrexate (MTX) as GVHD prophylaxis post allogeneic transplantation (HSCT) from matched siblings (MSD) or 7-8/8 unrelated donors (MUD), demonstrating a lower incidence of severe acute (a) and chronic (c) GVHD and better GRFS. However, the control arm did not contain ATG, and CSA was not included.

Methods: The study aim was to compare PTCy with TAC or cyclosporine A (CSA) and MMF (PTCy/TAC or CSA & MMF) vs. ATG with TAC or CSA and MTX (ATG/TAC or CSA & MTX) in AML patients (pts) undergoing MSD or 9-10/10 MUD HSCT in CR1. Statistical tests included a multivariate analysis (MVA) using a Cox proportional-hazards regression model for main outcomes. A propensity score matching was also performed as a sensibility analysis.

Results: 6050 pts met the inclusion criteria, 402 received PTCy/TAC or CSA & MMF and 5648 received ATG/TAC or CSA & MTX. Follow-up was 23.4 (IQR, 20.3-24.9) and 41.8 (IQR, 39.6-43.3) months (p < 0.0001). Pts in the PTCy/TAC or CSA & MMF group were younger, with a median age of 48.7 (range 18-5.6) vs. 51.5 (8-77.8) years (y) (p = 0.024). The cytogenetic risk category did not differ between pts in the PTCy/TAC or CSA & MMF and ATG/TAC or CSA & MTX groups, respectively (p = 0.35). More pts in the PTCy/TAC or CSA & MMF group received RIC 51.5% vs. 41.1% in the ATG/TAC or CSA & MTX group, respectively (p < 0001). Neutrophil engraftment (ANC > 0.5 x 109/L) was 98.7% vs. 98.6%, respectively (p = 0.84). Day 180 incidence of aGVHD grade II-IV and III-IV was 21.2% vs. 20.4% (p = 0.92) and 8.1% vs. 6% (p = 0.1), in pts receiving PTCy/TAC or CSA & MMF vs. the ATG/TAC or CSA & MTX, respectively. The 2- y total and extensive cGVHD were 33.7% vs. 30% (p = 0.09) and 10.7 % vs. 11.2%, respectively (p = 0.81). GVHD was the cause of death in 11.6% vs. 13.9% of pts who died. In the MVA, both aGVHD grade II-IV or III-IV) and cGVHD (total or extensive) did not differ between the groups with hazard ratios for PTCy/TAC vs CSA & MMF (HRs) = 0.95 (95% CI 0.71-1.27, p = 0.71), HR = 1.38 (95% CI 0.88-2.16, p = 0.16), HR = 1.2 (95% CI 0.91-1.56, p = 0. 19 and HR = 0.66 (95% CI 0.41-1.04, p = 0.074). Data were confirmed by the pair match analysis. The HRs for NRM and RI were 0.70 (95% CI 0.47-1.07, p = 0. 010) and 1.10 (95% CI 0.83-1.46, p = 0. 50). The HRs for LFS, OS, and GRFS were HR = 0.96 (95% CI 0.76-1.21, p = 0.71), HR = 0.93 (95% CI 0.72-1.21, p = 0.59) and HR = 1.03 (95% CI 0.84-1.26, p = 0.76).

Conclusions: In this retrospective analysis, comparing PTCy in combination with TAC or CSA and MMF to ATG in combination with TAC or CSA and MTX as GVHD prophylaxis, we observed a similar incidence and severity of both aGVHD and cGVHD. Likewise, NRM, RI, LFS, OS, and GRFS did not differ between the two study groups.

Disclosure: Nothing to declare

12: Graft-versus-host Disease – Clinical

O076 A PRETRANSPLANT INFLAMMATORY SIGNATURE IS ASSOCIATED WITH ACUTE GRAFT-VERSUS-HOST DISEASE AND MORTALITY IN PEDIATRIC PATIENTS

Anne B. Verbeek 1, Erik G J. von Asmuth1, Erik B. van den Akker1, Anja M. Jansen-Hoogendijk1, Marco W. Schilham1, Arjan C. Lankester1, Gertjan Lugthart1, Alexander B. Mohseny1, Emilie P. Buddingh1

1Leiden University Medical Center, Leiden, Netherlands

Background: In this explorative study we aimed to identify inflammatory serum proteins measured before allogeneic hematopoietic stem cell transplantation (HSCT) that are associated with acute Graft-versus-Host Disease (aGvHD) and mortality in pediatric HSCT recipients.

Methods: In this single-center retrospective cohort study, we measured 28 inflammatory serum proteins using a Luminex immunoassay in 384 pediatric patients (2010-2022). A sample before start of the conditioning (TP1) was included, as well as a sample on the day of HSCT (TP2). For patients who developed aGvHD we also included a sample at the time of diagnosis, before initiation of systemic treatment (TP3). Associations with aGvHD, steroid-refractory aGvHD, non-relapse mortality (NRM) and overall survival (OS) were analyzed using robust (cause-specific) Cox models. A sensitivity analysis for underlying disease subgroups was performed. We evaluated the dynamics in serum protein levels before and after conditioning. All reported p-values were significant (p ≤ 0.05) after multiple testing correction (Benjamini-Hochberg).

Results: We included 384 children (age range 0.2-18.6 years) with malignant (30%) and non-malignant (70%) indications for allogeneic HSCT. Patient and transplant characteristics are shown in Table 1. At 1-year post-HSCT OS was 86%, NRM was 10% and the incidence of aGvHD was 18%.

At TP1, TNFR1 (cause-specific hazard ratio (csHR) 1.61, p < 0.001), sIL2-Rα (csHR 1.54, p < 0.001) and TNFR2 (csHR 1.53, p < 0.001) were highly associated with the development of aGvHD. CXCL16, TNFR1 and SCF at TP1 were highly associated with NRM and OS. The associations of serum proteins with outcomes were not driven by one specific underlying disease subgroup.

At the onset of aGvHD (TP3) ST2 levels were significantly associated with the development of steroid-refractory aGvHD (csHR 2.21, p < 0.001, AUC 83.6), as previously reported in biomarker studies in predominantly adult HSCT populations.

Conclusions: Pre-conditioning inflammatory serum protein levels are associated with adverse outcomes after HSCT in children. To our knowledge, this is the largest aGvHD biomarker study in a pediatric HSCT cohort. TNFR1, sIL2-Rα and TNFR2 before conditioning had the strongest association with aGvHD and CXCL16, TNFR1 and SCF were most-strongly associated with NRM and OS. After confirmation of these findings by future studies, the potential prognostic biomarkers reported here might be used to select pediatric patients pre-HSCT for alternative prophylactic aGvHD strategies. ST2 levels at aGvHD diagnosis is a validated predictive biomarker for steroid-refractory aGvHD in children.

Table 1: Patient and Transplant characteristics

N = 384

Age (median, IQR)

8.2 (3.0-13.1)

Patient sex

Male

235 (61%)

Female

149 (39%)

Diagnosis

Hematologic malignancy

115 (30%)

Hemoglobinopathy and other non-malignant hematologic diseases

103 (27%)

Bone marrow failure

82 (21%)

Inborn error of immunity

81 (21%)

Other

3 (0.8%)

Donor type

Matched unrelated

129 (34%)

Mismatched unrelated

112 (29%)

Matched related

105 (27%)

Mismatched related

38 (9.9)

Graft type

Bone marrow

295 (77%)

Umbilical cord blood

50 (13%)

Peripheral blood stem cells

39 (10%)

Disclosure: Nothing to declare

12: Graft-versus-host Disease – Clinical

O077 DELAYED ADMINISTRATION OF IXAZOMIB AS PROPHYLAXIS FOR CHRONIC GRAFT-VERSUS-HOST DISEASE (CGVHD)

Javier Delgado Serrano 1,2,3, Lucía López Corral4,5, David Valcárcel6,7, Jorge Sierra8, Christelle Ferra-Coll9, Teresa Caballero Velázquez1,2,3, Francisco Martín Domínguez1,2,3, Reyes Jiménez León1,2,3, Juan Luis Reguera Ortega1,2,3, Cristina Blázquez Goñi1,2,3, Estefanía Pérez López4,5, Almudena Cabero Martínez4,5, Irene García Cadenas8, José Antonio Pérez Simón1,2,3

1Hospital Universitario Virgen del Rocío, Sevilla, Spain, 2Instituto de Biomedicina de Sevilla, Sevilla, Spain, 3Universidad de Sevilla, Sevilla, Spain, 4Hospital Universitario de Salamanca, Salamanca, Spain, 5IBSAL, Salamanca, Spain, 6Vall Hebron Institute of Oncology, Barcelona, Spain, 7Vall Hebron University Hospital, Barcelona, Spain, 8Hospital Santa Creu i Sant Pau, Barcelona, Spain, 9Hospital Universitari Germans Trias i Pujol, Badalona, Spain

Background: Most strategies of graft-versus host disease prophylaxis (GvHD) are based on early postrasplant interventions; nevertheless, the pathophysiology of chronic GvHD involves different cell subpopulations that remain abnormal at the long term and depend on nuclear factor kappa-beta (NF-kb) for their activation and, therefore, can be targeted using proteosome inhibitors. The aim of this study is to demonstrate the safety and efficacy of ixazomib administered from day +100 in the prevention of moderate or severe cGVHD.

Methods: We performed a prospective, randomised, multicentre trial including 73 patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) between 2019-22. Patients in the treatment arm received 4 mg of oral Ixazomib (Ixa) on days +1, +8 and +15 from +d100 every 28 days up to a maximum of 15 cycles. Immunological characterisation by flow cytometry was performed on peripheral blood at days +100, +180, +270, +365, +540 and +720.

Results: Thirty-nine patients were randomized to the treatment arm and thirty-four to the control arm. There were no significant differences between the two groups in terms of baseline characteristics, conditioning, acute GvHD (aGvHD) prophylaxis or history of previous aGVHD.At a median follow-up of 24 months, significant differences were observed in the 2-year cumulative incidence of moderate-severe cGvHD between the Ixa and control groups (13% vs 43% respectively, HR = 0.23, 95% CI = 0.07-0.071, p = 0.001), as well as overall cGvHD (44% vs 63% respectively, HR = 0.52, 95% CI = 0.27-1.01, p = 0.048). There were no significant differences in the risk of relapse, although there was a trend in favour of Ixa (14% vs 27%, p = 0.22). Event and GvHD-free survival (EGFS) was significantly better in the Ixa group (81% vs 51%, HR = 0.30, 95% CI = 0.12-0.72, p = 0.007). The main toxicity associated with ixazomib was digestive, observed in 36% vs 3% in the first 3 cycles (p = 0.001) and 25% vs 3% in cycles 4-9 (p = 0.013).On day +180 median fluorescence intensity (MFI) for Stat3 phosphorylation (pStat3) in IL-6 stimulated CD4 + T cells (HR = 6.78, p = 0.015), MFI for pStat3 in stimulated CD8 + T cells (HR = 5.4, p = 0.029), the proportion of B cells that have undergone class switching (SMBC) (HR = 12.8, p = 0.016) and the presence of circulating plasma cells (HR = 4.98, p = 0.042) were significantly related to the risk of developing moderate/severe cGvHD. In addition, the increase of expression of BAFF receptor (ΔBAFFR) (MFI on day 180 respect day 100) in B cells was significantly higher in patients with moderate/severe cGvHD (HR = 8.81, p = 0.042). The proportion of SMBC (16.94 vs 27.35, p = 0.012), ΔBAFFR (-1334.96 vs 1230.27, p = 0.009) and the concentration of soluble BAFF (ng/ ml) (0.03 vs 1.21, p = 0.013) were significantly different between Ixa and control group.

Table 1: Predictive biomarkers of moderate-severe chronic GVHD on day + 180 after allogeneic transplant

Biomarker D + 180

Hazard Ratio (IC)

p

pSTAT3 in CD8 (IL6)

5,4 (1,2 - 24,7)

0,029

pSTAT3 in CD4

5,34 (1,2 - 24,4)

0,030

pSTAT3 in CD4 (IL6)

6,78 (1,5 – 31)

0,013

pSTAT3 in CD3

12,5 (1,6 – 97,1)

0,015

p38 in CD4

5,27 (1,2 – 24,1)

0,032

SMBC CD19

12,8% (1,6 - 101)

0,016

∆ BAFF-R

0,042

(IFM D + 180 – D + 100)

8,8 (1,1 – 71,7)

Circulating plasma cells

4,98 cels/µL (1,05 – 23,49)

0,042

Conclusions: The administration of Ixazomib from day +100 post-allogeneic transplant prevents the development of cGvHD, especially in its moderate or severe form, improving EGFS and cGvHD. Several biomarkers related to T and B cells activation were associated with an increased risk of developing cGvHD.

Clinical Trial Registry: NCT03225417

https://ichgcp.net/es/clinical-trials-registry/NCT03225417

Disclosure: No conflict of interest

12: Graft-versus-host Disease – Clinical

O078 RUXOLITINIB IN ACUTE AND CHRONIC GRAFT-VERSUS-RECEPTOR DISEASE: LONG-TERM REAL-LIFE EXPERIENCE IN A MULTI-CENTRE STUDY IN PEDIATRIC POPULATION

Virginia Escamilla Gómez 1, Beatriz Astibia Mahillo2, Patricia Alcalde Mellado1, Francisco Manuel Martín Domínguez1, Marta González Vicent3, Pedro Asensi Cantó4, Juan Montoro Gómez4, Inés Gómez Seguí4, María Isabel Benítez Carabante5, Cristina Díaz de Heredia Rubio5, Luisa Sisinni6, Antonio Pérez Martínez6, José María Pérez Hurtado1, José Antonio Pérez Simón1, Valentín García Gutiérrez2

1Hospital Universitario Virgen del Rocío, Sevilla, Spain, 2Hospital Universitario Ramón y Cajal, Madrid, Spain, 3Hospital Niño Jesús, Madrid, Spain, 4Hospital Universitario y Politécnico La Fe, Valencia, Spain, 5Hospital Universitari Vall d´Hebron, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain, 6Hospital La Paz, Madrid, Spain

Background: The JAK1/2 inhibitor ruxolitinib has been approved for the treatment of adults and youngers above ≥12 years for acute or chronic graft-versus-receptor disease (GvHD) based on the REACH-2 and 3 studies. Recently, the REACH-4 trial evaluates its effectiveness in the pediatric population; however, experience in this population is scarce.

Methods: Analysis of 42 pediatric patients ( < 14 years) with acute or chronic GvHD refractory to corticosteroids through a retrospective, descriptive and multicenter study from 17 Spanish centers belonging to the Spanish Group of Transplantation and Cellular Therapy (GETH-TC) between October/2015 and September/2022. The severity of acute GvHD was evaluated using the Harris scale; for chronic GvHD, NIH consensus scale was used.

Results: The baseline characteristics and decrease in immunosuppression are shown in table 1 and figure 1.

Acute GvHD group. 29 patients were analyzed. The overall response (OR) was 82.7 % (51.7% complete remissions, CR). The median time to achieve maximum response was 4 weeks (range: 1-16). The responses by organ were: skin 88.8% (CR: 66.6%), gastrointestinal tract 69.5% (CR: 56.5%) and liver 66.6% (CR: 33.3%). No differences were observed in terms of response depending on the previous lines of treatment. 11 patients died due to the following causes: GVHD progression 3, relapse 2, infection 3, others 3. Overall, 3 patients relapsed from their underlying disease.

Among responders, 66.6% and 75% were able to withdraw corticosteroids and ruxolitinib, respectively. The 6-month OS between responders vs non-responders was 77.4% (95% CI: 53.6-90) vs 20% (95% CI: 0-58.2), p = 0.00.

Chronic GvHD group. 13 patients were analyzed. The OR and CR were 100% and 23%, respectively. By organs, all patients with gastrointestinal involvement achieved CR, and all patients with lung involvement and scleroderma achieved partial response. No differences were observed in terms of response depending on the previous lines of treatment. A single patient died due to relapse of his underlying hematological disease. In total, 2 patients relapsed in this group.

Among responders, 30.7% were able to withdraw corticosteroids and 30.7% were able to withdraw ruxolitinib. The 2-year OS was 100%.

Table 1. Patients characteristics

N (%)

Pediatrics (n = 42)

Gender

Male

26 (61.9)

Female

16 (38.1)

Age

Median (range)

6 (0-13)

Underlying disease

AML

8 (19)

ALL

14 (33.3)

MDS

2 (4.8)

AA

6 (14.3)

Primary inmunodeficiencies

6 (14.3)

Other

6 (14.3)

Disease status previous HSCT

CR

20 (47.6)

PR

2 (4.8)

SD

9 (21.4)

Others

11 (26)

Type of trasplant

Related HLA identical donor

5 (11.9)

Haploidentical

11 (26.2)

Unrelated donor

26 (61.9)

Conditioning regimen

Myeloablative

33 (78.6)

Reduced-intensity

9 (21.4)

Source of progenitor cells

Peripheral blood

20 (47.6)

Bone marrow

12 (28.6)

Umbilical cord

7 (16.7)

Table 1. Baseline characteristics of the study population. AA: aplastic anemia; ALL: acute lymphoblastic leukemia; AML: Acute myeloblastic leukemia; CR: complete remission; MDS: myelodysplastic syndrome; PR: partial response; SD stable disease.

The 50th Annual Meeting of the European Society for Blood and Marrow Transplantation: Physicians - Oral Session (O009-O154) (8)

Figure 1. Evolution of Immunosuppression among responding patients. The figure shows the total number of responding patients taking each drug at the beginning of treatment with ruxolitinib and at the end of treatment or at the last visit.

Conclusions:

  • Real-life ruxolitinib data show very favorable results in the pediatric population.

  • By organs, the results in acute GvHD are very favorable in the skin and gastrointestinal tract. In chronic GvHD all patients responded, achieving CR rates of 100% at the gastrointestinal level.

  • These results seem not to be influenced by lines of treatment (<2 vs ≥2; <3 vs ≥3).

  • In the group of responders, a reduction in the number of patients taking immunosuppressants was achieved at the end of treatment.

Disclosure: *This project has been carried out through the GETH-TC (Spanish Group for Transplantation and Cellular Therapy - Grupo Español de Trasplante Hematopoyético y Terapia Celular) and funded by Novartis.

12: Graft-versus-host Disease – Clinical

O079 CLINICAL EXPERIENCE IN THE USE OF MESENCHYMAL STROMAL CELLS IN PEDIATRIC GRAFT-VERSUS-HOST DISEASE: ON BEHALF OF THE SPANISH GROUP OF STEM CELL TRANSPLANTATION (GETH)

Carlos Echecopar Parente1, David Bueno Sánchez1, Blanca Molina Angulo2, María Isabel Benitez Carabante3, Iván López Torija4, María Trabazo5, Carolina Fuentes6, Mercedes Plaza7, Antonia Pascual Martínez8, Andrea Urtasun9, Susana Riesco10, Soledad González Muñíz11, Sara Vinagre2, Cristina Díaz de Heredia3, Julia Marsal 5, Marta González-Vicent2, Antonio Pérez-Martínez1,12,13

1La Paz University Hospital, Madrid, Spain, 2Niño Jesús University Hospital, Madrid, Spain, 3Vall d´Hebron University Hospital, Barcelona, Spain, 4Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, 5Sant Joan de Deu University Hospital, Barcelona, Spain, 6La Fe University Hospital, Valencia, Spain, 7Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain, 8Hospital Regional Universitario de Málaga, Málaga, Spain, 9Clínica Universidad de Navarra, Pamplona, Spain, 10Complejo Asistencial Universitario de Salamanca, Salamanca, Spain, 11Hospital Universitario Central de Asturias, Oviedo, Spain, 12University Hospital La Paz Research Institute (IdiPAZ), Madrid, Spain, 13Universidad Autónoma de Madrid, Madrid, Spain

Background: Graft-versus-host disease (GVHD) contributes to the elevated morbidity and mortality rates in hematopoietic stem cell transplantation. Mesenchymal stromal cells (MSCs) is a cell therapy used in several immune-mediated diseases, such as GVHD. Our objective was to evaluate the efficacy of MSCs in pediatric GVHD and identify factors associated with treatment response.

Methods: This is a retrosprospective, multicenter study that includes pediatric patients (0-18 years old) who have received MSCs for the treatment of GVHD (both acute and chronic) in spanish centers between June 2014 and July 2023.

Results: A total of 102 patients from 11 different centers were included in the study, 78 patients (76.5%) had acute GVHD, and 24 (23.5%) chronic GVHD.The median follow-up duration was 11 months. Overall response rate was 76.5% at day 28 [30.4% complete response (CR) and 46.1% partial response (PR)] without statistically significant differences between the type of GVHD. Response was associated with the dosage used in the infusions (p = 0.007), showing a CR rate of 37.3% in patients receiving ≥ 1x10e6 cells/kg vs a CR rate of 11.1% in patients receiving < 1x10e6 cells/kg (Table 1). Other treatment-related variable associated with response was MSCs source. There were no progressions in the group of patients who received MSCs extracted from Wharton’s jelly, whereas in patients who received MSCs from bone marrow and adipose tissue the progresion rate was 16.4% and 25%, respectively (p = 0.017) (Table 1). Finally, the total number of MSC infusions demonstrated a statistically significant association with the response level (p = 0.011). Patients receiving less than four infusions showed a CR rate of 14.3%, compared to 38.9% for those receiving a total of four infusions and 25.9% for those receiving more than four. The progression rate was 23.8% in the group with fewer than four infusions, 3.7% in the group with four, and 18.5% in the group with more than four infusions (p = 0.011) (Table 1). In acute GVHD, the organ that showed better results was the skin, with a complete response rate of 71.9% and no progressions. Response to MSCs, infusion dosage, and total number of infusions were correlated with three-year overall survival and transplant-related mortality.

TABLE 1. Response level at day 28 based on treatment-related variables

Complete response (n = 31)

Partial response (n = 47)

No response (n = 12)

Progression (n = 12)

p-value

Days from diagnosis to treatment

0.0981

- Median (IQR)

35 (3-196)

35.5 (4-406)

35.5 (7-1224)

39 (10-138)

Indication; n(%)

0.1142

- Steroid-refractory

16 (22.2)

37 (51.4)

9 (12.5)

10 (13.9)

- Steroid-dependent

13 (52)

9 (36)

1 (4)

2 (8)

- Steroid intolerance

2 (50)

1 (25)

1 (25)

MSCs source; n(%)

0.0172

- Bone marrow

16 (26.2)

32 (52.5)

3 (4.9)

10 (16.4)

- Fat tissue

3 (37.5)

2 (35)

1 (12.5)

2 (25)

- Wharton’s jelly

12 (36.4)

13 (39.4)

8 (24.2)

Infusions dosage; n(%)

0.0072

- ≥ 1x10e6 cells/kg

28 (37.3)

32 (42.7)

10 (13.3)

5 (6.7)

- < 1x10e6 cells/kg

3 (11.1)

15 (55.6)

2 (7.4)

7 (25.9)

Total infusions; n(%)

0.0112

- < 4

3 (14.3)

8 (38.1)

5 (23.8)

5 (23.8)

- 4

21 (38.9)

24 (44.4)

7 (13)

2 (3.7)

- > 4

7 (25.9)

15 (55.6)

5 (18.5)

  1. IQR: Interquartile range; MSCs: Mesenchymal stromal cells
  2. 1. ANOVA test
  3. 2. Chi-square test

Conclusions: MSCs represent a potentially effective treatment for pediatric GVHD, with promising results in this retrospective analysis. Treatment-related factors like MSCs dosage, source and total of infusions might be related to response to this therapy. The results of this study needs to be confirmed and validated through multicenter prospective randomized studies.

Disclosure: Nothing to declare

12: Graft-versus-host Disease – Clinical

O080 POST-TRANSPLANT CYCLOPHOSPHAMIDE, ABATACEPT, AND VEDOLIZUMAB TO PREVENT GVHD AFTER HSCT FROM HAPLOIDENTICAL DONORS IN CHILDREN WITH ACUTE LEUKEMIA: RESULTS OF A PROSPECTIVE TRIAL

Margarita Perminova1, Larisa Shelikhova1, Maria Klimentova1, Maria Dunaykina1, Anna Vasilieva1, Sergey Blagov1, Svetlana Kozlovskaya1, Dmitriy Balashov1, Alexander Popov1, Daria Kobyzeva1, Natalya Miakova1, Yakov Muzalevsky1, Galina Novichkova1, Alexey Maschan1, Michael Maschan1, Alexandra Laberko 1

1Dmitry Rogachev Federal Research Centre of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation

Background: GvHD remains a crucial complication associated with significant morbidity and mortality after allogeneic HSCT. High-dose PTCy targets alloreactive donor T cells proliferating early after HSCT, promotes regulatory T cells, and prevents severe GvHD. The effectiveness of PTCy-based regimens varies depending on the graft source and intensity of the preparative regimen. Improvement of GvHD control with novel targeted agents, added to the backbone of PTCy, could further increase the safety of HSCT and reduce the morbidity and complications of standard regimens of pharmacological immune suppression. In this pilot trial, we evaluated the safety and efficacy of abatacept and vedolizumab in unmanipulated haploidentical transplantation among children with leukemia.

Methods: A total of 58 pts with acute leukemia (AML- 20, ALL-38, 26 females, 30 males, the median age at HSCT - 7,4 years), underwent unmanipulated allogeneic BM (n = 56) or PBSC (n = 2) transplantation between March 2022 and May 2023. Fifty-four pts received haploidentical graft, 4 a graft from MUD. Disease status at transplant was CR1 in 27 pts, CR > 2 in 31 pts. For all patients it was the 1-st transplantation. All patients received myeloablative conditioning, either TBI-based (n = 31) or treosulfan-based (n = 27). Prophylaxis of GvHD consisted of CsA since day-1 to day 180, 50 mg/kg of PTCy on days +3 and +4, abatacept at 10 mg/kg on days +5, +14, +28, +45, +60 and vedolizumab at 10 mg/kg (capped at 300 mg) on days -1, +14, +28. The median dose of CD34+ cells was 4,79 x106/kg, and the CD3 dose was 42 x106/kg.

Results: Primary engraftment was achieved in 57 (98%) pts; the median time to neutrophil and platelet recovery was 20 and 23 days, respectively. One patient failed to engraft, relapsed, and required rescue with a second HSCT from an alternative donor. The regimen was generally well tolerated. Acute toxicity consisted of grade 3-4 mucositis (n = 10); hemorrhagic cystitis grade II-III (n = 4); severe VOD (n = 2) (all cases of VOD developed after pre-HSCT use of inotozumab); bloodstream infections (n = 8).

The median follow-up time for survivors was 12,5 months. TRM was 3,8% (95% CI:1-15): two patients died (one due to consequences of severe VOD and infection on day + 60, one due to the infection and GvHD on day +268). 19 patients had aGvHD, the CI of aGvHD grade II-IV was 33% (95% CI, 23 - 47), and grade 3-4 was 9% (95% CI, 4 - 20). The CI of gut aGvHD grade II-IV was 10% (95% CI, 4 - 24), all pts had norovirus infection. The CI of ChGvHD was 8% (95% CI, 3 - 21). The CI of relapse was 12% (95%CI:6-25) in the entire cohort. EFS and OS were 84% (95%CI: 74-94) and 94% (95%CI: 87-100), respectively. The GRFS (survival without aGVHD3-4, extensive chGvHD and relapse) was 73% (95%CI:62-85).

Conclusions: Our data suggest that adding vedolizumab and abatacept to the PTCy-based GVHD prophylaxis backbone is well tolerated and ensures high engraftment rate and low transplant-related mortality. This approach can be further developed to reduce exposure to calcineurin inhibitors and deploy additional anti-leukemia effectors after HSCT.

Clinical Trial Registry: NCT05515029

Disclosure: M. Maschan - Miltenyi Biotec Honoraria

D. Balashov - Octafarm - Lecturers fee

12: Graft-versus-host Disease – Clinical

O081 PTCY PLUS ATG COMPARED TO PTCY ALONE IN HAPLOIDENTICAL TRANSPLANTATION WITH PBSCS: A RETROSPECTIVE STUDY ON BEHALF OF THE CTIWP OF THE EBMT

Antoine Capes 1, Jarl Mooyaart2, Didier Blaise3, Stefania Bramanti4, Mi Kwon5, Mohamad Mohty1, Patrice Chevallier6, Jan Vydra7, Péter Reményi8, Edouard Forcade9, Lucía López Corral10, Maija Itäla-Remes11, Ali Bazarbachi12, Enrico Derenzini13, Jorinde D. Hoogenboom14, Jürgen Kuball15, Giorgia Battipaglia16, Florent Malard1, Annalisa Ruggeri17

1Hôpital Saint-Antoine, APHP, Paris, France, 2EBMT Statistical Unit, Leiden, Netherlands, 3Programme de Transplantation & Therapie Cellulaire, Marseille, France, 4IRCCS Humanitas Research Hospital, Milano, Italy, 5Hospital Gregorio Marañón, Madrid, Spain, 6CHU Nantes, Nantes, France, 7Institute of Hematology and Blood Transfusion, Prague, Czech Republic, 8Dél-pesti Centrumkórház, Budapest, Hungary, 9CHU Bordeaux, Hopital Haut-Leveque, Bordeaux, France, 10Hospital Clínico, Salamanca, Spain, 11Turku University Hospital, Turku, Finland, 12American University of Beirut Medical Center, Beirut, Lebanon, 13European Institute of Oncology, Milano, Italy, 14EBMT Leiden Study Unit, Leiden, Netherlands, 15University Medical Center Utrecht, Utrecht, Netherlands, 16Federico II University of Naples, Naples, Italy, 17San Raffaele Scientific Institute, Hematology and Bone Marrow Transplantation Unit, Milan, Italy

Background: The use of haploidentical hematopoietic cell transplantation (haplo-HCT) with peripheral blood stem cells (PBSCs) to treat high risk hematological malignancies is increasing worldwide. In this setting, prevention of graft-versus-host disease (GVHD) with post-transplant cyclophosphamide (PTCy) has emerged as a gold standard. Some centers add anti-thymocyte globulin (ATG) to PTCy aiming to reduce the risk of GVHD. In a few retrospective studies this approach decreased the GVHD incidence with no impact on overall survival (OS) or disease-free survival (DFS). However, those studies were limited to acute myelogenous leukemias in first or second remission and included only a small number of patients in the PTCy+ATG group. Here, we sought to compare patients’ outcomes after PBSC haplo-HCT using PTCy alone versus PTCy+ATG, on behalf of the Cellular Therapy and Immunobiology Working Party of the European Society of Blood and Marrow Transplantation (EBMT).

Methods: We compared the outcomes of 5326 adult patients receiving a haplo-HCT with PBSCs for a hematological malignancy, with either PTCy alone (n = 4639) or PTCy+ATG (n = 687) for GVHD prophylaxis, reported to the EBMT registry between January 2014 and December 2021. In addition, all patients received a calcineurin inhibitor and mycophenolate mofetil. All hematological malignancies except plasma cell dyscrasia, were included.

Results: The median follow-up was 29 months among surviving patients. The two groups were similar in terms of disease and transplant characteristics. Transplant indications were acute leukemias followed by myelodysplastic or myeloproliferative neoplasms then lymphomas. Two-year GVHD-relapse-free survival (GRFS) was similar between the PTCy+ATG and PTCy groups, being 36.1%, versus 39.5%, respectively (p = 0.074). This was confirmed in the multivariable analysis (HR 1.08 [0.97, 1.21], p = 0.02). The 2-year OS was significantly lower in the PTCy+ATG group (52.5%), versus the PTCy group (56.7%, p = 0.015), with no significant difference in the multivariable analysis (HR 1.13 [1.00, 1.28], p = 0.059). DFS was also lower in the PTCy+ATG group (46.9%), versus the PTCy group (52.5%, p = 0.006), and it was confirmed in the multivariable analysis, (HR 1.16 [1.03, 1.31], p = 0.0015). There was no difference in the cumulative incidence of relapse in the PTCy+ATG versus PTCy group (HR 1.14 [0.96, 1.36], p = 0.14), while the non-relapse mortality (NRM) was significantly higher with PTCy+ATG (HR 1.18 [1.00, 1.40], p = 0.048). There was no difference in the day-180 cumulative incidence of grade II-IV and III-IV acute GVHD between the PTCy+ATG and the PTCy groups (HR 0.93 [0.80-1.08], p = 0.4 and HR 1.21 [0.96-1.53], p = 0.11). The 2-year cumulative incidence of chronic GVHD (cGVHD) and extensive cGVHD was significantly lower in the PTCy+ATG group compared to the PTCy group, being 21.2% versus 31.4% (p < 0.001), and 10.4% versus 13.5% (p = 0.031), respectively. The lower incidence in the PTCy+ATG group was confirmed in the multivariable analysis for overall cGVHD (HR 0.66 [0.55-0.80], p < 0.001) and extensive cGVHD (HR 0.75 [0.57-0.99], p = 0.042).

Conclusions: Overall, while the addition of ATG to PTCy was associated with a lower DFS and a higher NRM after haplo-HCT with PBSCs compared to PTCy alone, GRFS and OS did not significantly differ and the CI of cGVHD, including extensive cGVHD were significantly lower in patients that received ATG+PTCy.

Disclosure: The authors declare having no conflict of interest on that topic

12: Graft-versus-host Disease – Clinical

O082 GITMO PROSPECTIVE STUDY IN 266 CGVHD PATIENTS, RECEIVING BEST AVAILABLE TREATMENT; VALIDATION OF A SOFTWARE FOR CGVHD SCORING AND RESPONSE EVALUATION ACCORDING TO NIH 2014

Attilio Olivieri 1, Giorgia Mancini1, Francesco Saraceni1, Ilaria Scortechini1, Irene Federici1, Alessandro Busca2, Luisa Giaccone2, Alessandro Rambaldi3, Maria Caterina Micò3, Alessandra Algarotti3, Giuseppe Milone4, Salvatore Leotta4, Jacopo Peccatori5, Maria Teresa Lupo Stanghellini5, Francesca Bonifazi6, Mario Arpinati6, Maura Faraci7, Fabio Benedetti8, Simone Cesaro8, Franca Fagioli9, Francesco Saglio9, Irene Maria Cavattoni10, Vincenzo Pavone11, Anna Mele11, Riccardo Saccardi12, Chiara Nozzoli12, Domenico Russo13, Michele Malagola13, Carlo Borghero14, Daniele Vallisa15, Adriana Balduzzi16, Francesca Patriarca17, Antonella Giromin17, Edoardo Benedetti18, Nicola Mordini19, Francesco Merli20, Fabio Ciceri5, Massimo Martino21

1AOU delle Marche, Marche University Hospital, Ancona, Italy, 2S.S.C.V.D Trapianto di Cellule Staminali, A.O.U Citta della Salute e della Scienza di Torino, Torino, Italy, 3Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, University of Milan, Bergamo, Italy, 4Azienda Policlinico Ferrarotto, Catania, Italy, 5San Raffaele Scientific Institute, Milano, Italy, 6University Hospital S. Orsola-Malpighi, Bologna University, Bologna, Italy, 7IRCCS Istituto Giannina Gaslini, Genova, Italy, 8Azienda Ospedaliera Universitaria Integrata, Verona, Italy, 9Regina Margherita Hospital, Torino, Italy, 10Ospedale Centrale di Bolzano, Bolzano, Italy, 11Hospital Card. G. Panico, Tricase, Italy, 12Careggi University Hospital, Firenze, Italy, 13ASST-Spedali Civili di Brescia, Brescia, Italy, 14San Bortolo Hospital, Vicenza, Italy, 15Ospedale di Piacenza, Piacenza, Italy, 16Clinica Pediatrica Università degli Studi di Milano Bicocca, Monza, Italy, 17S. Maria della Misericordia Hospital, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy, 18Pisa University Hospital, Pisa, Italy, 19A.O. S. Croce e Carle Hospital, Cuneo, Italy, 20Azienda Unità Sanitaria Locale-IRCCS, Reggio Emilia, Italy, 21BMM Hospital, Reggio Calabria, Italy

Background: We conducted a prospective study in 266 consecutive patients receiving HSCT and developing newly diagnosed cGVHD from 2017 to 2022, enrolled by 20 Italian GITMO centers by using a previously validated software which automatically calculates both the cGVHD NIH score and the kind of response to treatment according to the 2014 NIH consensus criteria.

Methods: The primary Endpoint was failure free survival (FFS) at 1 year, defined as the percentage of patients alive without cGVHD progression or not needing new immunosuppressive treatment, or experiencing malignancy relapse or severe (grade 3-4) toxicity. Secondary end points were overall response rate (ORR) at 6 and 12 months after systemic therapy (TX) (including both first&second line TX); other included OS and validation of our software in a multicenter prospective setting; this in order to collect the main standardized clinical informations of these patients, who received the current best available therapy (BAT) in 20 GITMO centers.

Total Patients

266

age at HSCT, median (range)

52 (18 – 75)

Year of HSCT, median (range)

2018 (2012-2022)

Diagnosis, n (%)

AML

114 (43)

ALL

52 (20)

MDS

25 (9)

Lymphoma

28 (11)

CML

6 (2)

PMF

11 (4)

Stem cell source, n (%)

BM

73 (28)

PBSC

184 (70)

Cord Blood

5 (2)

Conditioning intensity, n (%)

MAC

222 (83)

RIC

41 (16)

Other

3 (1)

TBI, n (%)

Yes / No

45 (17) / 215 (83)

Donor, n (%)

Matched sibling

74 (28)

Haploidentical

53 (20)

Unrelated

134 (50)

Cord Blood

5 (2)

Female to male sex mismatch, n (%)

Yes / No

64 (24) / 202 (76)

Donor age, median (range)

36 (18-69)

Median FU, months

40 (4-77)

Results: Among the 266 patients enrolled, 41 (17%) had mild cGVHD; 149 (61%) moderate and 56 (23%) severe cGVHD respectively. Most patients had multiorgan involvement with skin (66%), mouth (60%), eyes (35%), and gastrointestinal tract (25%) being the most frequently involved districts; less frequently involved were liver (23%), joints (16%), genitalia (13%) and lung (10%); the median reported Lee symptom scale score was 18 (0-66). The median follow-up was 40 months (4-77).

Among the 231 evaluable patients, 32 did not receive any treatment, 16 received only topical treatment, 173 required an immediate first line TX which was represented by steroids alone in 142 (82%) and the remaining patients received association therapy including ECP (8) or Ruxolitinib (6) or other drugs (17). The ORR, calculated by the physician (with the help of the software) at 6 months, was 67% (16% CR), with 33% patients experiencing NR/progressive cGVHD.

Overall, during the observational interval, 112 patients required a second line TX represented by: ECP in 33 patients (29.5%), Ruxolitinib in 17 (15%), Imatinib in 12 (5.4%), Ibrutinib in 3 (3%) and by other TX in the remaining 41 (32%), in most cases represented by a second steroid challenge; 27 patients never received any Tx while 14 received only topical treatment.

185 patients were evaluable at 12 months for response assessment, showing an ORR of 50% (16% of CR). Among the 222 patients evaluable for long term follow-up, the median FFS was 32 months (60% and 43% at one and two years respectively), while the 2 years OS was 84%.

Conclusions: This prospective observational study shows that a standardized cGVHD evaluation and the response evaluation according the 2014 NIH criteria, are feasible in a multicenter setting, when supported by a standard tool shared by all the investigators. Furthermore this study allows to evaluate the realistic ORR and the outcome of patients receiving the BAT in a real life scenario. Both the ORR and the hard outcomes should be considered as a reliable current benchmark reference for future studies aimed to evaluate the efficacy of new drugs when randomized clinical trials are not feasible.

Disclosure: Nothing to declare

12: Graft-versus-host Disease – Clinical

O083 ADDITION OF RUXOLITINIB TO STANDARD GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS FOR ALLOGENEIC STEM CELL TRANSPLANTATION IN APLASTIC ANEMIA PATIENTS

XiaoYu Zhang 1, Yi He1, Sizhou Feng1, Mingzhe Han1, Erlie Jiang1

1Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers rapid hematopoietic reconstitution and long-term wellness for aplastic anemia (AA). However, the high incidence of acute graft versus host disease (aGVHD) contributed to high treatment-related mortality (TRM). Since AA is a nonmalignant disorder, avoiding aGVHD remains a clinical concern. Our study aimed to determine the prophylactic value of ruxolitinib for aGVHD in HSCT recipients of AA.

Methods: Between August 2021 and January 2023, 35 consecutively aplastic anemia patients who applied for allo-HSCT were retrospectively enrolled. Despite the standard GVHD prophylaxis including cyclosporine A or tacrolimus, short-term methotrexate, ruxolitinib was initiated at the beginning of the conditioning regimen and continued to 3 months after transplantation.

Results: This study included 35 AA patients (median age: 32, ranging from 12 to 57). With the administration of ruxolitinib as prophylaxis, neutrophil and platelet engraftment took a median time of 14 (10-24) days and 23 (8-112) days, respectively, without primary graft failures (GF) cases observed. Ruxolitinib for GVHD prevention enhanced Tregs development after transplantation. Compared to the historical-matched control, the ruxolitinib group exhibited a significant advantage in decreasing the incidence of moderate (grade II ~ IV: 17.1% vs 48.6%, P = 0.033) and severe (grade III – IV: 8.6% vs 20%, P = 16) aGVHD. The ruxolitinib group exhibits a lower incidence of cGVHD as compared to the historical control (26.2 ± 9.5% vs 38.3 ± 8.7%, P = 0.24). The peri-transplant ruxolitinib didn’t increase infection incidence rate. After a median follow-up of 417 days (range, 112-725), only one patient in the HID-HSCT group died of TB-related treatment complications on +day 112. The 1-year overall survival (OS), failure-free-survival (FFS), and GFFS rate at 97.1 ± 2.82 (95%CI 91.8 ~ 100), 91.4 ± 4.73, (95%CI 82.6 ~ 100), and 85.7 ± 5.91, (95%CI 74.9 ~ 98.1), respectively. The treatment-related mortality (TRM) was 2.9 ± 2.82 (95%CI 0 ~ 8.2). Though nosignificant differences were documented, we noted more than 10% advantage of GVHD free-failure survival in the ruxolitinib group compared to the control group (85.7% vs 68.6%, p = 0.18).

Conclusions: This is the first study investigating the prophylactic application of ruxolitinib for aplastic anemia patients after allo-HSCT. Ruxolitinib would be a promising and safe choice in preventing aGVHD, but this awaits further study in larger cohorts.

Disclosure: The authors declare that they have no competing interests.

11: Graft-versus-host Disease – Preclinical and Animal Models

O084 LIPOCALIN-2 REDUCES ACUTE GRAFT-VERSUS-HOST DISEASE SEVERITY IN MICE

Marie Czech 1, Robert Zeiser2

1University Medical Center Freiburg, Freiburg, Germany, 2University Medical Center, Freiburg, Germany

Background: The success of allogeneic hematopoietic cell transplantations (allo-HCT) remains limited by acute graft-versus-host disease (aGVHD). We previously demonstrated that neutrophil granulocytes increase early aGVHD by releasing reactive oxygen species and promoting tissue damage. Additionally, they can migrate to mesenteric lymph nodes, where they present antigen and thereby activate allogeneic T cells. Here, we identified a neutrophil population in the gastrointestinal tract of allo-HCT recipients that was characterized by expression of Lipocalin-2 (LCN2). LCN2 is an antimicrobial peptide with protective functions against inflammatory bowel disease, making it an interesting target to study in the context of aGVHD.

Methods: To characterize neutrophils infiltrating the gastrointestinal tract, we implemented single-cell RNA sequencing, leading to the definition of a new neutrophil subset. We confirmed these initial findings by using major mismatch models of allo-HCT, where mice received treatment regiments or adoptive transfer of neutrophils or primary macrophages. For mechanistic analyses, we performed 16S rRNA gene sequencing, microarray and kinase array, the latter of which we confirmed with western blot and qPCR. Finally, we used biopsies, serum and stool samples from aGVHD patients to translate murine findings to the human system.

Results: Single-cell RNA sequencing identified a donor-derived neutrophil population, characterized by expression of the antimicrobial peptide LCN2. We confirmed the presence of LCN2+ neutrophils during aGVHD, which coincided with increased expression of Lcn2 in the small intestine and increased secretion of LCN2 into the intestinal lumen. Loss of hematopoietic LCN2 led to aggravated disease, as well as reduction of protective bacteria in the stool and increased infiltration of immunogenic immune cells into intestinal tissues. Transfer of LCN2-overexpressing neutrophils protected from aGVHD. Treatment with recombinant LCN2 also protected from aGVHD, while modifying the immune cell composition of the GI tract, where less immunogenic and more tolerogenic cell types were detected. To decipher the mode of action, we screened for expression of a LCN2 receptor (Slc22a17), and found high expression in macrophages. Treatment with LCN2 decreased the expression of MHC class II in macrophages and adoptive transfer of LCN2-primed tolerogenic macrophages reduced disease activity. Additionally, we found increased expression of Il10 in LCN2-treated macrophages. IL10-/- macrophages did not respond to LCN2 treatment with decreased MHC-II expression, strengthening our hypothesis of LCN2 being IL10-dependent in a treatment setting. Indeed, genetic or systemic loss of IL10 abrogated the protective effect of LCN2 in an in vivo model of aGVHD. To quantify the effect of LCN2 on macrophages, we performed a kinase array and found insulin-like growth factor receptor 1 (IGF1R) to be activated upon LCN2 treatment. Additionally, we found that loss of epithelial LCN2 in the gastrointestinal tract aggravates aGVHD, strengthening its position as protective disease modulator. Finally, we used samples from four different patient cohorts and could demonstrate increased expression of LCN2 in allo-HCT patients that developed GVHD, which correlated with expression of IL10 and serum LCN2.

Conclusions: We found a protective LCN2-expressing neutrophil population present in aGVHD, which led us to the identification of LCN2 as a potential treatment option for patients suffering from aGVHD.

Disclosure: RZ received honoraria from Novartis, INcyte, MNK and Sanofi outside of this study. This study was supported by the Deutsche Forschungsgemeinschaft, Germany, SFB-1479 – Project ID: 441891347 (P01 to RZ, S1 to MB, P03 to NK), Project-ID 259373024 – TRR 167 (Z01 to M.B.), Germany’s Excellence Strategy – (CIBSS - EXC 2189 Project ID: 390939984), DFG individual grant 872/4-2 to R.Z., SFB1160 (Project ID 256073931 - TP B09 to R.Z. and Z02 to M.B.), CRC1453 (Project ID 431984000-S1, M.B.), the European Union: GVHDCure (ERC consolidator grant to R.Z.), the Deutsche Krebshilfe (grant number 70113473), the Jose-Carreras Leukemia Foundation (grant number DJCLS 01R/2019) (R.Z.), by the Max Planck Society (D.G.), and by the German Research Foundation (DFG) (322977937/GRK2344 MeInBio) (D.G.). We also acknowledge funding from the German Federal Ministry of Education and Research (BMBF) within the Medical Informatics Funding Scheme - MIRACUM-FKZ 01ZZ1801B (M.B.) and EkoEstMed–FKZ 01ZZ2015 (G.A.).

11: Graft-versus-host Disease – Preclinical and Animal Models

O085 GALECTIN-9 RELEASED BY CHEMOTHERAPY-DAMAGED INTESTINAL EPITHELIUM ATTRACTS AND STIMULATES ACTIVATION OF ALLO T CELLS

Suze Anne Jansen 1,2, Alessandro Cutilli1, Coco de Koning2,1, Marliek van Hoesel2,1, Leire Saiz Sierra1, Stefan Nierkens2,1, Michal Mokry1, Edward Nieuwenhuis1,3, Alan Hanash4, Enric Mocholi1, Paul Coffer1, Caroline A. Lindemans2,1

1University Medical Center Utrecht, Utrecht, Netherlands, 2Princess Máxima Center of Pediatric Oncology, Utrecht, Netherlands, 3Utrecht University, Utrecht, Netherlands, 4Memorial Sloan Kettering Cancer Center, New York City, United States

Background: Chemotherapy (chemo) used in the conditioning regimen before allogeneic hematopoietic stem cell transplantation (HSCT) is thought to contribute to the development of acute graft-versus-host disease (GVHD). Whether damage to the intestinal epithelium induced by chemotherapy directly influences allogeneic (allo) T cell behavior is not exactly known.

Methods: Using a variety of 3D human intestinal organoid-based models we studied the direct effects of chemo-induced damage of intestinal epithelial cells (IEC) on allo T cell responses.

Results: Treatment of human intestinal epithelial organoids with clinically relevant chemo busulfan (Bu), fludarabine (Flu) and clofarabine (Clo) induced morphological changes, stalled DNA replication, reduced proliferation, induced oxidative stress and apoptosis. Functionally, chemo-treatment impaired single organoid cells to form new organoids, thus impairing regenerative capacity. On transcriptional level, chemo treatment induced relatively subtle changes with 66, 106 and 118 differentially expressed genes (DEGs) respectively. Organoids treated with the nucleoside analogs Flu and Clo shared more DEGs, than each did with alkylating agent Bu, reflecting common mechanisms of action. Interestingly, gene set enrichment analysis showed a transcriptional change related to an inflammatory response.

Using a transwell system we evaluated the effect of chemo-treatment of organoids in the lower compartment on functional migration of peripheral blood T cells placed in the upper compartment. Both resting and polyclonally preactivated (using anti-CD3/CD28) CD4+ and CD8 + T cells demonstrated increased migration to chemo-treated organoids. Next, the effect of chemo-damaged intestinal epithelium on concurrent polyclonal activation of T cells was evaluated in a co-culture system. T cell proliferation and activation markers were assessed by flow cytometry after 4 days of co-culture. Co-culture with chemo-treated organoids led to increased proliferation and IFNγ-production in CD4+ and CD8 + T cells. To gain insight in the mechanism underlying increased T cell migration and activation, we performed proteomic analysis of culture-medium (CM) exposed to chemo-treated organoids using the Olink platform. We found that galectin-9 (Gal-9) levels, a beta-galactoside-binding lectin with pleiotropic and divergent roles in inflammation, were increased in CM predominantly from Flu- and Clo-treated organoids. Interestingly, Gal-9 levels were also increased in plasma of pediatric patients that eventually developed gut GVHD after HSCT. To determine whether Gal-9 indeed played a role in the migration and activation of T cells we used Gal-9 blocking antibodies and organoids in which Gal-9 was genetically ablated using CRISPR/Cas9 technology (Gal-9-KO). Indeed, blocking of Gal-9 reduced migration and activation of T cells, and co-culture with Gal-9-KO organoids abrogated the increased activation of T cells that was found previously with Clo-treatment of organoids.

Conclusions: T cells demonstrate increased migration to chemotherapy-treated organoids, and upon exposure to them, proliferated more and expressed higher levels of IFNγ. Damaged organoid-derived Gal-9 appeared to be at least partially responsible for these effects. As such, Gal-9 serves as a potential biomarker for intestinal damage and inflammation, and a probable target for future prevention and/or treatment of GVHD and other immune-mediated disease.

Disclosure: Nothing to declare

11: Graft-versus-host Disease – Preclinical and Animal Models

O086 VASOACTIVE INTESTINAL POLYPEPTIDE SYNTHESIS BY THE GUT ENTERIC NEURAL PLEXUS PROMOTES A DIVERSE MICROBIOME AND CONFERS RESISTANCE TO GRAFT VERSUS HOST DISEASE

Edmund K. Waller 1, Yi-Wen Li1, Shuhua Wang1, Hanwen Zhang1, Yutong Liu1, Po-Chih Hsu1, Pankoj Das1, Passang Lim1, Tamas Nagy2, Zhaohui Qin1, Cynthia Giver1

1Winship Cancer Institure of Emory University, Atlanta, United States, 2University of Georgia College of Vetrinary Medicine, Athens, United States

Background: Graft-versus-host disease (GvHD) in allo-transplant recipients is characterized by donor T cell-mediated damage to recipient organs and changes in the gut microbiome. Vasoactive intestinal peptide (VIP), an immunosuppressive neuropeptide, directs T cell responses towards a Th2 phenotype while inhibiting proinflammatory cytokine production. Furthermore, VIP-producing enteric neurons contribute to the mucosal barrier and maintain gut microbiome homeostasis. We previously described the role of VIP-producing donor plasmacytoid dendritic cells in limiting GvHD. While diet and antibiotic treatment have been shown to affect the gut microbiota, the impact of genes expressed in the gut on GvHD and the composition of the microbiota needs to be clarified. We hypothesized that the absence of VIP in allogeneic bone marrow transplant (allo-BMT) recipients would increase GvHD compared to wild-type mice and that local VIP synthesis in the gut would regulate the microbiota.

Methods: We examined the effect of endogenous VIP synthesis in modulating GvHD in multiple murine MHC mismatched allo-BMT models. VIP KO mice and radiation chimeras in which either the hematopoietic or somatic tissue compartments were derived from VIP KO mice were used as BMT recipients. Measurements of serum cytokines and intracellular staining for cytokines and transcription factors characterized the immune polarization of donor T cells. Cell transplantation of luciferase+ donor T cells tracked tissue homing an in vivo expansion after allo-BMT. Gut microbiota was classified after shotgun DNA sequencing of stool pellets, characterizing bacterial species in wild-type and VIP KO mice before and after co-housing and following allo-BMT and treatment with a VIP-receptor antagonist.

Results: Lethally irradiated VIP knock-out (VIP-KO) mice rejected grafts composed of MHC mismatched T cell-depleted bone marrow (BM) without added donor T cells, consistent with heightened host cell allorreactivity. Transplanting donor splenocytes or purified T cells with T cell-depleted BM led to rapid death from GvHD, with histology of GVHD-target organs showing the predominance of GVHD in the gut. Heightened activation and expansion of Th1- and Th17-polarized T cells occurred in VIP-KO recipients. Transplanting radiation chimeric mice demonstrated that VIP production by non-hematopoietic tissues limited the GvHD activity of donor T cells. Immunofluorescence staining demonstrated VIP expression in enteric neurons in allo-BMT recipients, consistent with local effects of VIP on T cells and the gut microbiome. VIP-KO mice had less microbiome diversity, lower stool pH, and higher frequencies of the Bacillota phylum, including Lactobacillus murinus and Ruminococcus gnavus species, post-transplantation. Co-housing with wild-type mice did not mitigate alterations in the gut microbiome or the GvHD-susceptibility of VIP-KO mice undergoing allo-BMT. Daily treatment with a VIP-receptor antagonist recapitulated the increase in Lactobacillus murinus seen in VIP-KO mice, demonstrating that VIP-signaling on the gut epithelial cells regulates the gut microbiome.

Conclusions: These data support the crucial role of VIP in maintaining the diversity of the gut microbiome with beneficial commensal species and in modulating the alloreactivity of donor T cells after allo-BMT. Ongoing experiments on the impact of VIP receptor signaling on the gut microbiome composition and its relationship with anti-cancer activity will provide insights into the broader therapeutic applications of VIP and its antagonists.

Clinical Trial Registry: Not applicable

Disclosure: EKW and Y-WL have an intellectual property related to using VIP agonists to limit GvHD. EKW founded and has equity in Cambium Oncology LLC, which has licensed intellectual property from Emory University covering medicinal uses of VIP agonists and antagonists.

11: Graft-versus-host Disease – Preclinical and Animal Models

O087 TARGETING PI3KDELTA FUNCTION FOR TREATMENT OF CHRONIC GRAFT‐VERSUS‐HOST DISEASE

Yuxi Xu1,2, Guancui Yang1, Qing Xu1, Ya Zhou1, Rui Wang1, Xiaoqi Wang1, Shijie Yang1, Qingxiao Song 1,2, Xi Zhang1,2

1Medical Center of Hematology. Xinqiao Hospital of Army Medical University (Third Military Medical University), Chongqing, China, 2Jinfeng Laboratory, Chongqing, China

Background: Chronic graft‐versus‐host disease (cGVHD) is a leading cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (allo-HSCT). The expansion of pathogenic T helper cells (Th) and reduction of regulatory T cells (Tregs) result in cGVHD. Phosphoinositide-3 kinase (PI3K), a lipid kinase, plays a pivotal role in the proliferation, differentiation, survival, and metabolism of activated T cells. As a result, this study aimed to evaluate the efficacy of PI3K inhibitors in the treatment of cGVHD.

Methods: BALB/c recipients were conditioned with a total body irradiation of 7.5Gy. For the B10.D2 → BALB/c scleroderma model, recipients were transplanted with 10×106 bone marrow cells and 15×106 splenocytes from B10.D2 donors. For the C57BL/6 → BALB/c systemic GVHD model, recipients were transplanted with 5x106 bone marrow cells and 1.25x106 splenocytes from C57BL/6 donors. Treatment groups received PI3Kδ inhibitor (Parsaclisib (5mg/kg)) or solvent by daily gavage starting from day 10 post-HSCT. Mice were monitored for body weight change, clinical and cutaneous signs of cGVHD, and survival. HE staining was used to examine pathological changes in the target organs (skin, lung, liver, small intestine, and colon). Skin collagen content was detected by Masson staining. Lymphocytes from the target organs of the recipients are collected for flow cytometry analysis.

Results: Here, in a mouse model of minor histocompatibility mismatch model (B10.D2 → BALB/c) that presents with a cutaneous cGVHD and systemic inflammatory response. Treatment with (Parsaclisib) substantially reduced skin GVHD scores and extended overall survival among recipients. On day 30 post-HSCT, compared to the non-GVHD (syngeneic HCT) group, the recipients given solvent showed inflammatory cell infiltration, collagen deposition, and serious fat atrophy in the skin. In contrast, recipients given Parsaclisib significantly reduced cell infiltration and collagen deposition in the skin. Parsaclisib treatment significantly reduced CD4+ and CD8+ T cells infiltrated in the skin while inhibiting the transcription factor Hobit expression to suppress the CD69+CD103+ tissue-resident CD8+ T cells in the lung and liver. More importantly, Parsaclisib treatment upregulates Foxo1 and Foxo3α to promote Foxp3 expression and expands a population of Tregs that is stable and highly suppressive in the skin, which could contribute to the suppression of cutaneous cGVHD. The frequency and number of CD19+B220+ B cells and the CD11b+F4/80+ macrophages in GVHD target organs (skin, liver, and lung) were markedly reduced in the recipients treated with Parsaclisib compared to those given solvent. In addition, the therapeutic effect of Parsaclisib was validated in a major MHC mismatch model (C57BL/6 → BALB/c). Similarly, Parsaclisib effectively treated mice with active GVHD in the MHC mismatched model.

Conclusions: PI3Kδ inhibitor (Parsaclisib) modulates the tissue microenvironment by enriched Tregs while suppressing Trm cells, B cells, and macrophages in the tissue, effectively alleviating cGVHD. These data provide the scientific rationale for PI3Kδ inhibition as a therapeutic approach for patients with cGVHD.

Clinical Trial Registry: N/A

Disclosure: Nothing to declare

1: Haematopoietic Stem Cells

O088 VLA-4 AGONIST PROMOTE ENGRAFTMENT AND CELL IMMUNE RECONSTITUTION OF ALLOGENEIC HEMATOPOIETIC STEM CELLS

Qiaomei He 1, Xi Sun1, Lin Chen2, Jun Yang1, Huixian Wu1, Shixuan Tang1, Liping Wan1, Yan Zhang1, Bo O. Zhou2, Fang Zhang3, Xianmin Song1

1Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, 2State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China, 3Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is hinged on the successful engraftment of donor-derived hematopoietic stem cells (HSCs) and the achievement of full-donor chimerism (FDC) for the reconstitution of the recipient’s hematopoietic and immune system. Moreover, early cell immune reconstitution after allo-HSCT is pivotal to prevent pathogenic microorganism infection and original disease relapse, which are the two most important causes of transplantation failure. Therefore, it is of great clinical significance to effectively promote donor HSC implantation and accelerate immune reconstitution after allo-HSCT. However, little is known about how to promote implantation and early immune reconstitution of HSCs through regulating its own functions.

Methods: Single-cell transcriptome sequencing analysis on bone marrow cells from clinical samples and mouse models in two states, from mixed donor chimerism (MDC) to FDC, was performed to explore the key regulatory target affecting HSC implantation after allo-HSCT. The effects of the agonists that modulate this target on HSC implantation after transplantation were investigated in a novel MDC mouse model. The effects of the agonist regulating this target on HSC function were investigated by competitive transplantation mouse model and serial umbilical cord blood (UCB) xenograft transplantation model. The mechanisms of the agonist were further explored by single-cell sequencing.

Results: We identified very-late antigen (VLA-4) as a pivotal target in regulating HSC implantation. Critically, we screened out a VLA-4 agonist, which could promote the implantation and long-term hematopoietic reconstitution of donor HSCs in a MDC mouse model and serial xenotransplantation model of human CD34+ cells from UCB. Competitive transplantation mouse model and limited dilution assay for UCB CD34+ cells revealed that VLA-4 agonist could enhance the self-renewal capacity of HSCs and increase the number of severe combined immunodeficient (SCID)-repopulating cells (SRCs) to five-fold in vivo. Furthermore, the VLA-4 agonist could facilitate early post-transplant cell immune reconstitution by enhancing T cell output of HSCs. VLA-4 agonist regulates HSC functions and lymphoid progenitor differentiation through affecting the ERK1/2 phosphorylation process, whereas may not increase the risk of leukemia transformation.

Conclusions: Our research underscores the significant potential of the VLA-4 agonist in addressing two of the foremost challenges in allo-HSCT: enhancing engraftment efficiency and facilitating early immune reconstitution of HSCs. These findings pave the way for further clinical exploration and application of the VLA-4 agonist in HSCT.

Disclosure: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.This research was funded by National Natural Science Foundation of China (82270226 for Xianmin Song), National Natural Science Foundation of China (32270838 for Fang Zhang), Shanghai Shen Kang Hospital Development Center (SHDC2020CR1012B for Xianmin Song).

1: Haematopoietic Stem Cells

O089 AN AI MODEL TO OPTIMIZE DONOR SELECTION USING A CONTEMPORARY DATASET

Martin Maiers 1, Sapir Israeli2, Yoram Louzoun2, Stephen R. Spellman1, Heather E. Stefanski1, Jeffery J. Auletta1, Steven M. Devine1

1Center for International Blood and Marrow Transplant Research, National Marrow Donor Program, Minneapolis, United States, 2Bar-Ilan University, Ramat Gan, Israel

Background: We have devised a machine learning algorithm for forecasting hematopoietic cell transplantation (HCT) outcomes. This algorithm addresses the decision-making process when selecting among available donor sources based on the patient’s relatives and unrelated donors (URD) identified in a patient’s registry search. The four donor types considered were matched related donor (MRD), mismatched related donor (MMRD), matched unrelated donor (MUD), and mismatched unrelated donor (MMUD).

Methods: We analyzed a cohort of 31,515 U.S. transplants reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between 2016 and 2019 (Table 1). Using this dataset, we trained and validated multiple prediction algorithms for the following clinical endpoints at 1-year post-HCT: overall survival, disease relapse, graft rejection, chronic graft-versus-host disease (cGvHD) and the composite endpoint of event-free survival (EFS), representing survival in the absence of these events. We conducted searches in the U.S. URD registry for each recipient and applied predictions to each potential donor. Analysis included the best URD 1-year EFS risk predicted by the model compared to that of the donor actually selected for the transplant. Notably, GvHD prophylaxis strategy for the potential donor aligned with that actually used in the recipient. Matching criteria involved up to 1 mismatch out of 10 alleles for the loci HLA-A, -B, -C, -DRB1, and -DQB1.

Results: Key factors impacting predictive outcomes include donor age, sex, donor type, HLA match, and post-transplant cyclophosphamide (PTCy) use. Comparing HLA-10/10 to 9/10 URD, outcomes generally favor matched transplants although some mismatches yielded better predictions. MRDs are predicted to provide lower rates of GvHD and mortality. However, in specific cases, URDs surpass MRDs in survival predictions. URDs consistently show lower rejection risk than MRDs. Considering MMRD, predominantly HLA haploidentical relatives, URDs demonstrate better predicted EFS risk in the majority of cases. The EFS risk differences are driven by survival and rejection, influenced by donor age and higher HLA mismatch levels, respectively.

Conclusions: Post-transplant cyclophosphamide (PTCy) is increasingly recognized as a standard GvHD prophylaxis in recipients undergoing allogeneic HCT. This model is consistent with previous reports that PTCy use has reduced the outcome differential between MUD and MMUD transplants. A consequence of this substantial growth in alternative donor options has resulted in more scenarios wherein an URD presents a better predicted outcome than a relative. The analytical approach in this study employs a straightforward linear model, facilitating its implementation through a user-friendly nomogram. By scoring all donor options (both related and unrelated) based on a limited set of accessible variables, clinicians can effectively assess and compare potential outcomes for patients.

Disclosure: Nothing to disclose

Table 1 Characteristics of patients in the U.S. receiving adult donor HCT (2016-2019)

Characteristic

MRD

MMRD

MUD

MMUD

N

8855

6236

13497

2927

PTCy Prophylaxis- no. (%)

865 (9.8)

5511 (89.6)

1526 (11.4)

807 (27.9)

Age at HCT median(range)

51.2 (0.2-79.2)

51.7 (0.0-87.8)

57.2 (0.1-82.7)

49.1 (0.2-79.2)

Donor age

median(range)

49.6 (0.0-80.9)

35.0 (0.6-77.3)

27.2 (18,0-61.0)

28.9 (18.0-61.2)

Gender Male Race no.(%)

5077 (57.3)

3695 (59.3)

7873 (58.3)

1640 (56.0)

Non-Hispanic White

5324 (60.1)

3095 (49.6)

10899 (80.8)

1742 (59.5)

Hispanic or Latino

1440 (16.3)

1177 (18.9)

1038 (7.7)

481 (16.4)

Black or African American

838 (9.5)

1143 (18.9)

402 (3.0)

303 (10.4)

Asian

484 (5.5)

312 (5.0)

360 (2.7)

138 (4.7)

Other or Unknown

769 (8.7)

509 (8.2)

798 (5.9)

263 (9.0)

Comorbidity (HCT-CI)- no.(%)

0-2

4915 (55.9)

3352 (54.2)

6739 (50.3)

1534 (52.8)

>2

3884 (44.1)

2832 (45.8)

6649 (49.7)

1371 (47.2)

Disease – no.(%)

AML

3084 (34.8)

2247 (36.0)

5308 (39.3)

1016 (34.7)

ALL

1478 (16.7)

1050 (16.8)

1772 (13.1)

447 (15.3)

MDS

1204 (13.6)

858 (13.8)

2635 (19.5)

434 (14.8)

Other malignant

1874 (21.2)

1454 (23.3)

2733 (20.2)

595 (20.3)

Non-malignant

1215 (13.7)

627 (10.1)

1049 (7.8)

435 (14.9)

Graft source – no.(%)

Bone Marrow

2116 (23.9)

1868 (30.0)

2946 (21.8)

898 (30.7)

Peripheral blood stem cells

6739 (76.1)

4368 (70.0)

10551 (78.2)

2029 (69.3)

1: Haematopoietic Stem Cells

O090 OUTCOMES OF ALLOGENEIC HAEMATOPOIETIC STEM-CELL TRANSPLANTATION IN MYELOFIBROSIS: A MULTICENTER STUDY

Tatiana Fernández-Barge 1, Juan José Domínguez-García1, Miriam Sánchez Escamilla1, Jaime Sanz Caballer2, Pedro Chorão2, Juan Carlos Hernández Boluda3, Sara Redondo Velao4, Irene García Cadenas4, Rodrigo Martino Bufarull4, Rodrigo Cantera Estefanía1, Irene Francés Alexandre1, Ana Gea Peña1, Ana Tobalina García1, Raquel García Ruiz1, Sara Fernández Luis1, Enrique M. Ocio San Miguel1, Mercedes Colorado Araújo1, Sonia González de Villambrosia Pellón1, María Aranzazu Bermúdez Rodríguez1

1Hospital Universitario Marqués de Valdecilla, Santander, Spain, 2Hospital Universitari i Politècnic La Fe, Valencia, Spain, 3Hospital Clínico Universitario de Valencia, Valencia, Spain, 4Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

Background: Myelofibrosis (MF) in advanced stages still carries an unfavorable prognosis, with a survival range spanning from 1.5 to 10 years depending on disease and patient risk factors. Allogeneic haematopoietic stem-cell transplantation (HCT) remains the only curative option, with survival rates varying between 40-60% depending on the series.

The aim of this study is to analyze the outcomes of allogeneic HSCT in MF and potential predictive factors for increased survival that could contribute to enhancing the prognosis for these patients.

Methods: A retrospective analysis was conducted on 67 patients from four Spanish centers who underwent allogeneic HCT between January 2015 and September 2023. Demographic data, prognostic scales, comorbidity index (HCT-CI), transplant characteristics (source, compatibility, conditioning, GvHD prophylaxis, neutrophil and platelet recovery), as well as data on graft failure and acute and chronic GvHD, were collected.

Results: Patient, MF, and allogeneic HSCT characteristics are summarized in Table. The haematopoietic stem cell source was peripheral blood (94.0%) and the median of infused CD34 cell was 6.0 CD34x10e6/kg (IQR, 4.7-7.0). 75% of transplants were from HLA-matched compatible donors (43.2% unrelated).The median time to neutrophil (>0.5x109/L) and platelet (>20x109/L) engraftment were 20 (IQR 17-25) and 26 days (IQR 18-42) respectively. Primary graft failure occurred in 7.5% of patients.

Thirty-seven patients (57.8%) developed acute GvHD which was severe (grade III-IV) in 9 patients (24.3%). Twenty-seven (45%) patients had chronic GvHD.

With a median follow-up of 17 months (IQR, 5.5-52.9), overall survival (OS) at 1 and 5 years was 66.6% (95% CI, 54-77) and 51.0% (95% CI, 35-65). Transplant related-mortality (TRM) at day 100 was 21.0% (95% CI,12-31) and at one year was 31.8% (95% CI, 21-44). Concerning the donor, non-identical HLA donors significantly worsened survival (HR 3.6; p = 0.023). Primary graft failure was significantly related to higher mortality (HR = 11.2 p < 0.001) as well as severe acute GvHD (HR 1.6; p = 0.013). No differences were found in OS concerning the development of chronic GVHD (p = 0.307).

The presence of more than 6% circulating blasts (HR 4.8; p = 0.010) was significantly associated with worse survival. Neither splenomegaly (p = 0.403) nor spleen size (p = 0.257) was significantly related to increased mortality in our study, but there was data loss hindering conclusive results. Regarding patient characteristics, intermediate (p = 0.041) and high-risk (p = 0.014) HCT-CI, and Karnofsky score <90% (p < 0.001) worsened survival.

TBF conditioning versus BUFLU was associated with delayed platelet recovery (p = 0.037). Likewise, PTCy as GvHD prophylaxis versus ATLG was linked to haematological recovery delay (neutrophil p = 0.03 and platelet p = 0.003).

Excluding FLUMELT conditioning (4 patients), there were no significant differences in OS between different conditioning regimens.Though not statistically significant, there was an observed trend toward increased survival in patients receiving post-transplant cyclophosphamide (PTCy) as GvHD prophylaxis versus ATLG.

Age (median, IQR)

60.6 (IQR: 57-66; Range: 41-74)

Sex (%)

Male

46 (68.7)

Female

21 (31.3)

Disease (%)

Primary

27 (40.3)

Secondary

40 (59.7)

DIPSS-plus (%)

Intermediate-1

7 (10.5)

Intermediate-2

27 (40.3)

High

15 (22.4)

JAK-inhibitors (%)

27 (40.3)

Splenectomy (%)

4 (6)

Splenomegaly (%)

20 (29.9)

Peripheral blood blasts (SD)

2.2 (2.6)

HCT-CI

Low (0)

17 (25.4)

Interrmediate (1-2)

24 (35.8)

High (>=3)

25 (37.3)

Donor (%)

Related

29 (43.3)

Unrelated

38 (56.7)

HLA (%)

Matched

50 (74.6)

Mismatched

11 (16.4)

Haploidentical

6 (9.0)

Conditioning (%)

BUFLU

34 (50.7)

TBF

29 (43.3)

FLUMELT

4 (6.0)

GvHD prophylaxis (%)

CSP/FK + MMF + ATLG

22 (32.8)

PTCy (50 mg/kg/day) + MMF + Sirolimus

23 (34.3)

PTCy (30 mg/kg/day) + FK

15 (22.3)

CSP + MMF/MTX

7 (10.6)

  1. BUFLU (Busulfan and Fludarabine), TBF (Thiotepa, Busulfan), FLUMELT (Fludarabine, Melphalan, Thiotepa), CSP/FK (Cyclosporine/Tacrolimus), MMF (Mycophenolate mofetil), ATLG (anti-T lymphocyte globulin), PTCy (post-transplant cyclophosphamide), MTX (Methotrexate).

Conclusions: Results from this multicenter study highlight the importance of appropriate patient selection to enhance post-transplant survival, considering variables such as low HCT-CI, Karnofsky score >90% or low circulating blasts (<6%). Transplants from mismatch/haploidentical HLA donors, graft failure, and severe acute GvHD predict higher NRM.

Disclosure: Nothing to declare

1: Haematopoietic Stem Cells

O091 GAMMA DELTA T CELLS RECONSTITUTION IN LONG-TERM SURVIVORS AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION – HOMEOSTATIC STEADY-STATE?

Faisal Alagrafi 1,2, Arwen Stikvoort1, Thomas Poiret1, Ahmed Gaballa1, Martin Solders1, Lucas Arruda1, Michael Uhlin1,3

1karolinska Institutet, Stockholm, Sweden, 2King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia, 3Karolinska University Hospital, Stockholm, Sweden

Background: The success of allogeneic hematopoietic stem cell transplantation (allo-HCT) depends greatly on the effective restoration of T-cells. Although there is a growing interest in gamma delta (γδ) T-cells due to their early reconstitution is associated with fewer complications and improved clinical outcome, there is limited knowledge on the impact of γδ T-cells reconstitution in long-term survivors and their association with the previous history of complications.

Methods: Twenty paired samples of recipients/donors were collected at least 9 years after (allo-HCT). We then conducted a deep characterization of γδ T-cells at phenotypic, clonotypic, and functional levels to describe their reconstitution in the long-term after allo-HCT using high-parameter flow cytometry and next-generation sequencing (NGS) of TCR γ-chain (TRG).

Results: The study revealed that the frequency of total γδ, Vδ2, Vδ1, non-Vδ1/Vδ2 subsets were all comparable in both the recipients and donors. The recipient’s phenotype on Vδ2 subsets is characterized by a significant expression of NKG2D, HLA-DR, CD39, and PD-1. The immunosequencing analysis of the TCR γ chain showed no notable variations in the diversity of the TCR repertoire between the donors and recipients. Moreover, there is no disparity in TRGV9 usage in donors and recipients, and only a small number of clonotypes were observed to be shared within the recipients-matched donors. Recipients γδ T cells, Vδ2, and Vδ1 subsets displayed high level of cytokine production upon stimulation by PMA/I. A high percentage of effector memory phenotype was observed in CMV-specific cells in both Vδ1 and non-Vδ1/Vδ2 subsets as well as CMV-specific Vδ1 cells showed an increased expression of NKG2D in CMV-reactivated group compared to non-CMV reactive group of recipients. The frequency of Vδ1 subsets tended to enrich in recipients with ongoing moderate/severe cGVHD, and displayed elevated levels of HLA-DR.

Conclusions: Our data suggest that after long-term (allo-HCT), γδ T cells reconstitute and appear to achieve homeostasis with a normalized immune repertoire and high functional capacity. GVHD represent the most significant influence on the thymic-dependent reconstitution of γδ T cells after long-term, mainly cGVHD is a continuous complication which changes the γδ T cells phenotypic composition by enriching the Vδ1+ subset in ongoing moderate/severe cGVHD recipients. Also, there is a potential association between an elevated frequency of HLA-DR + Vδ1 + T cells in those recipients with moderate/severe cGVHD. Further investigation with a large size of sample is required to explore the impact of different transplant-related factors on the kinetics of γδ T cells reconstitution and their association with clinical outcome.

Disclosure: The authors declare the absence of any conflict of interest. This study was supported by the Stockholm County Council, Swedish Research Council, and Cancerfonden Sweden.

1: Haematopoietic Stem Cells

O092 HLA-HAPLOIDENTICAL HEMATOPOIETIC STEM CELL TRANSPLANTATION WITH PTCY IN VIVO DEPLETED T-CELL FOR NON-SCID INBORN ERRORS OF IMMUNITY: A MONOCENTRIC CENTER EXPERIENCE

Jean-Sebastien Diana 1, Benjamin Fournier1, Quentin Riller2, Martin Castelle1, Romain Levy1,2,3, Clotilde Aussel1,3, Elisa Margin1, Marwa Chbihi1,3, Agathe Escudier1, Paul Bastard1,2,3, Stephane Blanche1,3, Naim Bouazza1,3,2, Despina Moshous1,2,3, Benedicte Neven1,2,3

1Hôpital Necker-Enfants Malades, APHP, Paris, France, 2Institut Imagine, Paris, France, 3Université Paris Cité, Paris, France

Background: HLA-haploidentical HSCT (hHSCT) with either in vitro CD3 + TCRαβ/CD19 depleted graft or in vivo depletion of alloreactive T-cells by using post-transplant cyclophosphamide (PTCY) have been increasingly used for children without an HLA-matched donor for inborn errors of immunity (IEI), and results are encouraging in small series.

Methods: We provide a retrospective monocentric study on 72 consecutive non-SCID-IEI patients who underwent a first hHSCT with PTCY between November 2015 and December 2022. We analyzed the impact of pre-transplant comorbidities, diseases, and hHSCT characteristics on post-HSCT OS, EFS, outcomes, and immune reconstitution.

Results: Patients were mainly transplanted for Combined Immune Deficiency (CID) (47%), Hemophagocytic Lymphohistiocytosis (HLH) (33%), Chronic Granulomatous Disease (CGD) (8%) or IPEX (7%) at a median age of 1.38 years (range: 0.17; 16.22). The pre-transplant status evaluation reported a median IDDA (Immune deficiency with Dysregulation Activity) of 29.75 (range: 1.5-100) and a comorbidity score of 3 (range: 0-6). Notably, active infection was documented in 39% of cases, autoimmunity in 35% of patients, and 39% experienced intensive care unit admission within three months before the transplant. Busulfan-based CR was given to 97.2% with a median AUC exposure of 18494 µM*min. (range: 12781- 24456). All patients received up-front serotherapy starting at a median of D-11 (range: -8; -18) with alemtuzumab (median dose of 0.5 mg/kg, range 0.2 to 2 mg/kg). All also received rituximab, with bone marrow as the stem cell source. PTCY was given on D + 3 and D + 4 (50 mg/kg/dose). GVH prophylaxis started on D + 5 with ciclosporin and MMF. The neutrophil engraftment was reached at a median of D + 20 with full donor chimerism in 63 out of 65 patients (2 patients had mixed chimerism). Primary graft failure (GF) occurred in 7 patients (10%), and four were successfully retransplanted. Twelve patients died from infections (n = 6), primary GF (n = 2), toxicity, and/or GVHD (n = 4). The 3-years OS was 83.1%, and OS was significantly worsened by a high comorbidity index (p = 0.039), a high IDDA score ( > 25 found as the optimal cut-off, p = 0.048), and an HLH diagnosis (p = 0.06). Otherwise, OS was better in patients without active infection at transplant (p = 0.25) and for patients transplanted after 2018 (p = 0.06). 3-years EFS was 77% and was not significantly influenced by any factors studied.

Incidence of endothelium toxicities occurred in 29/72 patients (40%) and was noteworthy higher in HLH (17/24, 70%). Cumulative incidence (CI) of aGVHD grade II to IV, grade III to IV, and cGVHD were 23.3, 2.95, and 8.22%. CI of asymptomatic replication, clinically significant CMV, and adenovirus infection were 50%, 5.7%, and 6%, respectively. CI of post-HSCT autoimmune cytopenia was 12%. To implement immune reconstitution, a modelization by a Bayesian mechanistic inference model of the CD4+ and Naïve CD4 + T-cell count will be performed depending on specific covariates to hHSCT.

Conclusions: This retrospective monocentric study demonstrates that hHSCT with PTCY led to good outcomes in patients with non-SCID-IEI, especially in CID with low comorbidity and IDDA scores before HSCT advocated for early intervention. Endothelial toxicities remained a significant morbidity in high-risk patients.

Disclosure: Nothing to declare

23: Haemoglobinopathy

O093 UNRELATED DONOR TRANSPLANTATION OFFERS A REAL CURATIVE OPPORTUNITY FOR PATIENTS WITH TRANSFUSION-DEPENDENT THALASSAEMIA. EXPERIENCE OF THE SPANISH GROUP FOR BONE MARROW TRANSPLANTATION IN CHILDREN (GETH-TC)

Maria Isabel Benitez Carabante 1, Angela Menárguez1, Cristina Beléndez Bieler2, Laura Alonso García1, María Luz Uría Oficialdegui1, Melissa Panesso1, Mercedes Plaza Fornieles3, Carolina Fuentes4, Sara Vinagre Enríquez5, Graciela Gómez Silva6, Mónica López Duarte7, José María Pérez Hurtado8, Montserrat Torrent9, Cristina Díaz de Heredia Rubio1

1Hospital Universitario Vall d´Hebron, Barcelona, Spain, 2Hospital General Universitario Gregorio Marañón, Madrid, Spain, 3Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain, 4Hospital Universitario La Fe, Valencia, Spain, 5Hospital Universitario Niño Jesús, Madrid, Spain, 6Hospital Clínico de Santiago, Santiago de Compostela, Spain, 7Hospital Universitario Marqués de Valcecilla, Santander, Spain, 8Sevilla, Spain, Spain, 9Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

Background: The life expectancy of patients with transfusion-dependent thalassaemia (TDT) has improved due to advances in supportive therapy, but transfusion and iron overload remain a handicap.

The introduction of new drugs could alleviate the disease phenotype, however only a small group of patients have been able to achieve transfusion independence.

Although clinical trials in gene therapy and gene editing are promising, haematopoietic stem cell transplantation (HSCT) remains the most widely available curative treatment available to date.

Results with matched family donor (MFD) are excellent, however, the probability of having a healthy MFD is low and there is a need to explore alternative donors.

Our objective was to study the impact of the donor and the conditioning regimen in TDT patients.

Methods: A national multicenter retrospective study was conducted. Children (from birth to 18 years of age) diagnosed of TDT who underwent a first HSCT until December 31, 2021, were included.

Primary endpoint was Thalassemia Free Survival (TFS). Secondary endpoints included engraftment, graft versus host disease (GvHD), overall survival (OS) and cGvHD-TFS (cGTFS).

Results: Fifty-nine patients were included. Median age at transplantation was 5.6 years (0.7-16.6). The 81% received regular chelation and ferritin at HSCT was 1304 (698-2097) ng/mL. Four of twenty studied patients had signs of liver fibrosis.

Thirty-nine patients (66%) received an MFD transplant, 16 (27.1%) a matched unrelated donor (MUD), 3 (5%) an unrelated cord blood transplant (UCBT) and one an haploidentical transplant. Bone marrow (BM) was the most used stem cell source (n = 49;83%). Thirty-seven patients (62.1%) received BuCy-based conditioning and 22 (37.3%) TreoFluTT. Forty patients (67.8%) received lymphodepletion with Thymoglobulin.

Fifty-six patients engrafted (95%) and the median time to granulocyte recovery was 21 days. Three patients presented primary graft failure and 2 secondary graft failure. Six patients (13.3%) had sustained mixed chimerism but remained disease free without transfusions requirements.

The cumulative incidence of grade II-IV and grade III-IV aGvHD was higher with MUD compared to MFD: 67% vs 35%, p = 0.014 and 30% vs 9%, p = 0.0325 respectively. Overall, 7 patients presented cGvHD (12%) of whom 2 were moderate and one extensive.

With a median follow up of 7.4 years, no statistically significant differences were found in terms of OS, TFS and cGTFS between MSD and MUD: 97.2% vs 100%, p = 0.33; 94.4% vs 86.5, p = 0.63 and 86.1% vs 73.9%, p = 0.19 respectively.

Table 1. Patient and transplant characteristics

Characteristic

All TDT patients (n = 58)

MFD1 (n = 39)

MUD2 (n = 19)

p-value

Follow up (years)

7.42

7.6

7.25

(median, IQ)

(2.4—11.6)

(2.2 -11.6)

(1.8-12.4)

0.99

Age at HSCT (years)

5.63

5.38

5.33

(median, range)

(0.76-16.64)

(0.87-16.64)

(0.76-14.78)

0.47

Patient sex

Male

32 (55.2%)

20 (51.3%)

12 (63.2%)

Female

26 (44.8%)

19 (48.7%)

7 (36.8%)

0.39

Regular quelation

Yes

45 (81.8%)

28 (77.8)

17 (89.5%)

No

10 (18.2%)

8 (22.2%)

2 (10.5%)

0.46

Hepatomegaly

Yes

30 (51.7%)

23 (59%)

7 (36.8%)

No

28 (48.3%)

16 (41%)

12 (63.2%)

0.11

Ferritin (ng/mL)

1304

1470

1100

(median, IQ)

(698 – 2097)

(900 – 2500)

(662 – 2080)

0.21

Period of HSCT

< 2010

20 (34.5%)

15 (38.5%)

5 (26.3%)

≥ 2010

38 (65.5%)

24 (61.5%)

14 (73.7%)

0.36

Stem cell source

43 (74.1%)

29 (74.4%)

14 (73.7%)

Bone marrow

3 (5.2%)

1 (2.6%)

2 (10.5%)

Peripheral blood

6 (10.3%)

3 (7.7%)

3 (15.8%)

Cord blood BM + CB

6 (10.3%)

6 (15.4%)

0 (0%)

0.12

Conditionig regimen

Bu based

36 (62.1%)

22 (56.4%)

14 (73.7%)

Treo based

22 (37.9%)

17 (43.6%)

5 (26.3%)

0.20

T cell depletion (ATG)

Yes

40 (70.2%)

21 (55.3%)

19 (100%)

No

17 (29.8%)

17 (44.7%)

0 (0%)

0.0005

  1. 1MFD included MSD (n = 33) and other matched family donors (n = 3)
  2. 2MUD included UD (n = 16) and CB UD (n = 3)
  3. *One patient with Haploidentical transplant is excluded from table 1

The use of bone marrow was associated with increase OS, TFS and cGTFS.

No significant differences were found between BuCy vs TreoFluTT base regimens in terms of aGvHD, OS and TFS. Nevertheless, patients receiving BuCy presented a higher rate of sinusoidal obstruction syndrome and posterior reversible leukoencephalopathy.

Conclusions: The results obtained with MFD and MUD are comparable in terms of OS, TFS and cGTFS.

Treosulfan-based conditioning regimen offers similar results to busulfan-based conditioning in terms of survival, with the benefit of lower risk of endothelial complications.

In TDT pediatric patients, when a MFD is available, HSCT should be offered. In the absence of a MFD, the search of a MUD should be initiated.

Disclosure: Nothing to declare

23: Haemoglobinopathy

O094 ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION IN PATIENTS WITH SICKLE CELL DISEASE: PRELIMINARY RESULTS OF THE FIRST FOUR PATIENTS TRANSPLANTED IN TANZANIA

Fabio Giglio 1,2,3, David Mashala4, Stella Malangahe4, Shakilu Jumanne4,5, Merlikiad Mhozya4, Paola Erminia Ronchi1,3, Alessia Orsini1,3, Francis Ngiliule4, Zimbwe Bakari4, Alen Patrick Magoha4, Anna Carmagnola1,3, Musa Dubali1,6, Nunzia Manna1, Pietro Pioltelli1, Fabio Ciceri3, Alphonse Chandika4, Cornelio Uderzo1

1HELP3 ODV, Monza, Italy, 2IEO European Institute of Oncology IRCCS, Milano, Italy, 3IRCCS San Raffaele Scientific Institute, Milano, Italy, 4Benjamin Mkapa Hospital, Dodoma, Tanzania, United Republic of, 5University of Dodoma, Dodoma, Tanzania, United Republic of, 6Policlinico Universitario Tor Vergata, Roma, Italy

Background: Sickle cell disease (SCD) is the most common inherited hemoglobinopathy in Tanzania, with 11,000-14,000 newborns with the disease annually. While life expectancy of SCD patients in high-income settings has improved, the mortality rate is 50-90% in low-income countries. Curative options for SCD (allogeneic hematopoietic stem cell transplantation HSCT, gene therapy, gene editing) are unavailable in sub-Saharan Africa. Here we present preliminary results of the first four SCD patients transplanted in Tanzania.

Methods: Tanzania launched a development program in 2018 to establish HSCT at Benjamin Mkapa Hospital (BMH) in Dodoma. With the support of the Association HELP3-ODV (www.help3.it), starting from 2019 a series of videoconference lectures were done by international HSCT experts to train Tanzanian health professionals. Four nurses, two doctors and two laboratory scientists took part in an observational internship in Italy at different Centers. In January 2023 HSCT program started at BMH with the presence of experienced Italian staff in Tanzania for the first 4 months. Weekly online clinical-logistical round started in March 2023 and are ongoing.

Conditioning regimen consisted of Busulfan, Rabbit Antithymocyte Globulin (ATG) and Cyclophosphamide. GVHD Prophylaxis consisted of methotrexate and cyclosporine. Standard Levetiracetam and antimicrobial prophylaxis were used. All patients with symptomatic SCD, received bone marrow stem cells harvested from HLA-identical siblings.

Results: From January to March 2023 the first 3 HSCT were performed. A fourth patient was transplanted in May 2023. Three patients were male, one female, median age was 8 (4-11). Median TNC infused was 6.05 x 108/kg of patient BW (4.7-8.9).

Conditioning regimen was well tolerated without grade III-IV adverse events. All patients engrafted with a median ANC and PLT engraftment at day + 27 (19-41) and + 25 (15-35), respectively. All patients experienced febrile neutropenia, responding to broad-spectrum antibiotics. Microbiological findings on blood were P.Falciparum, Coagulase-negative Staphylococci and Gram positive rods, all resolved. Grade II Skin aGVHD was diagnosed on day +21 in one patient, treated with Methylprednisolone and Mycophenolate Mofetil, obtaining complete resolution.

At a median follow-up of + 309 (196-315) from HSCT, no other GVHD were diagnosed. One patient was diagnosed with oral HPV lesions, now receiving treatment. No other long-term complications were diagnosed. All patients remain transfusion free, without SCD events, with blood counts and HbS levels compatible with complete engraftment and chimerism.

Conclusions: Our preliminary results for the first SCD patients transplanted in Tanzania show that HSCT is feasible in LMICs without major adjustments on infrastructures and human resources. The first four patients are now asymptomatic with full chimerism. Of note, the fourth patient was transplanted without the Italian staff at BMH and the fifth patient was undergoing HSCT at the time of this submission. Tanzanian government has deliberated to support BMT at BMH Hospital.

It’ll be fundamental to ensure sustainability of the service considering the immense need of HSCT in Tanzania. Maintaining the cost affordable and creating a reliable supply chain of drugs and consumables will be crucial. Continuous training for health professionals is ongoing and needs to be implemented, ideally to make HSCT feasible also in other disorders.

Disclosure: HLA typing was provided by DKMS Group gGmbH

23: Haemoglobinopathy

O095 NON-MYELOABLATIVE HAEMATOPOIETIC STEM CELL TRANSPLANT FROM MATCHED RELATED DONORS IN ADULT PATIENTS WITH SEVERE SICKLE CELL DISEASE: THE UK REAL-LIFE EXPERIENCE

Fabio Serpenti 1, Ben Carpenter2, John Snowden3, Elisa Roldangalvan3, Rachel Kesse-Adu4, Eleni Tholouli5, Clare Samuelson3, Subarna Chakravorty1, Victora Potter1

1King’s College Hospital, London, United Kingdom, 2University College of London Hospital, London, United Kingdom, 3Sheffield Teaching Hospitals, Sheffield, United Kingdom, 4Guy’s and St Thomas’ Hospital, London, United Kingdom, 5Manchester University NHS FT, Manchester, United Kingdom

Background: Sickle cell disease is a genetic haemoglobinopathy with a high burden of morbidity and mortality, whose prevalence is increasing in developed countries. Hematopoietic stem cell transplant is the only curative option available today. Non-myeloablative matched sibling transplant has been associated with good engraftment and low toxicity rates in adults and has been approved by NHS England in 2021. We hereby report the nationwide real-life data after 2 years of activity.

Methods: All adult patients approved by the UK National Haemoglobinopathy Panel and who proceeded to Alemtuzumab TBI matched related transplant were analyzed. All patients underwent fertility and fitness assessment pre-transplantation. Target cell dose was 10 x 106 CD34 + /kg and cells could have been collected and cryopreserved before the start of conditioning to ensure adequate dose was available. All patients had red cell exchange pre-conditioning; ABO mismatch was managed with plasma exchange pre cell infusion. Data were collected locally by each transplant center and were shared with BSBMTCT and King’s College Hospital, who coordinated and led the analysis.

Results: A total of 15 patients, distributed among five transplant centers in the UK, were evaluable for the study, with a median follow-up of 622 days (29-774 days) – Table 1. Major ABO mismatch was present in 4 patients (28,5%), all with high antibody titers (>1:512). Median CD34+ cell dose was 10.26 x 106/kg of body weight of recipient (range 5 – 23,7). All but one patient engrafted with a median time of 28 days for neutrophils (10-48 days) and 26.5 days for platelets (16-42 days). One patient had graft rejection with autologous reconstitution. Other 2 patients had secondary graft failure and autologous reconstitution after initial engraftment at D + 48 and D + 134, respectively. Sickle-free survival post-transplant was thus 78,5%. In 2 out of 3 graft failure cases, CD34+ dose had been suboptimal (7,7 and 8,8) and 2 of them had major ABO mismatch. All engrafted patients showed fluctuating mixed chimerism over time until stabilization, with low Hb% and no vaso-occlusive crisis reported after transplant. Median whole blood chimerism / myeloid / lymphoid chimerism at D28 were 95.2/98/44%, at D100 were 99,4/94.8/10%, at 6M were 82/85/19,5% and at 1y were 76/81/61%. Five patients managed to stop sirolimus maintaining stable chimerism after a median of 488 days (216 – 520). G1 aGvHD was observed in 2 patients and treated topically; no cGvHD was observed. No viral reactivation required treatment. Three of the engrafted patients needed at least one hospitalization after transplant discharge (1 TB reactivation, 1 chest infection and 1 line related sepsis). All patients were alive at end of follow-up.

Patients

N = 15

Sex

• M

8

• F

7

Median age (range)

31y (18 – 43)

Primary indication

• >= 3 pain crises/year

3

• Recurrent ACS

3

• Neurological event

3

• Need of regular transfusion

6

Median n of indication (range)

2 (1-3)

Median HCT-CI (range)

2,5 (0-5)

Previous therapy

• HU

12

• Regular transfusion / RCE

9

• other

Donors

Sex

• M

8

• F

7

F to M transplant

5

Median age (range)

30,5y (12 -57)

Donor genotype

• HbAA

4

• HbAS

8

• Missing data

3

Blood group

• Matched

10

• Minor mismatch

1

• Major mismatch

3

• Bidirectional mismatch

1

CMV

• Pos/pos

12

• Pos/neg

1

• Neg/pos

1

• Neg/neg

1

Conclusions: Stable engraftment and sickle-free survival was achieved in 78,5% of patients, in line with previous reports using this transplant platform. Our chimerism data confirm that mixed whole blood nucleated cell chimerism is enough to ensure donor erythropoiesis and suppress recipient HbS production, reverting the sickle phenotype. Longer-term follow-up is warranted to better define the best therapeutic approach for these patients, especially in relation to the rapidly evolving treatment landscape for sickle cell disease.

Disclosure: JS - advisory boards for Vertex, Jazz and Medac

23: Haemoglobinopathy

O096 IMPACT OF ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION IN ADOLESCENTS AND ADULTS WITH SICKLE CELL DISEASE: COMPARISON OF THE OUTCOME IN TRANSPLANTED VERSUS NON-TRANSPLANTED PATIENTS

Cécile Pivert 1, Loïc Vasseur1, Edouard Flammarion2, Corinne Guitton3, Maryse Etienne-Julan4, Abdourahim Chamouine5, Laurent Cimasoni6, Claire Dichamp7, Annie Kandem8, Isabelle Genty8, Marie Lagarde9, Aude Marie Fourmont10, Florian Chevillon1, Jean-Benoît Arlet2, Corrine Pondarré8, Nathalie Dhedin1

1Hôpital Saint Louis, Paris, France, 2Hopital Européen Georges Pompidou, Paris, France, 3Hôpital du Kremlin Bicêtre, Kremlin Bicêtre, France, 4CHU de Guadeloupe, Pointe-à-Pitre, France, 5Centre Hospitalier de Mayotte, Mamoudzou, France, 6Hôpitaux Universitaires de Genève, Genève, Switzerland, 7CHU de Martinique, Fort de France, France, 8Centre Hospitalier Intercommunal de Créteil, Créteil, France, 9CHU de Bordeaux, Bordeaux, France, 10CHU de Nantes, Nantes, France

Background: Despite advancements in managing patients with sickle cell disease, the life expectancy of adolescents and adults remains reduced compared to the general population. Progressive organ damages contribute significantly to morbidity. Hematopoietic stem cell transplantation (HSCT) is the only validated curative treatment, yet it’s rarely performed in adults due to potential toxicity This retrospective study aims to evaluate the risk-benefit balance of HSCT in adolescents and adults with sickle cell disease.

Methods: Inclusion criteria comprised patients with an indication for HSCT, referred for pre-transplant consultation at the Adolescent Young Adult unit of Saint Louis Hospital between January 2011 and July 2022. Patients with history of solid organ transplantation and those older than 45 years (for HLA-identical HSCT) or older than 40 years (for haplo-identical HSCT) were excluded.

Treatment modalities: Patients underwent three HSCT modalities: HLA-identical HSCT after myeloablative or non-myeloablative conditioning, and haplo-identical HSCT with reduced conditioning using post-transplant cyclophosphamide.

Evaluation criteria: Primary evaluation criteria were overall survival (OS) and event-free survival (EFS) evaluated from the pre-transplant consultation date, with comparison between transplant and non-transplant groups. Events for EFS included death, acute GVHD (grades III-IV), moderate to severe chronic GVHD, ≥3 hospitalized painful crisis in 2 years, acute chest syndrome, delayed hemolytic transfusion reaction or complex alloimmunization, initiation of a new treatment (chronic transfusion, hydroxyurea or second transplantation).

Methods: HSCT’s impact on both OS and EFS was analyzed considering HSCT as a time-dependent variable. Patients were considered non-transplanted before HSCT and transplanted after HSCT. OS and EFS were estimated using the Simon-Makuch method, and HSCT’s impact was tested using a univariable Cox model.

Results: Patient characteristics are detailed in Table 1. Median follow-up was 2,9 years (IQR 1,76-4,3). At last follow up, there were 58 transplanted and 36 non transplanted patients. The main reasons for non-transplantation were : refusal by the patient or his family, absence of donor, and identification of anti-HLA antibodies.

Baseline characteristics

Total (n = 94)

Transplantation group (n = 58)

Standard of care group (n = 36)

p

Age, yr, median (IQR)

18,8 (16,9-26)

17,9 (16,3-21,1)

22,7 (17,7-32,7)

<0,001

Median follow-up, yr (IQR)

2,9 (1,76-4,3)

3,2 (1,9-4,6)

2,2 (1,4- 3,4)

0,03

Female sex, n (%)

47 (50)

30 (52)

17 (47)

ns

Disease-modifying therapy at pre-transplant consultation date, n (%)

- hydroxyurea

- 44 (46,8)

- 28 (48,3)

- 16 (44,4)

- chronic transfusion

- 42 (44,7)

- 26 (44,8)

- 16 (44,4)

ns

Number of VOC in the 2 years prior to the pre- transplant consultation date, median (IQR)

4 (1-7)

4 (1-6)

4 (1,25-10)

ns

Number of ACS in a lifetime, median (IQR)

2 (1-4)

2 (1-4)

3 (1-5,7)

ns

Cerebral vasculopathy (stroke, silent stroke, abnormal TCD, stenosis, Moya Moya), n (%)

38 (40,4)

22 (37,9)

16 (44,4)

ns

- DHTR, n (%)

- 9 (9,5)

- 6 (10,3)

- 3 (8,3)

- ns

- Complex allo immunization, n (%)

- 16 (17)

- 7 (12,1)

- 9 (25)

- 0,03

Nephropathy (microalbuminuria, proteinuria, renal insufficiency), n (%)

35 (37,2)

20 (34,4)

15 (41,6)

ns

Abnormal lung function (obstructive, restrictive, both obstructive and restrictive abnormalities), n (%)

28 (34,1)

21 (36,8)

7 (28)

ns

- Hypertension requiring treatment, n (%)

- 3 (3,2)

- 0

- 3 (8,3)

-0,006

- Cardiopathy, pulmonary hypertension, n (%)

- 6 (6,4)

- 4 (6,9)

- 2 (5,6)

- ns

Retinopathy

30 (37,9)

14 (31,1)

16 (47)

ns

Priapism (males), n (%)

9 (9,6)

6 (21,4)

3 (15,8)

ns

Table 1. Baseline characteristics. VOC : vaso-occlusive crisis. ACS : acute chest syndrome. TCD : transcranial Doppler. DHTR : delayed hemolytic transfusion reaction

The 3-years OS was estimated to 97,9% (95% CI: 94-100%) for transplanted patients and 91,5% (95% CI: 80,3-100%) for non transplanted patients (p = 0,56). Two patients died in the non transplanted group (one of a ruptured cerebral aneurysm and one of cardiac arrest of unknown cause) and 2 patients died after transplantation (one of grade IV acute GVHD and one of pneumococcal bacteriemia).

The 3-years EFS was 79,8% (95% CI: 68,1-93,4%) for transplanted patients and 7% (95% CI: 1,3-38,6%) for non transplanted patients (p < 0,0001).

Both incidence of VOC and ASC were decreased after transplantation (p < 0,0001 and p = 0,0002 respectively). In the non transplanted group, 2 patients had a worsening of their cerebral stenosis (versus none after transplantation).

Cumulative incidences of grades II, III-IV acute GVHD and moderate to severe chronic GVHD were 10.3%, 3.4%, and 3.5%, respectively.

Conclusions: In this population of adolescents and adults, there was no observed short-term excess mortality related to HSCT. Severe event-free survival was very poor in absence of transplant. Furthermore, event-free survival was improved after transplantation, with a low incidence of chronic GVHD, suggesting a benefit of transplantation..

Disclosure: Nothing to declare.

25: Immunodeficiency Diseases and Macrophages

O097 HAEMATOPOIETIC STEM CELL TRANSPLANTATION FOR CTLA-4 INSUFFICIENCY: AN EBMT INBORN ERRORS WORKING PARTY STUDY

Christo Tsilifis 1,2, Carsten Speckmann3, Su Han Lum1,2, Andrew R. Gennery1,2, Arjan C. Lankester4, Jennifer Tjon4, Emilie P. Buddingh4, Petr Sedlacek5, Alexandra Laberko6, Suzanne Elcombe7, Venetia Bigley7,2, Vassilios Lougaris8, Michele Malagola8, Robert Wynn9, Fabian Hauck10, Claudia Wehr3, Bodo Grimbacher3,11, Thomas Fox12,13, Emma C. Morris12,13, Adriana Margarit-Soler14, Yasmina Mozo15, Dolores Corral15, Anna-Maria Ewins16, Rosie Hague16, Christina Oikonomopoulou17, Krzysztof Kalwak18, Katarzyna Drabko19, Michael H. Albert10, Bénédicte Neven20, Mary A. Slatter1,2

1Great North Children’s Hospital, Newcastle upon Tyne, United Kingdom, 2Newcastle University, Newcastle upon Tyne, United Kingdom, 3University of Freiburg, Freiburg, Germany, 4Leiden University Medical Center, Leiden, Netherlands, 5Charles University Motol, Prague, Czech Republic, 6Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation, 7Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom, 8University of Brescia, Brescia, Italy, 9Royal Manchester Children’s Hospital, Manchester, United Kingdom, 10Ludwig-Maximilians-Universität München, Munich, Germany, 11University Hospital Freiburg, Freiburg, Germany, 12University College London, London, United Kingdom, 13University College London Hospitals NHS Foundation Trust, London, United Kingdom, 14Hospital Sant Joan de Déu, Barcelona, Spain, 15University Hospital La Paz, Madrid, Spain, 16Royal Hospital for Children, Glasgow, United Kingdom, 17Aghia Sophia Children’s Hospital, Athens, Greece, 18Wroclaw Medical University, Wroclaw, Poland, 19Medical University of Lublin, Lublin, Poland, 20Hôpital Necker-Enfants Malades, Paris, France

Background: Cytotoxic T-lymphocyte antigen-4 (CTLA-4) insufficiency causes a primary immune regulatory disorder characterised by lymphoproliferation, multi-organ autoimmunity including cytopenias, colitis, GLILD, and dysgammaglobulinaemia(1,2). HSCT has been shown to be curative in small case series(3). We report the largest cohort to date and examine the impact of pre-HSCT CTLA-4-Ig therapy (abatacept, belatacept) and degree of pre-HSCT immune dysregulation on survival and immunological outcome.

Methods: Retrospective data collection on HSCT for CTLA-4 insufficiency; patients with CTLA4 mutations or 2q33.2-3 deletion were included. Primary endpoints were overall survival (OS) and chronic GvHD and event-free survival (CEFS). Secondary endpoint was immunological outcome assessed by Immune Dysregulation and Disease Activity (IDDA) score(4). Cumulative incidence (CI) of graft failure was calculated using death as a competing risk; CI of grade III-IV acute, and moderate-severe chronic GvHD were calculated using death and graft failure as competing risks.

Results: Forty patients were included over a 25 year period. Median age at diagnosis was 13 years (birth – 50.0 years) - diagnosis was made pre-HSCT in 32/40 (80%) patients. Pre-HSCT, 24/40 (60%) received CTLA-4-Ig as well as other immunomodulatory therapies (including glucocorticoids, n = 34, 85%; rituximab, n = 20, 50%). Pre-HSCT IDDA was 23.3 (3.9–84.0) and did not differ significantly by CTLA-4-Ig receipt (p = 0.436).

Median age at HSCT was 14.2 (1.3–56.0) years. Patients received PBSC (23/40, 58%) or marrow (17/40, 43%) from MUD (n = 30, 75%), MMUD (n = 5, 12.5%) or MFD (n = 5, 12.5%). Conditioning was predominantly treosulfan-based (n = 30, 75%, Table 1) with serotherapy (alemtuzumab: 21/40, ATG: 16/40).

Median follow-up was 3 years (0.5–15 years) and 3-year OS was 76.7% (58–87%). Probability of OS was greater in patients transplanted ≥2014 (p = 0.05) and patients with lower disease activity (pre-HSCT IDDA < 23, p = 0.002); there was no impact of CTLA-4-Ig use on OS (p = 0.221). 3-year CEFS was 69.1% (50.5–81.9%), with greater probability in patients with pre-HSCT genetic diagnosis (p = 0.033) and pre-HSCT IDDA < 23 (p = 0.009). Graft failure CI was 11.8% (n = 4), and two patients had a second conditioned HSCT. CI of grade III-IV acute GvHD was 20.6%, and of chronic GvHD, 10.7%. Cause of death was transplant-related in 7/8 patients: acute or chronic GvHD, thrombotic microangiopathy, cardiac failure post-cyclophosphamide.

Median CD3+ donor chimerism at latest follow-up in 30 surviving and engrafted patients is 100% (40–100%). Median IDDA is 1.7 (range 0–61), having reduced a median of 16 points in 28/30 patients (p < 0.001).

Nine patients had relapse of autoimmunity, of which six had mixed CD3+ chimerism at relapse, including autoimmune cytopenia, GLILD, and panniculitis.

CTLA-4 diagnosis before HSCT, n (%)

32 (80.0)

Immunosuppression prior to HSCT, n (%)

None

2 (5.0)

Steroids

34 (85.0)

Rituximab

20 (50.0)

CTLA-4-Ig

24 (60.0)

Pre-HSCT disease activity

Median IDDA score (range)

23.3 (3.9 – 82.0)

Organ involvement, patients with grade 2 – 4 (moderate, severe, or life-threatening/irreversible) as per IDDA scoring, n (%)

Autoimmune cytopenia

13 (32.5)

Enteropathy

11 (27.5)

Lymphoproliferation

11 (27.5)

Parenchymal lung disease

12 (30.0)

Malignancy

5 (12.5)

Age at HSCT, years (median [range])

14.2 (1.3 – 56.0)

Time period of HSCT, n (%)

<2014

8 (20.0)

≥2014

32 (80.0)

Conditioning, n (%)

Treosulfan-based

30 (75.0), with thiotepa, 19 (47.5)

Busulfan-based

2 (5.0)

Melphalan-based

7 (17.5)

Fludarabine/cyclophosphamide

1 (2.5)

Serotherapy, n (%)

Alemtuzumab

21 (52.5)

ATG

16 (40.0)

Conclusions: This is the largest retrospective study of HSCT for CTLA-4 insufficiency to date. We demonstrate that HSCT is an effective therapy to prevent ongoing disease progression and morbidity, with improving survival rates over time and in patients with lower pre-HSCT disease activity. The risks and benefits of HSCT or of long-term CTLA-4-Ig therapy must be carefully balanced. Further data collection will help optimise treatment in this complex disorder and decide which patients might benefit from HSCT and at what stage in their illness.

Disclosure: Nothing to declare.

25: Immunodeficiency Diseases and Macrophages

O098 HAEMATOPOIETIC STEM CELL TRANSPLANTATION FOR STAT3 DOMINANT-NEGATIVE HYPER-IGE SYNDROME: INTERNATIONAL STUDY

Christo Tsilifis 1,2, Christina Oikonomopoulou3, Ramya Uppuluri4, Masakatsu Yanagimachi5, Ásgeir Haraldsson6, Melanie Wong7, Steven J. Keogh7, Paul Gray8, Richard Mitchell8,9, Michael Raum10, Peter Ciznar11, Corina Gonzalez12, Dimana Dimitrova12, Jennifer Kanakry12, Venetia Bigley13,2, Mary A. Slatter1,2, Niraj Patel14, Emilie P. Buddingh15, Michael Medinger16, Joanna Renke17, Fabian Hauck10, Michael H. Albert10, Austen Worth18, Alexandra F. Freeman12, Andrew R. Gennery1,2

1Great North Children’s Hospital, Newcastle upon Tyne, United Kingdom, 2Newcastle University, Newcastle upon Tyne, United Kingdom, 3Aghia Sophia Children’s Hospital, Athens, Greece, 4Apollo Hospitals, Chennai, United Kingdom, 5Kanagawa Children’s Medical Center, Yokohama, Japan, 6Landspitali – University Hospital, Reykjavík, Iceland, 7Children’s Hospital at Westmead, Westmead, Australia, 8Sydney Children’s Hospital, Sydney, Australia, 9University of New South Wales, Sydney, Australia, 10Ludwig-Maximilians-Universität München, Munich, Germany, 11Children’s University Hospital Bratislava, Bratislava, Slovakia, 12National Institutes of Health, Bethesda, United States, 13Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom, 14Duke University, Durham, United States, 15Leiden University Medical Center, Leiden, Netherlands, 16University Hospital Basel, Basel, Switzerland, 17Medical University of Gdańsk, Gdańsk, Poland, 18Great Ormond Street Hospital for Children, London, United Kingdom

Background: STAT3 dominant-negative hyper-IgE syndrome (STAT3-DN-HIES) is a multisystem disorder featuring recurrent skin and respiratory infection with development of bronchiectasis, pneumatocoeles, and aspergillosis; lymphoma; and extra-immune disease such as fractures and vasculopathy(1,2,3).

Allogeneic HSCT for STAT3-DN-HIES was initially reported as unsuccessful, though more recent publications have highlighted a potential role in improving skin and lung disease(4,5). Published data focus on small case reports or cohorts.

Methods: As part of an international multicentre study of STAT3-DN-HIES, data on allogeneic HSCT recipients were collected. Primary endpoints were overall survival (OS) and event-free survival (EFS; events were death, graft failure, chronic GvHD).

Results: We identified 35 patients receiving 37 HSCT over a 28-year period. Median follow-up for surviving patients was 4.2 years (1.0–27.5). HSCT indication was recurrent infection (n = 32, 91%) or lymphoma (N = 3, peripheral T-cell or non-Hodgkin; 9%). Median age at HSCT was 13.2 years (3.5–29.0). The majority of patients had pre-HSCT respiratory disease (n = 32, 91%) including parenchymal lung disease (overall, n = 22, 63%; bronchiectasis in n = 12, pneumatocoele in n = 15), confirmed aspergillus disease (n = 8, 23%), and suspected fungal disease with pulmonary nodules (n = 2, 6%). Two patients had pre-HSCT long-term home oxygen use. Patients received predominantly treosulfan-based conditioning (n = 21, 60%, with thiotepa: n = 12). Grafts were PBSC (n = 17, 49%) or marrow (n = 18, 51%) from MFD (n = 15, 43%), MUD (n = 15, 43%), or mismatched donors (n = 5, 14%, including three haploidentical). Median CD34+ cell dose was 6.0x106/kg. Three mismatched grafts underwent ex vivo TCRαβ/CD19 depletion. Five patients received post-transplant cyclophosphamide.

Four-year OS was 93.8% (77.4–98.4%) and EFS was 86.8% (68.2–94.9%). Cause of death (n = 3) was grade IV acute GvHD after second HSCT, disseminated adenovirus infection, Stenotrophomonas sepsis with haemoptysis. Two patients had graft failure and second conditioned HSCT. Acute GvHD incidence was 37% (grades I-II: 26%, III-IV: 11%). Two patients had chronic GvHD: one limited skin, one severe mixed acute/chronic following second HSCT, who subsequently died.

At latest follow-up, median donor chimerism in survivors was CD3 + 85% (29–100%) and CD15 + 100% (25–100%); median IgE was 170 kU/L (25–11813). Four patients, all with significant pre-HSCT lung disease, have post-HSCT fungal infection: aspergillus colonisation of pre-existing pneumatocoeles in three patients, and disseminated aspergillosis during aplasia, causing plexopathy, immune reconstitution inflammatory syndrome, and renal aspergillosis. Twenty-seven surviving patients (84%) have reduced frequency of respiratory infection at latest follow-up. No patients have eczema. Extra-immune outcome was mixed: seven patients have new fractures, and three patients have new or worsening scoliosis. Significant vasculopathy was seen in two patients post-HSCT, without pre-HSCT imaging for comparison. No patients had new/relapsed malignancy.

Table 1. Patient and HSCT characteristics.

Pre-HSCT lung disease

Recurrent infection

32 (91)

Pneumatocoele

15 (43)

Bronchiectasis

12 (34)

Lobectomy

4 (11)

Fungal infection

8 (23)

Time period of HSCT

<2010

5 (14)

≥2010

30 (86)

Conditioning

Treosulfan-based

21 (60), 12 with thiotepa

Busulfan-based

8 (23)

Melphalan-based

6 (17)

Serotherapy

Alemtuzumab

19 (54)

ATG

9 (26)

None

7 (20)

Donor type

10/10 MFD

15 (43)

10/10 MUD

15 (43)

MMFD

4 (12)

MMUD

1 (3)

Stem cell source

PBSC

17 (49)

Marrow

18 (51)

Conclusions: This multicentre study expands the published experience of HSCT for STAT3-DN-HIES in a heterogeneous cohort. Despite significant pre-HSCT pulmonary morbidity, overall survival was high and patients have improved skin and respiratory disease, though the impact of HSCT on extra-immune manifestations appears limited. As aspergillosis may cause complications in patients with pre-existing parenchymal disease post-HSCT, patient selection and timing of HSCT referral is important.

References:

1. Holland, NEngJMed 2007;357(16):1608-19

2. Minegishi, Nature 2007;448(7157):1058-62

3. Tsilifis, JClinImmunol 2021;41(5):864-880

4. Gennery, BMT 2000;25(12):1303-5

5. Harrison, JClinImmunol 2021;41(5):934-943

Disclosure: Nothing to declare.

25: Immunodeficiency Diseases and Macrophages

O099 OUTCOMES AFTER ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION IN PATIENTS WITH GATA2 DEFICIENCY

Alejandra Escobar Vasco 1, Soyoung Kim2, George Georges3, Andrew Gennery4,5, Kasiani Myers6,7, Rafeek Yusuf8, Wael Saber1, Mehdi Hamadani1, Stephanie Lee9, Brian Ball10, Larisa Broglie1

1Medical College of Wisconsin, Wauwatosa, United States, 2Medical College of Wisconsin, Wauwatosa, United States, 3Fred Hutchinson Cancer Research Center, Seattle, United States, 4Children’s Haematopoietic Stem Cell Transplant Unit, Great North Children’s Hospital, Newcastle upon Tyne, United Kingdom, 5Translational and Clinical Research Institute, Newcastle University, Newcastle, United Kingdom, 6University of Cincinnati College of Medicine, Cincinnati, United States, 7Cincinnati Children’s Hospital Medical Center, Cincinnati, United States, 8National Marrow Donor Program and Center for International Blood and Marrow Transplant Research, Minneapolis, United States, 9Fred Hutchinson Cancer Center, Seattle, United States, 10City of Hope National Medical Center, Duarte, United States

Background: GATA2 deficiency syndrome is an inherited immune and bone marrow failure disorder with a predisposition to myeloid malignancies. Allogeneic hematopoietic cell transplantation (alloHCT) is a potential curative treatment. However, patients usually enter transplant with significant comorbidities, including life-threatening infections and end organ dysfunction rendering them at a high risk for early transplant complications. Available reports on outcomes following HCT are scarce.

Methods: The Center for International Blood & Marrow Transplant Research (CIBMTR) registry was used to evaluate outcomes of patients with identified GATA2 deficiency who received alloHCT. The primary outcome was overall survival (OS) at 1 and 3-years post-HCT, assessed using Kaplan-Meier estimates. Causes of death were described. Secondary endpoints included the frequency of acute graft versus host disease (aGVHD), the frequency of graft failure, and the cumulative incidence of chronic GVHD (cGVHD). Regression analysis was performed to determine factors associated with developing aGVHD and cGVHD.

Results: We identified 127 patients that received HCT at 46 centers between 2008-2019 with a median age of 23 years (range 0.7-61), of which 63% were adults. Most patients (64%) had a high comorbidity index (HCT-CI) of > 3 with infection (40%), prior solid tumor (35%) and moderate/severe pulmonary disease (26%) being the most common comorbidities. 17% of patients had non-hematological GATA2 deficiency associated comorbidities, such as deafness, pulmonary alveolar proteinosis, HPV or mycobacterial infection and lymphedema. Immune deficiency and bone marrow failure were the indications for transplant in 76% (n = 97) of patients, with the remaining patients underwent alloHCT after developing MDS or leukemia (n = 30). Most received a myeloablative conditioning regimen (76%) and received HCT from unrelated donors (56%).

The median follow was 4 years (range 0.3-12 years). OS was 93% (95%CI 89-97%) at 1 year and 82% (95%CI 77-91%) at 3 years. OS was evaluated by age and indication for transplant with no statistical difference. The main cause of death was organ failure followed by infection. In a subgroup analysis of 40 patients with post-HCT infectious data, there was a high incidence of post-HCT infectious complications (87%), the majority being viral (67%). Endothelial complications (TA-TMA (2%) and VOD (5%)) were rare. All patients had primary engraftment. However, 4 patients had secondary graft failure requiring a second transplant. GVHD was frequently observed post-HCT: 60% of patients developed aGVHD, of which 71% were grade I-II, 26% grade III-IV and in 3% grade was not reported; the cumulative incidence of cGVHD was 44% (95%CI 34-54%) at 1 year with the majority (84%) experiencing extensive disease. GVHD was a contributing cause of death in 6 patients. Regression analysis evaluation including age, indication for transplant, performance status, HCT-CI, conditioning intensity, GVHD prophylaxis, donor, and graft source, were not found to be statistically significant.

Conclusions: In patients with GATA2 deficiency, mortality related to transplant was low, even with many patients having pre-HCT comorbidities. However, the incidence of GVHD was higher than expected, adding to post-HCT related morbidity. Future research should be directed towards assessing risk factors for developing GVHD and optimizing prevention strategies in this patient population.

Disclosure: Nothing to declare.

25: Immunodeficiency Diseases and Macrophages

O100 PRE-TRANSPLANT IMMUNE DYSREGULATION PREDICTS FOR POOR OUTCOME FOLLOWING ALLOGENEIC HAEMATOPOIETIC STEM CELL TRANSPLANTATION FOR ADOLESCENTS AND ADULTS WITH INBORN ERRORS OF IMMUNITY (IEI)

Thomas A. Fox 1, Valerie Massey1, Charley Lever1, Rachel Pearce2, Arian Laurence3, Kirsty Thomson4, Sarah Grace4, Filippo Oliviero4, Sarita Workman3, Andrew Symes3, David M. Lowe3, Valeria Fiaccadori4, Rachael Hough4, Susan Tadros3, Siobhan O. Burns1, Markus G. Seidel5, Ben Carpenter4, Emma C. Morris1

1University College London, London, United Kingdom, 2Kings College London, London, United Kingdom, 3Royal Free London Hospitals NHS Foundation Trust, London, United Kingdom, 4University College London Hospitals NHS Foundation Trust, London, United Kingdom, 5Medical University of Graz, Graz, Austria

Background: Allogeneic haematopoietic stem cell transplantation (alloHSCT) is safe and effective for adults and adolescents with inborn errors of immunity (IEI) and severe manifestations of their disease. IEIs are a heterogeneous group of diseases and transplant decisions must consider the underlying disease, clinical trajectory, and patient co-morbidities. Thehaematopoietic cell transplantation comorbidity index (HCT-CI) score predicts survival in non-malignant diseases, including IEIs. However, the revised immune dysregulation and disease activity (IDDA) score is a specific tool to assess disease activity in IEI. We hypothesised that the degree of immune dysregulation pre-transplant may influence outcomes. We applied the IDDA score to our cohort of 82 IEI patients aged ≥13 years who underwent alloHSCT between 2004 and 2023.

Methods: Retrospective data collection occurred between January and November 2023 from medical case notes and the transplant database. Data was censored on 3rd November 2023. Probabilities of overall survival (OS) and event-free survival (EFS) were calculated using the Kaplan-Meier method with groups compared using a log rank test. Paired data (e.g. IDDA scores pre- and post-transplant) were compared using a Wilcoxon matched pairs signed rank test. An event was defined as acute GVHD grades II or above, chronic GVHD of any grade, graft failure, recurrence of disease phenotype or death from any cause.

Results: Three-year OS for the whole cohort (n = 82) was 90% with a median follow up of 44.7 months (range 8.4 to 225.8). No significant difference in OS between the adolescent cohort (3-year OS 97% n = 35) and the adult cohort (3-year OS 89% n = 47, p = 0.31) was observed. Three-year EFS for the whole cohort (n = 82) was 70% (post-2010 n = 74 EFS was 70%).

Survival was significantly impacted by pre-transplant HCT-CI score (3-year OS; HCT-CI score<3 = 100%, HCT-CI score≥3 = 57%, p = <0.0001). IDDA score pre-transplant did not significantly affect OS (3-year OS; patients with pre-transplant IDDA score <20 = 98%, n = 47, IDDA score IDDA ≥ 20: 93%, n = 28, p = 0.49), however, pre-transplant IDDA score significantly influenced EFS. Patients with a pre-transplant IDDA score of <20 (n = 47) or ≥20 (n = 28) had a 3-year EFS of 81% and 59%, respectively (p = 0.01).

Furthermore, we used the IDDA score pre- and post-transplant to assess whether alloHSCT resulted in resolution of IEI-associated immune deficiency and dysregulation. The IDDA score was calculated at last follow up for all surviving patients who had a pre-transplant score (n = 60). In all but two patients who had issues with significant GvHD, the IDDA score was lower post-transplant (median 0, range 0-30) (p < 0.0001).

Conclusions: In the largest global single centre adolescent and adult IEI HSCT cohort of 82 patients, we describe for the first-time details of clinical phenotype reversal post-transplant and the potential use of IDDA score in predicting graft failure and EFS. Our data suggest that an increased IDDA score has an adverse effect on EFS. This emphasises the need to attempt to achieve adequate disease control prior to transplant and provides a tool which may be used to aid counselling patients about their individual risks for alloHSCT.

Disclosure: No relevant conflicts of interest to declare.

25: Immunodeficiency Diseases and Macrophages

O101 OUTCOMES OF SECOND CONDITIONED TRANSPLANT AFTER AN UNCONDITIONED STEM CELL INFUSION IN INFANTS AND CHILDREN WITH SEVERE COMBINED IMMUNODEFICIENCY (SCID)

Purushotham Ramachandran1, Su Han Lum1,2, Zohreh Nademi 1, Terry Flood1, Stephen Owens1, Eleri Williams1, Sophie Hambleton1,2, Andrew Gennery1,2, Mary Slatter1,2

1Great North Children’s Hospital, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom, 2Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom

Background: Severe combined immunodeficiencies (SCIDs) comprise a group of rare, monogenic diseases that are characterised by impaired T-lymphocyte differentiation resulting in life-threatening infections usually within the first year of life. Lack of host adaptive immunity allows the use of unconditioned stem cell transplant (SCT) in certain forms of SCID enabling engraftment of donor T-lymphocytes. Evidence shows that full myeloid chimerism is not mandatory, but a degree of myeloid engraftment will help to sustain B cell reconstitution and long-term thymic output. Conditioning is almost always required to achieve this. We describe the outcomes in patients who underwent a second conditioned SCT after an initial unconditioned SCT.

Methods: Of the 56 SCID infants who underwent first SCT at the Great North Children’s hospital between 2000 and 2022, 16(29%) received an unconditioned SCT. Of the 12 who survived an unconditioned SCT, 6(50%) underwent a second conditioned SCT. This is a retrospective analysis.

Results: The molecular diagnoses were ADA (n = 2), RAG1(n = 1), DCLRE1C (n = 1), IL2RG (n = 1) and undefined (n = 1). Median age at diagnosis of 1.2 months (at birth-6.0; 3 were diagnosed at birth due to positive family history). Median age at unconditioned SCT was 3.2 months (0.9 to 8.8) and median interval between diagnosis and SCT was 1.0 month (0.6-3.5). Reasons for unconditioned infusion were prematurity (n = 2), significant infection (n = 2), institutional practice at the time (n = 1) and parental choice (n = 1). Details for first unconditioned SCT are summarized in table 1.

Pre-emptive second conditioned HSCT was performed in 2 patients with RAG1 and DCLRE1 to achieve robust long-term immune reconstitution. The remaining 4 patients underwent second conditioned SCT for clinical indications: systemic juvenile idiopathic arthritis with poor immune function in 2 patients with ADA, refractory acute GvHD and autoimmune cytopenia in a IL2RG patient and secondary aplasia in an undefined SCID patient. Median interval between unconditioned SCT and conditioned SCT was 4.2 years (0.42 to 8.6). Conditioning was fludarabine+treosulfan (n = 2), fludarabine+treosulfan+thiotepa (n = 2) and treosulfan-cyclophosphamide (n = 2). All except one received serotherapy (alemtuzumab, n = 4; ATG, n = 1). Three patients received the graft from the same donor (MFD marrow, n = 2; TCRab/CD19depleted paternal haplo graft, n = 1) and 3 patients received a graft from a different donor (MSD marrow, n = 1; MUD PBSC, n = 1; TCRab/CD19depleted paternal haplo graft). Median CD34+ stem cell dose was 4.6x106/kg (1.6-9.5). All engrafted with a median time to neutrophil engraftment of 16 days (12-26). None had VOD or TMA. 2 had grade-II acute GvHD, none had grade III-IV or chronic GvHD. One developed CMV viraemia, 1 adenovireamia+HHV6 viraemia and 1 HHV6 + EBV viraemia. 2 patients received subsequent procedures (unconditioned marrow top-up for slipping chimerism; TCRab/CD19depleted graft+memory T-cell for HHV6-associated transient cytopenia). All 6 patients are alive with a median follow-up of 6.2 years (0.6 10 14.9). All patients with > 1 year follow-up are free from immunoglobulin replacement.

Full size table

Conclusions: These results demonstrate that a second conditioned SCT can successfully be performed following an initial unconditioned infusion. Pre-emptive conditioned SCT should be considered in a suitable candidate before onset of immune dysfunction.

Clinical Trial Registry: Not applicable

Disclosure: Nothing to declare

24: Inborn Errors, Granulocyte and Osteoclast Disorders

O102 HAPLOIDENTICAL STEM-CELL TRANSPLANTATION FOR CHRONIC GRANULOMATOUS DISEASE, AN EBMT-IEWP RETROSPECTIVE STUDY

Quentin Riller 1, Mathias Hauri2, Jeroen Knippenberg3, Tiar Sirait3, Alexandra Laberko4, Khalid Halahleh5, Musa Karakukcu6, Henrik Sengeloev7, Fulvio Porta8, Bénédicte Bruno9, Marco Zecca10, Despina Moshous1, Andy Gennery11, Alexei Maschan4, Michael Albert12, Mary Slatter11, Tayfun Gungor2, Bénédicte Neven1

1Pediatric Unit of Immunology, Hematology, Rhumatology, Necker Hospital, Paris, France, 2University Children’s Hospital, Zürich, Switzerland, 3EBMT Leiden Study Unit, Leiden, Netherlands, 4Federal Research Center for Pediatric Hematology, Moscow, Russian Federation, 5King Hussein Cancer Centre Adult BMT Program, Amman, Jordan, 6Erciyes University, Faculty of Medicine, Kayseri, Turkey, 7Rigshospitalet, Copenhagen, Denmark, 8Universitá degli Studi di Brescia, Brescia, Italy, 9Unité d’Hématologie Pédiatrique, Lille, France, 10San Matteo Pavia Transplant Programme, Pavia, Italy, 11RVI Newcastle, Newcastle, United Kingdom, 12Klinikum Grosshadern, Munich, Germany

Background: Chronic granulomatous disease (CGD) is an inherited defect of phagocytes due to NADPH-oxidase defect of phago-lysosomes. It leads to life-long predisposition to bacterial and fungal infections and granulomatous inflammation. Allogeneic hematopoietic stem cell transplantation (HSCT) has become the main curative approach, especially when an HLA identical donor is available. While T-cell depleted HSCT from haploidentical donors using post-transplant cyclophosphamide (PTCY) or TCR-alpha/beta and CD19 (TCRαβ/CD19) depletion is increasingly used in pediatric patients with inborn errors of immunity, a place for haploidentical HSCT (hHSCT) needs to be defined in the treatment strategy of CGD patients.

Methods: We conducted a retrospective study on CGD patients registered in the EBMT database, who received a first hHSCT. Additional data were collected with a dedicated questionnaire. Analysis focused on overall survival (OS), event-free survival (EFS) and cumulative incidence (CI) of acute and cGVHD.

Results: 64 patients from 20 centers were included. 53 patients were male (83%) and 46 (72%) had X-linked CGD. Median age at transplant was 4 years (IQR 2-7). Forty patients (62.5%) received a TCRαβ/CD19 depleted graft while 24 patients (37.5%) were transplanted using PTCY. CGD-related infection and inflammation < 6 months before transplant were documented in 29 (45%) and 44 (67%) patients respectively. Patients’ characteristics were not significantly different between TCRαβ/CD19 and PTCY groups even though there was numerically more active infection in partial remission (5/14 (35%) versus 1/15 (6%)) and there were more patients under immunosuppressive drugs at transplant (54% versus 28%) in PTCY as compared to TCRαβ/CD19 group, suggesting a trend for a more severe disease. Age at transplant, conditioning regimen (CR) and source of stem cells were significantly different between TCRαβ/CD19 and PTCY with younger age (p = 0.002), more treosulfan-based conditioning regimen (p < 0.001) and more PBSC (p < 0.001) graft in TCRαβ/CD19 while busulfan and bone marrow graft were most frequently used in PTCY. Fifty-four patients (84%) engrafted with full donor chimerism excepted in 7 patients who displayed mixed chimerism (85-94% donor) that remained stable overtime with a median FU of 1.9 years (IQR 0.9-3.2). Neutrophil recovery was observed on d + 14 (range 9-42) and was significantly faster with TCRαβ/CD19 than PTCY (13.6 versus 19.9, p < 0.001). Primary graft failure was detected in 10 patients (6/40 in TCRαβ/CD19 and 4/24 in PTCY (p = 1)) of whom 3 were successfully retransplanted. No secondary graft failure occurred. CGD related symptoms resolved in all engrafted patients. Twelve patients died (18.8%) (9/40 (22,5%) in TCRab/CD19 and 3/24 (12.5%) in PTCY (p = 0.5)) mainly of infection. The 3 years-OS and -EFS were 76% and 68% respectively. Type of T-cell depletion, age at transplant, presence of inflammation or CGD-related-infection before transplant did not significantly influence OS and EFS. CI of grade II to IV aGVHD, grade III to IV aGVHD, and cGVHD were 21.9%, 4.7% and 10.9% respectively.

Conclusions: hHSCT is a feasible option and is curative treatment for CGD patients including patients with high disease burden. Ex vivo or in vivo T cell depletion with respectively TCRαβ/CD19 depletion or PTCY are both applicable options.

Disclosure: Nothing to declare

24: Inborn Errors, Granulocyte and Osteoclast Disorders

O103 OUTCOME OF PATIENTS WITH SIGNAL-TRANSDUCER AND ACTIVATOR OF OF TRANSCRIPTION 1 MUTATIONS (STAT1) GAIN-OF-FUNCTION VARIANTS AFTER HAEMATOPOIETIC STEM CELL TRANSPLANTATION – AN IEWP/PIDTC STUDY

Emilie Pauline Buddingh 1, Mary Slatter2, Juan Carlos Aldave Becerra3, Laura Alonso Garcia4, Erik von Asmuth1, Safa Baris5, Oscar de la Calle-Martín6, Alice Chan7, Bianca Chan8, Shanmuganathan Chandrakasan9, Deepak Chellapandian10, Jasmeen Dara7, Hans Christian Erichsen Landsverk11, Susan Farmand12, Anders Fasth13, Lisa Forbes14, Renata Formankova15, Eyal Grunebaum16, Steven Keogh17, Ayça Kiykim18, Jörn-Sven Kühl19, Alexandra Laberko20, Arjan Lankester1, T.R. (Ronan) Leahy21, Caroline Lindemans22, Caridad Martinez14, Laura Martínez-Martínez23, William Glenn Mitchell9, Emma Morris24, Benedicte Neven25, Joe Oved26, Maria Prazenicova27, Jacques Gabriel Riviere4, Chaim Roifman16, Sara Şebnem Kiliç Gültekin28, Petr Sedlacek15, Ami Shah29, Linda Vong16, Jennifer Leiding10, Catharina Schütz27

1Leiden University Medical Centre, Leiden, Netherlands, 2Great North Children’s Hospital, Royal Victoria Infirmary, Newcastle, United Kingdom, 3Hospital Rebagliati, Lima, Peru, 4Vall d’Hebron Hospital, Barcelona, Spain, 5Marmara University, Istanbul, Turkey, 6Universitat Autònoma de Barcelona, Barcelona, Spain, 7University of California, San Francisco, United States, 8KK Women’s and Children’s Hospital, Singapore, Singapore, 9Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, United States, 10Johns Hopkins All Children’s Hospital, St. Petersburg, United States, 11Oslo University Hospital, Oslo, Norway, 12Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany, 13Queen Silvia Children’s Hospital, Ghotenborg, Sweden, 14Texas Children’s Hospital, Houston, United States, 15University Hospital in Motol, Prague, Czech Republic, 16The Hospital for Sick Children, Toronto, Canada, 17Children’s Hospital, Westmead, Australia, 18İstanbul Üniversitesi-Cerrahpaşa, Istanbul, Turkey, 19University Hospital Leipzig, Leipzig, Germany, 20Dmitry Rogachev National Medical Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation, 21Children’s Health Ireland at Crumlin, Dublin, Ireland, 22Prinses Maxima Centrum, Utrecht, Netherlands, 23Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, 24University College London, London, United Kingdom, 25Hopital Necker-Enfants Malades, Paris, France, 26Memorial Sloan Kettering Cancer Centre, New York, United States, 27Medizinische Fakultät Carl Gustav Carus, Technische Universität, Dresden, Germany, 28Bursa Uludağ Üniversitesi, Bursa, Turkey, 29Stanford University, Stanford, United States

Background: Gain of function mutations (GOF) in signal transducer and activator of transcription 1 (STAT1) are associated with a wide range of infections including chronic mucocutaneous candidiasis, and auto-immunity. Morbidity is high and the disease-manifestations can be life-threatening. Allogeneic hematopoietic stem cell transplantation (HSCT) is curative, but in a previous report of 15 transplanted patients, outcome after HSCT was very poor, mainly due to graft failure (Leiding et al. JACI 2017).

Methods: Here we present data on 36 patients with STAT1-GOF transplanted after 2010, including 7 patients previously reported by Leiding et al. Data was collected using an electronic case record form, from EBMT and PIDTC centers. Survival analyses were done using log rank methods and cox regression analysis in SPSS.

Results: Between 2010 and 2023, 40 HSCTs were performed in 36 STAT1-GOF patients. The median age at first transplant was 11 years (range 1 – 33). Indications for HSCT were combined immunodeficiency (14/36 patients, including two with hemophagocytic lymphohistiocytosis (HLH)), severe and/or refractory infections (12/36 patients) and auto-immunity or IPEX-like disease (10/36 patients). All patients, regardless of main HSCT indication, had prior infections, with mucocutaneous fungal infections in 34/36 patients. Four patients had an aneurysm prior to HSCT. Most transplants were from an HLA-matched donor (27/40 transplants). Acute graft versus host disease (GVHD) occurred in 22/40 transplant procedures, but only 5 patients (13.9%) suffered from grade III or IV acute GVHD. Chronic GVHD occurred in one patient.

Overall survival in this cohort was 72.2%, and event free survival was 55.6% (with events defined as aGVHD grade III or higher, graft loss, re-HSCT, severe chronic GVHD or death). 16 of 36 patients were pre-treated with Janus kinase (JAK) inhibitors, which was associated with a significantly better event free survival (75% vs 31.3%, log rank P value 0.004) and a trend for better overall survival (85% vs 56.3%, P value 0.071). Using a bivariate cox proportional hazard model for event free survival, including JAK inhibitor pre-treatment and HSCT before or after 2019, only JAK inhibitor treatment was significantly associated with event free survival (HR 0.23, P-value 0.008).

Causes of death were GVHD-related in 2 patients, infection-related/graft failure in 5 patients, likely pulmonary thrombotic microangiopathy (TMA) in one patient, ongoing HLH in 1 patient and hemorrhage from intracranial aneurysm in 1 patient. Of 26 surviving patients, 20 had full donor chimerism at last follow-up, and 6 had mixed chimerism.

Conclusions: In this cohort, overall survival of HSCT in STAT1-GOF patients was 72%, which is much improved as compared to the 40% overall survival reported in 2017. Pre-treatment with JAK inhibitors was associated with better event free and overall survival. HSCT should be discussed as curative option in all STAT1-GOF patients who have a severe phenotype or lack of response to conservativa management.

E. Buddingh and M. Slatter contributed equally.

J. Leiding and Catharina Schütz contributed equally.

Disclosure: Nothing to declare.

24: Inborn Errors, Granulocyte and Osteoclast Disorders

O104 LENTIVIRAL HAEMATOPOIETIC STEM CELL GENE THERAPY (ATIDARSAGENE AUTOTEMCEL) FOR LATE JUVENILE METACHROMATIC LEUKODYSTROPHY (MLD)

Vera Gallo 1,2, Valeria Calbi1,2, Fabiola De Mattia1, Alberto Zambon2, Salvatore Recupero2,1, Elena Fratini2, Francesca Ciotti2, Maddalena Fraschini2, Mara Sangalli2, Marina Sarzana2, Alessandra Clerici1, Francesco Morena3, Sabata Martino3, Jean Brooks4, Alan Richardson4, Laura Campbell4, Maria Ester Bernardo2,1,5, Alessandro Aiuti1,2,5, Francesca Fumagalli2,1

1San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Milano, Italy, 2IRCCS San Raffaele Scientific Institute, Milano, Italy, 3University of Perugia, Perugia, Italy, 4Orchard Therapeutics (Europe) Limited, London, United Kingdom, 5Università Vita e Salute San Raffaele, Milano, Italy

Background: Metachromatic Leukodystrophy (MLD) is a rare, disabling, and fatal lysosomal storage disease. Atidarsagene autotemcel (arsa-cel) is a haematopoietic stem cell (HSC) gene therapy (GT) and consists of autologous CD34+ cells transduced ex vivo with a lentiviral vector encoding for the human ARSA gene, infused after intravenous myeloablative busulfan conditioning. Arsa-cel has shown long-term favorable outcomes in early-onset MLD, however risk-benefit profile in late onset variants, in particular Late Juvenile variant (LJ), has not yet been investigated.

Methods: This ongoing phase III trial (NCT04283227) is investigating the safety and efficacy of arsa-cel in pre-symptomatic or early-symptomatic (able to walk independent and without cognitive decline) LJ-MLD patients (expected onset between 7th and 17th birthday).

Here we report preliminary engraftment and safety data from an ad hoc interim analysis.

Results: As of December 2023, all 6 patients planned in the protocol have been enrolled, 5 of whom have been treated. Four patients were pre-symptomatic and 2 were early-symptomatic. Before enrollment in this study, one patient underwent allogeneic HSC transplant; however, she experienced autologous reconstitution. This patient was eligible for HSC-GT as specified by the protocol due to confirmed absence of donor chimerism and normal morphological bone marrow findings. Among the 5 treated patients, median age at GT was 9.9 years (range 2.7-15.2 years). Stem cell source was mobilized peripheral blood collected after G-CSF (6-8 doses) and Plerixafor (administered 6-8 hours before the leukapheresis). Median yield was 33.19x10^6 CD34+cells/kg (range 30.26-36.27x10^6 CD34+cells/kg). After transduction, the infused drug product median dose was 25.6x10^6 CD34+cells/kg (range 16-28.94x10^6 CD34+cells/kg) with a median vector copy number (VCN)/cell of 3 (range 2-5). The patient with previous history of allogeneic HSC transplant showed CD34+ yield and graft characteristics similar to other patients treated.

All patients received myeloablative conditioning with Busulfan as single agent with final cumulative target area under the curve of 85 mg*h/L. After a median follow-up of 14 months (range 0 to 17.9 months) all patients are alive with no treatment-related serious adverse events. The type and nature of adverse events were consistent with the known safety profile of busulfan. There were no malignancies, no evidence of abnormal clonal expansion or replication-competent lentivirus, and no evidence of immune response against ARSA enzyme. All 4 patients with available post-treatment data achieved normal haematological reconstitution and engraftment of transduced cells in line with previous experience in early-onset MLD. Median time to neutrophil and platelet engraftment was 32.0 days (range 25-41) and 25 days (range 24-45), respectively. At 90 days post-treatment, median VCN in peripheral blood mononuclear cells (PBMCs) and CD15+ cells were 0.36 and 0.72 copies/cell, respectively; the percentage of transduced bone marrow progenitors ranged between 23.81 and 58.84%.

ARSA activity was restored and reached supranormal levels in PBMCs and restored to normal levels in cerebrospinal fluid (CNS pharmacodynamic efficacy measure) at 6 months post-treatment.

Conclusions: This analysis demonstrates that the initial results on engraftment, ARSA activity, safety, and drug product characteristics for arsa-cel in LJ-MLD were similar to those reported in early-onset (late infantile and early juvenile) MLD.

Clinical Trial Registry: NCT04283227

Disclosure: Valeria Calbi, Francesca Fumagalli, Vera Gallo have occasionally received consultant fees and/or reimbursement for travel costs and participation fees from Orchard Therapeutics.

Jean Brooks, Laura Campbell, Alan Richardson, are employees of and receive stock-based compensation from Orchard Therapeutics.

All other authors declare no conflicts. Atidarsagene autotemcel was licensed to GlaxoSmithKline (GSK) in 2014 and GSK became the clinical trial sponsor. In 2018 MLD development rights were transferred to Orchard Therapeutics (OTL) and OTL became the clinical trial sponsor

24: Inborn Errors, Granulocyte and Osteoclast Disorders

O105 VALIDATION OF COMORBIDITY INDEX FOR PATIENTS WITH INBORN ERRORS OF IMMUNITY UNDERGOING HEMATOPOIETIC STEM CELL TRANSPLANTATION

Alexandra Laberko 1, Kirill Voronin1, Michael Maschan1, Alexei Maschan1, Anna Shcherbina1, Dmitry Balashov1

1Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation

Background: Hematopoietic stem cell transplantation (HSCT) is used to treat patients with various IEIs, whose disease cannot be controlled by conservative therapy. However, uncontrolled disease complications or comorbidities worsen survival in HSCT recipients. The comorbidity index (CI) (1) is widely used in adults with malignant indications for HSCT to predict post-HSCT mortality. CIBMTR group demonstrated that this CI is also applicable for non-malignant diseases and pediatric patients (2). In our cohort of pediatric patients with IEI, CI showed inaccurate prediction of survival in those with scores >2. Thus, in this study we performed a validation of classic CI for pediatric patients with IEI.

Methods: 312 patients with various IEI received allogeneic HSCT in our center from 2012 to 2020. Median follow-up in survivors was 5,2 years (range 1,8-10,5). The patients were divided into 2 groups: one group contained 269 non-SCID patients and was used for adaptation of CI and the second contained 43 patients with SCID and was used for validation of CI. All non-SCID patients were divided into 3 age groups: 0-3 (n = 118), 3-12 (n = 114), 12-18 (n = 37) and had the following complications at HSCT: 41 – active infections, 80 active autoinflammation/ autoimmunity (excluding granulomas in chronic granulomatous disease), 14 active malignancy, 63 organ damage; 224 patients had normal nutrition, 22 moderate and severe malnutrition and 23 obesity. Multivariate analysis of hazard ratio (HR) included age, active infection, autoimmunity/ autoinflammation, malignancy, organ damage and nutrition status as risk factors. The interval of HR was used to calculate the risk score: 1 for HR 1-2, 2 for HR 2-3 and 3 for HR > 3. Kaplan-Meier method was used to assess survival in the validation group.

Results: According to the results of multivariate analysis of HR, active infection had the most impact on survival (HR 3,49 (95%CI 1,9-6,5)), and active infections were scored as 3. Active autoimmunity and malignancy lead to HR higher than 2 and were scored as 2, age older than 12, organ damage and obesity lead to HR higher than 1 and were scored as 1. These factors/ scores were added or reassessed in the classical CI. When CI was assessed in 43 patients with SCID, the CI scores were 0 in 3, 1-4 in 21 and >5 in 19 patients.

Overall survival was 1,0 in patients with 0 scores (n = 3), 0,57 (95%CI 0,36-0,78) in patients with 1-4 scores (n = 21) and 0,32 (95%CI 0,11-0,53) in patients with >5 scores (n = 19), р=0,09. When the adapted CI was applied to the whole group of 312 patients, OS was predictive for survival in each score group, р<0,0001 (picture 1).

The 50th Annual Meeting of the European Society for Blood and Marrow Transplantation: Physicians - Oral Session (O009-O154) (9)

Conclusions: Adaptation of classic CI for IEI patients allowed more accurate estimation of prognosis of survival in IEI with pre-HSCT comorbidities.

References

1. Sorror ML et al. Blood. 2005 Oct 15;106(8):2912–9.

2. Thakar MS et al. Blood. 2019 Feb 14;133(7):754–62.

Disclosure: nothing to declare

24: Inborn Errors, Granulocyte and Osteoclast Disorders

O106 HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR C1Q DEFICIENCY

Helena Buso 1, Peter Arkwright2, Etai Adam3, Maryam Behfar4, Alice Chan5, Christopher Dvorak5, Amir Ali Hamidieh4, Risa Matsumura6, Arjan Lankester7, Satoshi Okada6, Nima Parvaneh4, Stalin Ramprakash8, Samin Sharafian9, Robert Wynn10, Eleri Williams11, Mary Slatter11,12, Andrew Gennery11,12

1University of Padova, Padova, Italy, 2University of Manchester, Manchester, United Kingdom, 3Sheba Medical Center, The Edmond and Lily Safra Children’s Hospital, Ramat Gan, Israel, 4Tehran University of Medical Sciences, Tehran, Iran, Islamic Republic of, 5University of California (UCSF), San Francisco, United States, 6Hiroshima University Hospital, Hiroshima, Japan, 7Leiden University Medical Center, Leiden, Netherlands, 8Sankalp-People Tree Centre for Paediatric Bone Marrow Transplantation, Bangalore, India, 9Shahid Beheshti University Of Medical Sciences, Tehran, Iran, Islamic Republic of, 10Royal Manchester Children’s Hospital, Manchester, United Kingdom, 11Great North Children’s Hospital, Newcastle upon Tyne, United Kingdom, 12Translational and Clinical Research Institute, Newcastle University, Newcastle, United Kingdom

Background: C1q deficiency is a rare inborn error of immunity (IEI) characterized by an increased susceptibility to infections and autoimmune diseases. Considering that C1q is synthesized by monocytes, HSCT may be a definitive treatment for this disorder. To date, only four cases have been reported, with different results.

The aim of our study was an overall description of the outcome of HSCT for C1q deficiency.

Methods: Retrospective international data collection of unreported C1q deficient patients treated with HSCT and revision and updating of reported cases.

In all patients, the indications for HSCT were autoimmune manifestations not controlled by ongoing treatments, associated with infections in 6/13 patients, with meningitis reported in 2 cases. The spectrum of autoimmune manifestations was broad with mucocutaneous diseases in all 13 patients associated with cytopenia in 6/13, Central Nervous System (CNS) involvement in 5/13 and glomerulonephritis in 2/13 cases.

Results: 13 C1q deficient patients underwent HSCT from 9 referral centres, of whom, 9 were previously unreported and 2/4 already reported cases were updated (Table 1).

8/13 patients were female, median age at HSCT was 12 years (range, 2-19). One patient had two HSCTs, (14 HSCTs performed in total), with reduced toxicity conditioning using Treosulfan in 9/14 cases. The overall survival was 10/13 (77%). Eight had full donor chimerism at time of last follow up and one had mixed monocyte chimerism (45%) at 24 months maintaining the disease control.

In 9/13 patients, HSCT led to normalization of the classical complement pathway with autoimmune symptoms resolution and discontinuation of immunosuppressive treatment (median follow-up time 36 months; range, 1-84 months). In this group, the most severe HSCT-related complications were acute skin GVHD (grade II) in 2 patients, associated with bronchiolitis obliterans in one, and EBV-PTLD in only one patient resolved with Rituximab.

In 2 patients graft failure associated with persistence or recurrence of the autoimmune disorder. In particular, one patient had a severe disease relapse with CNS vasculitis 27 months after HSCT requiring a second HSCT at 19 years and died 32 days after second HSCT from progressive and irreversible respiratory failure caused by Aspergillus pneumonia. Two other patients died: a 9 year old boy 4 months after HSCT from multiorgan failure (MOF) due to gastrointestinal GVHD occurring after lymphocyte infusion for EBV-PTLD, and a 13 year old girl, 3 months after HSCT, for MOF with Transplant-Associated thrombotic Microangiopathy and gastrointestinal GVHD.

[1] Matsumura R et al. Int J Hematol. 2021;113(2):302-307. doi:10.1007/s12185-020-03004-7

[2] Arkwright PD et al. J Allergy Clin Immunol. 2014;133(1):265-267. doi:10.1016/j.jaci.2013.07.035

[3] Olsson RF et al. Transplantation. 2016;100(6):1356-1362. doi:10.1097/TP.0000000000000975

Conclusions: C1q deficiency is a disease with variable penetrance that may lead to the development of severe and life-threatening autoimmunity or infections. This generates an extra challenge when counselling patients with a positive family history. HSCT, especially if performed in the early course of the disease, may be a valid and definitive treatment. Further studies are needed to define criteria for identify patients in whom HSCT is the best treatment choice.

Disclosure: Nothing to declare

13: Infectious Complications

O107 RETROSPECTIVE STUDY ON THE INCIDENCE AND OUTCOME OF ADENOVIRUS INFECTIONS IN PATIENTS AFTER HAPLOIDENTICAL SCT. A STUDY OF INFECTIOUS DISEASE WORKING PARTY OF THE EBMT

Maura Faraci 1, Gloria Tridello2, Malgorzata Mikulska3, Elio Castagnola1, Musa Karakukcu4, Lotus Wendel2, Anna Maria Raiola3, Awatif AlAnazi5, Per Ljungman6, Gergely Krivan7, Giulia Prunotto8, Melissa Gabriel9, Sophie Ducastele Lepretre10, Jose Luis Pinana11, Katia Perruccio12, Johannes Clausen13, Sabrina Kraus14, Herbert Pichler15, Ilaria Cutini16, Eva Maria Wagner-Drouet17, Andreas H. Groll18, Michael Loschi19, Nicolaus Kröger20, Giorgia Saporiti21, Katharine Patrick22, Varun Mehra23, Akif Yesilipek24, Beatriz Aguado Bueno25, Sara Lozano Cerrada26, Krzysztof Kalwak27, Bruno Lioure28, Giuseppe Milone29, Cecile Renard30, Anna Torrent31, Domenico Russo32, Thomas Schroeder33, Bernd Gruhn34, Caroline Besley35, Andrei Colita36, Federica Galaverna37, Xavier Poiré38, Arcangelo Prete39, Matthias Woelfl40, Simona Sica41, Jan Styczynski42, Francesco Paolo Tambaro43, Peter von dem Borne44, Jan Vydra45, Diana Averbuch46, Rafael de la Camara25

1IRCCS Istituto Giannina Gaslini, Genova, Italy, 2EBMT Leiden Study Unit, Centre Hospitalier Lyon Sud, Lyon, France, 3IRCCS- Ospedale Policlinico San Martino, Genova, Italy, 4Erciyes University, Faculty of Medicine, Kayseri, Turkey, 5King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia, 6Karolinska University Hospital, Stockholm, Sweden, 7Central Hospital of Southern Pest, Budapest, Hungary, 8Fondazione IRCCS San Gerardo dei Tintori, Monza-Milano-Bicocca University, Monza, Italy, 9The Children`s Hospital at Westmead, Sydney, Australia, 10Centre Hospitalier Lyon Sud, Lyon, France, 11Hospital Clínico Universitario, University of de Valencia, Valencia, Spain, 12Pediatric Oncology Hematology, Santa Maria della Misericordia Hospital, Perugia, Italy, 13Ordensklinikum Linz - Elisabethinen, Linz, Austria, 14University Hospital Wuerzburg, Wuerzburg, Germany, 15St. Anna Children’s Hospital, Medical University of Vienna, Vienna, Austria, 16Azienda Ospedaliera Universitaria Careggi, Florence, Italy, 17University Medical Center Mainz, Mainz, Germany, 18Universitätsklinikum Münster, Münster, Germany to University Hospital Münster, Münster, Germany, 19Nice University Hospital, Cote d’Azur University, Nice, France, 20University Hospital Eppendorf, Hamburg, Germany, 21BMT Unit - Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy, 22Sheffield Childrens NHS Foundation Trust, Sheffield, United Kingdom, 23Kings College Hospital, London, United Kingdom, 24Medical Park Antalya Hospital, Antalya, Turkey, 25Hospital Universitario de la Princesa, Madrid, Spain, 26Imperial College Hammersmith, London, United Kingdom, 27Wroclaw Medical University, Wroclaw, Poland, 28ICANS - Institut de cancérologie Strasbourg Europe, Strasbourg, France, 29Ospedale Policlinico, Catania, Italy, 30Institut d`Hematologie et d`Oncologie Pediatrique, Lyon, France, 31ICO-Hospital Universitari Germans Trias i Pujol, Badalona, Spain, 32Unità di Malattie del sangue e Trapianto Midollo Osseo, ASST Spedali Civili di Brescia, Università di Brescia, Brescia, Italy, 33University Hospital Essen, West German Cancer Center, Essen, Germany, 34Jena University Hospital, Jena, Germany, 35University Hospitals Bristol and Weston NHSFT, Bristol, United Kingdom, 36University of Medicine and Pharmacy “Carol Davila”, Bucharest; Coltea Clinical Hospital, Bucharest, Romania, 37IRRCS Ospedale Pediatrico Bambino Gesù, Rome, Italy, 38Cliniques Universitaires St. Luc, Brussels, Belgium, 39IRCCS-Azienda Ospedaliero Universitaria di Bologna, Bologna, Italy, 40University Children`s Hospital, Wuerzburg, Germany, 41Universita Cattolica S. Cuore, Rome, Italy, 42University Hospital, Collegium Medicum UMK, Bydgoszcz, Poland, 43Azienda Ospedaliera di Rilievo Nazionale, Napoli, Italy, 44Leiden University Medical Center, Leiden, Netherlands, 45Institute of Hematology and Blood Transfusion, Prague, Czech Republic, 46Pediatric Infectious Diseases, Faculty of Medicine, Hebrew University of Jerusalem; Hadassah Medical Center, Jerusalem, Israel

Background: Adenovirus (ADV) is responsible for potentially serious infections occurring after allogeneic stem cells transplant (SCT). Aims of this study were to retrospectively evaluate the incidence of ADV in EBMT centres which perform haploidentical SCTs (haplo-SCT), to describe laboratory response to therapies and characteristics of ADV patients.

Methods: All consecutive paediatric and adult patients who underwent haplo-SCT for malignant or non-malignant diseases during the period between January 2015 to December 2020 were included in this study. In order to describe the centres’ policy and incidence, specific per-centre information was requested.

Results: 46 EBMT centres (10%) (18 paediatric, 21 adult and 7 mixed) which transplanted 3,144 haploidentical patients participated in this study. During the study period, 201 ADV infections were reported (65 paediatric, 76 adult and 60 mixed centre). The incidence was higher in paediatric than in adult centres (9.95% versus 4.30%) and the overall incidence was 6.39%.

ADV DNA was regularly monitored in blood in 65.2% (n = 30) of the centers, with a weekly frequency in 76.7% centers, twice a week in 16.7% and at different timing in 6.6% centers.

In 22 out of 26 centers (84.6%) the search of ADV was discontinued after 3 months, in 3 (11.5%) after 6 months, and one center ADV monitorinig was based on lymphocytes count. ADV-PCR was searched weekly in stools in 7 centers until 3 months after HSCT. Regarding ADV treatment, 65.2% (30) of centres treated ADV infections and 63.3% reported as blood ADV-cut off ≥ 1,000 copies/ml, 16.7% < 1,000 copies/ml; regarding the cut-off in stools 75% of centers considered a cut-off > 1,000 copies/ml.

In 109 patients were reported ADV infections, 72 out of 1,216 CY post SCTs (5.9%), 32 out of T- in vivo manipulated (9.7%), and 5 out of 193(2.6%) other platforms. Of them 82 (75.2%) were transplanted for malignant diseases. The median time from SCT to ADV infection was 48.5 days (range 0-173). Systemic viremia was reported in 59.6 % patients, local infections in 22%, probable diseases in 12.8% and proven diseases in 5.5% patients.

The univariate analysis of risk factors for the development of ADV infection included characteristic of patients and donors, type and number of SCTs, GVHD prophylaxis and its grading, age at ADV, status of CMV and EBV, conditioning regimen, and immunosuppression demonstrated that none of these factors were associated with ADV infection.

Considering viremia ≥1000 copies /ml, there was no statistically significant difference in clinical and virological response between patients treated with cidofovir or other therapeutic approaches including antiviral T lymphocytes, while the reduction of immunosuppression had an impact on the overall virological response (P = 0.005). The outcome was a complete resolution in 72.0% of the cases, progression and death in 15.9%, resolution of ADV but death due to other causes in 7.5% and stable disease in 4.6% of patients. The 1-year overall survival for patients with ADV positivity was 57.4% (47.6-66.1).

Conclusions: This study confirmed that ADV represents a cause of mortality after haplo-SCT and for this reason a post-transplant monitoring of ADV PCR is recommended.

Clinical Trial Registry: Non

Disclosure: None conflict of interest

13: Infectious Complications

O108 TOXOPLASMA QPCR KINETICS TO FOLLOW TREATMENT OF TOXOPLASMOSIS AFTER HAEMATOPOIETIC STEM CELL TRANSPLANTATION

Robina Aerts1, Alienor Xhaard 2, Christine Robin3, Andreas Groll4, Catherine Cordonnier3, Katrien Lagrou1, Stéphane Bretagne5

1University Hospitals Leuven, Leuven, Belgium, 2Hôpital Saint-Louis, Université Paris-Diderot, Paris, France, 3Assistance Publique Hôpitaux de Paris, Henri Mondor Hospital, Créteil, France, 4Center for Bone Marrow Transplantation, Children’s University Hospital Münster, Münster, Germany, 5Université Paris Cité, Assistance Publique Hôpitaux de Paris, Saint Louis Hospital, Paris, France

Background: Recent ECIL-guidelines suggest a qPCR guided pre-emptive treatment approach to toxoplasmosis in seropositive recipients of allogeneic hematopoietic cell transplantation(allo-HCT). While qPCR might serve as a sensitive tool for early Toxoplasma detection, its role in treatment follow-up remains unknown.

Methods: We analysed the qPCR kinetics of allo-HCT recipients experiencing either toxoplasmosis infection(TI, n = 71) or disease(TD, n = 14) in relation with different parameters. We included 85 patients with available qPCR values, from 4 centres(study cohort described in Table 1). Day 0(D0) was the day of anti-Toxoplasma treatment start or day of diagnosis(for untreated patients).

Results: Median qPCR(expressed as Ct-value) at D0 was 35.1 for patients with TI versus 32.1 in TD (p = 0.74). Median qPCR at D0 was the same(32.4) with and without primary prophylaxis. There was a significant difference depending on ongoing treatment with corticosteroids (31.3 with vs 33.8 without, p = 0.035).

Kinetic analysis was performed in 74 patients screened at least weekly with blood qPCR (median number of qPCRs performed <D28: 4 (IQR 2, including earlier deaths)). Median time from treatment start to first negative PCR was 7 days (IQR 6.3). Not reaching qPCR negativity at D10 and D14 was associated with a higher mortality at D30 (p = 0.023 and p < 0.001).

Time to negativity was inversely proportional to the Cq value at D0 (Spearman correlation coefficient -0.33, p = 0.0063). Having a Cq-value at D0 below 35.0 significantly increased the time to negativity (9.0 days (IQR 8.0) vs 6.0 days (IQR 4.0), p = <0.001). For cases with TI, median time to negativity was significantly shorter with 6.0 days (IQR 5.3) in comparison to cases with TD, for which this was a median of 10.5 days (IQR 8.0) (p = 0.032). Also, having received primary prophylaxis after HCT (11.0 vs 5.0 days), high-dose corticosteroids (≥0.5 mg/kg/d) (8.0 vs 6.5 days), graft-versus-host disease (9.0 vs 6.0 days) and a negative donor (9.0 vs 5.0 days) seem risk factors for slower negativation of blood qPCR, although these differences were all not significant in univariate analysis. These findings were confirmed also when looking at the patient cohort in its whole (n = 85 including the ones not weekly screened).

Regarding specific treatment, time to negativity was 6.5 days (IQR 5.5) for patients started on prophylactic regimens (trimethoprim-sulfamethoxazole or pyrimethamine-sulfadoxine) and 8.5 days (IQR 6.0) for patients started on curative regimens (trimethoprim-sulfamethoxazole, pyrimethamine-clindamycin or pyrimethamine-sulfadiazine), which was not significantly different (p = 0.16).

Table 1:

Characteristic

Number (%), total n = 85

Age at allo-HCT

Mean 47.9 years (SD 17.3)

Patients ≤18 years

5 (5.9%)

Female

33 (38.8%)

Underlying disease

AML

43 (50.6%)

Other

42 (49.4%)

GvHD before or at diagnosis

38 (44,7%)

Received high-dose corticosteroids

40 (47,1%)

Dose in mg prednisone/kg

Median 0,66 mg (IQR 0,32-1,50)

Toxoplasma serostatus

R+/D-

59 (69,4%)

R+/D+

15 (17,6%)

R+/D?

8 (9,4%)

R-/D+

1 (1,2%)

R-/D-

1 (1,2%)

R-/D?

1 (1,2%)

Received primary prophylaxis for toxoplasmosis

13 (15.3%)

TMP-SMX

9 (10.6%)

Toxoplasmosis

Toxoplasma infection

71 (83.5%)

Toxoplasma disease

14 (16.5%)

With CNS involvement

12 (14.1%)

Conclusions: This study supports the predictive value of qPCR kinetics follow-up in patients with toxoplasmosis after allo-HCT. The results can serve as an aid to clinical decision making when a positive PCR is observed. With the above-described risk factors, clinicians can identify patients at high-risk who need immediate treatment at first positive PCR (either with prophylactic or therapeutic regimens) and at least until two negative PCRs (and longer in case of disease), supporting the ECIL-guidelines. In addition to the guidelines, despite the retrospective design of the study, our results argue to strongly follow the parasitic load under treatment and consider a therapeutic change or reinforcement if the qPCR does not decrease after 10 days.

Disclosure: All authors: no conflict to declare.

13: Infectious Complications

O109 ANALYSIS OF PRE-TRANSPLANTATION CMV-SPECIFIC HUMORAL IMMUNITY AS A PREDICTOR OF CMV REACTIVATION AFTER HEMATOPOIETIC CELL TRANSPLANTATION (HCT) USING VIRSCAN SEROLOGIC PROFILING AND PENTAMERIC COMPLEX-SPECIFIC NEUTRALIZATION

Danniel Zamora 1, Elizabeth Krantz1, Khaleel Yahya1, Laurel Joncas-Schronce1, Rachel Blazevic1, Brad Edmison1, Elizabeth Wong1, Jocelyn Contreras1, Hu Xie1, Alicja Sadowska-Klasa1,2, Terry Stevens-Ayers1, Rachel Bender Ignacio1, Wendy Leisenring1, Joshua Hill1, Mariapia Degli-Esposti3, Geoffrey Hill1, Michael Boeckh1

1Fred Hutchinson Cancer Center, Seattle, United States, 2Medical University of Gdańsk, Gdańsk, Poland, 3Monash University, Melbourne, Australia

Background: Functional T-cell responses are important for the immune control of CMV infection after HCT, however, the protective role of CMV-specific humoral immunity remains unclear. Preclinical data propose a CMV strain-specific protective role for antibodies, yet recent qualitative (Portillo et al. CID 2023) and quantitative (Eberhardt et al. BMT 2023) evidence associates pre-HCT CMV-specific IgG positivity with an increased risk of post-HCT CMV reactivation. Using a discovery and validation cohort design, we examined CMV-specific humoral immunity in the CMV D-R+ setting where early CMV reactivation should exclusively be related to the recipient CMV antibody epitope repertoire, functionality, and strain-specificity.

Methods: Pre-HCT sera was tested using phage display immunoprecipitation and sequencing (VirScan) in allogeneic HCT recipients from 2007-17 who received CMV DNA PCR surveillance. We assessed the total number of peptide hits for CMV (repertoire) and the geometric mean epitope binding signal (EBS) of CMV epitope hits, a measure of antigen-antibody strength analogous to a titer. A subset of patients was tested for CMV neutralizing antibodies (nAb) directed against epithelial cell-specific viral entry presumably via pentameric complex (gH, gL, UL128, UL130, and UL131A). Patients were randomly divided into discovery and validation groups. CMV-specific antibody metrics were categorized into quartiles in the discovery group and used to estimate the cumulative incidence of CMV reactivation in the first 100 days post-HCT in both groups. Multivariable Cox regression models were developed for VirScan metrics using backwards selection in the discovery data, and resulting risk scores were evaluated using receiver operator characteristic analyses in the validation group.

Results: 478 patients were tested by VirScan (median of 25 days before HCT) and 174 also received nAb testing. The cumulative incidence of any CMV reactivation in the first 100 days post-HCT was significantly lower in patients in the discovery and validation groups with low (1st quartile) levels of all examined pre-HCT CMV-specific humoral immune parameters. Similar findings were noted using a higher CMV DNA PCR threshold of ≥150 IU/mL (data not shown). Using the discovery data, higher (≥2nd vs. 1st quartile) pre-HCT CMV-specific total peptide hits and geometric mean EBS were associated with a significantly increased rate of any CMV reactivation after HCT (Table 1). Similar significant associations were present at post-HCT CMV reactivation levels ≥150 IU/mL. In the validation group, risk scores including VirScan metrics predicted CMV reactivation up to 12 weeks post-HCT with area under the curve estimates ranging from 0.75 to 0.84.

Table 1 – Multivariable Model Estimates for Associations with CMV Reactivation in the first 100 days post-HCT in the Discovery Cohort (N = 239)

Any CMV

≥150 IU/mL

Adjusted1 (95% CI)

p-value

Adjusted2 (95% CI)

p-value

VirScan CMV Hits Score

0-10

1.0 (Reference)

1.0 (Reference)

11-18

2.6 (1.6 - 4.4)

<0.001

1.8 (1.0 - 3.3)

0.062

19-29

4.1 (2.5 - 6.8)

<0.001

2.1 (1.2 - 3.9)

0.014

≥30

4.6 (2.8 - 7.7)

<0.001

3.2 (1.8 - 5.8)

<0.001

Adjusted3 (95% CI)

p-value

Adjusted4 (95% CI)

p-value

VirScan CMV Geometric Mean Epitope Binding Signal (EBS)

0-15.5

1.0 (Reference)

1.0 (Reference)

>15.5-19.6

2.3 (1.4 - 3.9)

0.001

1.8 (1.0 - 3.3)

0.062

>19.6-24.8

3.3 (2.0 - 5.5)

<0.001

2.5 (1.4 - 4.5)

0.002

>24.8

3.2 (1.9 - 5.3)

<0.001

2.5 (1.4 - 4.6)

0.002

  1. Candidate adjustment variables considered for final multivariable models included: age, race, HLA-matching, stem cell source, and GVHD prophylaxis.
  2. 1Adjusted for VirScan CMV score, race, and stem cell source.
  3. 2Adjusted for VirScan geometric mean EBS, race, and stem cell source.
  4. 3Adjusted for VirScan CMV score and HLA group.
  5. 4Adjusted for VirScan geometric mean EBS and stem cell source.

Conclusions: Using a discovery and validation cohort study design, we observed a decreased incidence of CMV reactivation in the first 100 days post-HCT in patients with lower pre-HCT levels of multiple CMV-specific humoral immune parameters, suggesting factors other than pre-HCT nAb to CMV pentameric complex or the breadth of humoral responses control CMV reactivation. These data suggest that while some of the standard CMV-IgG test results in the lower quartile may be falsely positive, overall, high-level pre-HCT CMV-specific humoral immunity may be reflective of the burden of latent CMV, possibly due to infection with a high inoculum or by multiple strains.

Disclosure: Joshua A. Hill has served as a consultant for Moderna, Allovir, Gilead, Karius and Takeda and has received research support from Allovir, Gilead, Karius, Oxford Immunotec and Merck. Michael Boeckh has served as a consultant for Moderna, Symbio and has served on the advisory board for Allovir and EverysBio and received research support from Merck and Moderna. All other authors have nothing to declare.

13: Infectious Complications

O110 CMV SPECIFIC T-CELL ACTIVITY DETERMINES THE RISK OF CLINICALLY SIGNIFICANT CMV REACTIVATION FOLLOWING LETERMOVIR PROPHYLAXIS AFTER ALLO-HSCT

Timothé Duplessix 1, Ben-Niklas Baermann2, Alexander Hölscher2, Inga Ursula Henrike Tometten1, Felicitas Isabel Schultz2, Stefanie Munder2, Paul Sebastian Jäger2, Kathrin Nachtkamp2, Sascha Dietrich2, Joerg Timm1, Guido Kobbe2, Nadine Lübke1

1Institute of Virology, University Hospital Düsseldorf, Heinrich-Heine-University, Duesseldorf, Germany, 2Institute of Hematology, University Hospital Düsseldorf, Heinrich-Heine-University, Duesseldorf, Germany

Background: CMV is considered one of the most dangerous viral complications in patients undergoing allogeneic HSCT and is associated with high mortality and morbidity. Despite the use of letermovir, a CMV-specific antiviral prophylaxis that reduces the number of clinically significant CMV infections (Cs-CMVi) after transplantation, late CMV reactivation occurs in a significant number of patients after discontinuation of letermovir around day 100 after transplantation. Therefore, the aim of this study was to identify patients at risk for late CMV reactivation on day 100 post-transplantation by measuring CMV-specific T-cell responses.

Methods: A total of 49 allo-HSCT recipients (10 with lymphoid and 39 with myeloid disease) were prospectively monitored for CMV-specific T-cell immunity using an Elispot-CMV assay (T-SPOT®.CMV, Oxford Immunotec) during an observation period of 200 days. Inclusion criteria were: at least 18 years old, CMV-seropositive or a CMV-seropositive donor and letermovir start between day 0 and 28 after transplantation. Elispot analyses were performed at defined time points after transplantation (d100, d200, at CMV reactivation, 1 and 3 months after reactivation). A Cs-CMVi was treated with valganciclovir, untreated CMV infection (non Cs-CMVi) was defined by an isolated positive PCR result.

Results: In this study population, 39 recipients had detectable CMV-DNA by PCR (80%). While the number of CMV reactivations during letermovir prophylaxis was comparable to the number of reactivations after discontinuation of letermovir (n = 18 vs. n = 21), significantly more Cs CMVi were observed after stopping letermovir (n = 2 (11%) vs. n = 8 (38%)) confirming the protective activity of letermovir.

Elispot analysis showed that patients with CMV reactivation during prophylaxis had a significantly higher spot count at day 100 than those with no CMV reactivation (IE 1 spots: 46 and 3, p = 0.0066; pp65 spots: 618 and 34, p = 0.0004, respectively). These data demonstrate that CMV-specific T-cell activity is triggered by abortive CMV replication (blips) during letermovir prophylaxis.

Patients who had CMV reactivation after discontinuation of letermovir prophylaxis showed a lower median spot count in the d100 Elispot analysis than patients who had no CMV reactivation, both for IE1 (3 (95%CI: 1-8) and 12 (95%CI: 1-53), respectively), and for pp65 (74 (95%CI: 5-724) and 157 (95%CI: 50-374), respectively). These data indicate an increased risk of reactivation with a spot count of <10 for IE-1 and <100 for pp65 on d100. Furthermore, logistic regression analysis showed that patients who had abortive CMV reactivation during the first 100 days had a significantly lower risk of reactivation after stopping letermovir (OR = 0.062, 95%CI 0.08-0.470, p = 0.008).

Conclusions: Despite CMV prophylaxis after allo-HSCT, CMV reactivations occur. However, the risk of Cs-CMVi is significantly reduced and patients with non Cs-CMVi during letermovir prophylaxis may develop protective immunity and have a significantly lower rate of Cs-CMVi after discontinuation of letermovir.

Clinical Trial Registry: DRKS00031287

Disclosure: Nothing to declare

13: Infectious Complications

O111 INCIDENCE AND OUTCOME OF HHV-6 ENCEPHALITIS IN HLA-HAPLOIDENTICAL STEM CELL TRANSPLANT RECIPIENTS: A PROSPECTIVE ANALYSIS OF THE IDWP-EBMT

Katia Perruccio 1, Gloria Tridello2, Nina Knelange3, Alessandra Carotti1, Hélène Labussiere-Wallet4, Franco Locatelli5, Federica Galaverna5, Maija Itala-Remes6, Matthew Collin7, Malgorzata Sobczyk-Kruszelnicka8, Alessandro Rambaldi9, Emanuele Angelucci10, Anna Maria Raiola10, Malgorzata Mikulska10, Khalid Halahleh11, Antonio Pérez-Martinez12, Luisa Sisinni12, Francesco Onida13, Goda Choi14, Mathilde Hunault-Berger15, Robert Zeiser16, Jakob Passweg17, Maura Faraci18, Matthias Eder19, Melissa Gabriel20, Marta Gonzalez Vicent21, Lucia Lopez Corral22, Henrik Sengeloev23, Musa Karakukcu24, Alina Tanase25, John Snowden26, Raffaella Greco27, Dina Averbuch28, Simone Cesaro29, Rafael De La Camara30

1University of Perugia Transplant Program, Perugia, Italy, 2EBMT, Leiden Study Unit, Leiden, Netherlands, 3EBMT Leiden Study Unit, Leiden, Netherlands, 4Hospital Lyon Sud, Hospices Civils de Lyon, Lyon, France, 5IRCCS Ospedale Pediatrico Bambino Gesù, Università Cattolica del Sacro Cuore, Rome, Italy, 6Turku University Hospital, Turku, Finland, 7RVI Newcastle, Newcastle, United Kingdom, 8Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, Poland, 9ASST Papa Giovanni XXIII, Bergamo, Italy, 10IRCSS Ospedale Policlinico San Martino, Genova, Italy, 11King Hussein Cancer Center, Adult BMT and Cellular Therapy Program, Amman, Jordan, 12University Hospital La Paz, Madrid, Spain, 13IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy, 14University Medical Center, Groningen, Netherlands, 15CHRU, Angers, France, 16University of Freiburg, Freiburg, Germany, 17University Hospital, Basel, Switzerland, 18IRCCS G. Gaslini, Genova, Italy, 19Hannover Medical School, Hannover, Germany, 20The Children’s Hospital at Westmead, Sidney, Australia, 21Nino Jesus Children’s Hospital, Madrid, Spain, 22Hospital Clinico, Salamanca, Spain, 23Righospitalet, Copenhagen, Denmark, 24Erciyes University, Kayseri, Turkey, 25Fundeni Clinical Institute, Bucharest, Romania, 26Sheffield Teaching Hospitals NHS Foundation Trust, Sheffiled, United Kingdom, 27IRCCS Ospedale San Raffaele, Milan, Italy, 28Faculty of Medicine, Hebrew University of Jerusalem, Pediatric Infectious Diseases, Hadassah Medical Center, Jerusalem, Israel, 29Azienda Ospedaliera Universitaria Integrata, Verona, Italy, 30Hospital de la Princesa, Madrid, Spain

Background: Human Herpesvirus-6 (HHV-6) reactivation is observed in 30-70% of allogeneic hematopietic stem cell transplant (HSCT) recipients. The main complication of HHV-6 infection is encephalitis, which is associated with high morbidity and mortality. In a previous, retrospective Infectious Disease Working Party (IDWP)-European Bone Marrow Transplantation Society (EBMT) study, incidence of HHV-6 encephalitis was 0.5% and it was associated with 50% mortality (Perruccio K et al, submitted). According to some authors, patients who received HLA-haploidentical HSCT show higher incidence of HHV-6 reactivation and disease.

Thus, in this IDWP-EBMT prospective observational clinical study, we aimed at defining the incidence of HHV-6 central nervous system (CNS) infection in early post-HSCT phase in HLA-haploidentical transplant recipients. Secondary aims were to describe morbidity, management, treatment and toxicity, transplant outcomes (TRM, OS, EFS) associated to HHV-6 reactivation in this transplant setting.

Methods: From January the 1st 2020 to December the 31st 2021, we prospectively enrolled 269 patients who received a haploidentical HSCT. Of those, 163 were males and 106 females, with a median age of 48 years (range: 1-74), affected prevalently by acute leukemia (205), lymphoma (34) or myelodysplastic/myeloproliferative syndrome (30). All received a myeloablative conditioning regimen, in most cases graft was not manipulated with infusion of Cyclophosphamide post-HSCT as Graft-versus-Host-Disease (GvHD) prophylaxis. Most patients did not receive antiviral prophylaxis and 64/257 evaluable ones (25%) developed acute GvHD. More than 80% of patients engrafted, with polymorphonuclear (PMN) cells and platelets (PLT) reaching stable values at a median time of 16 and 24 days respectively (see Table 1).

Patients

269

Median age in years, median [min, max]

48 [1-74]

Disease:

• Acute leukemia (%)

205 (76.2)

• Lymphoma (%)

34 (12.6)

• Myelodisplastic/Myeloproliferative (%)

30 (11.2)

Haploidentical transplant:

• Haplo manipulated (%)

90 (33.5)

• Haplo unmanipulated (%)

179 (66.5)

HHV-6 reactivation:

• No

61 (22.7)

• Yes, qualitative

13 (4.8)

• Yes, quantitative

190 (70.6)

HHV-6 encephalitis:

• No

254 (94.4)

• Yes

3 (1.2)

CNS fluid positive:

• Yes

3/3 (100%)

Overall survival

At latest follow-up

98 events – 59.8% (53.1-65.9)

Results: 126 patients out of 264 evaluable ones (48%) reactivated HHV-6 at a median of 22 days after HSCT, with a cumulative incidence (CI) at 100 days post-HSCT of 61.2% (54.1-67.6). HHV-6 DNAmia was routinely monitored in 203 out of 269 patients (75%) at least once a week. Median peak DNA viral load in blood was 14.400 copies/mL, but only 63 patients out of 126 (50%) received antiviral treatment specific for HHV-6. Three out of 257 evaluable patients developed HHV-6 encephalitis according to ECIL criteria (1.2%). Two patients had received a manipulated graft and one unmanipulated graft, and none had acute GvHD at the moment of infection. All three patients showed CNS fluid positive for HHV-6, magnetic resonance imaging (MRI) scan and symptoms indicative of limbic encephalitis, but none died of HHV-6 disease. 243/269 (90%) patients were alive at day +100 post-HSCT, while at 1 year post HSCT, 185/269 (69%) patients were alive, and 170/269 (63%) were alive at latest follow-up.

Conclusions: HHV-6 reactivation and encephalitis incidence were higher in HLA-haploidentical HSCT recipients from data reported in our retrospective study (1.2% vs 0.5%, p < 0.05), but none of the patients died of HHV-6 disease compared to our retrospective series, in which mortality was high. Even if HHV-6 DNAmia monitoring in blood is not routinely recommended by ECIL guidelines, in this study it was applied in most patients and it was useful to demonstrate the viral reactivation to timely start an efficacious anti-viral treatment able to prevent fatal outcome.

Disclosure: No COI.

26: Lymphoma and Chronic Lymphocytic Leukaemia

O112 ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION IN PATIENTS WITH ADVANCED MYCOSIS FUNGOIDES AND SÉZARY SYNDROME: A RETROSPECTIVE ANALYSIS INCLUDING 63 CONSECUTIVE PATIENTS WITH LONG-TERM MEDIAN FOLLOW-UP

Francesco Onida 1, Francesca Cavallaro2, Silvia Alberti Violetti2, Maria Goldaniga2, Kordelia Barbullushi2, Fabio Serpenti2, Simona Iacobelli3, Giorgio Alberto Croci4, Gabriele Simontacchi5, Francesco Passamonti6, Emilio Berti2, Giorgia Saporiti2

1Hematology and ASCT Unit, ASST Fatebenefratelli-Sacco, University of Milan, Milano, Italy, 2Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy, 3University of Rome Tor Vergata, Rome, Italy, 4Pathology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy, 5Radiotherapy Unit, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy, 6Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milano, Italy

Background: Although over the last decade novel effective drugs became available, allogeneic hematopoietic cell transplantation (allo-HCT) still represents the only potential curative strategy in advanced stage mycosis fungoides (MF) and Sézary syndrome (SS). Here we report the results of a reduced-intensity conditioning-based allo-HCT program started in 09/2000 at the University of Milan - Fondazione IRCCS Ospedale Maggiore Policlinico, for patients with advanced phase MF and SS.

Methods: Data from consecutive patients who underwent allo-HCT since 09/2000 to 07/2023 for stage IIB/IV refractory MF or SS were retrospectively collected and analysed aiming to investigate factors associated with outcomes at a long-term median follow-up. Conditioning regimens were purine analogs-based, including pentostatin/TBI200 or fludarabine/melphalan in patients transplanted from MRD/MUD/mMUD and Thiotepa/CTX/Flu/TBI for patients with haploidentical mMRD. Survival endpoints (OS, DFS) were described by Kaplan-Meier curves and compared by the Log-Rank test. Cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were analysed as mutually competing risks, with crude cumulative incidence curves and Gray’s test.

Results: The series included 63 patients (40 MF and 23 SS), with a median age of 55 years (20-67) and a median time from diagnosis of 46 months (10-275). Donors were HLA-identical sibling in 22, MUD in 28 (mMUD in 13), and mMRD in 13 patients. At transplantation 15 patients (24%) were in CR, while a clinical CR was achieved in 48% of patients transplanted with active disease. 21 patients relapsed at a median time of 4 months post transplantation (range 23 days - 35 months), with 5 achieving a new and durable CR following withdrawal of immunosuppressive therapy (n = 1), RT/TSEB (n = 3), or chronic GvHD occurrence (n = 1). Acute grade II-IV GvHD occurred in 51% of patients, of grade III-IV in 22%. Chronic GvHD occurred in 36% of the 53 evaluable patients, extensive in 16%. With a median follow-up of 70 months for alive patients, outcomes at 5-years were OS 53% (40-66%), DFS 33% (21-44%), NRM 14% (5-22%) and relapse incidence 63% (50-75%). Outcomes were significantly better in SS than in MF (5-yr DFS 57% vs 22%, p = 0.012) and in patients in CR at the time of transplantation than in those transplanted with active disease (5-yr DFS 71% vs 22%, p = 0.001). According to donor type, 5-yr DFS in patients transplanted from MRD, MUD and mMRD was 50% (95% CI 28-71), 18% (95% CI 4-32) and 36% (95% CI 9-63), respectively. In particular, among 13 pts who underwent allo-SCT from mMRD, 8 were alive at the last follow-up (6 in CR), with a 5-yr NRM of 15%.

Conclusions: In selected patients with advanced stage MF and SS, RIC allo-SCT is a powerful strategy in maintaining long-term remission, with low risk of NRM. Transplant from mMRD appears feasible, with 5-yr survival outcomes in between those form MRD and MUD and superimposable 5-yr CIR in patients with MRD and mMRD. Disease relapse remains the major cause of transplant failure, especially in patients with MF undergoing transplantation with active disease, making the post-transplantation disease treatment particularly challenging.

Disclosure: Nothing to declare

26: Lymphoma and Chronic Lymphocytic Leukaemia

O113 COMPARISON OF THIOTEPA-BASED CONDITIONING REGIMENS FOR OLDER ADULTS WITH PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA RECEIVING AUTOLOGOUS HEMATOPOIETIC CELL TRANSPLANTATION

Othman Salim Akhtar 1, Qinghua Lian2, Kwang W. Ahn2, Anita D’Souza1, Binod Dhakal1, Meera Mohan1, Marcelo Pasquini1,2, Walter Longo1, Timothy S. Fenske1, Nirav N. Shah1, Mehdi Hamadani1,2

1Medical College of Wisconsin, Milwaukee, United States, 2Center for International Blood and Marrow Transplant Research, Milwaukee, United States

Background: Primary central nervous system lymphoma (PCNSL) is a rare subtype of extranodal non-Hodgkin lymphoma (NHL) with a median age at diagnosis of 65 years. The current accepted standard of care includes induction with a methotrexate-based regimen followed by consolidation with high-dose chemotherapy and autologous hematopoietic cell transplantation (HDC/autoHCT) in eligible patients. Thiotepa-based conditioning regimens have been found to be superior to carmustine/etoposide/cytarabine/melphalan (BEAM). However, data for older adults (≥65 years) are limited and the optimal thiotepa-based regimen for this patient population is unclear. In this observational cohort study, we compare outcomes of older adults with PCNSL undergoing autoHCT with either thiotepa/carmustine (TT/BCNU) or thiotepa/busulfan/cyclophosphamide (TBC) conditioning.

Methods: We used registry data made available post-publication (Scordo et al, JAMA Oncol 2021) by the Center for International Blood and Marrow Transplantation Research (CIBMTR) for this analysis. Patients included were ≥65 years in age with PCNSL and underwent autoHCT as initial or subsequent consolidation with TBC or TT/BCNU conditioning, between January 2010 and December 2018. We excluded patients <65 years, those with other NHL diagnoses and those receiving alternate conditioning regimens. Primary outcome was overall survival (OS) and secondary outcomes included progression-free survival (PFS), non-relapse mortality (NRM), relapse rate and hematopoietic recovery.

Results: Overall, 147 patients were included; n = 84 received TT/BNCU and n = 63 received TBC. Median follow up was 24.7 months (95% CI, 22.9, 26.5 months) in the TT/BCNU group, and 37.6 months (95% CI, 25.3, 48.72 months) in the TBC group. A higher proportion of patients in the TT/BCNU group had a Karnofsky Performance Status (KPS) < 90 (60% vs 43%, p = 0.02). There were no significant differences in median age, comorbidity index or remission status prior to HDC/autoHCT between the two groups (Table 1). The 30-day cumulative incidence of neutrophil recovery in the TT/BCNU group was 99% versus 95% in the TBC group (p = 0.23). The 100-day incidence of platelet recovery in the TT/BCNU and TBC groups was 98% and 89% respectively (p = 0.056). The 1-year NRM in the TT/BCNU group was 10% versus 22% in the TBC group (p = 0.05) and the 1-year relapse rate was 5% versus 3%, respectively (p = 0.60). The 1-year PFS in the TT/BCNU group was 85% versus 74% in the TBC group (p = 0.11) and 1-year OS was 89% vs 76% (p = 0.04). In a multivariable regression model, TT/BCNU was associated with a lower risk for NRM [Hazard Ratio (HR), 0.37, p = 0.015], improved PFS (HR, 0.41, p = 0.008) and OS (HR, 0.37, p = 0.007), but there was no association with relapse.

Conclusions: In older adults (≥65 years) with PCNSL undergoing consolidation with autoHCT, TT/BCNU conditioning is associated with lower NRM and improved OS compared to TBC.

Table 1: Baseline Characteristics and Outcomes in Older Adults Receiving BCNU/TT or TBC

Characteristic

BCNU/TT, N = 84

TBC, N = 63

P

Age – Median (IQR)

68.10 (66.32, 70.67)

67.38 (65.99, 69.48)

0.12

Karnofsky score prior to HCT < 90 – N (%)

50 (60%)

27 (43%)

0.020

Co-morbidity index – N (%)

0.2

15 (18%)

17 (27%)

1-2

20 (24%)

19 (30%)

≥3

49 (58%)

27 (43%)

Rituximab used in conditioning (Yes) – N (%)

4 (4.8%)

9 (14%)

0.044

Remission Status – N (%)

0.3

CR1

54 (64%)

33 (52%)

CR2+

11 (13%)

13 (21%)

PR

19 (23%)

17 (27%)

Neutrophil recovery, 30 day - % (95% CI)

99% (82% – 99%)

95% (85% –99%)

0.23

Platelet recovery, 100 day - % (95% CI)

98% (85% – 100%)

89% (77% – 95%)

0.056

Relapse, 1-year - % (95% CI)

5% (2% – 12%)

3% (1% – 10%)

0.60

Non-relapse mortality – 1 year - % (95% CI)

10% (5% – 17%)

22% (13% - 34%)

0.05

Progression-free survival – 1 year - % (95% CI)

85% (78% - 93%)

74% (62% - 86%)

0.11

Overall survival – 1 year - % (95% CI)

89% (83% - 96%)

76% (66% - 87%)

0.04

The 50th Annual Meeting of the European Society for Blood and Marrow Transplantation: Physicians - Oral Session (O009-O154) (10)

Disclosure: Nothing to declare

26: Lymphoma and Chronic Lymphocytic Leukaemia

O114 ALLOGENEIC TRANSPLANTATION AFTER IMMUNOTHERAPY OR DRUG-CONJUGATED ANTIBODY FOR RELAPSED/REFRACTORY NON-HODGKIN LYMPHOMA: A COMPARISON WITH A HISTORICAL COHORT

Jacopo Mariotti 1, Cristina Zucchinetti1, Laura Giordano2, Chiara De Philippis1, Daniele Mannina1, Barbara Sarina1, Daniela Taurino2, Rachele Carbon1, Armando Santoro1, Stefania Bramanti1

1IRCCS Humanitas Research Hospital, Rozzano (milan), Italy, 2Biostatistic Unit, IRCCS Humanitas Research Hospital, Rozzano (milan), Italy

Background: The treatment landscape of patients with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) has been rapidly evolving due the introduction of new effective salvage strategies, such as chimeric antigen receptor (CAR) T cells, bispecific T cell engager antibodies (BiTe), checkpoint inhibitors (CPI) and antibody-drug conjugates (ADC). Durable responses and a low toxicity profile contributed to positioning CAR-T therapy as a widely accepted first choice for R/R DLBCL and PMBL. Nevertheless, most patients with R/R B-NHL relapse or do not respond to CAR-T therapy. For these patients, new immunotherapy drugs are employed as salvage treatments and may be followed by consolidation with allogeneic hematopoietic stem cell transplantation (Allo-SCT). The increased use of such new drugs in the management of R/R B-NHL raises the issue of improving our understanding of their potential long-term effects when Allo-SCT is performed as consolidation treatment. Therefore, we performed a retrospective study in the pre-CAR-T era to analyze the outcome of patients receiving Allo-SCT after new immunomotherapy drugs (IMT) and to compare these results with a historical cohort of subjects treated with Allo-SCT after standard therapy regimens (ST).

Methods: From 1/4/ 2017 to 30/9/2021, 55 patients with NHL were treated with Allogeneic-SCT either after immunotherapy drugs (n = 27) or standard therapy (n = 28). Only patients achieving pre-transplant disease response, either complete (CR) or partial remission (PR), were included. The primary endpoint was GVHD/relapse free survival (GRFS). Secondary endpoints comprised overall survival (OS), non-relapse mortality (NRM), acute and chronic GVHD

Results: Patients’ characteristics and outcomes are summarized in Table I. The two cohorts were comparable in terms of most characteristics. The only differences were represented by disease diagnosis, number of lines of therapy (4 vs 3), and previous autologous transplant. With a median follow-up 50 months, the IMT cohort had similar outcomes relative to SCT in terms of GRFS (4-yeras: 59% vs 46%), OS (4-years: 77% vs 44%), NRM (4-years:19% vs 22%), acute (six months: 15% vs 21%) and chronic (4-years: 18% vs 24%) GVHD. Of note, cumulative incidence of relapse was lower, but not statistically significant, after immunotherapy (4-years: 4% vs 14%). Cumulative incidence of CMV reactivation (37% vs 61%, p = 0.07) and invasive fungal infection (7% vs7%) did not differ among the two cohorts. Of note, even with the limit of the small sample size, we noticed that the subset of patients treated with loncastuximab and the one receiving 2 different immunotherapy lines had lower GRFS (at 4 years 33% and 0%, respectively) and OS (at 4 years 33% and 0%, respectively), and this was due to increased NRM (at 4-years: 33% and 100%, respectively).

Conclusions: Allo-HSCT as consolidative strategy in R/R DLBCL achieving disease response after new immunotherapy strategy was safe and effective in the pre-CART era. These results suggest its potential use as curative strategy without unexpected toxicity for patients relapsing after CART and rescued with immunomodulatory therapies

Disclosure: The authors have no conflict of intrest to disclose

27: Multiple Myeloma

O115 OUTCOMES IN AFRICAN-AMERICAN (AA) AND WHITE PATIENTS WITH NEWLY DIAGNOSED MULTIPLE MYELOMA RECEIVING RVD-ALONE VS RVD + ASCT IN DETERMINATION: EFFICACY, SAFETY, AND SECOND PRIMARY MALIGNANCIES (SPMS)

Paul G. Richardson 1, Jeffrey A. Zonder2, Abdullah M. Khan3, Susanna J. Jacobus4, Hani Hassoun5, Larry D. Anderson Jr6, Lauren E. Merz1, Rebecca L. Zon1, Yvonne Efebera7, Tondre Buck8, Racquel D. Innis-Shelton9, Monique A. Hartley-Brown1, Sagar Lonial10, Erica L. Campagnaro11, Peter M. Voorhees12, Robert Z. Orlowski13, Edward N. Libby14, David D. Hurd15, Caitlin L. Costello16, Noopur S. Raje17, Eva Medvedova18, Philip L. McCarthy19, Carter P. Milner Milner20, Cristina Gasparetto21, Mounzer E. Agha22, Krisstina Gowin23, Rammurti T. Kamble24, Sundar Jagannath25, Nitya Nathwani26, Melissa Alsina27, Sergio Giralt5, Jacob P. Laubach1, Omar Nadeem1, Irene M. Ghobrial1, Clifton C. Mo1, Mehmet K. Samur1, Nikhil C. Munshi1, Kenneth C. Anderson1

1Dana-Farber Cancer Institute, Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School, Boston, United States, 2Barbara Ann Karmanos Cancer Institute / Wayne State University School of Medicine, Detroit, United States, 3The Ohio State University Comprehensive Cancer Center, Columbus, United States, 4Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States, 5Memorial Sloan Kettering Cancer Center, New York, United States, 6Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, United States, 7OhioHealth, Columbus, United States, 8Gibbs Cancer Center & Research Institute, Spartanburg, United States, 9Alabama Oncology–Birmingham, Birmingham, United States, 10Winship Cancer Institute of Emory University, Atlanta, United States, 11University of Michigan, Ann Arbor, United States, 12Levine Cancer Institute, Atrium Health, Charlotte, United States, 13The University of Texas MD Anderson Cancer Center, Houston, United States, 14University of Washington, Division of Medical Oncology and Fred Hutchinson Cancer Center, Seattle, United States, 15Atrium Health Wake Forest Baptist Medical Center, Winston-Salem, United States, 16Moores Cancer Center at University of California San Diego, San Diego, United States, 17Massachusetts General Hospital, Harvard Medical School, Boston, United States, 18Knight Cancer Institute, Oregon Health and Science University, Portland, United States, 19Roswell Park Comprehensive Cancer Center, Buffalo, United States, 20University of Mississippi Medical Center, Jackson, United States, 21Duke University Medical Center, Durham, United States, 22University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, United States, 23University of Arizona Cancer Center, UA College of Medicine – Tucson, Tucson, United States, 24Baylor College of Medicine and Houston Methodist Hospital, Houston, United States, 25Icahn School of Medicine at Mount Sinai, New York, United States, 26Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope Comprehensive Cancer Center, Duarte, United States, 27H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States

Background: DETERMINATION demonstrated a significant progression-free survival (PFS; primary endpoint) difference with lenalidomide-bortezomib-dexamethasone (RVd)-alone vs RVd+ASCT (median 46.2 vs 67.5 months, HR 1.53) but differing benefit in AA and White patients (Richardson, NEJM 2022). Multivariable analyses showed PFS prognostic factors, including race and body mass index (BMI), varied by treatment (Hassoun, EBMT 2023). We expand upon these findings with hypothesis-generating analyses of outcomes with RVd-alone vs RVd+ASCT in AA and White patients, and explore prevalence of Duffy-null genotype, a common variant in AA patients associated with lower circulating neutrophil count without increased infection risk.

Methods: Patients received RVd (3 cycles), stem cell mobilization, and then RVd (5 cycles; RVd-alone, n = 357) or ASCT and RVd (2 cycles; RVd+ASCT, n = 365), plus R maintenance. PFS was analyzed by race and in subgroups defined by BMI and sex; treatment exposure, response, overall survival (OS), safety/SPMs, and subsequent therapy were also analyzed.

Results: RVd-alone and RVd+ASCT arms included 66 (18.5%)/268 (75.1%) and 66 (18.1%)/272 (74.5%) AA/White patients. AA patients were less frequently aged ≥60 years (RVd-alone: 18%/38% AA/White patients; RVd+ASCT: 24%/29%) and more commonly were female (68%/37%; 44%/41%), had BMI ≥ 30 (42%/38%; 55%/42%), and had hemoglobin ≤10 g/dL (47%/24%; 58%/24%), with lower median baseline neutrophil count (2.8/3.3 x109/L, both arms). In samples tested to date, AA patients (11/17; 64.7%) were more commonly Duffy-null than non-AA patients (2/136; 1.5%). Median treatment duration from randomization (RVd-alone vs RVd+ASCT arms) was 27.5 vs 36.1 months in AA and 28.7 vs 36.2 months in White patients; 77% vs 74% of AA patients started R maintenance, compared with 83% vs 80% of White patients, and median maintenance duration was 43.3 vs 45.2 months in AA and 35.8 vs 40.4 months in White patients. With RVd-alone vs RVd+ASCT, ≥complete response rates were 45.5% vs 30.3% and 41.8% vs 51.5%, respectively. Among 48/212 (RVd-alone) and 49/208 (RVd+ASCT) AA/White patients who had discontinued study treatment, 68.7/82.6% and 59.2/71.6% had received subsequent therapy, including 27.1/28.3% (RVd-alone) with subsequent ASCT. There was no difference in OS with RVd-alone vs RVd+ASCT in AA (5-year 83.2% vs 78.7%, HR 0.99) and White (77.1% vs 80.3%, HR 1.08) patients (median follow-up 76.0 months). Toxicities are summarized in the Table. Updated SPMs analysis (cut-off December 2023) showed similar rates in AA/White patients in the RVd-alone and RVd+ASCT arms: 0/1.1% and 4.5/3.3% had acute myeloid leukemia/myelodysplastic syndromes, 1.5/2.6% and 1.5/1.1% had acute lymphoblastic leukemia, and 6.1/4.5% and 3.0/2.9% had solid tumors, respectively.

Treatment-related grade ≥3 adverse events (AEs)

RVd-alone

RVd+ASCT

AA patients

White patients

AA patients

White patients

Overall, across all treatment

n = 66

n = 268

n = 66

n = 272

Any grade ≥ 3 AE, %

80.3

77.2

93.9

94.5

Any hematologic grade ≥ 3 AE, %

60.6

60.1

84.8

91.5

Neutropenia

45.5

41.4

78.8

88.2

Thrombocytopenia

13.6

21.6

75.8

84.2

Anemia

27.3

16.0

34.8

29.4

Other grade ≥ 3 AE, %

Hypophosphatemia

9.1

9.7

7.6

8.5

Pneumonia

3.0

5.6

10.6

9.6

Febrile neutropenia

1.5

5.2

6.1

10.3

All neuropathy events

9.1

4.9

10.6

6.3

Diarrhea

6.1

3.4

4.5

5.1

All thromboembolic events

3.0

2.6

3.0

4.8

Nausea

1.5

0.4

3.0

7.4

During maintenance

n = 51

n = 222

n = 49

n = 218

Any grade ≥ 3 AE, %

47.1

43.2

59.2

61.5

Any hematologic grade ≥ 3 AE, %

29.4

23.9

36.7

43.6

Neutropenia

25.5

21.6

34.7

37.6

Conclusions: DETERMINATION data suggest similar PFS/OS with RVd-alone and RVd+ASCT in AA patients (as with RVd+ASCT in AA/White patients overall) but indicate possible meaningful PFS benefit from RVd-alone upon exploratory analyses in certain subgroups. Overall grade ≥3 hematologic toxicity rates were similar in AA/White patients within each arm despite Duffy-null prevalence of 65% in AA patients and associated lower baseline neutrophil counts, but grade ≥3 neuropathy rates were higher in AA patients (consistent with GRIFFIN; Nooka, Blood Cancer J 2022), which taken together may reflect differential effects on the inflammasome and differences in myeloma pathobiology.

Clinical Trial Registry: ClinicalTrials.gov number, NCT01208662

Disclosure: PGR:Advisory committees:BMS/Celgene,GSK,Karyopharm,Oncopeptides,Adaptive,Sanofi; Research funding:BMS/Celgene,Karyopharm,Oncopeptides.

JAZ:Consultancy:BMS,Janssen,Prothena,Regeneron,Alexion/AstraZeneca; Research support:BMS,Janssen.

AMK:Consultancy:SecuraBio; Research funding:BMS,SecuraBio; Honoraria:Janssen; Speakers Bureau:Amgen,Sanofi.

HH:Research funding:Celgene, Takeda,Janssen.

LDA:Advisory committees/Consultancy/Honoraria:AbbVie,Amgen,Beigene,BMS,Celgene,Cellectar,GSK,Janssen,Prothena,Sanofi; Research funding:BMS,Celgene,Janssen.

LEM:Consultancy/Research funding:Alexion Pharmaceuticals; Honoraria:X4 Pharmaceuticals.

RLZ:Consultancy/Equity holder:Amagma Therapeutics.

YE:Honoraria/Speakers Bureau:Adaptive,Janssen,Pfizer,Sanofi.

MAH-B:Consultancy/Honoraria:AbbVie,BMS/Celgene,GSK,Janssen,Karyopharm,Pfizer,Sanofi.

SL:Advisory committee/Consultancy:AbbVie,Amgen,BMS,Celgene,Genentech,GSK,Janssen,Novartis,Pfizer,Takeda; Research funding:BMS,Janssen,Novartis,Takeda; Board of Directors/Stock ownership:TG Therapeutics

PMV:Advisory committees:AbbVie, BMS, Janssen, Sanofi; Consultancy:AbbVie, BMS, GSK, Janssen, Karyopharm, Novartis, OncoPeptides, Regeneron; DSMB:BMS; Research funding:AbbVie, GSK, Janssen, Nervianos Medical Sciences.

RZO:Consultancy/Honoraria:AbbVie, Adaptive, Asylia Therapeutics, BioTheryX, BMS, Karyopharm, Meridian, Monte Rosa Therapeutics, Nanjing IASO Biotherapeutics, Neoleukin Corporation, Oncopeptides, Pfizer; Research funding: Asylia Therapeutics, BioTheryX, BMS/Celgene, CARsgen Therapeutics, Exelixis, Heidelberg Pharma, Janssen, Sanofi/Genzyme, Takeda; Equity holder/Patents and royalties: Asylia Therapeutics.

ENL:Consultancy:Adaptive.

DDH:Equity holder:BMS/Celgene.

CLC:Consultancy:BMS, Janssen, Pfizer, Takeda; Honoraria:Regeneron; Research funding:BMS, Harpoon Therapeutics, Ionis, Janssen, Pfizer, Poseida, Takeda.

NSR:Advisory committees/Consultancy/Research funding:AbbVie, BMS, Caribou, GSK, Immuneel, Janssen, K36 Therapeutics, Pfizer, Sanofi.

PLM:Honoraria:BMS, GSK, Karyopharm; DSMB:BMS, Karyopharm.

CPM:Speakers Bureau:AstraZeneca, BeiGene, Blueprint Medicines, BMS.

CG:Advisory committees:Amgen, BMS, GSK, Janssen, Karyopharm, Sanofi; Speakers bureau:BMS, Karyopharm, Sanofi.

MEA:Equity holder:GenCART.

SJ:Consultancy:Janssen, BMS, Regeneron, Caribou, Sanofi, Takeda, Karyopharm, Legend; DMC chair:Genmab, Sanofi; Honoraria:BMS, Janssen.

MA:Consultancy:BMS, Genzyme, Janssen; Honoraria:Genzyme, RevHealth, RedMed; Research funding:BMS; Speakers Bureau:Janssen.

SG:Advisory committees:Amgen, Actinuum, Celgene/BMS, Janssen, Jazz, Johnson&Johnson, Kite, Novartis, Spectrum, Takeda; Research funding:Amgen, Actinuum, Celgene/BMS, Johnson&Johnson, Miltenyi, Omeros, Takeda.

ON:Advisory committees:BMS, GPCR Therapeutics, GSK, Janssen, Sanofi, Takeda; Honoraria:Janssen; Research funding:Janssen, Takeda.

IMG:Consultancy: AbbVie, Amgen, Aptitude Health, BMS, GSK, Huron Consulting, Janssen, Menarini, Novartis, OncoPeptides, Pfizer, Regeneron, Sanofi, Takeda, The Binding Site, Window Therapeutics; Honoraria:10xGenomics, AbbVie, Adaptive, BMS, GSK, Janssen, Menarini, Novartis, Pfizer, Regeneron, Sanofi, Takeda, Vor Biopharma; Equity owner/employment (spouse):Disc Medicine; Research funding:Novartis; Speakers bureau:Vor Biopharma.

CCM:Advisory committees:AbbVie, Janssen; Consultancy:AbbVie, BioLine, GSK, Janssen, Karyopharm, Pfizer, Pharmacyclics, Sanofi, Spectrum, Takeda.

NCM:Consultancy:Adaptive, Amgen, BMS, Janssen, Karyopharm, Legend, OncoPep, Takeda; Stock ownership:OncoPep.

KCA:Advisory committees:C4 Therapeutics, Dynamic Cell Therapies, Starton, Window; Consultancy:Astrazeneca, Daewoong, Janssen, OncoPep, Pfizer, Starton; Equity holder:C4 Therapeutics, Dynamic Cell Therapies, NextRNA, Oncopep, Starton, Window.

28: Myelodysplastic Syndromes

O116 POST-TRANSPLANT CYCLOPHOSPHAMIDE (PTCY) COMPARED TO ATG IN PATIENTS WITH MDS ALLOGRAFTED WITH UNRELATED DONOR: A STUDY OF THE CHRONIC MALIGNANCIES WORKING PARTY OF THE EBMT

Yves Chalandon 1, Diderik-Jan Eikema2, Ivan Moiseev3, Fabio Ciceri4, Linda Koster5, Jan Vydra6, Jakob Passweg7, Montserrat Rovira8, Mutlu Arat9, Tobias Gedde-Dahl10, Nicolaus Kröger11, Victoria Potter12, Ibrahim Yakoub-Agha13, Alessandro Rambaldi14, Maija Itäla-Remes15, Alina Tanase16, Francesco Onida17, Carmelo Gurnari18, Christof Scheid19, Joanna Drozd-Sokolowska20, Kavita Raj21, Donal P. McLornan21, Marie Robin22

1Hôpitaux Universitaire Genève (HUG) and Faculty of Medicine, Geneva, Switzerland, 2EBMT Statistical Unit, Leiden, Netherlands, 3RM Gorbacheva Research Institute, Pavlov University, St Peterburg, Russian Federation, 4Ospedale San Raffaele s.r.l., Milano, Italy, 5EBMT Leiden Study Unit, Leiden, Netherlands, 6Institute of Hematology and Blood Transfusion, Prague, Czech Republic, 7University Hospital | Basel, Basel, Switzerland, 8Hospital Clinic, Barcelona, Spain, 9Demiroglu Bilim University Istanbul Florence Nightingale Hospital, Istanbul, Turkey, 10Oslo University Hospital, Rikshospitalet, Oslo, Norway, 11University Hospital Eppendorf, Hamburg, Germany, 12Kings College Hospital, London, United Kingdom, 13CHU de Lille, Lille, France, 14University of Milan and ASST Papa Giovanni XXIII, Milano, Italy, 15Turku University Hospital, Turku, Finland, 16Fundeni Clinical Institute, Bucharest, Romania, 17Fondazione IRCCS - Ca’ Granda - Ospedale Maggiore Policlinico IRCCS, Milano, Italy, 18University of Rome Tor Vergata, Rome, Italy, 19University of Cologne, Cologne, Germany, 20University Clinical Centre, Medical University of Warsaw, Warsaw, Poland, 21University College London Hospitals NHS Trust, London, United Kingdom, 22Hôpital Saint-Louis, AP-HP, Paris, France

Background: Prospective randomized trials have reported a benefit for ATG-based GVHD prophylaxis in the setting of alloHSCT with UD. However, the best GVHD prophylaxis has been recently challenged using PTCY. We here present the outcomes of PTCY vs ATG as GVHD prophylaxis in MDS patients from the EBMT registry transplanted with UD.

Methods: A total of 969 patients transplanted from 2012 to 2019 in 92 participating centers, receiving either PTCY or ATG, were included. The primary outcomes were PFS and OS. Competing risks analyses were performed for NRM, aGvHD grade II-IV, cGvHD and engraftment. Cox proportional hazards regression with a predefined covariate constellation (age, IPSS-R cytogenetics, donor HLA matching, age, hypomethylating agents (HMA) prior to transplantation, comorbidity score and MDS classification (MDS with or without EB) was used to obtain adjusted effect estimates of ATG compared to PTCY for OS and PFS.

Results: Overall, 214 patients received PTCY and 755 received ATG. Patients of the ATG group were older (60.1 year-old [IQR: 50.6-65.2] vs 57.2 year-old [IQR: 46.4-61.1], p = 0.008). Disease characteristics were similar in both groups: there were a total of 583 MDS with EB at diagnosis, 510 MDS-EB at transplantation, and 207 patients transformed into AML. Among patients with available data for IPSS-R at MDS diagnosis (n = 760) 44 (5.8%) were Very Low, 114 (15%) Low, 209 (27.5%) Intermediate, 232 (30.5%) High and 161 (21.2%) Very High. Patients of the PTCY group received more frequently HMA before transplantation (72.4% vs 57.3%, p = 0.001) and were preferentially transplanted from an HLA mismatched 9/10 donor (37.9% vs 21.6%, p < 0.001). Conditioning regimen was more frequently myeloablative in the PTCY group (55.4% vs 38.7%, p < 0.001). Engraftment at 28 days was significantly better with ATG (93% vs 84%, p < 0.001). With a median follow-up of 4.4 (95% CI 4.2 - 4.8) years, five-year OS was 57% (49-64) with PCTY and 49% (95% 46-53%) in ATG group, p = 0.127. Five-year CIR was similar in both groups (22%, 95%CI 16-29 in PTCY vs 25%, 95%CI 22-28 in ATG; p = 0.28). 5-year PFS was marginally higher for PTCY with 52% (95%CI 44-59) vs 44% (95%CI 40-48) for ATG, p = 0.075, whereas 5-year NRM was 26% (95% CI 20-32%) vs 31% (95% CI 27-34) in PTCY and ATG, respectively, p = 0.28. Grade II-IV aGVHD was lower using PTCY (22% [95% CI 17-28%] vs 30% [95% CI 26-33%]), p = 0.035 while there was no difference for cGVHD (36% (29-43% with PTCY vs 38% (34-41%) in ATG at 5 years).

Multivariable analyses confirmed a better OS and PFS for PTCY, with a HR of ATG of 1.34 (95% CI 1.02-1.76), p = 0.04, and a better PFS for PTCY with a HR for ATG of 1.31 (95%CI 1.01-1.69) (Table). There was no apparent interaction between GvHD prophylaxis and IPSS-R or HLA matching, suggesting an effect exclusive to the type of GVHD prophylaxis used.

OS

p value

PFS

p value

HR (95% CI)

HR (95% CI)

GVHD prophylaxis

PTCY

1

1

ATG

1.34 (1.02-1.76)

0.04

1.31 (1.01-1.69)

0.04

IPSS-R Cytogenetics

Good

1

1

Intermediate

1.22 (0.92-1.63)

0.17

1.27 (0.97-1.67)

0.08

Poor

1.12 (0.81-1.55)

0.5

1.09 (0.80-1.48)

0.6

Very poor

2.26 (1.73-2.95)

<0.001

2.29 (1.77-2.97)

<0.001

Donor-patient HLA matching

10/10

1

1

< 10/10

1.41 (1.13-1.77)

0.003

1,34 (1.08-1.66)

0.008

Age at this treatment

1.02 (1.01-1.03)

0.003

1.01 (1-1.02)

0.005

HMA given before HSCT

No

1

1

Yes

1.17 (0.94-1.46)

0.15

1.19 (0.97-1.47)

0.1

HCT-CI risk group

Low risk

1

1

Intermediate risk

1.13 (0.87-1.45)

0.4

1.10 (0.86-1.41)

High risk

1.30 (1.02-1.65)

0.04

1.34 (1.07-1.69)

0.2

MDS classification

Without EB

1

1

With EB

1.06 (0.85-1.32)

0.6

1.14 (0.92-1.41)

0.2

Conclusions: This study suggests that MDS patients who received transplant from UD had a better OS and PFS using PTCY compared to ATG. This confirms that PTCY instead of ATG in this setting is a valid option.

Disclosure: YC: Y.C. has received consulting fees for advisory board from MSD, Novartis, Incyte, BMS, Pfizer, Abbvie, Roche, Jazz, Gilead, Amgen, Astra-Zeneca, Servier; Travel support from MSD, Roche, Gilead, Amgen, Incyte, Abbvie, Janssen, Astra-Zeneca, Jazz, Sanofi all via the institution.

MA: speaker bureau Neovii.

All the others do not have any conflict of interest.

22: Myeloproliferative Neoplasm

O117 ASSOCIATION BETWEEN STEM CELL SOURCE, CD34 + CELL DOSE AND OUTCOMES AFTER HAPLOIDENTICAL HEMATOPOIETIC CELL TRANSPLANTATION FOR MYELOFIBROSIS: AN ANALYSIS FROM THE CMWP OF THE EMBT

Tomasz Czerw 1, Luuk Gras2, Laurien GA Baaij3, Emanuele Angelucci4, Didier Blaise5, Patrizia Chiusolo6, Mi Kwon7, Jakob Passweg8, Alessandro Busca9, Hélène Labussière-Wallet10, Patrice Ceballos11, Mohamad Mohty12, Fabio Ciceri13, Radovan Vrhovac14, Antonio Bianchessi15, Matteo Parma16, Hakan Ozdogu17, Johannes Clausen18, Linda Koster3, Joanna Drozd-Sokolowska19, Kavita Raj20, Giorgia Battipaglia21, Nicola Polverelli22,23, Juan Carlos Hernández-Boluda24, Donal P. McLornan20

1Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland, 2EBMT Statistical Unit, Leiden, Netherlands, 3EBMT Leiden Study Unit, Leiden, Netherlands, 4IRCCS Ospedale Policlinico San Martino, Genova, Italy, 5Programme de Transplantation & Therapie Cellulaire, Marseille, France, 6Universita Cattolica S. Cuore, Rome, Italy, 7Hospital Universitario Gregorio Marañon, Instituto de Investigación Sanitaria Gregorio Marañon, Madrid, Spain, 8University Hospital, Basel, Switzerland, 9S.S.C.V.D Trapianto di Cellule Staminali, Torino, Italy, 10Centre Hospitalier Lyon Sud, Lyon, France, 11CHU Lapeyronie, Montpellier, France, 12Hopital Saint Antoine, Paris, France, 13Ospedale San Raffaele s.r.l., Milano, Italy, 14University Hospital Center Rebro, Zagreb, Croatia, 15San Matteo Pavia Transplant Programme, Pavia, Italy, 16Ospedale San Gerardo, Monza, Italy, 17Baskent University Hospital, Adana, Turkey, 18Elisabethinen-Hospital, Linz, Austria, 19University Clinical Centre, Medical University of Warsaw, Warsaw, Poland, 20University College London Hospitals NHS Trust, London, United Kingdom, 21Federico II University of Naples, Naples, Italy, 22ASST Spedali Civili di Brescia, Brescia, Italy, 23Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, 24Hospital Clínico Universitario, Valencia, Spain

Background: In myelofibrosis (MF), haplo-HCT may be associated with increased risk of graft failure or delayed engraftment. We aimed to determine whether graft source and infused CD34+ cell dose impacted upon key transplantation outcomes.

Methods: Adult patients undergoing haplo-HCT between 2012-2020 for primary or post-polycythaemia/post-essential thrombocythaemia MF were selected from the EBMT registry. Both bone marrow (BM) and peripheral blood (PB) as stem cell source and post-transplantation cyclophosphamide-based GVHD prophylaxis were inclusion criteria. Blast phase disease was excluded. Main outcomes were OS, PFS with competing events of RI and NRM. We further analysed neutrophil and platelet engraftment, primary and secondary graft failure, and acute and chronic GvHD. Cox multivariable models were used to evaluate differences according to graft source and CD34+ cell dose. Confounders considered in MVA were disease stage, DIPSS score and Karnofsky performance status (KPS) of the patient at allo-HCT, donor age and year of allo-HCT.

Results:

Baseline characteristics

Total N (%)

PB N (%)

BM N (%)

Number of patients

263 (100)

163 (62)

100 (38)

Sex

Male

157 (60)

102 (63)

55 (55)

Female

106 (40)

61 (37)

45 (45)

Age at haplo-HCT in years, median (IQR)

60 (54-65)

61 (54-67)

59 (53-63)

DIPSS score, missing for 71 (27%)

Low risk (0)

7 (4)

4 (3)

3 (5)

Intermediate-1 risk (1-2)

75 (39)

50 (37)

25 (42)

Intermediate-2 risk (3-4)

79 (41)

58 (44)

21 (36)

High risk (5-6)

31 (16)

21 (16)

10 (17)

Karnofsky performance status, missing for 12 (5%)

≥90

151 (60)

94 (60)

57 (60)

<90

100 (40)

62 (40)

38 (40)

Year of haplo-HCT, median (IQR)

2018 (2016-2019)

2019 (2017-2020)

2017 (2015-2018)

Donor age in years, median (IQR), (missing for 27, 10%)

36 (28-43)

37 (29-44)

34 (25-42)

Transplanted CD34+ dose, cell number ×106/kg recipient body weight, median (IQR), missing for 98 (37%)

5.5 (3.9-7.5)

7.0 (5.5-8.7)

3.6 (2.4-5.1)

Conditioning intensity, missing for 1 (1%)

Standard

140 (53)

61 (37)

79 (80)

Reduced

122 (47)

102 (63)

20 (20)

ENGRAFTMENT

PB

BM

Transplanted CD34+ dose (×106/kg)

Transplanted CD34+ dose (×106/kg)

<7.0

≥7.0

<3.5

≥3.5

Neutrophil engraftment

Median time to recovery (IQR), days

25 (21-37)

20 (17-27)

25 (21-NR)

22 (18-36)

28-day cumulative incidence (95% CI)

65 (52-79)

83 (72-94)

57 (39-74)

64 (47-80)

Gray’s test p-value

0.009

0.50

Platelet engraftment (>20 G/l)

Median time to recovery (IQR), days

47 (30-NR)

40 (25-NR)

84 (29-NR)

41 (32-NR)

100-day cumulative incidence (95% CI)

60 (47-74)

62 (49-75)

67 (47-87)

71 (49-92)

Gray’s test p-value

0.55

0.60

A total of 263 patients were included. Baseline characteristics are summarized in Table 1. Median follow-up was 42 (IQR 26-67) months. Stem cell source was BM and PB in 100 (38%) and 163 (62%) allo-HCT, respectively. At 1 and 4 years, respectively, OS was 63% (95% CI, 58-69%) and 51% (45-58%), PFS 59% (53-65%) and 41% (34-48%), RI 10% (7-14%) and 22% (16-28%), and NRM 31% (25-36%) and 36% (30-43%). The cumulative incidence of day+100 grade II-IV acute GVHD was 27% (22-32%) and 1-year and 4-years overall/extensive chronic GVHD cumulative incidence was 27% (22-33%)/12% (8-16%) and 32% (26-38%)/15% (10-19%), respectively. Factors independently associated with an unfavorable OS were a KPS < 90 (HR 1.59, 95% CI 1.04-2.43, p = 0.03), and intermediate/high (3-6) risk DIPSS (HR 1.91 (1.21-3.04), p = 0.01). The same variables were significantly associated with worse PFS, whereas more recent allo-HCT associated with better PFS (HR per year later 0.88 (0.78-0.99), p = 0.04). Overall, regarding stem cell source, there was no significant difference in OS, PFS, RI, NRM and GVHD between PB and BM groups. We found a borderline significant interaction effect between source and the number of CD34+ cells on OS (p = 0.04) and PFS (p = 0.05) suggesting that the association of transplanted CD34+ dose and outcome was different in PB and BM (HR for each 10^6/kg increase 0.74 (0.53-1.04) in BM and HR 1.08 (0.97-1.21) in PB).Cumulative incidence of primary and 1-year secondary graft failure was 13% (9-17%) and 11% (7-15%), respectively. No significant differences were observed according to stem cell source or CD34+ dose. In patients transplanted from PB with higher CD34+ dose (above median value of 7 ×10^6 cells/kg), time to neutrophil recovery was shorter and cumulative incidence of 28-day neutrophil engraftment was higher (p = 0.009). We did not notice association between CD34+ dose and platelet recovery (Table 1).

Conclusions: In the present study, representing the largest series of MF patients undergoing haplo-HCT reported to date, no significant impact between graft source and main transplantation outcomes was observed. For those transplanted with PB-derived stem cells, a higher CD34 cell dose associated with earlier neutrophil recovery.

Clinical Trial Registry: Not applicable.

Disclosure: Nothing to declare.

22: Myeloproliferative Neoplasm

O118 MUTATION CLEARANCE AFTER AND DISEASE BURDEN BEFORE TRANSPLANTATION PREDICT RELAPSE IN PATIENTS WITH MYELOFIBROSIS

Nico Gagelmann 1, Anita Badbaran1, Christine Wolschke1, Evgeny Klyuchnikov1, Silke Heidenreich1, Kristin Rathje1, Johanna Richter1, Radwan Massoud1, Christian Niederwieser1, Boris Fehse1, Francis Ayuk1, Nicolaus Kröger1

1University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Background: Allogeneic hematopoietic cell transplantation is the only potentially curative treatment for patients with myelofibrosis. However, relapse remains a major treatment failure, occurring in 10-30%. Prediction of relapse is an unmet clinical need. We herein report the first comprehensive study aiming to dissect driver mutation clearance after transplantation and to dynamically determine whether the persistence of these driver mutations can predict relapse.

Methods: We used quantitative PCR technology to detect each of the driver mutations JAK2, CALR, and MPL (with a high sensitivity of 0.01%). Patient samples for molecular analysis were prospectively collected from peripheral blood at 5 different timepoints over a total period of 15 years: at start of conditioning prior to stem cell infusion, day 30, day 100, day 180, and 1 year after transplantation. We used a homogenous transplantation platform using reduced intensity conditioning with busulfan and fludarabine and ATG for graft-versus-host disease prophylaxis. We used baysian maximization-expectation algorithms for time-dependent analysis of prediction of relapse.

Results: A total of 312 patients receiving first reduced intensity conditioning transplantation were included. Distribution of driver mutation genotype at time of transplantation was as follows: 67% with JAK2, 19% with CALR, 4% with MPL. Median follow-up was 6 years.

Despite significantly higher mutation burden at time of transplantation (median of 20% for JAK2, 44% for CALR, and 60% for MPL; P < 0.001), CALR and MPL showed earlier mutation clearance after transplantation compared with JAK2. Mutation clearance was achieved at day 30 and 100 after transplantation in 46% and 66% with JAK2, 67% and 75% for CALR, and 30% and 100% for MPL (P = 0.02). At day 100, 66% of JAK2, 75% of CALR, and 100% of MPL showed complete mutation clearance.

Mutation clearance at day 30 after transplantation was predictive of post-transplantation relapse at 1 year (P = .0.009), showing cumulative incidence of relapse of 6% versus 16%. Mutation clearance at day 30 and 100 after transplantation explained 80% and 90% of variance of later timepoints, suggesting early clearance as best predictor of relapse post-transplantation. Moreover, day 30 complete mutation clearance predicted disease-free survival in JAK2, showing rates of 60% for negative versus 47% in JAK2-positive patients (P = 0.05). Importantly, achievement of mutation clearance at day 30 after transplantation could also distinguish different risk groups in patients with onset better prognosis harboring CALR/MPL mutations. The 6-year disease-free survival was 76% for patients with mutation clearance versus 59% for CALR/MPL-positive patients (P = 0.02).

Last, dynamic bayesian modelling showed independent effects of post-transplant mutation clearance at day 30 (irrespective of driver mutation), in addition to presence of TP53, ASXL1, and increased blast counts at time of transplantation on relapse at 1 year.

Conclusions: This is the first study to show that CALR and MPL are associated with earlier mutation clearance after transplantation compared with JAK2. Furthermore, mutation clearance at day 30 together with high-risk features at time of transplantation is the best predictor of relapse, facilitating patient selection for prophylactic studies. In sum, molecular monitoring is essential for prediction and timely treatment of relapsed myelofibrosis.

Disclosure: None.

22: Myeloproliferative Neoplasm

O119 SPLENIC IRRADIATION PRIOR TO HEMATOPOIETIC CELL TRANSPLANTATION REDUCES RISK OF RELAPSE IN MYELOFIBROSIS

Nico Gagelmann 1, Gabriela Hobbs2, Edoardo Campodonico3, Grzegorz Helbig4, Polona Novak5, Thomas Schroeder6, Christina Rautenberg6, Hans Christian Reinhardt6, Michael Heuser7, Victoria Panagiota7, Carmelo Gurnari8, Jaroslaw Maciejewski8, Fabio Ciceri3, Kristin Rathje1, Marie Robin9, Simona Pagliuca10, Vanderson Rocha11, Vaneuza Funke12, Nelson Hamershlak13, Rachel Salit14, Bart Scott14, Fernando Duarte15, Tomasz Czerw16, Raffaella Greco17, Nicolaus Kröger1

1University Medical Center Hamburg-Eppendorf, Hamburg, Germany, 2Massachusetts General Hospital, Harvard Medical School, Boston, United States, 3San Raffaele, Milano, Italy, 4School of Medicine in Katowice, Katowice, Poland, 5University Medical Center, Ljubljana, Slovenia, 6University Hospital of Essen, Essen, Germany, 7Medical School Hannover, Hannover, Germany, 8Cleveland Clinic, Cleveland, United States, 9Hopital St Louis, Paris, France, 10CHU Nancy, Nancy, France, 11Hospital de Clinicas, Hematology, Transfusion and Cell Therapy Service, University of São Paulo, Sao Paulo, Brazil, 12Blood and Marrow Transplantation Programme, Hospital de Clínicas, Federal University of Parana, Curitiba, Brazil, 13Israelita Albert Einstein Hospital, Sao Paolo, Sao Paolo, Brazil, 14Fred Hutchinson Cancer Research Center, Seattle, United States, 15Hospital Universitario Walter Cantídio, Universidade Federal do Ceara, Fortaleza, Brazil, 16Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland, 17Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Hospital, Milano, Italy

Background: Splenomegaly is the clinical hallmark of myelofibrosis. Splenomegaly at time of allogeneic hematopoietic cell transplantation (HCT) is associated with graft failure and poor graft function. Strategies to reduce spleen size before HCT especially after failure to JAK inhibition represent unmet clinical needs in the field. Here, we leveraged a global collaboration to investigate the safety and efficacy of splenic irradiation as part of the HCT platform for patients with myelofibrosis.

Methods: We retrospectively collected data from patients with primary or secondary myelofibrosis, receiving splenic irradiation as part of the HCT algorithm. Radiation therapy had to be given within 3 months prior to or be part of conditioning therapy for HCT. Detailed information on irradiation was collected in addition to usual patient-, disease-, and transplant-related variables. Primary outcomes were spleen size reduction and safety after irradiation. Other outcomes were days until neutrophil engraftment, days until platelet engraftment, relapse incidence, non-relapse mortality, and overall survival.

To minimize selection bias and enable a more representative comparison in terms of outcomes after irradiation, a matched-pair analysis of patients with splenomegaly who received irradiation vs no therapy (immediate HCT) vs splenectomy was designed. Patients were matched according to transplant-specific risk (MTSS), using a greedy caliper algorithm.

Results: We included 59 patients, receiving irradiation within a median of 2 weeks (range, 0.9-12 weeks) before HCT. Overall, median spleen size prior to irradiation was 23 cm (range, 14-35). Splenic irradiation resulted in significant and rapid spleen size reduction in 97% of patients (57/59), with a median decrease of 5.0 cm (95% confidence interval, 4.1-6.3cm). Most frequent adverse event was thrombocytopenia, with no correlation between irradiation dose and hematological toxicities. The 3-year overall survival was 62% (95% CI, 48-76%) and 1-year non-relapse mortality was 26% (95% CI, 14-38%).

A multivariable model on overall survival showed independent effects for worse survival of severe anemia (hazard ratio, 3.73; 95% CI, 1.08-12.88; P = 0.04), severe thrombocytopenia (hazard ratio, 2.58; 95% CI, 1.00-6.78; P = 0.05), higher MTSS score (hazard ratio, 1.61; 95% CI, 1.00-2.66; P = 0.05), higher intensity conditioning (hazard ratio, 3.52; 95% CI, 1.34-9.23; P = 0.01), and PVT (hazard ratio, 1.44; 95% CI, 1.57-11.45; P = 0.004). In this model, increased spleen size prior to irradiation was not significantly associated with increased risk of death (continuous hazard ratio, 1.06; 95% CI, 0.97-1.16; P = 0.22).

When using a propensity score matching adjusted for common confounders, splenic irradiation was associated with significantly reduced relapse incidence (P = 0.01), showing 3-year incidence of 13% (95% CI, 3-22%) for irradiated vs 29% (95% CI, 18-41%) for patients with immediate HCT vs 38% (95% CI, 25-50%) for patients receiving splenectomy. 3-year overall survival was similar (P = 0.86), showing rates of 61%, 63%, and 62%, respectively; and there was also no significant difference in non-relapse mortality (P = 0.38).

Conclusions: This first international and multicenter study on splenic irradiation followed by HCT suggest splenic irradiation as a reasonable approach in patients with splenomegaly and JAK inhibition failure. Irradiation may be preferred over splenectomy, as it was associated with significantly reduced relapse after HCT, pointing towards actual disease modification capacity.

Disclosure: None.

22: Myeloproliferative Neoplasm

O120 IMPACT OF ATG/ATLG ON OUTCOMES AFTER HEMATOPOIETIC CELL TRANSPLANTATION FOR PATIENTS WITH MYELOFIBROSIS: A PROPENSITY SCORE MATCHED ANALYSIS

Kristin Rathje 1, Nico Gagelmann1, Rachel B. Salit2, Thomas Schroeder3, Carmelo Gurnari4,5, Simona Pagliuca6, Victoria Panagiota7, Christina Rautenberg3, Bruno Cassinat8, Felicitas Thol7, Christine Wolschke1, Marie Robin8, Michael Heuser7, Marie-Thérèse Rubio6, Jaroslaw P. Maciejewski5, Hans Christian Reinhardt3, Bart L. Scott2, Nicolaus Kroeger1

1University Medical Center Hamburg-Eppendorf, Hamburg, Germany, 2Fred Hutchinson Cancer Research Center, Seattle, United States, 3University Hospital Essen, Essen, Germany, 4University of Rome Tor Vergata, Rome, Italy, 5Taussig Cancer Institute, Cleveland, United States, 6Centre Hospitalier Régional Universitaire, Nancy, France, 7Hannover Medical School, Hannover, Germany, 8Hopital Saint-Louis, Paris, France

Background: Despite recent improvements in the field of JAK inhibitors and novel agents with alternative targets, allogeneic hematopoietic stem cell transplantation (alloHCT) to date remains the only potentially curative treatment for patients with myelofibrosis. However, alloHCT is associated with a non-negligible treatment-related morbidity and mortality. Acute and chronic graft-versus-host disease (GvHD) are two major complications for patients undergoing an alloHCT and they appear to occur more frequently in patients with myeloproliferative neoplasms than in patients with other hematological malignancies. In vivo T-cell depletion with antithymocyte/antilymphocyte globulin (ATG/ATLG, short ATG) as part of the conditioning regimen prior to alloHCT is widely used as an addition to the standard GvHD prophylaxis, but data on its role in the setting of myelofibrosis is scarce. The aim of this study was to evaluate the impact of ATG on clinical outcomes of myelofibrosis patients undergoing first alloHCT in controlled fashion using a large international cohort.

Methods: We leveraged a multicenter collaborative network of European and US academic transplant centers to accrue myelofibrosis patients who underwent first alloHCT. The primary endpoint was GvHD-free and relapse-free survival (GRFS). A Dependent Dirichlet Process model for censored data was developed, which can adjust for potential violations of the ubiquitous proportional hazards assumption. In addition, we used a propensity score matching to minimize selection bias.

Results: Overall, we identified 805 patients, of whom 526 received ATG-based GvHD prophylaxis, while 279 received non-ATG-based GvHD prophylaxis. Propensity score matching achieved 150 patient pairs of well-balanced patient- and transplant-characteristics. The median follow-up was 6.5 years for the ATG group and 7 years for the non-ATG group (P = 0.10).

In terms of the primary endpoint of GRFS, ATG independently resulted in significantly reduced risk for GvHD, relapse or death (HR 0.90, 95% CI, 0.82-0.98; P = 0.03). The corresponding 5-year estimates for GRFS were 47% (95% CI, 43-51%) vs. 44% (95% CI, 38-50%; P = 0.007), respectively.

The cumulative incidence of acute GvHD grade II-IV was 35% (95% CI, 31-39%) for the ATG group vs. 58% (95% CI, 52-64%) for the non-ATG group (P < 0.001). No difference in incidence of chronic GvHD was observed, showing 53% (95% CI, 49-57%) for the ATG group vs. 52% (95% CI, 47-57%) for the non-ATG group (P = 0.52).

The 5-year cumulative incidence of relapse was 14% (95% CI, 10-18%) vs. 13% (95% CI, 8-18%; P = 0.62) and the 5-year cumulative incidence of death without relapse for both groups was 28%, respectively (P = 0.59). Remarkably, 5-year OS was similar, being 63% (95% CI, 59-67%) for the ATG group vs. 62% (95% CI, 58-68%) for the non-ATG group (P = 0.56).

Multivariable modelling for GRFS (adjusting for donor type, performance status, conditioning intensity, and DIPSS categories) showed an independent significant reduction in risk for GvHD, relapse, or death in the ATG group (HR = 0.85, 95% CI 0.79-0.91; P = 0.007).

Conclusions: In conclusion, the use of ATG as GvHD prophylaxis in patients with myelofibrosis undergoing first alloHCT resulted in significantly reduced GRFS.

Disclosure: Nothing to declare.

7: New Drugs and Cell-based Immune Therapies

O121 TRIPLEX VACCINE TO INDUCE PROTECTIVE AND DURABLE CYTOMEGALOVIRUS-SPECIFIC CELLULAR IMMUNITY IN PEDIATRIC HEMATOPOIETIC STEM CELL TRANSPLANT PATIENTS AT RISK FOR CYTOMEGALOVIRUS COMPLICATIONS

Anna Pawlowska 1, Corinna La Rosa1, Yoonsuh Park1, Dongyun Yang1, Qiao Zhou1, Teodora Kaltcheva1, Nicole Karras1, Jerry Cheng2, Weili Sun3, Don J. Diamond1

1City of Hope National Medical Center, CA, Duarte, United States, 2Southern California Permanente Medical Group, Los Angeles, United States, 3The Janssen Pharmaceutical Companies of Johnson & Johnson, Los Angeles, United States

Background: Cytomegalovirus (CMV) reactivation continues to cause substantial morbidity following allogeneic hematopoietic cell transplantation (HCT), in pediatric CMV seropositive recipients. There is an unmet need for an alternative and safer approach than antivirals for controlling CMV reactivation post-transplant. Triplex is a modified vaccinia Ankara (MVA) vectored vaccine which expresses 3 immunodominant CMV antigens; pp65, IE1-exon4, and IE2-exon5. It demonstrated tolerability and immunogenicity in healthy adults, autologous and allogeneic HCT recipients, in whom it reduced CMV viremia. Hence, we investigated this immune therapeutic strategy in pediatric HCT recipients undergoing letermovir prophylaxis. We aimed to expand and maintain protective antiviral cellular immunity after letermovir discontinuation, when toxic antivirals are frequently required to control CMV reactivation.

Methods: We designed a non-randomized, open label, phase 1b pilot trial to evaluate safety, optimal dose, and immunogenicity of Triplex vaccine in CMV seropositive pediatric allogeneic HCT recipients. This study was conducted at City of Hope. Fifteen pediatric HCT recipients were consented to be enrolled in the study. Triplex injections were administered to nine eligible recipients (age 3-21 years) with diagnosis of acute leukemia (n = 7) and severe aplastic anemia (n = 2), on days 28 and 56 post-transplant. Two Triplex vaccine dose levels (DL1 = 108 PFU and DL2 = 5 x 108 PFU) were evaluated in two age groups (11-21 and 1-10 years old). Longitudinal immune monitoring was performed by measuring CD137 surrogate marker of T cell activation and CD28/CD45RA memory phenotype markers.

Results: Both Triplex DLs were well tolerated and no adverse events grade ≥ 2 possibly or probably related to the vaccine were recorded. We found high levels of functional CMV-specific T cells following Triplex vaccination, which had similar kinetics and often surpassed those observed in healthy adults and HCT recipients. The elevated responses may have restored protective cellular immunity post-HCT in the Triplex vaccinated pediatric recipients, who did not receive antivirals to control CMV reactivation. A possible explanation of the vigorous response to Triplex in pediatric recipients may be linked to the effective activity of the thymus, which is highly functional in children. Functionally activated pp65, IE1, IE2-specific T-cells expanded post-transplant during immune-reconstitution. Levels of pp65-specificCD8 T-cells significantly increased (p = 0.013) and showed a memory phenotype mainly consisting of antigen-experienced central memory T cells (TCM), early post-HCT. The TCM subset decreased following the first Triplex injection (p = 0.043) acquiring enhanced effector functions (p = 0.026), through study end. Strong predominance of long-lived and functional effector T-cells has been reported during primary CMV infection in healthy individuals, since these cells are critical for viremia control.

Conclusions: These encouraging preliminary results suggest that in allogeneic HCT pediatric patients receiving letermovir, as well as in three patients receiving post-transplant cyclophosphamide for graft-vs-host disease prophylaxis, Triplex safely expands large numbers of long lasting functional CMV-specific T cells, which may prevent subsequent CMV reactivation requiring antivirals. Triplex vaccination can overcome the letermovir-induced immune impairment. Novel successful strategies of vaccinating the immunocompetent HCT donor and the recipient with Triplex may suffice to prevent CMV reactivation by promoting early post-HCT sustained, protective CMV-immune reconstitution.

Clinical Trial Registry: ClinicalTrials.gov identifier: NCT 03354728

Disclosure: Corinna La Rosa reports receiving consulting fees and research funding from Helocyte Inc.. Don Diamond reports receiving fees for royalties, research funding, and fees for serving on the advisory board of Helocyte Inc.. Don. Diamond, Corinna La Rosa, Yoonsuh Park, Dongyun Yang, Qiao. Zhou, Teodora Kaltcheva are supported by grants from the National Cancer Institute (NCI) 5R01 CA077544; NCI P30 CA033572; P50 SPORE CA107399; 1R01 CA18045; NCI-SAIC-Frederick 28XS061; 1R01 CA266783.

MVA was provided under a Material Transfer Agreement to City of Hope national medical Center from the National Institute of Allergy and Infectious Diseases, Laboratory of Viral Diseases (Dr. Bernard Moss, Director). The following reagents were obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: HCMV pp65 Peptide Pool

8: Non-haematopoietic Stem Cells and Regenerative Medicine

O122 RECIRCULATING REGULATORY T CELLS MEDIATE THYMIC REGENERATION

Andri Leo Lemarquis1,2, Kimon Argyropoulos1, Anastasia Kousa 1, Lorenz Jahn1, Brianna Gipson1, Jarrod Dudakov3, Susan DeWolf1, Marcel van den Brink1

1Memorial Sloan Kettering Cancer Center, New York, United States, 2Göthenburg University, Göteborg, Sweden, 3Fred Hutchinson Cancer Center, Seattle, United States

Background: T cell reconstitution correlates with outcomes in patients undergoing stem cell transplantation. A functional thymus is needed for the maturation of T cells, but unfortunately, the thymus is sensitive to acute injury, such as cytoreductive conditioning given to patients. To enhance T cell reconstitution, therapies that can boost thymic regeneration and T cell output are needed. Regulatory T cells (Tregs) are known to mediate tissue regeneration in a variety of tissues, but their role in thymic injury is not known.

Methods: We used flow cytometry and immunohistochemistry to evaluate Treg kinetics in the thymus following therapy-induced thymic injury and regeneration in mice receiving sublethal total body irradiation, cyclophosphamide, dexamethazone, MCMV, LCMV and LPS. We used RAG2GFP mice to evaluate de novo production of Tregs, and a parabiotic model of RAG2GFP mice to evaluate active T cell recirculation into the injured thymus. To deplete Tregs we used a FOXP3DTR model and adoptive transfer of Tregs sorted from FOXP3RFP mice. We performed single cell RNA sequencing of CD45 + RAG2- cells in 2- and 18-month-old RAG2GFP mice before and on days 1, 4 and 7 after sublethal irradiation. We applied machine learning preprocessing methods and a highly selective recirculating Treg gene regulatory network to identify conserved pathways in human thymic CD4 T cells and Tregs. To evaluate the role of a transcriptionally upregulated factor, we used a FOXP3Cre-Aregflox mouse model.

Results: A significant increase in regulatory T cells (Tregs) was observed during thymic injury. On immunohistochemistry, Tregs were found to be increased in both medullary and cortical areas of the thymus after injury. Targeted ablation of Tregs using the FOXP3DTR mouse model at the onset of injury resulted in a significant delay in thymic regeneration, indicating a positive role for Tregs in thymic regeneration. The use of RAG2GFP mice revealed that the expansion of Tregs after SL-TBI was mainly due to RAG2-GFP- Tregs, which were identified as recirculating through a parabiotic model. Using adoptive transfer of Tregs of these recirculating Tregs furthermore improved regeneration. Single-cell sequencing revealed two distinct gene regulatory networks specific to recirculating thymic Tregs, with one program being enriched for regenerative factors such as Amphiregulin (Areg). Amphiregulin was found to be increased in thymic lysates after injury and the expression of its receptors EGFR and HER2B was found to be increased in thymic epithelial cells after injury. Selective ablation of amphiregulin in Tregs using FOXP3Cre-Aregflox mice significantly impaired regeneration, indicating its selective importance in the regenerative capacity of Tregs. Mapping gene orthologs to human thymic samples identified an analogous population of human recirculating thymic Tregs which expressed CD39 and TIGIT and were positive for Amphiregulin after stimulation. Furthermore, human thymic epithelial cells cultured with recombinant Amphiregulin had enhanced growth and signalling through ERK1/2 in a dose dependent manner.

Conclusions: In summary, we identified a novel recirculating thymic Treg population mediating regeneration in an Areg-dependent manner and a putatively analogous human thymic Treg subset expressing CD39 and TIGIT. This reveals new therapeutic targets for improving thymic regeneration after cytoreductive therapy and stem cell transplantation.

The 50th Annual Meeting of the European Society for Blood and Marrow Transplantation: Physicians - Oral Session (O009-O154) (11)

Disclosure: This study was funded by DKMS and NIH grants.

14: Non-infectious Early Complications

O123 DARATUMUMAB FOR PURE RED CELL APLASIA AFTER HEMATOPOIETIC CELL TRANSPLANTATION: A STUDY FROM THE TRANSPLANT COMPLICATIONS WORKING PARTY OF EBMT

Nico Gagelmann 1, Moniek De Witte2, Christophe Peczynski3, William Boreland3, Abboek Broers4, Edgar Jost5, Alexander Kulagin6, Albert Esquirol7, Simona Sica8, Jürgen Kuball2, Jennifer Byrne9, Wolfgang Bethge10, Johan Maertens11, Friedrich Stölzel12, Edouard Forcade13, Matthew Collin14, Matteo Parma15, Goda Choi16, Nicolaus Kröger1, Paolo Corradini17, Maria Chiara Finazzi18, Lucia Corral19, Sara Villar20, Alberto Mussetti21, Adrian Bloor22, Marco Ladetto23, Hélène Schoemans11, Olaf Penack24, Ivan Moiseev6, Zinaida Peric25

1University Medical Center Hamburg-Eppendorf, Hamburg, Germany, 2University of Utrecht, Utrecht, Netherlands, 3EBMT Paris Study Unit, INSERM UMR-S 938, Sorbonne University, Paris, France, 4Erasmus MC Cancer Institute, Rotterdam, Netherlands, 5University of Aachen, Aachen, Germany, 6RM Gorbacheva Research Institute, Pavlov University, St Petersburg, Russian Federation, 7Hospital Santa Creu i Sant Pau, Barcelon, Spain, 8Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy, 9Nottingham City Hospital, Nottingham, United Kingdom, 10Universitaet Tuebingen, Tübingen, Germany, 11University Hospital Gasthuisberg, Leuven, Belgium, 12University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany, 13CHU Bordeaux, Bordeaux, France, 14RVI Newcastle, Newcastle, United Kingdom, 15Ospedale San Gerardo, Monza, Italy, 16University Medical Center Groningen, Groningen, Netherlands, 17University of Milano, Milano, Italy, 18UOC Ematologia, ASST Papa Giovanni XXIII, Bergamo, Italy, 19Hospital Clínico, Salamanca, Spain, 20Clínica Universidad de Navarra, Navarra, Spain, 21Institut Catalá d’Oncologia, Hospital Duran i Reynals, Barcelona, Spain, 22Christie Hospital Manchester, Manchester, United Kingdom, 23H SS. Antonio e Biagio, Alessandria, Italy, 24Charité-CVK, University Medicine Berlin, Berlin, Germany, 25University Hospital Centre Rijeka and School of Medicine, University of Rijeka, Rijeka, Croatia

Background: Pure red cell aplasia (PRCA) is a relevant complication after ABO-mismatched allogeneic hematopoietic cell transplantation (HCT), possibly associated with other life-threatening complications such as graft rejection as well as with significant reduction of quality of life by prolonged red blood cell (RBC) transfusion dependency. No standard treatment exists, and practice is heterogenous. Recent case reports have shown impressive results with the anti-CD38 monoclonal antibody daratumumab for post-transplant PRCA in patients with complete donor chimerism.

Here we took advantage of the first and large international collaboration to describe characteristics and outcomes of patients receiving daratumumab for PRCA after HCT.

Methods: This is a retrospective study of patients who received daratumumab for PRCA after first allogeneic HCT. After identifying potential patients, centers were asked to fill in detailed data about patient-, disease-, and treatment-specific variables as well as outcome features. Primary endpoint was transfusion-independence after daratumumab (defined as 12 consecutive weeks without need for transfusions). Secondary endpoints were improvement of hemoglobin and reticulocytes, and overall survival (OS). Starting point of the analysis was the date of first infusion of daratumumab.

Results: We identified 45 patients receiving daratumumab for PRCA after first allogeneic HCT. Median patient age at allogeneic HCT was 56 years (interquartile range [IQR], 45-65), and the median donor age was 33 years (IQR, 25-39). Most patients (78%) and donors (84%) were male. Most frequent patient blood group was O (87%), and the most frequent donor blood group was A (61%).

Twenty patients (44%) were transplanted for acute leukemia and 12 (27%) for myelodysplastic/myeloproliferative neoplasms. Predominant donor platforms were matched unrelated (53%), identical sibling (18%), and 9/10 mismatched unrelated (16%). Pre-HCT conditioning was myeloablative in 58% and reduced intensity in 42%, with busulfan-fludarabine being the most frequent regimen used.

The median time from HCT to PRCA was 55 days (IQR, 36-116) and all patients were transfusion-dependent at time of daratumumab start. Daratumumab was first-line treatment in 16 patients (36%), whereas the remaining 29 patients received other treatments before daratumumab, predominantly rituximab (26 patients, 90%). Other treatments included steroids and cyclosporine A, among others. Median time from PRCA diagnosis and daratumumab start was 88 days (IQR, 59-219) and most patients (67%) received daratumumab intravenously. Median of total duration of daratumumab therapy was 21 days (IQR, 10-39) and daratumumab was given over a median of 4 infusions (range, 1-8).

Median follow-up was 17 months. Incidence of transfusion independence defined as 12 weeks without transfusions was 68.5% (95% confidence interval [CI], 51.9-80.4%) at 6 months and 79.5% (95% CI, 62.2-89.6%) at 12 months. Incidences of hemoglobin and reticulocyte recoveries were respectively 56.4% and 77.8% at 6 months and 64.6% and 83.3% at 12 months. OS at 12 months was 81.2% (95% CI, 70.2-94.0%), and of 8 deaths, 7 were GVHD- or infection-related. One death was associated with hemolytic anemia.

Conclusions: This is the first and largest study on the use of daratumumab for PRCA after allogeneic HCT, showing safety and high response rates superior to that reported for other treatments.

Disclosure: None.

14: Non-infectious Early Complications

O124 EARLY POST-TRANSPLANTATION HEMOPHAGOCYTOSIS (PTHPS) IS ASSOCIATED WITH HIGH MORTALITY AFTER HAPLOIDENTICAL HCT: DECIPHERING THE RISK FACTORS AND PATHOGENESIS

Sarita Rani Jaiswal 1,2,3, Mahak Agarwal1, Aakash rajendra Gupta1, Subhrajit Biswas2, Suparno Chakrabarti3,1,2

1Dharamshila Narayana SS Hospital, New Delhi, India, 2Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Noida, India, 3Cellular Therapy and Immunology, Manashi Chakrabarti Foundation, New Delhi, India

Background: Early PTHPS (<45 days post-HCT) also known as Macrophage-Activation Syndrome, is one of the dreaded complications encountered following haploidentical HCT (Haplo-HCT), the genesis of which is poorly understood and defined by our group earlier (doi: 10.1007/s12185-015-1905-y). We studied the incidence and risk factors of PTHPS in 231 patients receiving PTCy based GVHD prophylaxis following haploidentical graft, before and after introduction of abatacept as a novel approach, along with a better understanding of the pathogenesis.

Methods: The study cohort included patients with hematological disorders (non-malignant diseases (NMD) = 60 malignant diseases (MD) = 171, who received mostly myeloablative conditioning for MD and hemoglobinopathies and non-myeloablative conditioning in SAA. The GVHD prophylaxis consisted of PTCy(Day3&Day4) with MMF/CNI in non-Abata group (n = 45) and in the Abata-group (n = 186) with low dose CNI/Sirolimus along with Abatacept on day 0 and abatacept-primed DLI on days+7, +21 and +35 for MD. Those with NMD received abatacept in the same but extended schedule without DLI, to 6 months on a monthly dosage. CMV, EBV and Adeno copies were monitored weekly from day 0 until day 100. We compared the overall outcomes in non-Abata and Abata-groups and analysed the risk factors associated with PTHPS to improve the outcomes. We also studied the early reconstitution of Tregs and NK cells and its impact on PTHPS.

Results: The median age of the cohort was 19.0years and the median follow-up was 5 years(1-11). Both groups were comparable in terms of patient and donor characteristics. 12 patients experienced PTHPS with a cumulative incidence of 5.1%. On further categorization, overall incidence of PTHPS was 13.4% in non-Abata group (6/45) and 3.2% (6/186) in Abata-group (p = 0.01). The median time to develop PTHPS was 30 days (12-45 days). The overall incidence of NRM was 11.3%, however, the PTHPS-related mortality was 67%(8/12) (p = 0.001), and most importantly, it was 83.4% in non-Abata group (5/6) vs 50% (3/6) in the Abata group. Primary graft failure was seen in 2% of patients with PTHPS accounting for the majority.

Univariate analysis showed an increased incidence of PTHPS in patients with NMD. This was more pronounced in non-Abata compared to Abata group (HR, 4.2; 95% CI, 1.3 to 13.2; P = .001]. Younger age was a risk factor (<10years was 11.8 ± 4.2 compared to 3 ± 1.3% in > 10 years(HR, 3.9; 95% CI 1.3- 12.5, p = 0.0001). Higher CD34+ [HR, 1.2; 95% CI, 1.1 – 1.4; P = 0.006) and CD3+ cells [HR, 1.02; 95% CI, 1.0 - 1.1; p = 0.0001) in the grafts were contributing factors as well. Poor reconstitution of Tregs and mature NK cells correlated with PTHPS and was higher in Abata group. Multivariate analysis confirmed the introduction of Abatacept as one of the protective interventions against PTHPS [Table-1].

Table 1. Risk factors for PTHPS

Risk factors

Comparison

Hazard ratio

p-value

Non-malignant disorders

Non-Abata Vs Abata

4.2[1.3-13.2]

0.001

Age

<10 years Vs >10 years 11.8 ± 4.2 Vs 3.0 ± 1.3

3.9[1.3-12.5]

0.0001

CD34+ cells X106/kg in graft

9.4 ± 1.9 Vs 7.2 ± 2.6

1.2[1.1-1.4]

0.006

CD3+cells X107/kg in graft

45.4 ± 34 Vs 26.3 ± 21

1.02[1.0-1.1]

0.0001

matureNK cells/ml on D + 30 reconstitution

125 ± 105 Vs 20.5 ± 12.7

1.5[1.02-1.3]

0.01

Tregs% on D + 30 Reconstitution

8.3 ± 6.2 Vs 2.3 ± 1.2

1.04[1.0-1.2]

0.0001

Conclusions: Early PTHPS is associated with high mortality and tends to have a greater propensity in younger patients with NMD receiving a bigger graft. Abatacept seemed to reduce the incidence and severity of PTHPS, probably contributed by improving early recovery of Tregs and mature NK cells.

Clinical Trial Registry: Not applicable

Disclosure: Nothing to disclose

14: Non-infectious Early Complications

O125 SALVAGE HAPLOIDENTICAL TRANSPLANTATION FROM A DIFFERENT HAPLOIDENTICAL DONOR USING FLU/CY REGIMEN FOR GRAFT FAILURE AFTER FIRST HAPLOIDENTICAL ALLOGENEIC STEM CELL TRANSPLANTATION: AN UPDATED FOLLOW-UP

Rui Ma1, Xiao-Hui Zhang1, Yu Wang1, Lan-Ping Xu1, Ying-Jun Chang1, Kai-Yan Liu1, Xiao-Jun Huang1, Yu-Qian Sun 1

1Peking University People’s Hospital, Peking University Institute of hematology, National clinical research center for treatment of hematological disease, Beijing, China

Background: Graft failure is a rare but fatal complication after haploidentical stem cell transplantation. Second transplantation was almost the only salvage for graft failure. However, there is no recommended regimen, and the prognosis of second transplantation in previous reports is usually poor. We recently developed a novel method: salvage haploidentical transplantation from a different donor after conditioning with fludarabine 30mg/m2 from -6 to -2 and cyclophosphamide 1g/m2 from -5 to -4. The result in the previously reported 13 patients was very encouraging (Front Med (Lausanne), 2021, 8: 604085.). Herein, we reported our updated experience in patients who experience GF after haplo-SCT.

Methods: Patients who met the following criteria will receive second transplantation using novel regimen: (1) diagnosis of acute leukemia, myelodysplastic syndromes, or lymphoma; (2) graft failure after the first haploidentical allogeneic stem cell transplantation. Patients will be excluded if with any of the following criteria: (1) uncontrolled active infection; (2) uncontrolled active GVHD; (3) significant organ dysfunction: serum total bilirubin≥2ULN or serum creatine ≥1.5 upper limit of normal (ULN), or ejection fraction<50%, or symptomatic heart failure; (4) poor performance (ECOG > 2); (5) expected life <28 days. The conditioning regimen for second transplantation consisted of : fludarabine (30 mg/m2/day, injected i.v.) from day -6 to day -2; cyclophosphamide (1000 mg/m2/day, injected i.v.) on days -5 and -4. A different HID was selected for the second transplantation; If there is no different donor available, a similar donor was used. Graft-versus-host disease (GVHD) prevention consisted of basixilimab 20 mg on days -1 and + 4, plus cyclosporine A (trough concentration 150-250 ng/ml), and mycophenolate mofetil. To further decrease aGVHD, a third dose of basixilimab on day +15 was prescribed for the latter 17 patients.

Results: A total of 30 patients were analyzed (13 patients have been reported before). The median time of second transplantation was 96.5(33-215) days after first transplantation. Among the 30 patients, 28 patients received transplantation from a different haploidentical donor and only 2 used the same haploidentical donor since there is no other donor available. Among the 30 patients, 1 died before engraftment at 19 days after second transplantation. For the 29 evaluable patients, neutrophil engraftments were achieved in all patients at a median of 11 (8-24) days, while platelet engraftment achieved in 22 patients at a median of 17.5 (9-140) days after the second transplant. The 1-year OS and DFS was 60% and 53.3%, respectively. The 1-year CIR and TRM was 6.7% and 33.3% respectively. Compared with historical group (n = 34), the neutrophil engraftment (100% versus 58.5%, p < 0.001), platelet engraftment (75.8% versus 32.3%, p < 0.001) was significantly better in novel regimen group. And the 1-year OS was significant improved in novel regimen group (60.0% versus 26.4%, p = 0.011).

Conclusions: In conclusion, salvage haploidentical transplantation from a different donor using Flu/Cy regimen represent a promising option to rescue patients with graft failure after first haploidentical stem cell transplantation.

Disclosure: none

14: Non-infectious Early Complications

O126 OUTCOMES OF DEFIBROTIDE-TREATED PATIENTS WITH VENO-OCCLUSIVE DISEASE/SINUSOIDAL OBSTRUCTION (VOD/SOS) FOLLOWING POST-TRANSPLANT CYCLOPHOSPHAMIDE (PT-CY): RESULTS FROM THE DEFIFRANCE REGISTRY

Mohamad Mohty 1, Régis Peffault de Latour2, Virginie Gandemer3, Cécile Renard4, Charlotte Jubert5, Deborah Gutierrez6, Nalina Dronamraju7, Vian Amber8, Didier Blaise9

1Hôpital St Antoine, Université Sorbonne, INSERM UMRs 938, Paris, France, 2Hôpital Saint-Louis, Université Paris Cité, Paris, France, 3University Hospital of Rennes, Rennes, France, 4The Pediatric Hematology and Oncology Institute, Hospices Civils de Lyon, Université Lyon 1, Lyon, France, 5CHU Bordeaux, Bordeaux, France, 6Jazz Pharmaceuticals, Lyon, France, 7Jazz Pharmaceuticals, Philadelphia, United States, 8Jazz Pharmaceuticals, Oxford, United Kingdom, 9Institut Paoli-Calmettes, Aix Marseille Université, Management Sport Cancer Laboratoire, Marseille, France

Background: VOD/SOS is a potentially fatal complication of haematopoietic cell transplantation (HCT). Treatment with PT-Cy is becoming more common for patients at risk of graft-versus-host disease, especially following haploidentical HCT, although little is known about the relationship of PT-Cy treatment and subsequent VOD/SOS incidence or severity. Defibrotide is approved for the treatment of severe hepatic VOD/SOS post-HCT in patients aged >1 month in the EU and VOD/SOS with renal or pulmonary dysfunction post-HCT in the US. The DEFIFrance registry collected real-world data of defibrotide use. This post hoc analysis presents the outcomes of patients treated with defibrotide for VOD/SOS after allogeneic-HCT with or without PT-Cy.

Methods: DEFIFrance collected retrospective and prospective data on defibrotide-treated patients from 53 transplant centres in France. VOD/SOS diagnosis was at the investigator’s discretion and severity was categorised using adult or paediatric EBMT criteria. Primary endpoints were Kaplan-Meier (KM)–estimated Day 100 post-HCT survival and complete response (total serum bilirubin <2 mg/dL and multiorgan failure resolution per the investigators’ assessment). A secondary endpoint was the incidence of treatment-emergent serious adverse events (SAEs) of interest: haemorrhages, coagulopathies, injection-site reactions, infections and thromboembolic events.

Results: In total, 288 patients were treated with defibrotide for VOD/SOS after allogeneic-HCT; 286 had information on PT-Cy treatment: 59 (20.6%) with PT-Cy and 227 (79.4%) without PT-Cy. The PT-Cy group included 44 (74.6%) patients with haploidentical donors, whereas only 5 patients (2.2%) in the non-PT-Cy group received haploidentical HCT. Patient baseline characteristics at the time of diagnosis are summarised in Table 1. The time from HCT to VOD/SOS diagnosis was longer in the PT-Cy group (median 16 days) vs the non-PT-Cy group (median 11 days) and very severe VOD/SOS was more common in patients receiving PT-Cy (48.3%) than in those without PT-Cy (39.8%). KM-estimated Day 100 post-HCT survival was lower (54.2%; 95% confidence interval [CI]: 40.8%, 65.9%) in patients with PT-Cy treatment compared with those without (66.1%; 95% CI: 59.5%, 71.8%), consistent with the higher rates of very severe VOD/SOS in the PT-Cy group. Similarly, KM-estimated survival at 1-year post-HCT was 37.3% (95% CI: 25.2%, 49.4%) for PT-Cy treated patients and 47.9% (95% CI: 41.2%, 54.2%) for non-PT-Cy patients. Defibrotide treatment-emergent SAEs of interest occurred in 37.3% (22/59) of PT-Cy patients and 28.6% (65/227) of non-PT-Cy patients; the most common categories were haemorrhage (27.1% vs 15.4%) and infection (22.0% vs 15.9%) for PT-Cy vs non-PT-Cy treated patients, respectively.

Demographic and baseline characteristics of patients treated with or without

PT-Cy

PT-Cy

Non-PT-Cy

n = 59

n = 227

Age (year)

Median (Min, Max)

46.7 (9, 74)

46.2 (0, 71)

Sex (%)

Male

33 (55.9)

134 (59.0)

VOD/SOS severitya

Mild

1 (1.7)

3 (1.3)

Moderate

9 (15.5)

53 (23.5)

Severe

20 (34.5)

80 (35.4)

Very severe

28 (48.3)

90 (39.8)

Primary disease, n (%)b

ALL

13 (22.0)

52 (22.9)

AML

20 (33.9)

67 (29.5)

MDS

11 (18.6)

31 (13.7)

Lymphoma

8 (13.6)

27 (11.9)

  1. aVOD severity data was missing from 1 patient in each group. The denominators used to calculate the percentage of severity were 58 and 226 for patients with and without PT-Cy, respectively.
  2. bPrimary disease occurred in ≥12.0% patients in either group.
  3. ALL, acute lymphoblastic leukaemia; AML, acute myeloid leukaemia; MDS, myelodysplastic syndrome; PT-Cy, post-transplant cyclophosphamide; SOS, sinusoidal obstruction syndrome; VOD, veno-occlusive disease.

Conclusions: VOD/SOS tended to be diagnosed later and be more severe in patients who had treatment with PT-Cy. Day 100 post-HCT survival tended to be lower in patients with PT-Cy therapy. Multiple factors may have contributed to this, including but not limited to the higher rates of very severe VOD/SOS and the higher proportions of patients undergoing haploidentical HCT. The safety profile of defibrotide observed in this subgroup from the DEFIFrance registry was consistent with previous studies.

Clinical Trial Registry: N/A

Disclosure: M Mohty has received research funding and honoraria from Jazz Pharmaceuticals.

R Peffault de Latour, V Gandemer, C Jubert and D Blaise have received honoraria from Jazz Pharmaceuticals.

C Renard has received research funding from Jazz Pharmaceuticals.

D Gutierrez, N Dronamraju and V Amber are employees of Jazz Pharmaceuticals and hold stock and/or stock options in Jazz Pharmaceuticals.

14: Non-infectious Early Complications

O127 HOW RISKY IS A SECOND ALLOGENEIC STEM CELL TRANSPLANTATION? AN EBMT REGISTRY ANALYSIS BY THE TRANSPLANT COMPLICATIONS WORKING PARTY

Olaf Penack 1, Mouad Abouqateb2, Christophe Peczynski2, William Boreland2, Nicolaus Kröger3, Robert Zeiser4, Ciceri Fabio5, Thomas Schroeder6, Peter Dreger7, Jakob Passweg8, Johannes Schetelig9, Matthias Stelljes10, Igor Blau1, Uwe Platzbecker11, Helene Schoemans12, Ivan Moiseev13, Zinaida Peric14

1Charité Universitätsmedizin, Berlin, Germany, 2EBMT Statistical Unit Paris, Paris, France, 3University Hospital Hamburg, Hamburg, Germany, 4University Hospital Freiburg, Freiburg, Germany, 5Ospedale San Raffaele, Milano, Italy, 6University of Essen, Essen, Germany, 7University Hospital Heidelberg, Heidelberg, Germany, 8University of Basel, Basel, Switzerland, 9University Hospital TU Dresden, Dresden, Germany, 10University of Muenster, Muenster, Germany, 11University Hospital Leipzig, Leipzig, Germany, 12University Hospitals Leuven and KU Leuven, Leuven, Belgium, 13Pavlov University, St. Petersburg, Russian Federation, 14University of Rijeka, Rijeka, Croatia

Background: Relapse of the underlying malignancy after the first allogeneic stem cell transplantation (alloSCT) is a frequent problem. A second alloSCT is often considered, especially in younger and fitter patients. Procedures of conditioning, as well as GVHD prophylaxis, often differ from first alloSCT. A previous EBMT analysis including patients with second transplants before 2009 found a high treatment-related mortality of approximately 40% and overall survival of 20% at five years after second alloSCT. There is no comprehensive recent large data file analyses available on non-relapse mortality (NRM) after second alloSCT, impeding evidence-based clinical decision making.

Methods: In this study, we present a comprehensive analysis of a recent EBMT cohort on the outcomes of a second alloSCT performed due to relapse of a hematologic malignancy. We included adult patients with a second alloSCT between 2011 and 2021 from related or unrelated donors.

We performed multivariate analyses using the Cox proportional-hazards model including known risk factors.

Results: We identified 3356 second alloSCTs. The median age at second alloSCT was 48 years (min 18, max 78). The main underlying malignancies were AML 60%, ALL 15% and MDS 8%. Myeloablative conditioning was used in 44%. Most frequent donor types were matched unrelated 10/10 (35%), haploidentical (22%) and identical sibling (18%). In 20% of cases the same stem cell donor was used in first- and second alloSCT.

Median follow up was 3.7 years. Cumulative incidences of major outcomes at two years after second alloSCT were: NRM 22.1% (IC95% 20.6 – 23.6), relapse incidence 50% (48.1 - 51.8), overall survival 38.2% (36.4 - 39.9), progression-free survival 28% (26.3 - 29.7), chronic GVHD all grades 29.9% (28.2 - 31.6) and at 100 days, acute GVHD grades II-IV 23.8% (22.2 - 25.4)).

In multivariate analyses of NRM, key risk factors for adverse outcome of a second alloSCT were: patient gender male, older age, low performance score, very high disease risk index (DRI), early relapse after the first alloSCT, donor type, GVHD before second alloSCT, year of transplant and TBI.

Any type of GVHD after first alloSCT was the most important risk factor for acute GVHD grades II-IV (HR 1.43 [1.20 to 1.71] p < 0.001) and chronic GVHD all grades (HR 1.59 [1.35 to 1.87] p < 0.001) after second alloSCT.

Interestingly, in the setting of matched related or unrelated donors, the use of the same alloSCT donor for second alloSCT vs. a different donor was not associated with any of the survival or GVHD endpoints.

Conclusions: NRM after second alloSCT in this recent EBMT cohort is considerably lower compared to previous EBMT reports. Relapse is the biggest challenge, but PFS at two years after second alloSCT was 28%. This data can be used as rationale for clinical decision making on second alloSCT indications.

Disclosure: HS: personal fees from Incyte, Janssen, Novartis, Sanofi and from the Belgian Hematological Society (BHS), as well as research grants from Novartis and the BHS, all paid to her institution and not directly related to this work. She has also received non-financial support (travel grants) from Gilead, Pfizer, the EBMT (European Society for Blood and Marrow transplantation) and the CIBMTR (Center for International Bone Marrow Transplantation Research).

OP has no COIs directly related to this work. OP has received honoraria or travel support from Gilead, Jazz, MSD, Neovii, Novartis, Pfizer and Therakos. He has received research support from Incyte and Priothera. He is member of advisory boards to Equillium Bio, Jazz, Gilead, Novartis, MSD, Omeros, Priothera, Sanofi, Shionogi and SOBI.

RZ: Honorarium from: Novartis, Incyte, MNK (Therakos), medac, Neovii

14: Non-infectious Early Complications

O128 VENO-OCCLUSIVE DISEASE AND EARLY CARDIAC EVENTS IN CHILDREN RECEIVING ALLOGENIC STEM CELL TRANSPLANTATION WITH POST-TRANSPLANT CYCLOPHOSPHAMIDE

Alice Corsia 1, Bénédicte Neven1, Charles De Marcellus1, Marina Cavazzana1, Marilyne Lévy1, Despina Moshous1

1Université de Paris, Paris, France

Background: Post-transplant cyclophosphamide (PT-Cy) has become a standard treatment for the prevention of graft-versus-host disease in HLA-haploidentical stem cell transplantation (haplo-HSCT). In adult patients, recent reports show an association between PT-Cy and early cardiac events (ECEs). Our aim was to assess whether PT-Cy induces endothelial injury-related events also in children, including veno-occlusive disease (VOD) and ECEs.

Methods: We reviewed retrospectively the charts of all children who received allogenic stem cell transplantation between January 2015 and May 2023 in the pediatric immuno-hematology unit of Necker-Enfants Malades Hospital. Patients who had received conditioning prior to a first HSCT were included. Incidence and the clinical features of VOD and ECE in PT-Cy and non PT-Cy recipients were compared.

Results: We identified 346 patients who received HSCT at a median age of 3.6 years (range 4 weeks to 20 years): 99 (28.6%) received PT-Cy (50 mg/kg/day on day +3 and +4 post HSCT) and 247 (71.4%) did not. PT-Cy recipients were younger than non-PT-Cy recipients (median age at transplantation 3.5 (±4.0) and 6.6 (±6.0) years respectively, p < 0.001). Most PT-Cy recipients were transplanted from a haplo-identical donor (89.9%) while non-PT-Cy patients were transplanted mainly with HLA identical donors (88.2%). Hemophagocytic lymphohistiocytosis (HLH) (29.6%) were over-represented in the PT-Cy group while severe combined immunodeficiency (SCID) belonged mostly to the non PT-Cy group. Predominantly used conditioning was Busulfan in association to Fludarabine in both groups. Median total AUC of Busulfan and were similar among the two groups, as well as the proportion of patients receiving defibrotide for VOD prophylaxis. In PT-Cy recipients, VOD was more frequent (35.4% versus 18.6%, p = 0.001) and more severe (48.4% versus 25.6% of severe VOD, p = 0.04) than in non-PT-Cy patients. In univariate analysis, age ≤ 1 year (OR = 5.8 [3.45;9.9], p < 0.001), PT-Cy (OR = 2.3 [1.4;3.9], p = 0.002) and the diagnosis of primary HLH (OR = 2.49 [1.4;4.6], p = 0.005) were associated with VOD. In multivariate analysis, only age ≤ 1 year at transplant was associated with higher risk of VOD (OR = 4.1, [2.3 ; 7.4], p < 0.001). Thirty-five ECEs occurred. Diagnosis were pulmonary hypertension (n = 16), pericardial effusion (n = 9), arrhythmia (n = 5), cardiogenic choc (n = 2), pericarditis (n = 2) and myopericarditis (n = 1). ECEs occurred in 20 (20.2%) PT-Cy recipients versus 15 (6.1%) non-PT-Cy recipients (p < 0.001), with a higher rate of pulmonary hypertension in the PT-Cy group: n = 12 (12.1%) versus n = 4 (1.6%), p < 0.001. In multivariate analysis, risk factors for ECEs were PT-Cy (OR = 2.9, 95% HC [1.3; 6.4], p = 0.008), female gender (OR = 2.7, 95% HC [1.3; 5.9], p = 0.01), and age at transplantation ≤ 1 year (OR = 6.1, 95% HC [2.7; 13.8], p < 0.001).

PT-Cy

No N = 247

Yes N = 99

p-Value

Gender

Male

151 (61.1%)

58 (57.8%)

0.511

Female

94 (37.7%)

43 (42.2%)

Age at transplant (years)

6.55 (±5.99)

3.51 (±4.04)

<0.001

Range: (0.08 ; 20.23)

Range: (0.2 ; 17.1)

Diagnosis

SCID

43 (17.4%)

9 (9.2%)

0.001

CID

46 (18.6%)

18 (18.4%)

CGD

24 (9.7%)

11 (9.8%)

Wiskott-Aldrich

17 (6.9%)

7 (7.2%)

IPEX

5 (2.0%)

4 (4.1%)

LAD

3 (1.2%)

3 (3.1%)

Other PID

17 (6.8%)

9 (8.2%)

HLH

39 (15.8%)

29 (29.6%)

Hemoglobinopathy

32 (13.0%)

0 (0.0%)

Osteopetrosis

5 (2.0%)

7 (7.4%)

Other

16 (6.5%)

6 (6.2%)

Donor

Matched related

111 (44.27%)

0 (0.0%)

Haploidentical

26 (10.6%)

89 (89.9%)

Matched unrelated

98 (39.8%)

10 (10.1%)

Pheno-related

9 (3.6%)

0 (0.0%)

Cord Blood

2 (0.8%)

0 (0.0%)

Busulfan (AUC, mg*h/L)

67.2 (±34.4)

64.9 (±31.0)

0.994

No Busulfan

16 (5.3%)

8 (7.1%)

Defibrotide

0.054

Yes

67 (27.13%)

38 (38.38%)

No

180 (72.87%)

61 (61.62%)

VOD

0.001

Yes

46 (18.62%)

35 (35.35%)

No

201 (81.38%)

64 (64.65%)

VOD grade

0.036

mild

33 (70.2%)

15 (48.4%)

severe

12 (25.3%)

15 (48.4%)

N = 31

Cardiac events

Yes

15 (6.1%)

20 (20.2%)

<0.001

No

231 (93.9%)

79 (79.8%)

HTAP

Yes

4 (1.6%)

12 (12.2%)

<0.001

No

243 (93.8%)

87 (87.8%)

Pericardial effusion

Yes

7 (2.8%)

4 (4.0%)

0.525

No

240 (97.1%)

95 (96.0%)

Thrombopatic microangiopathy

Yes

15 (6.1%)

12 (12.2%)

0.075

No

232 (93.9%)

87 (87.9%)

Outcome

Deceased

29 (11.8%)

14 (14.1%)

0.308

Alive

217 (88.2%)

85 (85.9%)

Conclusions: In children, PT-Cy is associated with a higher incidence of events related to endothelial damage, younger children being particularly at risk. These findings should alert clinicians to carefully monitor these patients for ECEs, particularly pulmonary hypertension, for which timely combination therapy has shown improved survival. They may also prompt them to evaluate the efficacy of PT-Cy dose reduction, a strategy that has recently proved successful in adult patients.

Disclosure: Nothing to declare

14: Non-infectious Early Complications

O129 EASIX SCORE AS A PREDICTIVE TOOL FOR SINUSOIDAL OBSTRUCTION SYNDROME IN PEDIATRIC PATIENTS UNDERGOING ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION

Edoardo Muratore 1, Davide Leardini1, Giacomo Gambuti1, Leyna Larcinese1, Francesco Baccelli1, Francesca Gottardi1,1, Tamara Belotti1, Francesco Venturelli1, Arcangelo Prete1, Riccardo Masetti1

1Pediatric Hematology and Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy

Background: Endothelial damage after allogeneic hematopoietic stem cell transplantation (allo-HCT) is related to the occurrence of complications such as sinusoidal obstruction syndrome/veno occlusive disease (SOS/VOD) and acute graft versus host disease (aGvHD). The “Endothelial Activation and Stress Index” score (EASIX score, [(creatinine × LDH) ÷ platelets]) has been shown to predict non relapse-mortality and endothelial complications in adult patients undergoing allo-HCT. However, few data exist in the pediatric setting.

Methods: Retrospective analysis of consecutive pediatric patients undergoing allo-HCT at the Pediatric Hematology and Oncology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna between 2010 and 2023 for any indications. EASIX score was calculated at admission, before conditioning and weekly from the day of transplantation to day +35. EASIX was normalized using log2 according to the literature. EASIX score was analyzed in association with SOS/VOD onset which was diagnosed according to the pediatric EBMT criteria.

Results: Of 167 patients included, 27 (16.2%) developed SOS/VOD after a median of 11 days after allo-HCT (range 8-25 days). EASIX score increased post-transplant in the whole cohort from admission to day +35. Median EASIX score of the SOS/VOD group was significantly higher from day +7 to +21 compared with those who did not develop SOS/VOD ( + 7 2.29 vs 0.80 p = 0.005; +14 3.12 vs 1.04 p = 0.020; +21 3.31 v 1.40 p = 0.012), with no significant pre-transplant differences. Increased EASIX score at day +7 was significantly correlated with higher incidence of SOS/VOD (Odds ratio (OR) 1.41; Confidence Interval (CI) 95% 1.04-1.92; p = 0.047). The parameters composing EASIX + 7, namely creatinine, LDH and platelets, were note predictors of SOS/VOD when considered singularly. The other variable significantly predictive of SOS/VOD in the univariate analysis was the use of busulfan in the conditioning regimen (OR 2.90; CI 95% 1.14-7.81; p = 0.027). No difference was observed between patients developing and not developing SOS/VOD regarding age of the patients, disease type, type of transplant and GvHD prophylaxis. In the multivariate analysis, the only independent predictor of SOS/VOD onset was EASIX + 7 (p = 0.017). No correlations were found between EASIX at any time point and aGvHD. Age correlated linearly with EASIX + 7 (p = 0.01), with EASIX increasing by age. However, EASIX + 7 was confirmed as a predictor of SOS/VOD even if age is added in the multivariate model. EASIX + 7 was also a predictor of overall mortality in the multivariate analysis (OR 1.68; CI 95% 1.03-2.73; p = 0.036), after a median follow-up time of 396 days.

Conclusions: EASIX + 7 has been shown to be a predictor of the onset of SOS/VOD in pediatric patients undergoing allo-HCT for any indication. Moreover, promising data are observed regarding the association between increased EASIX score at +7 and higher overall mortality. There is a strong correlation between age and EASIX score, but the predictive value seems independent of the age of the patients. EASIX score may represent a promising prognostic tool to stratify the risk of developing endothelial complications after allo-HCT.

Disclosure: nothing to declare

14: Non-infectious Early Complications

O130 APPLICATION OF RECENTLY PROPOSED EBMT/ ASTCT/CIBMTR/APCMT CONSENSUS RISK STRATIFICATION FOR TRANSPLANT ASSOCIATED THROMBOTIC MICROANGIOPATHY (TA-TMA) IN CHILDREN

Michelle Schoettler 1,2, Elyse Bryson1,2, Kathleen Spencer1,2, Muna Qayed1,2, Satheesh Chonat1,2, Adrianna Westbrook1,2,3, Kirsten Williams1,2

1Emory University, Atlanta, United States, 2Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, United States, 3Pediatric Biostatistics Core, Atlanta, United States

Background: Consensus diagnostic criteria and risk stratification of transplant associated thrombotic microangiopathy (TA-TMA) were recently published (Schoettler et al.,JTCT, 2023) but have yet to be applied to real world cohorts.

Methods: In this retrospective cohort IRB-approved study, all children undergoing an allogeneic HCT or autologous HCT for neuroblastoma were prospectively screened for TA-TMA, diagnosed and risk-stratified using Jodele criteria from August 2019- October 2023. Our institutional practice during the study period was treat all Jodele intermediate and high-risk patients (IR, HR) with eculizumab. Harmonization risk stratification criteria were retrospectively applied (Table 1). All survival analyses were calculated from the day of TA-TMA diagnosis. To identify which specific harmonization high-risk feature(s) were the most important predictors for NRM, full and reduced logistic regression models were tested. The lowest BIC and optimal Mallows’ CP statistic were used to identify the best subset. SAS 9.4 (Cary, NC) was used to complete the analysis.

Results: Fifty-two children were diagnosed with TA-TMA during the study period a median of 37.5 days post HCT (range 3 to 735). Using Jodele risk stratification, 11 (21%) were SR, 21 (40%) intermediate risk, and 20 (39%) high- risk (HR). Forty (77%) were treated with eculizumab. There were no statistically significant differences in NRM among Jodele risk groups, though overall survival was significantly different. Using the harmonized stratification, 49 (94%) of children were stratified as HR and 3 as SR, there were no statistically significant differences in NRM or OS between groups. Eight (15.4%) children were classified as SR using Jodele risk stratification but stratified as HR using the harmonization criteria. One (12.5%) died in the setting of severe GVHD and the remaining 7 patients are alive at last follow up. In a best subset model, LDH >2x ULN (OR 6.52, 95% CI 0.96-44.3, p = 0.05), grade 2-4 acute GVHD at the time of TA-TMA diagnosis (OR 15.4, 95% CI 2.14- 110.68, p = 0.01), and multi-organ dysfunction at the time of TA-TMA (OR 21.5, 95% CI 2.96-156.37, p = 0.002) were significantly associated with NRM; elevated sC5b-9, rUPCR, and viral infections were not significantly associated with NRM. Using these best fit criteria, 14 patients were classified as SR and 38 as HR; NRM was significantly higher and OS significantly lower.

Table 1: Risk Stratification Approaches

Jodele Risk Stratification

Harmonization Risk Stratification

Best Fit of Harmonization Risk Stratification

Standard Risk (SR)

Neither MOD, elevated sC5b-9, nor rUPCR > 2 mg/mg

None of the 5 HR criterion

None of the 3 HR criterion

Intermediate Risk (IR)

MOD and elevated sC5b-9 or rUPCR > 2 mg/mg

--

--

High Risk (HR)

Elevated sC5b-9 (>ULN) and rUPCR > 2 mg/mg

Any of the following:

- Grade 2-4 acute GVHD

- MOD

- rUPCR > 1 mg/mg

- Viral infection

- elevated sC5b-9 (>ULN)

- LDH > 2X ULN

Any of the following:

- MOD

- Grade 2-4 acute GVHD

- LDH > 2X ULN

Conclusions: In this cohort of children with TA-TMA, retrospective application of harmonization criteria resulted in more patients stratified as HR than previously described Jodele criteria. The intention of the harmonization criteria was to identify those at highest risk of poor outcomes, and it is notable that all harmonization SR patients survived and one newly classified HR patient died. Previous criticisms of harmonization risk stratification include limited access to sC5b-9 testing-- these data suggest that concurrent MOD, acute GVHD, and LDH > 2X ULN are the most important predicators of NRM in this cohort, supporting the use of harmonization risk stratification even in the absence of available sC5b-9 testing. Additional studies are needed to validate these findings.

Disclosure: MLS is a consultant and has received honorarium for Alexion and Omeros. SC- consultant, research funding: Agios, Alexion, Daichi Sankyo, Forma Therapeutics, Pfizer Inc., Novartis, Novo Nordisk, Takeda Pharmaceuticals. MQ- honorarium Novartis, Vertex

15: Non-infectious Late Effects, Quality of Life and Fertility

O131 SALVAGE THERAPY WITH NINTEDANIB AND LOW-DOSE RUXOLITINIB LEADS TO SIGNIFICANT IMPROVEMENT IN PATIENTS WITH BRONCHIOLITIS OBLITERANS SYNDROME WHO FAILED CALCINEURIN AND GLUCOCORTICOIDS AFTER ALLOGENEIC TRANSPLANTATION

Ya Luo 1, Meng Lv1, Jing Liu1, Xiao-Lu Zhu1, Xiao-Dong Mo1, Yu-Qian Sun1, Yu Wang1, Lan-Ping Xu1, Xiao-Hui Zhang1, Xiao-Jun Huang1,2

1Peking University People’s Hospital, Beijing, China, 2Peking-Tsinghua Center for Life Sciences, Beijing, China

Background: Bronchiolitis obliterans syndrome (BOS) is a common pulmonary complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients who do not respond to standard treatment with glucocorticoids (GCs), calcineurin inhibitors (CNIs), and/or inhaled fluticasone, azithromycin, and montelukast (FAM) experience poor survival and quality of life. Phase II trial supported the use of ruxolitinib in BOS (Zachariah, et al. ASH 2023). Nintedanib, an anti-fibrotic drug that works by targeting multiple tyrosine-kinase pathways and is approved for idiopathic pulmonary fibrosis, may be a potential salvage treatment option for BOS.

Methods: In this pilot study between Jan 2018 to Jun 2023, consecutive patients with BOS defined by NIH criteria (Jagasia et al. BBMT. 2015) were enrolled. Patients who were refractory to standard treatment with glucocorticoids and calcineurin ≥4 weeks were enrolled to receive salvage treatment, which included low-dose ruxolitinib (5mg bid po.) and nintedanib (150mg bid po.) continuously in 28-d cycles (RN cohort), for up to 6 cycles. Other contemporary patients with BOS were enrolled as controls. The response rate was assessed by % change in FEV1 compared to baseline and NIH lung-specific score. The primary endpoint was the 3-month overall response rate (ORR), and the second endpoints included a 3-month best response rate (BOR), 3-year non-relapse mortality(NRM), 3-year overall survival(OS) and treatment-related toxicities.

Results: Forty-eight subjects were enrolled, comprising 12 patients in the RN cohort and 36 in the control group. The median age for the entire cohort was 33 years (range, 7-57). Survivors had a median follow-up of 42 months post BOS diagnosis (range, 3-60.5) as of the last cutoff date (12/01/23). At enrollment, the NIH lung score based on %FEV1 of predicted in the RN cohort was NIH1 (16.7%), NIH 2 (16.7%), or NIH 3 (66.7%). The median number of cycles of RN treatment was 3 (range, 1-6). Reasons for discontinuation included completion of therapy (n = 5), BOS or GVHD progression (n = 2), relapse (n = 1), adverse events (n = 2), and other reasons (n = 2).When comparing the 3-month %FEV1 to baseline, 9 subjects (ORR 75%) showed a ≥ 10% increase (median 26.5%, range 15.6-58.2%), 2 subjects had a ≥ 5% decrease, and 1 subject remained stable. Comparing the best response %FEV1 to baseline, 9 subjects showed a ≥ 10% increase (median 27.5%). According to the NIH response criteria, the best NIH lung-specific overall response rate (ORR) for the RN cohort was 58.3% (16.7% complete response, 41.7% partial response), with 41.7% remaining stable, while no patients worsened. In the control cohort, the ORR was only 13.9% (5.6% CR, 8.3% PR), with 66.7% remaining stable and 19.4% worsening. In the RN and control cohorts, the 3-year NRM was 26.0% (2.9-59.6%) vs. 31.7% (16.9-47.5%) (p = 0.6), respectively, while the 3-year OS was 64.9% (39.2-100%) vs. 67.1% (49.2-91.5%) (p = 0.5), respectively. The major adverse effects were grade 2 blood bilirubin increase (n = 2) and grade 3-4 platelet decrease (n = 3).

Conclusions: The RN protocol, featuring low-dose Ruxolitinib and Nintedanib, has demonstrated positive clinical responses in BOS. These findings provide support for the prospective evaluation of the RN protocol in a phase II study in the near future.

Disclosure: Nothing to declare

15: Non-infectious Late Effects, Quality of Life and Fertility

O132 SUBSEQUENT NEOPLASMS AFTER UMBILICAL CORD BLOOD TRANSPLANTATION IN THE JAPANESE AND EUROPEAN POPULATIONS

Junya Kanda 1, Fernanda Volt2, Hanadi Rafii2, Hideki Nakasone3,4, Annalisa Ruggeri2,5, Nobuharu Fujii6, Chantal Kenzey2, Naoyuki Uchida7, Régis Peffault De La Tour8, Hikaru Kobayashi9, Graziana Maria Scigliuolo2,10, Koji Kato11, Barbara Cappelli10,2, Fumihiko Ishimaru12, Tatsuo Ichinohe13, Satoshi Takahashi14, Vanderson Rocha15,2, Teshima Takanori16, Yoshiko Atsuta17, Eliane Gluckman2,10

1Kyoto University, Kyoto, Japan, 2Eurocord, Paris, France, 3Jichi Medical University Saitama Medical Center, Saitama, Japan, 4Jichi Medical University, Tochig, Japan, 5IRCCS San Raffaele Scientific Institute, Milan, Italy, 6Okayama University Hospital, Okayama, Japan, 7Toranomon Hospital, Tokyo, Japan, 8Hôpital Saint Louis, Paris, France, 9Nagano Red Cross Hospital, Nagano, Japan, 10Monacord, Monako, Monaco, 11Central Japan Cord Blood Bank, Tokyo, Japan, 12Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan, 13Hiroshima University, Hiroshima, Japan, 14The University of Tokyo, Tokyo, Japan, 15São Paulo University, São Paulo, Brazil, 16Hokkaido University, Sapporo, Japan, 17Japanese Data Center for Hematopoietic Cell Transplantation, Nagakute, Japan

Background: A small proportion of patients develop subsequent neoplasms (SN) after umbilical cord blood transplantation (UCBT). To describe and compare the characteristics and outcomes of SN in Japan and Europe, we conducted a collaborative study between the Japanese Society for Transplantation and Cellular Therapy (JSTCT)/ Japanese Data Center for Hematopoietic Cell Transplantation (JDCHCT) and Eurocord/European Society for Blood and Marrow Transplantation (EBMT).

Methods: We included patients who received unrelated UCBT at EBMT or JSTCT centers for hematologic malignant or non-malignant diseases, from 1989 to 2018, and developed SN after the procedure. We excluded those who received UCBT for Fanconi anemia, Diamond-Blackfan anemia, or solid tumors, and those who received UCBT combined with other graft sources. Overall survival (OS) was calculated using the Kaplan-Meier method and compared using the log-rank test.

Results: Among 16,241 (Japan) and 10,358 (Europe) UCBT recipients, 534 (3.3%) and 233 (2.2%), respectively, were reported to develop SN after UCBT. The numbers of PTLD/mature lymphoid malignancies, acute leukemia/myelodysplastic syndromes, and solid malignancies were, respectively, 198, 145, and 52 in the Japanese and 23, 277, and 65 in the European populations. In patients with myeloid malignancies, donor cell origin was reported in 30 out of 52 (58%) and 3 out of 23 (13%), respectively. The proportion of upper gastrointestinal malignancies among solid tumors was higher in the Japanese populations (20% vs. 5%), whereas the proportion of thyroid tumors (4% vs. 14%), sarcomas (1% vs. 9%), and skin tumors (8% vs. 14%) was higher in the European populations. Survival after the development of PTLD/mature lymphoid malignancies was higher in the Japanese than in the European populations (3-year OS, 51% vs. 25%, P < 0.001), whereas OS after the development of acute leukemia/myelodysplastic syndromes (3-year OS, 25% vs. 34%, P = 0.815), and solid malignancies (3-year OS, 62% vs. 53%, P = 0.269) were comparable between the 2 populations.

Conclusions: Donor-derived malignancies were more frequent in the Japanese cohort, occurring in more than half of the Japanese patients with subsequent myeloid malignancies. The cell origin for the subsequent leukemia in UCBT and its mechanism should be further explored in both populations. The frequencies of observed subsequent solid tumors may reflect the epidemiologic differences between the two populations, indicating that follow-up systems for patient monitoring should be tailored to the unique geographic areas and population characteristics. The reason for the higher survival post PTLD in Japan should be further investigated.

Clinical Trial Registry: Not applicalbe

Disclosure: Nothing to declare.

15: Non-infectious Late Effects, Quality of Life and Fertility

O133 FRAILTY SYNDROME IN ADULTS UNDERGOING AUTOLOGOUS HEMATOPOIETIC CELL TRANSPLANTATION. PROSPECTIVE STUDY ON BEHALF OF THE GRUPO ESPAÑOL DE TRASPLANTE HEMATOPOYÉTICO Y TERAPIA CELULAR (GETH-CT)

Maria Queralt Salas 1,2, María Teresa Solano1,2, Mónica Baile-Gonzalez3,2, Marina Acera-Gómez3,2, Laura Fox4,2, María del Mar Pérez-Artigas4,2, Ana Santamaría5,2, María del Carmen Quintela-González5,2, Andrés Sánchez-Salinas6,2, Joaquina M. Salmerón-Camacho6,2, Verónica Illana-Álvaro7,2, Zahra Abdallahi-Lefdil7,2, Javier Cornago-Navascues8,2, Laura Pardo8,2, Sara Fernández-Luis9,2, Leddy Patricia Vega-Suárez9,2, Sara Villar10,2, Patricia Beorlegui-Murillo10,2, Albert Esquirol11,2, Isabel Izquierdo-García12,2, Sonia Rodríguez-González13,2, Alberto Mussetti13,2, Aitor Abuin-Blanco14,2, Javier Lopez-Marín15,2, Silvia Filarerro2,2, Leyre Bento16,2, Anna Sureda13,2

1Hospital Clínic de Barcelona, Barcelona, Spain, 2Grupo Español de Trasplante de Progenitores Hematopoyéticos y Terapia Celular, Madrid, Spain, 3Complejo Asistencial Universitario de Salamanca/IBSAL, Salamanca, Spain, 4Hospital Universitari Vall d’Hebron, Barcelona, Spain, 5Hospital Álvaro Cunqueiro, Vigo, Spain, 6H.C.U. Virgen de la Arrixaca, Murcia, Spain, 7Hospital Universitario de la Princesa, Madrid, Spain, 8Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain, 9Hosptal Universitario Marqués de Valdecilla, Santander, Spain, 10Clínica Universidad de Navarra, Pamplona, Spain, 11Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, 12Hospital Universitario Miguel Servet, Zaragoza, Spain, 13Institut Català d’Oncologia - Hospital Duran i Reynals, L’Hospitalet de Llobregat, Spain, 14Hospital Universitario Lucus Augusti, Lugo, Spain, 15Hospital Universitario de Alicante, Alicante, Spain, 16Hospital Universitario Son Espases, Mallorca, Spain

Background: Since February 2022, fifteen institutions members of the GETH-TC are undertaking a multicenter, prospective, and observational study to evaluate the frailty syndrome of adult candidates to auto-HCT and of investigating the effect of frailty in transplant results.

Methods: All patients consulted for auto-HCT are considered eligible to be included in the study after providing informed consent. Patients are classified into fit, pre-frail and frail categories using HCT Frailty Scale (Salas et al. BMT, 2023). Frailty is measured longitudinally at first consultation, HCT admission, and day +100. Frailty is evaluated clinical practice and utilizing existing resources. Patient´s cognition and quality of life (QoL) are additionally explored (Mini-Cog and EQ-5D-EL tests). The median time to complete the evaluation is 10 minutes. These results are not used to determine HCT eligibility or to design the HCT process. Prospective data was updated in December 2023.

Results: The 404 consecutive adult candidates for auto-HCT evaluated for frailty at first consultation and HCT admission between February 2022 and September 2023 were included. The median age was 58 (range, 18-76), 227 (56.0%) patients were male, plasma cell disorders (PCD) (n = 235, 58.0%) and lymphoproliferative disorders (SLP) (n = 131, 32.4%) were the most prevalent diagnosis. The first consultation was performed at a median of 33 days (IQR 15 and 91) before transplantation, and mostly before the stem cell collection.At first consultation, 113 (27.9%) adults were classified as fit, 228 (56.3%) as pre-frail, and 64 (15.8%) as frail. Frail patients were more likely to be older than 60, to have a KPS < 90%, a higher number of comorbidities (HCT-CI > 3), and an abnormal Mini-Cog test (<3). Additionally, frailty was more prevalent in patients with PCD (p = 0.028) (Table 1).

The impact of frailty in auto-HCT results was explored with data obtained at HCT admission (Table 1). Frailty did not impact on hospitalization duration (p = 0.143). A trend to higher incidence of readmissions was observed in frail patients compared than pre-frail and fit ones (Day +180: 10.4% vs. 6.4% vs. 3.1%, p = 0.059). The impact of frailty in outcomes was evaluated in the subsample of 254 adults with a minimum of follow-up of 100 days among survivors (Table 1). Frailty at HCT admission did not impact on the probability of OS (p = 0.125) and NRM (P = 0.602) [1-year OS of fit, pre-frail, and frail adults: 96.6%, 93.5%, and 89.5% (p = 0.125)]. However, a trend to lower OS was observed in frail patients with PCD.

Lastly, the impact of frailty in QoL measured using the EQ-5D-EL test was investigated based on data obtained at day +100. Compared with fit patients, pre-frail and frail adults had lower mobility, self-care, limitations on daily living activities higher pain, discomfort and anxiety (Table 1).

Frailty at First Consultation Baseline Characteristics N = 404

Fit, n = 113 (27.9%)

Pre-Frail, n = 228 (56.3%)

Frail, n = 64 (15.8%)

P-Value

Median Age (range)

56 (18-73)

58 (18-73)

62 (19-74)

0.001

Older 60 years

39 (34.5)

97 (42.5)

41 (64.1)

0.001

Sex, male

64 (56.6)

129 (56.6)

34 (53.1)

0.876

Diagnosis

Plasma Cell Disorders (PCD)

58 (51.3)

76 (63.3)

46 (71.9)

0.028 (Compares patients wiht PCD vs. others)

Lymphoproliferative Disease

39 (34.5)

131 (57.5)

16 (25.1)

Others

16 (14.2)

21 (9.2)

2 (3.1)

KPS < 90% (n = 306)

16/97 (16.5)

70/173 (40.5)

46 (71.9)

<0.001

HCT-CI > 3 (n = 306)

3/96 (3.1)

23/168 (13.7)

16 (25.1)

0.007

Abnormal Mini-Cog ( < 3)

1 (0.9)

22 (9.6)

20 (31.3)

<0.001

Frailty at HCT Admission

Impact on HCT Results

N = 404

Fit, n = 99 (24.5%)

Pre-Frail, n = 237 (58.6%)

Frail, n = 72 (17.8%)

P-Value

Median days HCT admission

(from day 0) (IQR)

14 (12-16)

15 (13-18)

15 (4-20)

0.142

Cumulative Incidence of Readmission (due to HCT complications). % (95% CI)

3.1 (1.4-6.1)

6.4 (2.6-12.6)

10.4 (4.5-19.1)

0.059

Frailty at HCT Admission

Impact on HCT Results

N = 354

Fit, n = 85 (24%)

Pre-Frail, n = 203 (57.4%)

Frail, n = 66 (18.6%)

P-Value

1-year OS % (95% CI)

96.6 (87.7-99.3)

93.2 (87.1-96.8)

89.5 (75.2-95.8)

0.125

1-year NRM % (95% CI)

1.3 (1.4-6.1)

2.7 (0.8-6.6)

3.1 (0.6-9.7)

0.602

Frailty at Day + 100

Impact on Quality of Life

N = 133

Fit, n = 46 (26.6%)

Pre-Frail, n = 74 (55.9%)

Frail, n = 13 (9.7%)

P-Value

Mobility

1

40 (87.0)

50 (67.6)

8 (61.5)

<0.001

2

6 (13.0)

24 (32.4)

4 (30.8)

3

1 (7.7)

Self-Care

1

45 (97.8)

67 (90.5)

9 (69.2)

<0.001

2

1 (2.2)

7 (9.5)

2 (15.4)

3

2 (15.4)

Daily Activities

1

42 (91.3)

44 (59.4)

4 (30.8)

<0.001

2

4 (8.7)

29 (39.2)

8 (61.5)

3

1 (1.4)

1 (7.7)

Pain / Disconfort

1

29 (63.0)

37 (50.6)

4 (30.8)

<0.001

2

17 (37.0)

34 (46.6)

6 (46.1)

3

2 (2.7)

3 (23.0)

Anxiety / Depression

1

33 (73.3)

50 (56.6)

4 (30.8)

<0.001

2

12 (26.7)

22 (29.7)

6 (46.1)

3

2 (2.7)

3 (23.0)

Current Health Status Perception (%) (range)

80% (70-90)

60% (50-80)

50% (35-65)

<0.001

Conclusions: This study validates the applicability of the HCT Frailty Scale in adult candidates for auto-HCT. At first consultation, frailty had an incidence of 15.8%, and was more prevalent in older adults, patients with PDC, worse performance status, and comorbidities. Frailty did not impact on transplant results, but it was associated with worse QoL.

Clinical Trial Registry: No applicable

Disclosure: Nothing to declare

18: Paediatric Issues

O134 MODEL-BASED DOSING OF ANTI-THYMOCYTE GLOBULIN IN PEDIATRIC ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION IMPROVES SURVIVAL CHANCES: UPDATED RESULTS FROM THE PHASE II PARACHUTE-TRIAL COMBINED WITH REAL-WORLD DATA

Rick Admiraal 1, Stefan Nierkens1,2, Marc Bierings1,3, Mirjam Belderbos1, Alwin Huitema4,5, Robbert Bredius6, Yilin Jiang4, Kevin Curran7, Andrew Harris7, Andromachi Scaradavou7, Maria Cancio7, Elizabeth Klein7, Wouter Kollen1, Dorine Bresters1, Friso Calkoen1, Birgitta Versluijs1,8, Jaap Jan Boelens7, Caroline Lindemans1,3

1Pediatric Blood and Marrow Transplantation Program, Princess Maxima Center for Pediatric Oncology, Utrecht, Netherlands, 2Center for Translational Immunology, University Medical Center, Utrecht, Netherlands, 3University Medical Center, Utrecht, Netherlands, 4Princess Maxima Center for Pediatric Oncology, Utrecht, Netherlands, 5Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, Netherlands, 6Leiden University Medical Center, Leiden, Netherlands, 7Stem Cell Transplantation and Cellular Therapies, Memorial Sloan Kettering Cancer Center, New York, United States, 8Erasmus MC-Sophia Children’s Hospital, Rotterdam, Netherlands

Background: Anti-thymocyte globulin (ATG) is used in the conditioning for pediatric hematopoietic cell transplantation (HCT) to prevent graft-versus-host-disease (GvHD) and graft failure (GF). Toxicity includes poor T-cell recovery, associated with viral reactivations and higher mortality. The PARACHUTE-trial1 (non-randomized prospective trial investigating model-based dosing [MBD] compared to historical fixed dose of ATG Thymoglobulin) showed that MBD of ATG improves T-cell recovery compared to fixed dosing, while maintaining an anti-GvHD effect. We now evaluated outcome after 5-year follow-up combined with real-world data.

Methods: We included those enrolled on the PARACHUTE-trial and all consecutive real-world pediatric patients treated as per the trial protocol in Utrecht, the Netherlands (NL) and New York, USA. The cumulative MBD dose (based on body weight, lymphocyte counts and graft source) ranged 2-10 mg/kg, starting on day -9 before HCT. Results were compared to a historical cohort receiving fixed weight-based dose of 10 mg/kg starting 5 ± 1 days before HCT (FIX)1. Primary endpoint was overall survival (OS); secondary endpoints included therapy-related mortality (TRM), successful CD4+ recovery (CD4IR; defined as >50/mm3 CD4+ twice within 100 days after HCT), acute and chronic GvHD and GF. Multivariable Cox proportional hazard and Fine-Gray competing risk models were used.

Results: A total of 214 patients were dosed according to MBD (58 trial patients and 124 (NL) and 32 (USA) real-world treated 2015-22); the historical controls included 100 patients (treated in NL 2004-12). Age (median 8.4 vs 6.1), graft source (bone marrow and cord blood) and conditioning (mostly BuFlu±Clo) was comparable in MBD and FIX, respectively. MBD led to superior OS (81%) as compared to FIX (63%; HR 0.56, 95% CI 0.34-0.93, p = 0.026), mainly due to lower TRM (HR 0.52, 95% CI 0.29-0.92, p = 0.025). Relapse incidence was comparable. Successful CD4IR was comparable amongst all MBD-groups, and significantly than FIX (87% vs 49%; HR 2.93, 95% CI 2.03-4.23, p = <0.0001). Successful CD4IR was strongly associated with improved survival (HR 0.28, 95% CI 0.17-0.47, p < 0.0001) due to lower TRM, with no additional effect of MBD vs FIX (ie. historical patients), underlining the effect was CD4-driven rather than treatment-period driven (HR 0.18, 95% CI 0.09-0.34, p < 0.0001). Reducing the dose of ATG was safe, with comparable rates of aGvHD (p = 0.14), while the incidence of cGvHD (7% vs 17%; HR 0.35, 95% CI 0.17-0.72), p = 0.004) and GF (5% vs 15%; HR 0.36, 95% CI 0.13-0.97, p = 0.044) were lower in MBD compared to FIX.

Conclusions: MBD of ATG leads to improved OS and lower TRM, likely due optimized CD4IR, while also reducing cGvHD and GF. This approach can be a major breakthrough in improving outcomes after pediatric HCT and is easy to implement.

Ref: Admiraal et al, Lancet Haem 2022

Clinical Trial Registry: NTR4960; Dutch Trial Registry https://onderzoekmetmensen.nl/

Disclosure: Nothing to declare

18: Paediatric Issues

O135 IMPACT OF MINIMAL RESIDUAL DISEASE AT HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA WITHIN THE FORUM TRIAL

Adriana Balduzzi 1,2, Evgenia Glogova3, Peter Bader4,5, Jean-Hugues Dalle6,7, Franco Locatelli8,9, Rachel Staciuk10, Jacek Wachowiak11, Petr Sedlacek12,13, Jochen Buechner14, Tayfun Güngör15, Luisa Sisinni16, Marc Bierings17,18, Peter Svec19, Krzysztof Kalwak20, Ulrike Poetschger3, Christina Peters21, Marianne Ifversen22

1Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy, 2Milano-Bicocca University, Milano, Italy, 3Children’s Cancer Research Institute, Vienna, Austria, 4Goethe University, Frankfurt am Main, Germany, 5University Hospital Frankfurt, Frankfurt am Main, Germany, 6Hôpital Robert Debré, Paris, France, 7GH APHP-Nord Université de Paris, Paris, France, 8IRCCS Bambino Gesù Children’s Hospital, Rome, Italy, 9Catholic University of the Sacred Heart, Roma, Italy, 10Prof. Dr. Juan P. Garrahan Hospital, Buenos Aires, Argentina, 11University of Medical Sciences, Poznan, Poland, 12Teaching Hospital Motol, Prague, Czech Republic, 132nd Medical School, Charles University Motol, Prague, Czech Republic, 14Oslo University Hospital, Oslo, Norway, 15University Children`s Hospital, Zürich, Switzerland, 16Hospital de Sant Pau, Barcelona, Spain, 17Princess Maxima Center, Utrecht, Netherlands, 18University Hospital for Children, Utrecht, Netherlands, 19Comenius University and National Institute of Children’s Diseases, Bratislava, Slovakia, 20Wroclaw Medical University, Wroclaw, Poland, 21Anna Kinderspital, Vienna, Austria, 22University Hospital Rigshospitalet, Copenhagen, Denmark

Background: The prognostic role of minimal residual disease (MRD) has been consistently shown in the HSCT setting throughout multiple cooperative groups.

Methods: The primary aim of this study is to assess the impact of MRD at HSCT, either by PCR or flow cytometry within the extended cohort of the prospective FORUM trial, beyond randomization, which demonstrated a superiority of TBI over chemo-conditioning (BU-FLU-TT or TREO-FLU-TT) in patients >4 years, <18 years at diagnosis/21 years at HSCT, transplanted from a compatible donor for ALL in CR. The secondary aim is to assess the impact of aGVHD, after GVHD prophylaxis with CSA in HLA identical sibling recipients or CSA-MTX-ATG in 10/10 or a 9/10 HLA-matched recipients, either related or unrelated.

A MRD threshold of 1x10-4, alias 0.01%, was selected to stratify patients in a MRDneg-low versus a MRDpos-high. cohort.

Results: Enrolment. Out of the 1066 FORUM patients, 728 (36% female), transplanted (74% bone marrow graft) from a MSD (30%) or a MD (70%), after conditioning with TBI (67%) or chemotherapy only (busulfan 21% or treosulfan 12%), for ALL (59% B-lineage) in CR1 (50%), CR2 (43%) or >CR3 (7%), had MRD levels at HSCT available (79% by PCR and 21% by FCM).

MRD upon HSCT. At the time of HSCT 67% of the recipients were MRDneg-low, whereas 33% were MRDpos-high.

Overall outcome by MRD. 3-year OS was 0.80 (SE 0.02) and 0.66 (SE 0.04) for the patients who had pre-HSCT MRDneg-low and MRDpos-high, respectively, whereas 3-year EFS was 0.71 (SE 0.02) and 0.55 (SE 0.05) for the patients who had pre-HSCT MRDneg-low and MRDpos-high, respectively. Three-year CIR was 0.21 (SE 0.02) and 0.36 (SE 0.04) and 3-year TRM was 0.07 (SE 0.01) and 0.07 (SE 0.02) for the MRDneg-low patients and MRDpos-high, respectively.

50% developed grade I-II and 8% grade III-IV aGVHD within the MRDneg-low patients and 41% developed grade I-II and 13% grade III-IV aGVHD within the MRDpos-high patients. Cumulative incidence of cGVHD was 13% (extensive 8%, limited 5%) within the MRDneg-low and 18% (extensive 7%, limited 10%) within the MRDpos-high patients.

Multivariate. The HR of failure from any cause (1-EFS) of presenting with MRD POS-HIGH versus NEG-LOW upon HSCT was 2.03 (p-value < 0.0001), of having developed aGVHD grade I-II versus absent was 0.72 (p-value 0.046), or of having developed aGVHD grade III-IV versus absent was 1.61 (p-value 0.03), after adjustment for age (>10 years versus 10 years or younger, n.s.), immunophenotype (B-lineage vs others, n.s.), remission phase (CR2 after early relapse and CR3 vs CR1 and CR after late relapse, HR 2.32, p-value < 0.0001), type of conditioning (chemo vs TBI, HR 1.75, p-value < 0.0001), type of donor (MD vs MSD, n.s.). Furthermore, age (HR 20.85, p-value 0.002) and aGVHD grade III-IV (HR 4.07, p-value < 0.0001) were associated with the HR of TRM.

Conclusions: MRD at HSCT was highly predictive of EFS and relapse and the occurrence of mild GVHD was protective for EFS.

Clinical Trial Registry: EudraCT: 2012-003032-22; ClinicalTrials.gov: NCT01949129

Disclosure: Nothing to declare regarding this abstract.

18: Paediatric Issues

O136 ACUTE GVHD IN PATIENTS ENROLLED IN THE PROSPECTIVE, INTERNATIONAL FORUM TRIAL: CLINICAL RESULTS

Pietro Merli 1, Mattia Algeri1, Ulrike Poetschger2, Peter Bader3, Marianne Ifversen4, Jerry Stein5, Petr Sedlacek6, Jochen Buechner7, Marc Ansari8, Krzysztof Kalwak9, Jean-Hugues Dalle10, Christina Peters11, Franco Locatelli1,12, Anita Lawitschka11

1IRCCS Bambino Gesù Children’s Hospital, Rome, Italy, 2CCRI, Vienna, Austria, 3Goethe University, University Hospital, Frankfurt a. Main, Germany, 4Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark, 5Schneider Children’s Medical Center of Israel, Petach Tikva, Israel, 6University Hospital Motol, Prague, Czech Republic, 7Oslo University Hospital, Oslo, Norway, 8Hopital Universitaire de Genève, Geneve, Switzerland, 9Wroclaw Medical University, Wroclaw, Poland, 10Hôpital Robert Debré, Paris, France, 11St. Anna Children’s Hospital, Vienna, Austria, 12Catholic University of the Sacred Heart, Rome, Italy

Background: Acute Graft-versus-Host Disease (aGvHD) is a major cause of morbidity and mortality after allogeneic HSCT. We analyzed the incidence, risk factors and clinical outcome of subjects experiencing aGvHD in the prospective, international phase III FORUM study which enrolled pediatric patients transplanted for ALL in CR from either a MSD or an UD (Peters et al, JCO 2021).

Methods: Patients <18 years at ALL diagnosis, 4-21 years at HSCT, in CR pre-HSCT, and with an HLA-compatible related or unrelated donor (UD) (9/10 or 10/10) were enrolled in the study and received a myeloablative conditioning either TBI-etoposide or chemo-based (thiotepa/fludarabine and busulfan or treosulfan). Patients received a homogeneous GvHD prophylaxis based on cyclosporine-A in patients transplanted from a MSD, while UD recipients also received methotrexate and antithymocyte globulin (ATLG).

Results: Between 04/2013 and 11/2022, 1438 patients were enrolled into the trial. Of these, 1323 had data available for GvHD analysis (Table 1). Cumulative incidence of all grades GvHD at 180 days was 57%; in details, it was 32% for grade II-IV and 11% for grade III-IV. The only variable associated with GvHD incidence was HLA-match, with patients transplanted from 9/10-compatible donors experiencing more frequently grade III-IV aGvHD (13% vs 8% of fully matched transplants, p = 0.03). The occurrence of aGvHD did not have an influence on the incidence of relapse (25%, 20% and 21% at 3 years for grade 0-I, II and III-IV, respectively), while patients developing grade III-IV aGvHD had a higher non-relapse mortality as compared to the other patients (17% at 3 years versus 2% and 5% for grade 0-I and II, respectively; p < 0.001). This translated into better survival for patients with grade 0-I and grade II aGvHD: indeed, 3-year OS was 80%, 84% and 69% for grade 0-I, II and III-IV aGvHD, respectively (p = 0.009), while, for the same groups, EFS was 72%, 75% and 61% (p = 0.02). Finally, we confirm that the occurrence of aGvHD is associated with the incidence of chronic GvHD (cGvHD). In details, the 3-year cumulative incidence of cGvHD was 8%,20% and 27% for patients with grade 0-I, II and III-IV aGvHD, respectively (p < 0.001). Moreover, the cumulative incidence of extensive cGvHD was similar for patients who experienced grade II or grade III-IV aGvHD (13% and 10%, respectively), while it was lower for patients who had grade 0-I aGvHD (2%; p < 0.001).

Conclusions: For children transplanted for ALL from a 9/10 or 10/10 matched donor after a myeloablative conditioning, grade III-IV aGvHD is associated with higher NRM and inferior OS and EFS. Moreover, we observed that a higher grade of aGvHD correlated with an increased risk of developing cGvHD. Given the association in univariate analysis of grade III-IV aGvHD and 9/10 matched HSCT, not paralleled by a reduction of disease relapse, more efficacious strategies for GvHD prophylaxis strategies are warranted in patients transplanted with a donor other than HLA fully matched.

Clinical Trial Registry: EudraCT: 2012-003032-22; ClinicalTrials.gov: NCT01949129

Disclosure: None related to the present study.

18: Paediatric Issues

O137 CLINICAL, MICROBIOLOGICAL CHARACTERISTICS AND OUTCOME OF BLOODSTREAM INFECTIONS IN PEDIATRIC HCT RECIPIENTS: RETROSPECTIVE MULTICENTER, ANALYSIS BY INFECTION WORKING GROUP OF ITALIAN PEDIATRIC HEMATOLOGY ONCOLOGY ASSOCIATION

Francesco Baccelli 1, Daniele Zama1, Paola Muggeo2, Rosamaria Mura3, Maura Faraci4, Federica Barzagho5, Monica Cellini6, Antonella Colombini7, Elisabetta Calore8, Francesca Compagno9, Katia Perruccio10, Laura Luti11, Raffaella De Santis12, Manuela Spadea13, Giulia Caddeo14, Gloria Tridello14, Simone Cesaro15

1IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy, 2Azienda Ospedaliero Universitaria Policlinico, Bari, Italy, 3Azienda Ospedaliera Brotzu, Cagliari, Italy, 4IRCCS Istituto Giannina Gaslini, Genova, Italy, 5IRCCS San Raffaele Scientific Institute, Milano, Italy, 6Azienda Ospedaliero Universitaria Modena, Modena, Italy, 7Ospedale San Gerardo, Monza, Italy, 8University of Padova, Padova, Italy, 9IRCCS Policlinico San Matteo, Pavia, Italy, 10Santa Maria della Misericordia Hospital, Perugia, Italy, 11Azienda Ospedaliero Universitaria Pisana, Pisa, Italy, 12Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy, 13University of Torino, Torino, Italy, 14Azienda Ospedaliera Universitaria Integrata, Verona, Italy, 15Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy

Background: Bloodstream infections (BSIs) are a major cause of mortality and morbidity in pediatric patients undergoing HCT. The incidence of antibiotic resistance, particularly multidrug resistant (MDR) pathogens, represents an emerging relevant issue.

Methods: We retrospectively collected clinical and microbiological data of febrile BSI episodes with documented bacteremia occurring in pediatric HCT recipients among twelve AIEOP transplant centers during a 2 years period (2018-2019).

Results: We included 85 patients (M/F = 50/35) with median age of 9 years (0.4-18) at HCT. The indication of HCT was an underlying malignant disease in 55 patients (65%). One-hundred bloodstream infections (BSI) were reported, with a prevalence of 5 cases per 1000 days of hospitalization. Apart from fever > 38°C, other specific characteristics of BSI episodes were high-grade of fever ( > 39°C), hypoxemia (SpO2 < 91%), hypotension (TAS < 90 mmHg) and seizures in 23, 12, 11 and 1 cases, respectively. The risk factors for BSI and the list of the bacteria cultured form the blood are showed in the Table. One-hundred seventeen pathogens were isolated in blood cultures, including 60 (51%) Gram positive (most frequent species S. epidermidis, S. aureus and E. faecalis) and 57 (49%) Gram negative (most frequent species E. coli and K. pneumoniae) bacteria. Gram positive bacteria resulted resistant to oxacillin, ampicillin, clindamycin and daptomycin in 69%, 68%, 21% and 3% of cases, respectively, while no resistances to vancomycin and linezolid was documented. Gram negative strains were resistant to 3rd-4th generation cephalosporins, quinolones, piperacillin-tazobactam, aminoglycosides and carbapenems in 31%, 30%, 27%, 13% and 12% of cases, respectively. Among gram-negative bacteria, the prevalence of multiple antibiotic resistance (MDR strains) was 13%. Nine (10,6%) patients died by 30-day post HCT, 6 (7,1%) of them due to infection and 3 (3,5%) due to disease progression.

Table. Clinical and microbiological details of included BSI episodes in pediatric HCT recipients, CONS, coagulase-negative staphylococci

Risk factors for BSI in HCT patients

n = 100

Isolated bacteria

n = 117

Presence of CVC / urinary cathether

97 / 2

Staphylococcus epidermidis / other CONS

12 / 15

Intestinal colonization

12

S. Aureus

6

Neutropenia < 500/mmc /<100/mmc

64 / 58

Streptococci

14

Steroid therapy (previous 7 days)

28

Enterococcus faecium/faecalis

8

Antibacterial prophylaxis

36

Other gram-positive ¶

5

Antifungal prophylaxis

81

Escherichia coli

16

Antiviral prophylaxis

84

Klebsiella pneumonia

13

Acute GVHD g I-II / g III-IV

8 / 7

Pseudomonas aeruginosa

9

Chronic GVHD limited / extensive

4 / 7

Other gram-negative †

19

  1. ¶ including Corynebacterium tubercolostearicum, Corynebacterium jeikeium, Bacillus cereus, Micrococcus luteus, Lysteria Monocytogenes
  2. † including Enterobacter cloacae, Enterobacter kobei, Burkholderia cepacian, Acinetobacter ursingii, Acinetobacter iwoffii, Strenotrophomonas maltophilia, Proteus mirabilis, Rhizobium radiobacter, Leptotrichia, Neisseria mucosa

Conclusions: This retrospective study showed that short-term attributable mortality due to BSI is 7.1% and that BSIs by MDR strains were 13%, while the antibiotic resistance to a single class of antibiotics, used in empiric therapy, ranged from 31% to 12%. These data are in favor of an empiric antibiotic therapy based on the combination of 2 or more antibiotics followed by de-escalation policy, to avoid the risk of inappropriate antibiotic monotherapy in the first 48-96 hours of treatment or until the results of blood cultures are known. Comprehensive microbiological epidemiology surveillance represents an essential tool for the management of bacterial infections in pediatric HCT recipients.

Disclosure: Nothing to declare

18: Paediatric Issues

O138 FACTORS INFLUENCING IMMUNE RECOVERY (IR) AFTER HAEMATOPOIETIC STEM CELL TRANSPLANT (HSCT) IN 114 PATIENTS WITH SEVERE COMBINED IMMUNODEFICIENCY (SCID)

Andrea Meinhardt 1,2, Rachel Pearce3, Arnold Awuah1, Mercedes Selby1, Kimberly Gilmour1,4, Daisy Shillingford5, Emma Gravett5, Susanne Kricke5, Stuart Adams5,4, Kanchan Rao1,4, Reem Elfeky1,4

1Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom, 2University Children’s Hospital, Giessen, Germany, 3British Society for Blood and Marrow Transplantation, Guy’s and St. Thomas’ NHS Foundation Trust, London, United Kingdom, 4UCL Great Ormond Street Institute of Child Health, London, United Kingdom, 5SIHMDS-Haematology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom

Background: We investigated factors affecting IR in 114 SCID patients transplanted at Great Ormond Street Hospital.

Methods: 157 patients with SCID received first HSCT between 2000-2018. Patients who were alive at 1-year post-HSCT, available for follow-up, have no prior gene therapy or known thymic defect were included in the analysis (n = 114). We studied factors affecting IR, 10-year overall survival (OS) and event free survival (EFS). Factors studied included patient, disease, HSCT and donor characteristics, post-HSCT complications and chimerism. Lymphocyte subsets, immunoglobulin (Ig) levels were analysed at 1, 3, 5 and 10 years post-HSCT. We investigated IR time points, median time to CD4 ≥ 300/µl, CD4 ≥ 500/µl, CD3 ≥ 1000/µl and Ig independence at last follow-up. For multivariate models, variables statistically significant (p < 0.05) in the univariate analysis were included with backward stepwise selection using Cox regression (table 1, only significant shown).

Results: Ten-year OS and EFS were 95% (CI:89-98%) and 84% (CI:76-90%) respectively in this cohort with a median age at HSCT of 7 months and median follow-up of 12.8 years post-HSCT. Age at HSCT was <3 months in 21%; 67% were males. IL2RG (20%), RAG (20%) and ADA (19%) were the most frequent genotypes;10% had Omenn phenotype. 77/114(68%) had matched donors, 56% received preparative conditioning regimen, 37% received serotherapy. 91 patients had GVHD prophylaxis. Incidence of significant aGVHD, cGVHD and autoimmunity in the first-year post-transplant was 38%, 18% and 10% respectively. The median time to CD3 ≥ 1000/µl, CD4 ≥ 300/µl and independence from Ig replacement therapy (IgRT) for the entire cohort was 214, 117 and 528 days respectively. At last follow-up, 20 patients were still on IgRT. In multivariate analyses, age at HSCT ≤ 3 months (HR 2.9, p = 0.002) and cord transplant (HR 2.54, p = 0.001) were associated with quicker CD4 count recovery ≥300/µl, while use of serotherapy and treatment with Rituximab (HR 0.36, p = 0.001) were associated with delayed CD4 recovery. Of note, 20/23 cords were infused without serotherapy. Age at HSCT of ≤3 months (HR 0.42, p = 0.008) was associated with earlier CD3 counts of ≥1000/µl. Use of steroids >3 months was associated with delayed CD3 recovery (HR 0.47, p = 0.003).Time to reach Ig independence was negatively influenced by presence of aGvHD of any grade (HR 0.5, p = 0.007) and by Rituximab therapy (HR 0.5, p = 0.05). SCID genotype, Omenn syndrome, conditioned HSCT, blood viral infections, autoimmunity in the first-year post-HSCT and level of CD15 chimerism did not influence IR. Autoimmunity within the first year post-HSCT was associated with inferior 10-year OS (60% vs 99%; HR 35.9, p = 0.002). EFS at 10 years (but not OS) was significantly better in those who attained CD4 > 300/µl within 6 months post-HSCT (96% vs 84%, p = 0.018) and was negatively impacted following Rituximab (71% vs 90%; HR 12.2, p = 0.001) and in presence of low levels of donor CD3 engraftment (HR 0.95, p = 0.001).

Full size table

Conclusions: Transplanting SCID patients before the age of 3 months was associated with quicker immune recovery of CD3 and CD4 cells. Treatment with Rituximab was associated with delayed Ig independence and worse 10-year EFS. Autoimmunity in the first year had a negative impact on OS.

Disclosure: Nothing to declare.

18: Paediatric Issues

O139 HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR SICKLE CELL DISEASE IN CHILDREN USING THIOTEPA-BUSULFAN-FLUDARABINE CONDITIONING WITHOUT SEROTHERAPY IN 101 MATCHED RELATED DONOR TRANSPLANTS –A SINGLE-CENTER STUDY

Mohammed Essa 1,2,3, Rodaina Abujoub1, Shahbaz Memon1, Abdulaziz AlSaud1, Nada AlShaikh1, Enas Elbashir1, Abdulrahman Alsultan4

1King Abdulaziz Medical City - MNGHA, Riyadh, Saudi Arabia, 2King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia, 3King Abdullah International Medical Research Center and Saudi Society of Blood and Marrow Transplantation, Riyadh, Saudi Arabia, 4King Saud University, Riyadh, Saudi Arabia

Background: Utilization of myeloablative conditioning (MAC) regimen in matched related donor (MRD) hematopoietic stem cell transplantation (HSCT) for sickle cell disease (SCD) is still considered the standard of care in children. Our center does not routinely include serotherapy in the preparative regimen.

Methods: We are reporting all patients who underwent HSCT for SCD using MRD at our institution using the following TBF conditioning regimen without the use of serotherapy: Thiotepa 8 mg/kg, IV busulfan weight-based dosing every 6 hours for four days, and fludarabine 160 mg/m2.GVHD prophylaxis included cyclosporin and methotrexate (10mg/m2) on days 1, 3, and 6. Calcineurin inhibitor was continued up to one year post HSCT then tapered slowly. Bone marrow was the source of stem cells in all the patients. Supportive therapy included standard SCD care, such as maintaining platelet count above 50,000/ul and administering levetiracetam for at least 6 months post HSCT.

Results: 101 patients underwent MRD HSCT with a mean age of 8.8 (2.1-14) years and 58/43 male-to-female ratio. The indications for transplant were recurrent painful crises in 32%, Stroke/CNS vasculopathy in 29%, acute chest syndrome in 22%, history of intensive care admission in 7%, recurrent splenic sequestration in 7%, and avascular necrosis in 3%. Patient and transplant characteristics are shown in the Table. The median cumulative busulfan AUC was 65.5 (50-77) mg.h/L. All patients engrafted successfully. Grade II-IV acute GVHD occurred in 4 (4%) patients who responded well to therapy. Chronic GVHD occurred in 4 (4%) patients: 3 mild and 1 moderate. CMV reactivation occurred in 28% but none had CMV disease, none had EBV reactivation that required treatment, veno-occlusive disease, mostly mild, in 15%, posterior reversible encephalopathy syndrome in 4 %, resolved bacterial infections in 4% and resolved upper respiratory viral infections (such as COVID and influenza) in 5%. One patient died on day 88 post-HSCT due to idiopathic pneumonia syndrome. 100 (99%) patients are alive and free of SCD with a median follow-up of 33 months. Full donor chimerism was present in 87% and mixed donor chimerism in 13% of patients. 13 post-pubertal females had amenorrhea.

Table 1.

Patient and Transplant Characteristics (n = 101)

Median (range) or N (%)

Median age in years

8.7 (2.1-14)

Gender (M/F)

58/43

Gender mismatch

45

ABO mismatch (major/minor)

31 (14/17)

Positive Recipient RBC Antibody screen

4

Median cumulative Busulfan AUC (mg.h/L)

65.5 (50-77)

Median Infused nucleated cell dose (X 108/kg)

4.1 (0.9-10.5)

Median Infused CD34 cell dose (X 106/kg)

6.5 (1.1-25)

Median neutrophil engraftment, days

20 (13-28)

Median platelet engraftment, days

29 (13-77)

Chimerism (whole): Full donor /Mixed donor /Graft failure

88/13/0

Acute GVHD: Grade II-IV

4

Chronic GVHD: Mild /Moderate/Severe

3/1/0

Veno-occlusive disease (VOD)

15 (12 mild, 3 moderate)

CMV reactivation/disease

28/0

Hypogonadism/Amenorrhea in post pubertal Females

13

Survival

100 (99)

Median follow up duration, months

33(4-78)

Conclusions: MRD HSCT using a TBF conditioning regimen without serotherapy was safe and effective, with no graft failure and a very low rate of GVHD. A targeted busulfan AUC of 65 mg.h/L was sufficient. It is important to conduct an extended follow-up in order to assess the long-term complications of this regimen.

Disclosure: Nothing relevant to disclose for this study.

18: Paediatric Issues

O140 POST-TRANSPLANT RELAPSE IN PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA IN THE ERA OF CAR-T CELL THERAPY. A MULTICENTER ANALYSIS OF GRUPO ESPAÑOL DE TRASPLANTE HEMATOPOYETICO Y TERAPIA CELULAR (GETH-TC) PEDIATRIC COMMITTEE

Marta Gonzalez Vicent 1, Blanca Molina1, Melissa Panesso2, David Bueno3, Antonia Pascual4, Sara Vinagre1, Yasmina Mozo3, Jose Luis Fuster5, Raquel Olivas6, Carolina Fuentes7, Monica Lopez8, Alexandra Regueiro9, Pilar Palomo10, Cristina Diaz de Heredia2

1Hospital Niño Jesus, Madrid, Spain, 2Hospital Vall de Hebron, Barcelona, Spain, 3Hospital La Paz, Madrid, Spain, 4Hospital Regional de Malaga, Malaga, Spain, 5Hospital Virgen de la Arrixaca, Murcia, Spain, 6Hospital Clínico, Valencia, Spain, 7Hospital La Fe, Valencia, Spain, 8Hospital Marques de Valdecilla, Santander, Spain, 9Hospital Clinico Universitario, Santiago, Spain, 10Hospital Central, Asturias, Spain

Background: Relapse following allogeneic hematopoietic stem cell transplant (HSCT) remains the major cause of transplant failure in acute lymphoblastic leukemia (ALL) patients. Treatment has evolved from palliative care, through salvage chemotherapy and second transplant to current situation based on immunotherapy and CAR-T cell therapy. We analyzed post-transplant relapse of pediatric ALL in 10 Spanish hospitals of Pediatric Committee of Grupo Español de Trasplante Hematopoyético (GETH).

Methods: A total of 73 children (38 male, 35 female) with ALL (median age 7 years; range; 1-21) who relapsed after an allogeneic HSCT performed since 2013 to 2021 were included in this retrospective study. ALL phenotype was B in 54 patients (74%), T in 17 (23%) and mixed phenotype in 2 (3%). Disease phase at transplant was 1st CR in 12 (16%), 2nd CR in 53 (73%) and > 2nd CR in 8 patients (11%). All patients were in hematological remission but 21 (29%) were MRD positive at time of first allogeneic HSCT. Donors were MSD in 24 cases (32%), MUD in 20 (27%), Haploidentical in 27 (37%), and CBU in 2 (4%). Conditioning was myeloablative in 62 patients (85%) and TBI-based in 17 (24%). Eleven patients (15%) had developed chronic GvHD.

Results: Median time to relapse was 7 months after transplant (range; 1-59). CAR-T cell therapy was used in 30 patients (10 preceded by chemotherapy and 3 by monoclonal antibody). CR with negative MRD was obtained in 27 CAR-T patients (90%), 2 patients died because of cytokine release syndrome and 1 did not achieve CR. Eleven out of 27 patients relapsed after CAR-T cell therapy (CI of relapse: 39 ± 11%). 18 out of 30 patients are alive in CR (DFS: 52 ± 13%). DFS was worse in patients who relapsed before 6 months than after 6 months postransplant (15 ± 6% vs 48 ± 6%, p = 0.0001).

Second allogeneic HSCT was performed in a total of 19 patients (17 using a different donor of 1st transplant). In 2 cases HSCT was used after CAR-T cell therapy. Donors were MUD in 8 cases (42%), haploidentical in 10 (53%) and 1 CBU (5%). 3 patients died of TRM (CI of TRM: 25 ± 14%). 12 patients relapsed (CI of relapse; 65 ± 11%) and 2 of them were rescued by CAR-T cell therapy. Eight out of 19 patients are alive in CR after second transplant (DFS: 38 ± 12%). No patient who relapsed before 6 months after the first transplant survived the second transplant.

Fifteen patients were treated with chemotherapy but progressed before they could receive consolidation therapy. Nine patients only received palliative care.With a median follow-up of 4 years (range; 1-8), 28/73 patients are alive, 24 of them in CR which means a DFS of 21 ± 6%.

Conclusions: 1. Patients who relapse more than 6 months after a transplant today have a real chance of being rescued with immunotherapy or a second transplant.

2. Our results suggest that treatment of relapsed ALL patients after allogeneic transplant is evolving towards cellular and immunotherapies rather than a second allogeneic HSCT.

Disclosure: No disclosures

18: Paediatric Issues

O141 COMPARISON OF EARLY IMMUNE RECONSTITUTION AFTER HAPLOIDENTICAL HSCT IN CHILDREN WITH ACUTE LEUKEMIA: PBSC WITH TCRΑΒ+/CD19+ DEPLETION VERSUS BM WITH POST-TRANSPLANT CYCLOPHOSPHAMIDE

Mariia Igonina1, Dmitriy Pershin 1, Svetlana Glushkova1, Viktoria Vedmedskaya1, Oyuna Lodoeva1, Tatiana Sozonova1, Yakov Muzalevskii1, Alexei Kazachenok1, Elena Kurnikova1, Svetlana Radygina1, Maria Ilushina1, Rimma Khismatullina 1, Larisa Shelikhova 1, Alexei Maschan 1, Michael Maschan 1, Alexandra Laberko 1

1Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation

Background: Allogeneic haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is an important and effective method of treating hematological malignancies. Posttransplant cyclophosphamide (PTCy) and depletion of TCRαβ+ cells are increasingly being utilized as a principal graft-versus-host disease (GvHD) prophylaxis strategy. It is known that, HSCT + TCRαβ depletion platform is combined with a delayed immune reconstitution (IR). In turn, using PTCy is associated with a greater occurrence of GvHD. Nowadays, few studies are devoted to comparing early IR after each of these methods. The purpose of our study was to compare features of IR of different HSCT platforms among two similar cohorts of patients transplanted at a single center.

Methods: The study included 50 patients after PBSC transplantation with the automated procedure of depletion of TCRαβ + /CD19+ cells (CliniMACS Prodigy®) (PBSC+TCRab/CD19 group) and 49 patients after bone marrow (BM) transplantation with PTCy (BM+PTCy group). All patients received their first haplo-HSCT, without ATG treatment. IR was evaluated in peripheral blood by flow cytometry on the +30, +60, +90, +120, +180, +270 and +360 days after HSCT. The unpaired Mann-Whitney test was used to compare the two groups.

Results: An earlier appearance of B lymphocytes was observed in group BM+PTCy on +60d (the median 74 cells/μl vs 0 cells/μl for PBSC + TCRαβ/CD19, p < 0,0001). Achieving values of CD19+ cells >100 cells/μl were delayed in group PBSC + TCRαβ/CD19 and reached only on +270d (142 cells/μl).

NK cells from PBSC + TCRαβ/CD19 patients’ cohort showed large concentrations up to +180d (320 cells/μl versus 179 cells/μl, p = 0,04); subsequently, the values normalized to physiological values.

Regarding T lymphocytes, there was a variable dynamics of cell persistence up to +90d (median BM+PTCy vs. PBSC + TCRαβ/CD19, 707 cells/μl vs 203 cells/μl, p = 0,0004). Achieving of CD3+ cells >1500 cells/μl was only by 1 year in a both groups. In BM+PTCy, CD8 + T cells lymphopenia persisted for a longer period up to +180d. Recovery of CD4 + T cells was delayed to +90d. Harmonization of the immunoregulatory index was not achieved in both groups for all period of observation. A significantly greater number of Treg cells per microliter was observed in BM+PTCy group up to +90d (3 cells/μl vs 6 cells/μl, p = 0,0094).

Noteworthy are the statistically significant differences in the ratio of TCRαβ/γδ lymphocytes between the groups during the entire observation period. Group PBSC + TCRαβ/CD19 did not achieve a normal relationship between TCRαβ/γδ (83%:17%). The ratio of BM+PTCy was normalized after +90d (97%:3%).

The 50th Annual Meeting of the European Society for Blood and Marrow Transplantation: Physicians - Oral Session (O009-O154) (12)

Conclusions: Our study shows important roles for stem cell source and GvHD prophylaxis in IR. In general, restoration of the individual components of the immune system occurs with different dynamics and the most pronounced differences occurs in the first 90 days after HSCT. However, some patients did not have complete IR at 360 days, which requires a more thorough study.

Disclosure: M.M. received speakers fee from Miltenyi Biotec

18: Paediatric Issues

O142 HAEMATOPOIETIC STEM CELL TRANSPLANTATION FOR TEENAGE AND YOUNG ADULT PATIENTS WITH ACUTE LEUKAEMIA IN THE UK AND IRELAND: COMPARISONS WITH CHILDREN AND ADULTS

Graham McIlroy 1, Ben Carpenter2, Rachael Hough2, Caroline Besley3, Emma Nicholson4, Persis Amrolia5, Oana Mirci-Danicar3, Caroline Furness4, Victoria Potter6, Rachel Pearce7, Julia Lee7, Clementina Abamba7, Anna Castleton8, Ram Malladi9

1University of Birmingham, Birmingham, United Kingdom, 2University College London Hospitals, London, United Kingdom, 3University Hospitals Bristol, Bristol, United Kingdom, 4The Royal Marsden, Sutton, United Kingdom, 5Great Ormond Street Hospital for Children, London, United Kingdom, 6King’s College Hospital, London, United Kingdom, 7British Society of Blood and Marrow Transplantation and Cellular Therapy, London, United Kingdom, 8The Christie, Manchester, United Kingdom, 9Cambridge University Hospitals, Cambridge, United Kingdom

Background: Teenage and young adult (TYA) patients receiving haematopoietic stem cell transplant (HSCT) have clinical and psychosocial needs that distinguish them from both younger children and older adults. In the UK, the TYA population comprises those aged between 16 and 24 years, and they are offered treatment at centralised Principal Treatment Centres for TYA care. The transplant patterns and outcomes for this unique group have not been explored.

Methods: This is a retrospective analysis of data from the British Society of Blood and Marrow Transplantation and Cellular Therapy (BSBMTCT) registry. Eligible TYA patients were aged between 16 and 24 at the time of their first transplant, and treated between 1999 and 2018 for acute lymphoblastic leukaemia (ALL) or acute myeloid leukaemia (AML). Patient, disease and transplant characteristics, transplant outcomes, and survival data underwent exploratory analysis to identify factors associated with patient outcomes. TYA patients were compared with children (aged between 1 and 15 years) and adults (25 to 39 years). Written consent for research using this routine, prospectively-collected data, entered onto the BSBMTCT registry, was gained in line with EBMT standards.

Results: A total of 515 TYA patients underwent allogeneic HSCT for treatment of ALL (median follow-up 7.5 years), 732 children and 561 adults contemporarily treated patients are included in comparative analyses (median follow-up 7 years and 7.2 years, respectively). For AML, 425 TYA patients were included (median follow-up 7.4 years), alongside 413 children and 870 adults (median follow-up 6.4 years and 7.9 years, respectively). Amongst TYA patients with ALL, 83% received myeloablative conditioning (MAC), similar to children (86%) and adults (89%); rates of total body irradiation (TBI) were also similar across the cohorts (91%, 88% and 89%, respectively). More TYA patients (85%) and children (89%) with AML received MAC, compared with adults (77%); however use of TBI was less amongst children (29%) compared with the TYA (69%) and adult (66%) cohorts.

Unadjusted overall and leukaemia-free survival were similar across all age cohorts, for both ALL and AML. Rates of non-relapse mortality were higher amongst adults compared with TYA patients treated for ALL (hazard ratio (HR) 1.43, 95% confidence interval (CI) 1.12 to 1.82) and AML (HR 1.19, 95% CI 1.04 to 1.37). There was no difference in NRM rates between TYA and paediatric cohorts. By contrast, TYA patients had higher rates of chronic graft-versus-host disease (cGvHD) than children in both ALL (HR 2.6, 95% CI 2.1 to 3.4) and AML (HR 2.3, 95% CI 1.8 to 3.1) patient groups. Rates of cGvHD suffered by TYA patients were much closer to the substantially higher burden of disease experienced by adults. Across all age groups for both ALL and AML, approximately half of NRM deaths were due to infection.

Children

ALL TYA

Adults

Children

AML TYA

Adults

Overall survival 1y

71% (68% - 74%)

71% (67% - 74%)

66% (62% - 70%)

70% (65% - 74%)

69% (65% - 74%)

67% (64% - 70%)

5y

55% (51% - 59%)

55% (51% - 60%)

51% (47% - 55%)

55% (50% - 60%)

53% (48% - 58%)

51% (48% - 54%)

10y

50% (46% - 54%)

50% (46% - 55%)

47% (43% - 52%)

53% (48% - 58%)

48% (42% - 53%)

48% (44% - 51%)

Leukaemia free survival 1y

64% (61% - 68%)

62% (58% - 66%)

59% (55% - 63%)

64% (59% - 69%)

60% (55% - 64%)

60% (57% - 63%)

5y

50% (47% - 54%)

49% (45% - 54%)

45% (41% - 50%)

51% (46% - 56%)

47% (42% - 52%)

47% (44% - 50%)

10y

47% (43% - 51%)

46% (41% - 50%)

43% (38% - 47%)

48% (43% - 53%)

43% (37% - 48%)

45% (41% - 48%)

Non-relapse mortality 100d

8% (6% - 10%)

9% (6% - 11%)

12% (10% - 15%)

6% (4% - 8%)

6% (4% - 9%)

9% (7% - 11%)

1y

17% (14% - 20%)

16% (13% - 20%)

22% (19% - 26%)

9% (7% - 12%)

12% (9% - 15%)

16% (13% - 19%)

5y

20% (18% - 24%)

21% (17% - 24%)

28% (24% - 31%)

12% (9% - 16%)

15% (11% - 18%)

21% (18% - 23%)

10y

23% (19% - 26%)

22% (18% - 26%)

30% (26% - 34%)

14% (10% - 17%)

17% (13% - 21%)

22% (19% - 25%)

Relapse rate 1y

19% (16% - 22%)

22% (18% - 26%)

18% (15% - 22%)

27% (22% - 31%)

28% (24% - 32%)

24% (22% - 27%)

5y

29% (26% - 33%)

30% (26% - 34%)

27% (31% - 23%)

37% (32% - 42%)

38% (34% - 43%)

32% (29% - 36%)

10y

30% (27% - 34%)

32% (28% - 36%)

28% (24% - 32%)

38% (33% - 43%)

40% (35% - 45%)

33% (30% - 37%)

Chronic GvHD 1y

13% (11% - 16%)

32% (28% - 37%)

39% (35% - 44%)

15% (12% - 20%)

33% (29% - 39%)

36% (32% - 40%)

5y

17% (14% - 21%)

42% (37% - 47%)

51% (46% - 56%)

22% (18% - 27%)

45% (40% - 51%)

51% (47% - 56%)

10y

20% (16% - 24%)

42% (37% - 48%)

51% (46% - 56%)

23% (19% - 29%)

47% (41% - 53%)

54% (50% - 59%)

  1. Rate (95% confidence interval)

Conclusions: In the UK and Ireland, TYA patients undergoing HSCT for ALL or AML have similar overall survival to children and adults. The high rates of cGvHD experienced by TYA patients represents an important unmet need, and the impact of transplant survivorship at a time of complex psychosocial development demands further research.

Disclosure: CB: honoraria and advisory board - Takeda, Novartis, Kite, Janssen. EN: honoraria - KITE/Gilead, Novartis, BMS/Celgene, Takeda, Sanofi, Pfizer, Amgen; grant: KITE/Gilead, DSMB-Autolus. All other authors report no conflict of interest.

18: Paediatric Issues

O143 HAPLOIDENTICAL STEM CELL TRANSPLANTATION WITH POST-TRANSPLANT CYCLOPHOSPHAMIDE IN CHILDREN AND ADOLESCENTS WITH HEMATOLOGIC MALIGNANCIES: A RETROSPECTIVE MULTICENTRIC STUDY FROM THE SFGM-TC AND THE SFCE

Charlotte Calvo*1,2, Cléo Hautefeuille* 1, Loïc Vasseur3, Charlotte Nazon4, Bénédicte Bruno5, Marc Ansari6, Arthur Sterin7, Anne Sirvent8, Audrey Grain9, Marie Angoso10, Virginie Gandemer11, Pascale Schneider12, Carine Halfon-Domenech13, Pierre-Simon Rohrlich14, Cécile Pochon15, Catherine Paillard4, Stéphanie Nguyen Quoc16, Nicole Raus17, Françoise Méchinaud1, Nathalie Dhedin3, Jean-Hugues Dalle1,2

1Robert Debré Hospital, GHU APHP Nord Université Paris Cité, Paris, France, 2INSERM UMR-976, Institut de Recherche Saint-Louis (IRSL), Paris, France, 3St-Louis Hospital, GHU APHP Nord Université Paris Cité, Paris, France, 4University Hospital of Strasbourg, Strasbourg, France, 5Jeanne de Flandre Hospital, Lille, France, 6Geneva University Hospitals, Geneva, Switzerland, 7La Timone Children’s Hospital, Marseille, France, 8University Hospital of Montpellier, Montpellier, France, 9University Hospital of Nantes, Nantes, France, 10University Hospital of Bordeaux, Bordeaux, France, 11University Hospital of Rennes, Rennes, France, 12Unviversity Hospital of Rouen, Rouen, France, 13Institut d’Hémato-Oncologie Pédiatrique (IHOP), Lyon, France, 14University Hospital L’Archet, Nice, France, 15Hôpital d’Enfants de Brabois, Vandoeuvre Les Nancy, France, 16Pitie-Salpetriere Hospital, Sorbonne University, Paris, France, 17Hôpital Lyon Sud, SFGM-TC, Lyon, France

Background: Haploidentical stem cell transplantation (Haplo-HSCT) with post-transplant cyclophosphamide (PT-Cy) is an important option for pediatric patients with hematologic malignancies without an available HLA matched sibling or unrelated donor. Its use is expanding, but pediatric transplant teams still have concerns about graft-versus-host-disease (GVHD), toxicity, and viral infections. In adults, Haplo-HSCT with PT-Cy has been largely studied and comparable results with matched unrelated donor have been published. Here, we describe the outcome of pediatric patients’ who underwent Haplo-HSCT with PT-Cy for hematologic malignancies, on behalf of the Francophone Society of bone marrow transplantation and cell-therapy (SFGM-TC) and the French Society of Pediatric Cancer (SFCE).

Methods: We retrospectively analyzed data from 86 patients who received a first Haplo-HSCT with PT-Cy under the age of 18 to treat hematologic malignancies in centers affiliated to SFGM-TC between January 2013 and December 2022. We evaluated (i) overall survival (OS), (ii) relapse free survival (RFS), (iii) cumulative incidence of relapse (CIR) and non-relapse mortality (CI-NRM) and (iv) survival without relapse nor severe graft versus host disease (GRFS) (defined by grade III-IV acute GVHD or moderate to severe chronic GVHD). We also described incidence of grade III-IV aGVHD and moderate to severe cGVHD. Finally, we investigated viral replications and infections.

Results: Median age at diagnosis and at transplant were 12.7 (interquantile range [IQR]: 5.9-16.4) and 15.0 (IQR: 9.6-17.8) years, respectively. They received Haplo-HSCT either for acute lymphoblastic leukemia (ALL) (49%), acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) (43%) or other (8%). Among ALL, AML, and MDS, 56% were in first complete remission (CR1), 41% in second or ulterior complete remission (CR2 + ) and 3% in primary refractory disease. Conditioning regimen was myeloablative (MAC) for 87%, and stem cells source was bone marrow (BM) in 69% of transplants.

Median follow-up was 28.3 (IQR:15.0-46.9) months. Cumulative incidence of day-60 neutrophil and platelet engraftment were 90.7% and 96.3% respectively. Four patients experienced primary graft failure, all had received MAC and BM allograft. The 2-y OS, RFS and GRFS were 74.8% (95%CI 65.1-86.1), 66.4% (95%CI 56.5-78.0) and 51.5% (95%CI:41.5-64.1), respectively. At 2 years, CIR was 27.5% (95%CI 17.9%-38.0%) and CI-NRM was 6.1% (95%CI 2.2%-12.7%). Cumulative incidence of grade III-IV aGVHD at day 100 and moderate and severe cGVHD at 2 years were 16.5% (95%CI 9.5%-25.1%), 9.6% (95%CI 4%-18.1%) and 1.3% (95%CI 0.1%-6.1%) respectively. Viral reactivations were reported: 12.8% of CMV, 8% of BKv, 4.6% of EBV and 27.9% >1 virus replication.

Multivariate analysis identified disease status (CR2+ vs CR1) as the only risk factor associated with significant impact on OS (HR = 12.46, 95%CI:2.5-62.1, p = 0.002), RFS (HR = 4.88, 95%CI:1.68-14.14, p = 0.003), GRFS (HR = 4.26, 95%CI:1.76-10.31, p = 0.001), and relapse (csHR=6.28, 95%CI:1.84-21.46, p = 0.003) but not NRM.

Baseline Characteristic

All patients n = 86

Female n (%)

31 (36)

Age at transplant years median [range]

15 [0,6-18,9]

Year of transplant median [range]

2020 [2013-2022]

Disease, n (%)

ALL

42 (49)

AML + SMD

32 (37) + 5 (6)

Hodgkin/JMML/CML, n (%)

3/3/1 (8)

Disease status, n (%)

70

CR1

39 (56)

CR2

29 (41)

Active disease

2 (3)

MRD pre-transplant, n (%)

59

Positive

19 (32)

Negative

40 (68)

Stem cell source, n (%)

BM

59 (69)

PBSC

27 (31)

Conditionning regimen, n (%)

RIC / MAC, n(%)

11 (12) / 75 (88)

Conclusions: Our data confirm that Haplo-HSCT with PT-Cy is a pertinent and safe clinical option for pediatric patients with high-risk hematologic malignancies requiring hematopoietic stem cell transplantation. The low non relapse mortality rate and incidence of acute and chronic GVHD are comparable to other donor sources and seem comparable to other type of T-cell depletion, notably alpha/beta CD19 depletion.

Clinical Trial Registry: Health DataHub registry number F20230327154245

Disclosure: Nothing to declare

18: Paediatric Issues

O144 SECOND HAPLOIDENTICAL HEMATOPOIETIC CELL TRANSPLANTATION (HCT) WITH POST-TRANSPLANT CYCLOPHOSPHAMIDE (PT-CY) IN CHILDREN WITH HIGH-RISK HEMATOLOGIC MALIGNANCIES RELAPSED OR GRAFT FAILURED

Francesca Gottardi1, Davide Leardini 1, Francesco Baccelli1, Tamara Belotti1, Francesca Vendemini2, Marek Ussowicz3, Simone Cesaro4, Maura Faraci5, Jean Hugues Dalle6, Adriana Balduzzi2, Francesco Saglio7, Arcangelo Prete1, Riccardo Masetti1

1Pediatric Hematology Oncology, IRCCS Azienda Ospedaliero Universitaria di Bologna, Bologna, Italy, 2Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy, 3Wroclaw Medical University, Wrocław, Poland, 4Azienda Ospedaliera Universitaria Integrata, Verona, Italy, 5Istituto G. Gaslini, Hematopoietic Stem Cell Transplantation Unit Hematology-Oncology, Genova, Italy, 6Hôpital Robert Debré, GH APHP-Nord Université de Paris, Paris, France, 7Pediatric Onco-Hematology, Stem Cell Transplantation and Cellular Therapy Division, Regina Margherita Children’s Hospital, Torino, Italy

Background: Outcome of children with high-risk hematological malignancies relapsing or experiencing graft failure (GF) after a first HCT is still unsatisfactory. A second HCT can represent a savage treatment, but finding good feasibility and timing may be an issue. Haploidentical HCT with PT-Cy as graft-versus-host disease (GvHD) prophylaxis can be rapidly appliable and easily achievable. Experience with this platform in high-risk pediatric hematologic malignancies showed efficacy and safety, but data about outcomes of second procedures are lacking.

Methods: From January 2010 to July 2023, we conducted a multicenter retrospective analysis of pediatric patients with high-risk hematological malignancies receiving a second haplo-HCT with PT-Cy, including relapse and graft failure (GF) indications. The following outcomes were evaluated: overall survival (OS), event-free survival (EFS), cumulative incidences of relapse, acute II-IV and III-IV GvHD, chronic GvHD, and transplant-related mortality (TRM). Cox proportional hazards regression was performed to test the effect of major transplant-related variables on outcomes.

Results: Forty-three patients (median age 8.8 years) were included, being acute lymphoblastic leukemia and acute myeloblastic leukemia the most frequent diagnosis, respectively in 23 (53.5%) and 10 (23.3%) patients. Twenty-nine (67.4%) were re-transplanted for relapse, and 12 for GF (27.9%), one patient for secondary malignancy and for one for indication is unknown. All children received myeloablative conditioning and PT-Cy as GvHD prophylaxis (50 mg/Kg on day+3 and +4, together with calcineurin inhibitors and mycophenolate mofetil. Source was bone marrow in 32 (74.4%) and peripheral blood stem cell (PBSC) in 11 (25.6%).

Thirty-nine (90.7%) engrafted at median 17 days, while two presented graft-failure and two early relapses. With a median follow-up of 55.9 (4.8-111.0 months), 2 years OS and EFS were 60.1% (95% CI, 44.7% to 75.5%) and 46.2% (95% CI, 30.6% to 61.8%), respectively. Incidence of relapse was 27.6% (95% CI, 16.6% to 45.7%), but separately evaluating patients re-transplanted for GF and relapse, incidence was 0% and 40.1% (25.2% to 63.5%). Day 100 TRM was 13.9% (95% CI, 6.6% to 29.3%). Only two patients died after day 100 for late infections in cGvHD (at 155 and 653 days).

Cumulative incidence of grade II-IV and III-IV aGvHD at 180 days post-HCT were 44.2% (95% CI, 31.6% to 61.8%) and 11.7% (95% CI, 5.1% to 26.7%), respectively. Cumulative incidence of cGvHD at 24 months was 33.9% (95% CI, 21.8% to 53.0%), being extensive in 25% of cases.

No differences according to stem cell source, time from the first to second HCT or type of conditioning were demonstrated on TRM, relapse, cGvHD and grade II-IV aGvHD by univariate and multivariate Cox regression. Among infectious complications, only 5/49 episodes were reported as fatal in the whole cohort. Viral reactivations were the most frequent and occurred in 28 (65.1%) of the cases, being CMV reactivation reported in 11 (25.6%).

Conclusions: Use of PT-Cy haplo-HCT as a second procedure in high-risk pediatric malignancies resulted feasible and safe, with acceptable transplant mortality rate. Efficacy was remarkable in patients transplanted for graft-failure, but was satisfactory also in relapsed, heavily pre-treated children.

Disclosure: No disclosures

18: Paediatric Issues

O145 LONG-TERM RESULTS OF RANDOMISED PHASE 2 TRIAL TO COMPARE TREOSULFAN WITH BUSULFAN BASED CONDITIONING IN CHILDREN WITH NON-MALIGNANT DISEASES

Rita Beier 1, Peter Bader2, Jan Styczynski3, Ansgar Schulz4, Johann Greil5, Dirk Reinhardt6, Johannes Schulte7, Franca Fagioli8, Bernd Gruhn9, Franco Locatelli10, Simona Piras11, Manfred Hönig4, Petr Sedlacek12, Sonia Bonanomi13, Marco Zecca14, Maurizio Caniglia15, Simone Cesaro16, J. Gozdzik17, Karl-Walter Sykora1, M. Mielcarek-Siedziuk18, Krzysztof Kalwak18

1Hannover Medical School, Hannover, Germany, 2Goethe University, Frankfurt, Germany, 3University Hospital, Bydgoszcz, Poland, 4University Medical Center Ulm, Ulm, Germany, 5University Hospital Heidelberg, Heidelberg, Germany, 6University Hospital Essen, Essen, Germany, 7Charite Campus Virchow-Klinikum, Berlin, Germany, 8Children’s Hospital Regina Margherita, Torino, Italy, 9Jena University Hospital, Jena, Germany, 10Children’s Hospital Bambino Gesú, Rom, Italy, 11Children’s Hospital Antonio Cao, Cagliari, Italy, 12University Hospital Motol, Prague, Czech Republic, 13Children’s Hospital Ospedale San Gerardo, Monza, Italy, 14Pediatric Hematology/Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, 15Children’s Hospital S. Maria della Misericordia, Perugia, Italy, 16Azienda Ospedaliera Universitaria Integrata, Verona, Italy, 17Jagiellonian University Medical College, Cracow, Poland, 18Wroclaw Medical University, Wroclaw, Poland

Background: Different myeloablative conditioning regimens are recommended for allogeneic haematopoietic stem cell transplantation (alloHSCT) in children suffering from a variety of non-malignant diseases (NMD). We present updated long-term efficacy results of the recently published (Sykora et al., Bone Marrow Transplant, 2023) prospective, open label, randomised phase 2 trial comparing treosulfan versus busulfan based preparative regimens in children with inborn errors of metabolism (IEM), primary immunodeficiencies (PID), haemoglobinopathies HBP), or bone marrow failure syndromes (BMF).

Methods: Children with NMD received treosulfan (10 [17.6%], 12 [62.7%], or 14 [19.6%] g/m2/day on Days -6, -5, -4, adapted to actual body surface area of ≤0.5, >0.5 to 1.0, or >1.0 m2) or busulfan (4.8 to 3.2 mg/kg/day on Days -7, -6, -5, -4, according to the actual body weight). Thiotepa (2 x 5 mg/kg on Day -2) was additionally administered in 84% of children. Matched sibling, family, unrelated or umbilical cord blood (MSD, MFD, MUD or UCB) donors were accepted for first alloHSCT. No formal confirmatory testing approach for efficacy was planned. This exploratory analysis is focused on engraftment, graft failures (GF), treatment-related mortality (TRM), overall survival (OS), acute and chronic Graft-versus-Host Disease (GvHD) at 3 years after alloHSCT.

Results: All of 101 treated patients (busulfan 50, treosulfan 51, median age: 5.5 years) with at least 36 (median 49) months follow-up are analysed. Randomization imbalances were seen for subjects with PID (busulfan 28, treosulfan 23) and HBP (busulfan 13, treosulfan 21). TRM at 36 months reached 14.0% (90% CI: 7.8, 24.5) after busulfan and remained at 3.9% (90% CI: 1.2, 12.0) after treosulfan (p = 0.1189, HR of 0.28, 90% CI: 0.07, 1.07), confirming the previously reported trend towards less TRM after treosulfan. OS at 36 months was 86.0% (90% CI: 75.5, 92.2) after busulfan versus 94.1% (90% CI: 85.4, 97.7) after treosulfan (p = 0.2157, HR of 0.42, 90% CI: 0.13, 1.33). Favourable cumulative incidence of primary and secondary graft failure for busulfan was confirmed: Busulfan 2 patients with IEM, 4.0% (90% CI: 0.0, 8.6) compared to finally 22.0% (90% CI: 12.3, 31.6) after treosulfan (p = 0.0338, HR of 5.59, 90% CI: 1.47, 21.22). Most of the 11 GF after treosulfan were secondary (91%) and were reported in 4/23 PID, 4/21 HGP and 3/5 BMF patients. Chronic GvHD-free survival at 36 months was 70.0% (90% CI: 57.9, 79.2) for busulfan versus 84.5% (90% CI: 72.9, 91.4) for treosulfan (p = 0.0872, HR of 0.45, 90% CI: 0.21, 0.97).

Conclusions: This comparative, explorative analysis after at least three years of follow-up revealed that children transplanted for non-malignant disorders with treosulfan-based conditioning had improved survival, including cGvHD-free survival. However, a higher risk of secondary graft failure when compared with busulfan-based conditioning was observed. Nevertheless, all but one of the 11 subjects with graft failure after treosulfan were successfully rescued and alive at last follow-up. This updated long-term evaluation confirms previously reported efficacy results analysed at 12 months after alloHSCT and contributes to reasonable clinical risk-benefit considerations on preparative treatment options for individual paediatric transplant candidates with non-malignant diseases.

Clinical Trial Registry: EudraCT number 2013-005508-33;

Clinicaltrials.gov Identifier NCT02349906

Disclosure: This study is part of the medac pediatric investigation plan for Treosulfan in HSCT. It was sponsored and fully financed by medac GmbH, Wedel, Germany.

Karl-W. Sykora: speaker fees Jazz, research and travel grants medac, travel grant Neovii;

Rita Beier: research and travel grants medac, travel grant Neovii;

Peter Bader: research grant and payment for lectures from Novartis, royalties and consulting fees from Medac, payment for lectures from Medac, Neovii and Amgen and support for attending meetings from Neovii and Medac.

Krzysztof Kalwak: speaker’s bureau: JazzPharma, medac, Novartis.

Jan Styczynski: Travel grant and conference fee: Medac.

All other co-authors have no relevant disclosures to make.

10: Stem Cell Donor

O146 YOUNG MATCHED UNRELATED DONORS SHOULD BE PRIORITIZED OVER OLDER-AGED MATCHED SIBLING DONORS AND YOUNG HAPLOIDENTICAL DONORS IN ALLOGENEIC TRANSPLANTATION WITH POST-TRANSPLANT CYCLOPHOSPHAMIDE IN RECIPIENTS ≥ 50-YEARS

Karthik Nath 1, Mei-Jie Zhang2, Matthew Bye2, Stephanie Lee3, Yung-Tsi Bolon4, Cara Benjamin5, Brian Betts6, Shahinaz Gadalla7, Steven GE Marsh8, Parinda Mehta9, Filippo Milano3, Stephen Spellman4, Hannah Choe10, Brian Shaffer1

1Memorial Sloan Kettering Cancer Center, New York, United States, 2CIBMTR® (Center for International Blood and Marrow Transplant Research), Medical College of Wisconsin, Milwaukee, United States, 3Fred Hutchinson Cancer Research Center, Seattle, United States, 4CIBMTR® (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, United States, 5University of Miami, Miami, United States, 6Roswell Park Cancer Institute, Minneapolis, United States, 7National Cancer Institute, Bethesda, United States, 8Anthony Nolan Research Institute, University College London, London, United Kingdom, London, United Kingdom, 9Cincinnati Children’s Hospital Medical Center, Cincinnati, United States, 10Ohio State Medical Center, Columbus, United States

Background: Post-transplant cyclophosphamide-based (PTCy) graft-vs-host-disease (GvHD) prophylaxis results in favorable outcomes after HLA-matched and mismatched allogeneic hematopoietic stem cell transplantation (allo-HCT). Whether younger alternative donors are superior when an older-aged, matched sibling donor (MSD) is available remains unclear. We hypothesized that use of younger alternative donors, including HLA-matched unrelated donors (MUD, HLA-8/8), HLA-mismatched unrelated donors (MMUD, HLA- ≤ 7/8), or related/haploidentical donors (haplo), would result in improved outcomes compared to older-aged, MSDs using PTCy.

Methods: This retrospective analysis accessed data from the CIBMTR database from allo-HCT recipients aged ≥50-years with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) or myelodysplastic syndromes (MDS) who underwent their first allo-HCT between 2014-2021 using an older-aged MSD (donor age: ≥50-years) or young (donor age: ≤35-years) MUD, haplo, or MMUD. All recipients of allo-HCT received PTCy-based GvHD prophylaxis. The primary endpoint was overall survival (OS). Secondary endpoints were disease-free survival (DFS), relapse, non-relapse mortality (NRM), acute and chronic GvHD, and platelet/neutrophil engraftment. A Bonferroni stepdown model was used for multiple comparison adjustment.

Results: Amongst 3,746 allo-HCT recipients (61% male; mean age, 63-years; 57% AML, 31% MDS, 12% ALL), 540 underwent allo-HCT with older-aged MSDs (mean donor age, 60-years), 1,221 with young MUDs (26-years), 1,518 with young haplo (28-years) and 467 with young MMUDs (26-years). Patient baseline characteristics were similar between donor groups (Table 1).

The estimated 5-year OS was 44% (95% CI 38-49%) with older-aged MSDs versus 52% with younger MUD (48-56%; p = 0.07), 45% with haplo (41-48%; p = 1.0) and 46% with MMUD (39-52%; p = 1.0).

On multivariable analysis, there was no significant difference in OS with older-aged MSDs versus haplo (HR 1.02, 95% CI 0.88-1.18, p = 1.0) or MMUDs (HR 1.00, 0.83-1.21, p = 1.0), and the 8% difference in OS with young MUDs did not reach statistical significance (HR 1.20, 1.03-1.41, p = 0.09).

Compared to older-aged MSD recipients, DFS was improved after young MUD allo-HCT (HR 1.21, 1.05-1.40, p = 0.048), and similar to haplo donor (HR 1.04, 0.90–1.19, p = 1.0) and MMUD allo-HCT (HR 1.07, 0.90-1.28, p = 1.0). Allo-HCT with older-aged MSDs also associated with a significantly higher relapse compared to recipients of both MUDs (HR 1.29, 1.08-1.53, p = 0.02) and haplo donors (HR 1.30, 1.10-1.54, p = 0.02).

NRM was significantly lower with older-aged MSDs versus haplo donors (HR 0.68, 0.53–0.88, p = 0.01), but there was no significant difference with MUDs (HR 1.00, 0.77-1.30, p = 1.0). Regarding young MMUDs versus older-aged MSDs, there was no significant difference in DFS, relapse or NRM. All groups had similar rates of acute and chronic GvHD, and platelet and neutrophil engraftment.

Within the younger donors, haplo donors had a significantly lower OS compared to MUDs (HR 1.18, 1.05-1.33, p = 0.04), which was driven by NRM. HLA-DPB1 matching status did not impact the primary or secondary outcomes.

Conclusions: In allo-HCT recipients aged ≥ 50-years receiving PTCy-based GvHD prophylaxis, use of a young MUD resulted in superior DFS, lower relapse and similar OS compared to an older-aged MSD, and improved OS compared to young haplo donors, suggesting a benefit of young MUDs in this setting.

Table 1: Patient Demographics

Characteristic

Older MSD

Younger MUD

Younger Haplo

Younger MMUD

Total

Patient age - median (min-max)

62.2 (50.2-77.2)

65.1 (50.2-82.2)

60.5 (50.0-82.0)

63.5 (50.0-79.1)

62.5 (50.0-82.2)

HCT-Comorbidity Index Score - no. (%)

3+

281 (52.0)

670 (54.9)

774 (51.0)

263 (56.3)

1988 (53.1)

Donor age, years - median (min-max)

59.7 (50.0-79.2)

25.8 (18.0-35.0)

28.4 (18.0-35.0)

26.3 (18.0-35.0)

28.2 (18.0-79.2)

Primary disease - no. (%)

AML

329 (60.9)

662 (54.2)

857 (56.5)

283 (60.6)

2131 (56.9)

ALL

50 (9.3)

119 (9.7)

211 (13.9)

61 (13.1)

441 (11.8)

MDS

161 (29.8)

440 (36.0)

450 (29.6)

123 (26.3)

1174 (31.3)

Time from diagnosis to transplant, days - median (Q1-Q3)

162.0 (113.0-294.0)

186.0 (136.0-293.0)

188.0 (133.0-323.0)

199.0 (144.0-337.0)

186.0 (133.0-312.0)

Conditioning regimen intensity - no. (%)

MAC

242 (44.8)

438 (35.9)

457 (30.1)

136 (29.1)

1273 (34.0)

RIC

206 (38.1)

614 (50.3)

396 (26.1)

203 (43.5)

1419 (37.9)

NMA

92 (17.0)

168 (13.8)

665 (43.8)

127 (27.2)

1052 (28.1)

Not reported

0 (0.0)

1 (0.1)

0 (0.0)

1 (0.2)

2 (0.0)

Year of transplant - no. (%)

2014-2017

175 (32.4)

175 (14.3)

415 (27.3)

80 (17.1)

845 (22.6)

2018-2021

365 (67.6)

1046 (85.7)

1103 (72.7)

387 (82.9)

2901 (77.4)

Follow-up of survivors - median (range)

36.1 (3.4-101.2)

25.6 (3.3-99.7)

36.3 (3.4-103.8)

26.7 (3.3-89.4)

35.5 (3.3-103.8)

Disclosure: Brian Betts: Research support from CTI BioPharma, VITRAC Therapeutics, and Incyte. Holds a patent (WO2019165156) for CD83 CAR T in hematologic malignancies licensed to CRISPR Therapeutics.

Stephanie Lee: NMDP Board of Directors (uncompensated)

10: Stem Cell Donor

O147 EVALUATING THE IMPACT OF ABO COMPATIBILITY ON ALLOGENEIC STEM CELL TRANSPLANTATION OUTCOMES A CONTEMPORARY AND COMPREHENSIVE STUDY FROM THE EBMT TRANSPLANT COMPLICATIONS WORKING PARTY

Mustafa Güven 1,2, Christophe Peczynski3, William Boreland3, Didier Blaise4, Régis Peffault de Latour5, Ibrahim Yakoub-Agha6, Tobias Gedde-Dah7, Urpu Salmenniemi8, Jakob Passweg9, Patrice Chevallier10, Hélène Labussière-Wallet11, Stephan Mielke12, Annoek Broers13, Patrice Ceballos14, Jennifer Byrne15, Cristina Castilla- Llorente16, Johan Maertens17, Anne Huynh18, Raffaella Cerretti19, Claude Eric Bulabois20, Gwendolyn Van Gorkom21, Charles Crawley22, Hélène Schoemans17, Olaf Penack23, Ivan Moiseev24, Zinaida Peric25

1Dr. Abdurrahman Yurtaslan Oncology Training and Research Hospital, Ankara, Turkey, 2Ankara Bilkent City Hospital, Ankara, Turkey, 3EBMT Paris Study Unit, Saint Antoine Hospital, INSERM UMR-S 938, Sorbonne University, Paris, France, 4Programme de Transplantation & Therapie Cellulaire, Marseille, France, 5Saint-Louis Hospital, BMT Unit, Paris, France, 6CHU de Lille, Lille, France, 7Oslo University Hospital, Rikshospitalet, Oslo, Norway, 8HUCH Comprehensive Cancer Center, Helsinki, Finland, 9University Hospital Basel, Basel, Switzerland, 10CHU Nantes, Nantes, France, 11Centre Hospitalier Lyon Sud, Lyon, France, 12Karolinska University Hospital, Stockholm, Sweden, 13Erasmus MC Cancer Institute, Rotterdam, Netherlands, 14CHU Saint Eloi, Montpellier, France, 15Nottingham City Hospital, Nottingham, United Kingdom, 16Gustave Roussy Cancer Campus, Villejuif, France, 17University Hospitals Leuven, Leuven, Belgium & KU Leuven - University of Leuven, Leuven, Netherlands, 18CHU - Institut Universitaire du Cancer Toulouse, Toulouse, France, 19Tor Vergata University of Rome, Rome, Italy, 20CHU Grenoble Alpes - Université Grenoble Alpes, Grenoble, France, 21University Hospital Maastricht, Maastricht, Netherlands, 22Addenbrookes Hospital Cambridge, Cambridge, United Kingdom, 23Medical Clinic, Charité Universitätsmedizin Berlin, Berlin, Germany, 24RM Gorbacheva Research Institute, Pavlov University, St Petersburg, Russian Federation, 25Rijeka University Hospital Centre, Rijeka, Croatia

Background: Up to 50% of transplantations are reported as ABO incompatible due to the independent genetic inheritance of HLA and the ABO blood group system. Despite being a topic of research since the first allo-SCT, data on the impact of ABO incompatibility remains inconclusive. In this study, we provide contemporary data on behalf of the TCWP of the EBMT, highlighting the impact of ABO compatibility on allo-SCT outcomes, with a primary endpoint being non-relapse mortality (NRM).

Methods: A total of 30,487 adult patients who underwent their first allo-SCT between 2010 and 2021, with available data on ABO compatibility between patients and donors were retrospectively analyzed using the EBMT registry. Only patients transplanted for a hematological malignancy from an identical sibling, unrelated or haploidentical donor were included. The median ages of the patients and donors were 54 (IQR 42.1-62.2) and 36 (IQR 26.8-48.6), respectively. The median follow-up was 51 months. Of all the transplantations, ABO-compatible transplants accounted for 56.3% (n = 17,173), major incompatible transplants for 18.1% (n = 5,509), minor incompatible transplants for 20.1% (n = 6,136), and bidirectional transplants for 5.5% (n = 1,669). Our study included predominantly patients with acute leukemia 57%. Among the donors, 31.7% were matched siblings, 41.2% were 10/10 HLA-matched unrelated donors, 10.7% were 9/10 HLA-mismatched unrelated donors, and 16.3% were haploidentical. Reduced-intensity conditioning was used in 58.8% (n = 17748) cases. A detailed study of population characteristics regarding ABO compatibility status were given in Table 1. The primary endpoint of the study was to evaluate NRM. Secondary endpoints were: overall survival (OS), relapse incidence, acute GvHD incidence, chronic GvHD (cGvHD) incidence at two years, and non-engraftment.

Results: In multivariate analysis, there was no significant association between the compatibility status and NRM, OS, PFS, relapse, acute GvHD (grade II-IV) and cGvHD with the compatible group as reference. Major (HR 1.00, 95% CI 0.93-1.08, p = 0.97), minor (HR 1.05, 95% CI 0.98-1.13, p = 0.16) and bidirectional incompatibilities (HR 1.03, 95% CI 0.91-1.17, p = 0.65) had no significant impact on NRM. Non-engraftment rates were significantly slightly higher in the major (HR 1.04, 95% CI 1.01-1.07, p = 0.021) and bidirectional (HR 1.09, 95% CI 1.03-1.15, p = 0.003) incompatibility groups, while severe acute GvHD occurrence was lower in major (HR 0.85, 95% CI 0.77-0.94, p = 0.001) incompatibility.

Full size table

Conclusions: Although an important number of ABO incompatible transplantations are performed, controversial data exists regarding its effects on allo-SCT and only a limited number of extensive cohorts have been published so far. Herein, we present the largest study on ABO incompatibility and allo-SCT outcomes. Our findings suggest that the impact of ABO incompatibility with modern SCT technologies has a moderate impact on engraftment and acute GVHD and no significant impact on other outcomes.

Disclosure: HS reports having received personal fees from Incyte, Janssen, Novartis, Sanofi and from the Belgian Hematological Society (BHS), as well as research grants from Novartis and the BHS, all paid to her institution and not directly related to this work. She has also received non-financial support (travel grants) from Gilead, Pfizer, the EBMT (European Society for Blood and Marrow transplantation) and the CIBMTR (Center for International Bone Marrow Transplantation Research).

10: Stem Cell Donor

O148 SUPERIOR DISEASE CONTROL WITH YOUNGER MATCHED UNRELATED DONOR VS OLDER-AGED MATCHED SIBLING DONOR IN RECIPIENTS ≥ 50-YEARS WITH ALL, AML, OR MDS USING CNI-BASED GVHD PROPHYLAXIS

Karthik Nath 1, Mei-Jie Zhang2, Matthew Bye2, Stephanie Lee3, Yung-Tsi Bolon4, Cara Benjamin5, Brian Betts6, Shahinaz Gadalla7, Steven GE Marsh8, Parinda Mehta9, Filippo Milano3, Stephen Spellman4, Brian Shaffer1, Hannah Choe10

1Memorial Sloan Kettering Cancer Center, New York, United States, 2CIBMTR® (Center for International Blood and Marrow Transplant Research), Medical College of Wisconsin, Milwaukee, United States, 3Fred Hutchinson Cancer Research Center, Seattle, United States, 4CIBMTR® (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, United States, 5University of Miami, Miami, United States, 6Roswell Park Cancer Institute, Minneapolis, United States, 7National Cancer Institute (NCI), Bethesda, United States, 8Anthony Nolan Research Institute, University College London, London, United Kingdom, London, United Kingdom, 9Cincinnati Children’s Hospital Medical Center, Cincinnati, United States, 10Ohio State Medical Center, Columbus, United States

Background: There has been a significant rise in the age of allogeneic hematopoietic stem cell transplant (HCT) recipients. Because sibling age typically correlates with patient age, clinicians are often faced with the choice of either an older-aged matched sibling donor (MSD) or younger matched unrelated donor (URD). Increasing donor age is associated with a higher incidence of inferior outcomes within donor types. We hypothesized that overall survival (OS) is better with young (18-35 years) MUD compared to older-aged, MSD in transplant recipients aged ≥50-years receiving calcineurin inhibitor (CNI)-based graft versus host disease (GVHD) prophylaxis.

Methods: We compared OS and other outcomes in recipients aged ≥50-years receiving first allogeneic HCT for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) between 2014 and 2021 reported to CIBMTR. Univariate probabilities for survival were calculated using K-M estimator. Cumulative incidence estimator for acute-GVHD (aGVHD), chronic-GVHD (cGVHD) and non relapse mortality (NRM) accommodated competing risks. Cox proportional hazards models were used to compare OS and MVA to identify risk factors. Proportional hazards for each factor were tested in a forward stepwise selection. Risk factors analyzed included: recipient age, KPS, recipient sex, recipient race/ethnicity, HCT-CI, time from diagnosis to HCT, donor age groups, donor sex, disease/disease stage, graft type, GVHD prophylaxis, conditioning intensity, CMV match, and year of HCT. We evaluated HLA-DPB1 matching status within the MUD cohort considering two groups: HLA-DPB1 matched/mismatched-permissive versus HLA-DPB1 mismatched-permissive based on the TCE system.

Results: Total 10,916 patients were included: 4,906 MSD and 6,010 MUD. Mean recipient age was 62.6 years, 59% male, 41% female; Disease: AML 56%, ALL 10%, MDS 34%. Conditioning: MAC 42%, RIC/NMA 58%. Mean donor age 60.1-years for MSD, 25.7-years MUD HLA-DP matched, and 26.1-years MUD HLA-DP non-permissive. Other baseline characteristics were well-balanced (Table 1).

OS did not significantly differ between older-aged MSD and younger MUD (HR 1.03, 95% CI: 0.97-1.09, p = 0.3703). HLA-DPB1 match/permissive vs non-permissive mismatching was not associated with OS in the MUD group. HLA-DPB1 groups were combined for the full analysis for comparison to the older MSD group. MUD showed superior DFS to MSD (HR 1.09, 95% CI: 1.04-1.15, p = 0.0012). MSD had higher relapse than MUD (HR 1.16, 95% CI: 1.08-1.24, p < 0.0001). MSD had lower rates of grade II-IV aGVHD (HR 0.82, 95% CI: 0,77-0.88, p < 0.0001). aGVHD 3-4 and cGVHD did not significantly differ. There was no significant difference in NRM. Neutrophil and platelet engraftment and graft failure rates were similar.

Conclusions: OS did not significantly differ among older-aged MSD and younger MUD when CNI-based GVHD prophylaxis was used. Younger MUD was associated with a decreased risk of relapse resulting in improved disease-free survival (DFS). Acute-GVHD 2-4 risk was higher in younger MUD, but this did not translate into increased risk of acute-GVHD 3-4, chronic-GVHD or NRM. HLA-DPB1 TCE matching was not associated with OS. Therefore, for patients ≥50-years old with AML, ALL or MDS, younger (18-35 years) MUD compares favorably to older MSD with superior disease control (improved DFS and lower relapse) and may be preferred when available.

Table 1. Demographics

Characteristic

Older MSD

Younger MUD

Total

Patient age - median (min-max)

61.5 (50.0-79.5)

63.9 (50.0-82.7)

62.7 (50.0-82.7)

HCT-Comorbidity Index Score - no. (%)

3+

2430 (49.5)

3418 (56.9)

5848 (53.6)

Donor age, years - median (min-max)

59.8 (50.0-151.8)

25.6 (18.0-35.0)

32.0 (18.0-151.8)

Primary disease - no. (%)

AML

2791 (56.9)

3331 (55.4)

6122 (56.1)

ALL

555 (11.3)

582 (9.7)

1137 (10.4)

MDS

1560 (31.8)

2097 (34.9)

3657 (33.5)

Time from diagnosis to transplant, days - median (Q1-Q3)

160.0 (113.0-266.0)

182.0 (133.0-299.0)

173.0 (124.0-287.0)

Conditioning regimen intensity - no. (%)

MAC

2290 (46.7)

2297 (38.2)

4587 (42.0)

RIC

2261 (46.1)

3391 (56.4)

5652 (51.8)

NMA

346 (7.1)

307 (5.1)

653 (6.0)

Not reported

9 (0.2)

15 (0.2)

24 (0.2)

Year of transplant - no. (%)

2014-2017

2755 (56.2)

2533 (42.1)

5288 (48.4)

2018-2021

2151 (43.8)

3477 (57.9)

5628 (51.6)

Follow-up of survivors - median (range)

49.7 (3.3-10861.4)

47.8 (3.4-107.9)

48.4 (3.3-10861.4)

Disclosure: Brian Betts: Research support from CTI BioPharma, VITRAC Therapeutics, and Incyte. Holds a patent (WO2019165156) for CD83 CAR T in hematologic malignancies licensed to CRISPR Therapeutics.

Stephanie Lee: NMDP Board of Directors (uncompensated)

10: Stem Cell Donor

O149 DONOR AGE AND CMV STATUS ARE ASSOCIATED WITH T-CELL IMMUNOPHENOTYPE IN G-CSF MOBILIZED GRAFTS: AN INITIAL ANALYSIS FROM THE DKMS AND NMDP GRAFT COMPOSITION STUDY

Hugh MacMillan1, Hans Minderman2, Ashley Spahn3, Orla Maguire2, Xiaojun Liu2, Huy Pham4, Elke Rucker-Braun5,6, Bose Falk5,6, Henning Baldauf5, Nicole Heymann5,6, Heike Uhlemann Uhlemann5,6, Lisa Heiduschke5,6, Kieran O’Loughlin2, Alexander Schmidt5, Steven Devine3, Jeffrey Auletta3, Falk Heidenreich5,6, Jay Feinberg7, Marcel van den Brink8, Evan Newell1, Johannes Schetelig5,6, Stephen Spellman3, Kate Markey 1,9

1Fred Hutchinson Cancer Center, Seattle, United States, 2Roswell Park Comprehensive Cancer Center, Buffalo, United States, 3Center for International Blood and Marrow Transplant Research, National Marrow Donor Program/Be The Match, Minneapolis, United States, 4Seattle Apheresis Collection Center, National Marrow Donor Program, Seattle, United States, 5DKMS Clinical Trials Unit, Dresden, Germany, 6University Hospital Dresden, Dresden, Germany, 7Gift of Life Marrow Registry, Boca Raton, United States, 8City of Hope, Los Angeles, United States, 9University of Washington, Seattle, United States

Background: We have established an international collaboration between the DKMS (Germany) and the National Marrow Donor Program (NMDP; USA) to immunophenotype more than 2000 donor peripheral blood stem cell (PBSC) graft products in unprecedented detail. The overarching goal of the project is to correlate immunophenotypic features with donor characteristics as well as patient outcomes, to define novel aspects of transplant biology, and to develop new graft manipulation strategies. Here we present an initial analysis of the first 355 graft products, exploring the relationships between donor features and graft phenotype.

Methods: 303 PBSC graft samples were collected, processed, freshly stained (34-color panel for immunophenotyping of lymphocytes and hematopoietic stem cells), and analyzed using an Aurora Cytek instrument at the NMDP contract laboratory (Roswell Park, Buffalo, NY). 52 additional samples were processed in the DKMS laboratory in Dresden, Germany (equivalent antibody panel and instrument). To integrate data from both the US and German analytical laboratories, we separately cluster (and then subcluster) 10-20 samples per starting population (e.g. CD4 T, CD8 T), from each site, then cluster the centroids of all batch-specific subclusters. This gives a global “metacluster” assignment for each cell, and a decomposition, in terms of cluster frequencies, for each sample. Site- and/or batch-driven technical effects were mild, and accounted for by parameter-specific mean-centering of arcsinh(MFI/500) distributions, first among files within each batch, then within site, before centering sites. Initial statistical comparisons of cluster frequencies in relation to metadata were performed using ANOVA to adjust for CMV serostatus and age).

Results: 355 total donor products were included in this interim analysis. The median donor age was 28.5 years (range 18 - 60), 41.3% were female and 35.2% were CMV positive. Within the CD8 T cell compartment, we discovered several phenotypic differences between CMV seronegative and seropositive donors. Fewer cells belonged to Cluster 1 (enriched for naïve CD8 T cells expressing CD45RA and CCR7) in CMV seropositive donors compared with CMV negative donors (age-adjusted p < 0.0001). Conversely, CD57 + TEMRA cluster 5 was enriched in donors with prior CMV exposure (age-adjusted p < 0.0001). Clusters 9 and 10, representing mucosal-associated invariant T (MAIT) cells and Vδ2 cells, were significantly reduced in CMV+ donors (p = 0.00005 and p = 0.0002 respectively). Within the CD4 compartment, we observed a similar decrease in naïve T cells with age and CMV exposure (p < 0.0001 and p = 0.004 respectively). Parallel analyses of the myeloid and HSC compartments did not reveal significant independent associations with CMV or age.

Conclusions: Initial findings from our multi-center flow cytometric data analysis demonstrate that CMV positive serostatus and younger donor age are both associated with an increased frequency of MAIT and Vδ2 cells in the graft. Within the CD4 and CD8 compartments we observed a loss of naïve T cells and a gain of CD57-expressing TEMRA with age. These findings may explain historical data relating to improved outcomes with younger donors. Sample collection is ongoing at both US and German sites and our future work will focus on relationships between graft phenotypes and patient outcomes.

Disclosure: Marcel van den Brink: has received research support and stock options from Seres Therapeutics and stock options from Notch Therapeutics and Pluto Therapeutics; he has received royalties from Wolters Kluwer; has consulted, received honorarium from or participated in advisory boards for Seres Therapeutics, Vor Biopharma, Rheos Medicines,

Frazier Healthcare Partners, Nektar Therapeutics, Notch Therapeutics, Ceramedix, Lygenesis, Pluto Therapeutics, GlaskoSmithKline, Da Volterra, Thymofox, Garuda, Novartis (Spouse), Synthekine (Spouse), Beigene (Spouse), Kite (Spouse); he has IP Licensing with Seres Therapeutics and Juno Therapeutics; and holds a fiduciary role on the Foundation Board of DKMS (a nonprofit organization).

Kate Markey: serves on the advisory board and holds equity in PosbioticsPlus Research, and she has consulted for Incyte and Crestone.

10: Stem Cell Donor

O150 COMPARING THE OUTCOMES OF USING NON-FIRST-DEGREE RELATED DONORS TO FIRST-DEGREE RELATED DONORS IN HAPLOIDENTICAL HSCT FOR HEMATOLOGICAL MALIGNANCIES: A CASE-CONTROL ANALYSIS

Yue Lu1, Jianping Zhang1, Xingyu Cao1, Min Xiong1, Yanli Zhao1, Deyan Liu1, Ruijuan Sun1, Xu Fang 1

1Hebei Yanda Lu Daopei Hospital, Langfang, China

Background: Non-first-degree (NFD) related donors are a suitable alternative option when there are no first-degree (FD) related donors available for haploidentical hematopoietic stem cell transplantation (haplo-HSCT). However, the outcomes of haplo-HSCT from NFD-related donors remain uncertain.

Methods: Between April 2012 and February 2020, our study enrolled 86 patients who underwent haplo-HSCT from NFD-related donors in our center, forming the NFD cohort. The FD cohort, comprising patients who received haplo-HSCT from FD-related donors, was randomly selected from our database to serve as controls. The matching principles were as follows: 1) patients with the same sex/type of disease/risk classification at diagnosis /disease status before HSCT as their counterparts in the NFD cohort, 2) Age difference ≤ 10 years between the FD donor and the NFD donor counterpart and 3) the transplant date for the control was within 1 year of his/her corresponding NFD patient. The ratio of NFD to FD donors was 1:2.

Results: The NFD donors consisted of 37 male cousins, 11 female cousins, 18 uncles, 12 aunts, 6 nephews, 1 niece, and 1 grandson. The patient median age was 29 (4–71) years and 25(range: 1-69) years for the NFD and FD cohorts, respectively. The primary diagnosis in both cohorts was acute myeloid leukemia (AML, 51%), acute lymphoblastic leukemia(ALL,39%), myelodysplastic syndrome(MDS, 5%), and mixed phenotype acute leukemia (MPAL, 3%). At diagnosis, 30% were categorized as standard risk and 69% as high risk. Disease status according to morphology before HSCT was 34% in the first complete remission (CR1), 34% in ≥ the second complete remission (CR2), and 24% in non-remission (NR). All patients achieved myeloid engraftment, and the 100-day cumulative platelet engraftment was [95.3%(95%CI:91.1-99.9) vs. 98.2%(95%CI:96.2-100), p = 0.200] for the NFD and FD cohorts, respectively. Median follow-up periods were 36 (11–102) for NFD and 36 (11–128) months for FD. The cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were comparable between NFD and FD groups with the 3-year CIR of [15.8%(95%CI:10.2-20.4) vs. 10.9%(95%CI:8.2-13.6)], p = 0.659] and TRM of [28.1%(95%CI:23.1-33.1) vs. 19.6%(95%CI:16.2-23.0), p = 0.072]. There were also no significant differences in overall survival (OS) and leukemia-free survival (LFS) with the 3-year OS of [63.3%(95%CI:58.0-68.6) vs. 71.5%(95%CI:67.8-75.2), p = 0.112] and LFS of [63.3%(95%CI:58.0-68.6) vs 71.5%(95%CI:67.8-75.2), p = 0.112]. The two cohorts show no difference in terms of the 100-day cumulative incidences (CIs) of grade II-IV aGVHD (NFD, 35.2%(95%CI:29.9-40.3) vs. FD, 28.5%(95%CI:25.1-31.9); p = 0.433) and grade III-IV aGVHD (NFD, 16.3%(95%CI:12-20.6) vs. FD, 12.8%(95%ci:10.1-15.5); p = 0.672) and no difference in the 3-year CIs of cGVHD (NFD, 39.3%(95CI:32.6-34.0) vs. FD, 29.1%(95%CI:25.2-34.0); p = 0.290) and moderate -serve cGVHD (NFD, 36.0% (95CI:29.3-42.7)vs. FD, 23.5%(95%CI:19.0-27.2); p = 0.147). Multivariate analysis indicated that donor type (NFD vs. FD) did not impact OS, LFS, CIR, TRM, grade II-IV aGVHD, or moderate-severe cGVHD. HCI-CI(score ≥3) [HR(95%CI),0.511(1.114-1.996), p = 0.004), disease status at NR before HSCT[HR(95%CI),1.090(1.040-1.143), p = 0.000), received CAR-T before HSCT[HR(95%CI),1.942(1.191-3.168), p = 0.008), donor age ≥40 years[HR(95%CI),0.622(1.049-2.508), p = 0.030), and second transplantation [HR(95%CI),0.528(0.297-0.939), p = 0.030) were associated with a lower LFS.

Conclusions: In haplo-HSCT for patients with hematological malignancies, NFD donors provided a feasible and important alternative when FD donors are not available, showing comparable outcomes.

Disclosure: Nothing to declare

10: Stem Cell Donor

O151 IMPACT OF HAPLOIDENTICAL OR MISMATCHED UNRELATED DONOR AGE (<35 VS >35 YEARS) ON TRANSPLANTATION WITH PTCY OUTCOMES: ON BEHALF OF THE ALWP OF THE EBMT

Arnon Nagler 1, Myriam Labopin2,3, Didier Blaise4, Emanuele Angelucci5, Jan Vydra6, Lucia Lopez Corral7, Stefania Bramanti8, Simona Sica9, Mi Kwon10, Yener Koc11, Maija Itäla-Remes12, Massimo Martino13, Alexander Kulagin14, Alessandro Busca15, Fabio Ciceri16, Mohamad Mohty2,3

1Sheba Medical Center, Division of Hematology, Tel Hashomer, Israel, 2EBMT Paris study office; Saint Antoine Hospital, Paris, France, 3Sorbonne University, Saint-Antoine Hospital, AP-HP, INSERM UMRs 938, Paris, France, 4Programme de Transplantation & Therapie Cellulaire, Marseille, France, 5Ospedale San Raffaele s.r.l., Milano, Italy, 6Institute of Hematology and Blood Transfusion, Prague, Czech Republic, 7Hospital Clínico, Salamanca, Spain, 8IRCCS Humanitas Research Hospital, Milan, Italy, 9Fondazione Policlinico Universitario A. Gemelli IRCCS, Cattolica del Sacro Cuore, Roma, Italy, 10Hospital General Universitario Gregorio Marañon, Institute of Health Research Gregorio Marañon, Madrid, Spain, 11Medicana International Hospital Istanbul, Istanbul, Turkey, 12Turku University Hospital, Turku, Finland, 13Stem Cell Transplantation and Cellular Therapies Unit (CTMO), Grande Ospedale Metropolitano “Bianchi-Melacrino-Morelli”, Reggio Calabria, Italy, 14RM Gorbacheva Research Institute, Pavlov University, Petersburg, Russian Federation, 15S.S.C.V. D Trapianto di Cellule Staminali, Torino, Italy, 16IRCCS Osspedale San Raffaele, Vita-Salute San Raffaele University Hematology and BMT, Milano, Italy

Background: Whether the choice between haploidentical (haplo) vs. mismatched) (8-9/10) unrelated donors (MMUD) for transplantation (HSCT) with post-transplant cyclophosphamide (PTCy) should be based in part on donors being younger, is unknown.

Methods: The study aimed to assess whether a younger haplo donor (yH), aged <35 years (median donor age of the study population), be preferred over an older (>35 years) MMUD (oMMUD) and vice versa, should a young MMUD (yMMUD) be preferred over an older haplo donor (oH) in AML patients (pts) undergoing HSCT in CR1 with PTCy.

Results: The first comparison included 1212 pts, 1065 (88%) yH, and 147 oMMUD. Median FU was 27.1 (IQR, 24.5-29.6) and 22.5 (IQR, 14.5-29.7) months(mos) (p < 0.0007). Median pt age was 56.5 (range 18.1-81.8) vs. 55.1 (20.2-73.3) years (p = 0.49), while the median donor age was 27.8 (range 18-35) vs. 41.8 (range 35-59.1) years. HSCTs from MMUD were performed more recently, 2020 vs. 2019 (p = 0.002). BM was the more frequent graft source in haplo 27.6% vs. 3.4% (p < 0.0001). All other pt and transplant parameters did not differ significantly between the two cohorts. In MVA, aGVHD grade II-IV was significantly lower in HSCT from yH vs. oMMUD, hazard ratio (HR) = 1.62 (95% CI 1.14-2.31, p = 0.007). All other outcome parameters including severe aGVHD, chronic GVHD, NRM, RI, LFS, OS, and GRFS did not differ. The second comparison included 1586 pts, 1315 oH and 271 yMMUD. Median FU was 31.8 (IQR, 29.9-34.2) and 19.8 (IQR, 14.9-24) mos (p < 0.0001). Median pt age was 57.9 (range 18.1-82.5) vs. 55.8 (18.1-75.6) years (p = 0.19), while the median donor age was 45 (range 35-73.3) vs. 25.8 (range 18.4-34.9) years. HSCTs from MMUD were performed more recently, 2020 vs.2019 (p = 0.002). More pts in the oH group had de novo AML 86.6% vs. 81.9% in the yMMUD group. More pts and donors in the oH group were CMV seropositive, 79.7% and 68.2% vs. 71.3% and 42.1% in the yMMUD group (p = 0.02; p < 0.0001). MAC was more frequent in the yMMUD group 53.3% vs. 46.8% in the oH group (p = 0.049). BM was more often used in haplo (27%) than in MMUD (4.4%) grafts (p < 0.0001). Other pt and transplant parameters did not differ significantly. In MVA, aGVHD grade II-IV but not grade III-IV or chronic GVHD was significantly lower in HSCT from yMMUD vs. oH, HR = 0.69 (95% CI 0.51-0.92, p = 0.013). NRM was also lower in HSCT from yMMUD vs. oH, HR = 0.6 (95% CI 0.38-0.93, p = 0.022). All other outcomes including RI, LFS, OS, and GRFS did not differ.

Conclusions: In this retrospective analysis of alternative donor HSCT with PTCy in pts with AML in CR1, comparing young haplo or MMUD vs. old MMUD or haplo donors, we demonstrated that yH donor vs. oMMUD and yMMUD vs. oH resulted in a lower incidence of grade II-IV aGVHD. In addition, transplants from yMMUD vs. oH resulted in lower NRM. Thus, a younger donor (<35 years) is preferable for alternative donor transplants, a finding that may assist in choosing an alternative donor.

Disclosure: Nothing to declare

10: Stem Cell Donor

O152 IMPACT OF GVHD PROPHYLAXIS ON THE OUTCOMES OF 8/10 HLA-MISMATCHED UNRELATED DONOR ALLOGRAFT: AN ANALYSIS ON BEHALF OF THE TRANSPLANT COMPLICATIONS WORKING PARTY OF EBMT

Ivan Moiseev 1, Mouad Abouqateb2, Christophe Peczynski2, Alessandro Busca3, Nicolaus Kröger4, Raffaella Cerretti5, Robert Zeiser6, Thomas Schroeder7, Matteo Parma8, Régis Peffault de Latour9, Wolfgang Bethge10, Jan Vydra11, Didier Blaise12, Matthias Eder13, Franca Fagioli14, William Boreland2, Hélène Schoemans15, Olaf Penack16, Zinaida Peric17

1RM Gorbacheva Research Institute, Pavlov University, Saint Petersburg, Russian Federation, 2Transplant Complications Working Party of EBMT, Saint Antoine Hospital, INSERM UMR-S 938, Sorbonne University, Paris, France, 3S.S.C.V.D Trapianto di Cellule Staminali, Torino, Italy, 4University Hospital Eppendorf, Hamburg, Germany, 5Fondazione Policlinico Tor Vergata of Rome, Rome, Italy, 6University of Freiburg, Freiburg, Germany, 7Essen University Hospital, Essen, Germany, 8Ospedale San Gerardo, Monza, Italy, 9Saint-Louis Hospital, BMT Unit, Paris, France, 10Universitaet Tuebingen, Tuebingen, Germany, 11Institute of Hematology and Blood Transfusion, Prague, Czech Republic, 12Programme de Transplantation & Therapie Cellulaire, Marseille, France, 13Hannover Medical School, Hannover, Germany, 14Ospedale Infantile Regina Margherita, Torino, Italy, 15University Hospitals Leuven and KU Leuven, Leuven, Belgium, 16Medical Clinic, Charité Universitätsmedizin Berlin, Berlin, Germany, 17Rijeka University Hospital Centre, Rijeka, Croatia

Background: Allogeneic hematopoietic cell transplantation (alloHCT) from 8/10 HLA-mismatched unrelated donor is performed in the minority of patients with no available matched related, unrelated or mismatched related donor. Due to small number of such patients, no published data exists on the outcomes and approaches to such alloHCTs. The aim of this study was to analyze the impact of GVHD prevention on outcomes for these types of allografts registered in the EBMT database.

Methods: The study analyzed the data of patients in the EBMT database matching the following criteria: adults (≥18 years) with malignant diseases and 8/10 HLA-mismatched unrelated donors, first alloHCT (bone marrow or peripheral blood) between 2005 and 2021. The study cohort comprised 884 patients with median age of 52 years (range 40-61). Patients were divided into 3 groups regarding GvHD prevention regimen: ATG +/- other drugs without PtCy (n = 621), PtCy +/- other drugs without ATG (n = 141) and those who received no in vivo T-cell depletion (TCD) (n = 122). Patients with ex vivo TCD or combination regimens for TCD were excluded. Predominant indications for alloHCT were acute myeloid leukemia (41%), acute lymphoblastic leukemia (17%) and myelodysplastic syndrome (12%). Patients with PtCy were older (p = 0.03), allografted in later years (p = 0.01) and received myeloablative conditioning less frequently (p = 0.01). Median follow-up was 4.5 years.

Results: In the whole cohort, outcomes at 4 years after transplant were as follows: overall survival (OS) - 47.5% (95%CI 43.8-51.0%), event-free survival (EFS) - 41.1% (95%CI 37.4%-44.7%), GVHD-relapse-free survival (GRFS) accounting both acute and chronic GVHD - 29.2% (95%CI 25.9-32.6%), relapse incidence - 32.1% (95%CI 28.7-35.6%) and non-relapse mortality (NRM) - 26.8% (95%CI 23.7-30%). Incidence of acute GVHD grade II-IV at 100 days was 36.9% (95%CI 33.6 - 40.3%), grade III-IV was 15.4% (95%CI 13-18%). Incidence of extensive chronic GVHD at 4 years was 18.4% (95%CI 15.6 - 21.4%).

Major causes of death included original disease (46%), infection (22%), and GVHD (19%). In the multivariate analysis (with ATG-based regimen as the reference group), prophylaxis with PTCY was associated with better OS (HR 0.70, 95%CI 0.49-1.00, p = 0.047, table), reduced incidence of grade III-IV acute GVHD (HR 0.37, 95%CI 0.17-0.81, p = 0.013) and better GRFS (HR 0.69, 95%CI 0.52-0.92, p = 0.013).

No significant differences were observed between types of GVHD prophylaxis for other outcomes (p > 0.05). The other significant factors for OS in the multivariate analysis were Karnofsky =>90% (p = 0.028), high or very high Disease Risk Index (p < 0.001) and age at alloHCT (p = 0.002). Reduced NRM in more recent alloHCTs was observed (p = 0.016), while transplantation from female donor to male recipient was associated with higher NRM (p = 0.04) (Table).

Full size table

Conclusions: AlloHCT from 8/10 HLA-matched unrelated donor is feasible for a group of patients lacking other types of donors. GVHD and infections are the major causes of relatively high NRM. Use of PTCY as GVHD prophylaxis and avoiding female donors in male recipients might improve outcomes.

Disclosure: Nothing to disclose.

10: Stem Cell Donor

O153 OLD MATCHED SIBLING DONOR VERSUS YOUNG HAPLO-IDENTICAL DONOR FOR ELDERLY PATIENTS WITH ACUTE MYELOID LEUKEMIA TRANSPLANTED IN FIRST REMISSION

Xavier Poiré 1, Myriam Labopin2,3,4,5, Emmanuelle Polge2,3,4,5, Didier Blaise6, Patrice Chevallier7, Johan Maertens8, Nicolaus Kröger9, Caroline Besley10, Stéphanie Nguyen11, Cristina Castilla-Llorente12, Gerard Socié13, Edouard Forcade14, Anne Huynh15, Igor Wolfgang Blau16, Jaime Sanz17, Simona Piemontese18, Mohamad Mohty2,3,4,5, Fabio Ciceri2,18

1Institut Roi Albert II, Cliniques Universitaires St-Luc, Brussels, Belgium, 2Acute Leukemia Working Party of the EBMT, Paris, France, 3Université Pierre et Marie Curie, Paris, France, 4INSERM UMR 938, Paris, France, 5Service d’Hématologie, Hôpital Saint-Antoine, Paris, France, 6Institut Paoli Calmette, Programme de Transplantation et Thérapie Cellulaire, Marseille, France, 7CHU Nantes, Nantes, France, 8University Hospital Gasthuisberg, Leuven, Belgium, 9University Hospital Eppendorf, Bone Marrow Transplantation Centre, Hamburg, Germany, 10University Hospitals of Bristol and Weston NHSFT, Bristol, United Kingdom, 11Université Paris IV, Hôpital la Pitié-Salpétrière, Paris, France, 12Gustave Roussy Cancer Campus, Villejuif, France, 13Bone Marrow Transplantation, Hôpital Saint-Louis, Paris, France, 14CHU Bordeaux, Hôpital Haut-Leveque, Pessac, France, 15Institut Universitaire du Cancer de Toulouse – Oncopole, Toulouse, France, 16Medizinische Klinik m. S. Hämatologie, Onkologie und Tumorimmunologie, Charité Universitätsmedizin, Berlin, Germany, 17Hospital Universitari I Politècnic La Fe, Valencia, Spain, 18IRCCS Ospedale San Raffaele, Milan, Italy

Background: Selection of a suitable donor for allogeneic hematopoetic stem cell transplantation (Allo-HCT) has been mainly relied on HLA matching, and a matched sibling donor (MSD) remains to date the first choice. However, patients with acute myeloid leukemia (AML) are older and have therefore old siblings. Donor age has been associated with worse outcomes after allo-HCT, mainly related to higher risk of graft-versus-host disease (GvHD). With the widespread use of post-transplant cyclophosphamide (PTCy), haplo-identical donors (HID) have been extensively used with impressive results, which increases the number of potential donors. As matched unrelated donor search takes time and HID are easily available, we decided to retrospectively compare old MSD over young HID donor for elderly AML transplanted in first remission (CR1).

Methods: We selected from the EBMT registry patients with AML, aged 60-year-old (yo) or older and transplanted in CR1, either from MSD aged 50 yo or older or HID younger than 40 yo. All HID received PTCy as GvHD prophylaxis and we kept only MSD receiving in vivo T-cell depletion with ATG or alemtuzumab.

Results: A total of 1247 patients were identified, including 721 MSD and 526 HID. Median patients’ age was 65 yo (Interquartile range (IQR) 62-67) and median follow-up was 24 months (IQR 22-26), significantly longer for MSD than HID. Median MSD age was 61 yo (IQR 63-67) and median HID age was 33 yo (IQR 29-37). No difference in terms of cytogenetic risk categories or secondary AML between groups. We found more female donor to male recipient in MSD, and more CMV positivity in HID. Bone marrow (BM) as stem cell source was used in 3% of MSD but 21% of HID (p < 0.0001). A myeloablative conditioning regimen was administered in 20% of the patients. ATG was used in 83% of MSD and 8% of HID.

In univariate analysis, HID was associated with lower relapse incidence (RI) (p = 0.01), higher non-relapse mortality (NRM) (p = 0.01) and higher incidence of grade II-IV acute GvHD (p = 0.01). The 2-year probability of overall survival (OS), leukemia-free survival (LFS) and graft-versus-host and leukemia-free survival (GRFS) were respectively 62.5%, 56% and 47%, without any significant difference between groups. There was no difference in severe acute and chronic GvHD between groups.In multivariate analysis, the type of donor didn’t show any impact on outcomes. Adverse cytogenetics and a diagnosis of secondary AML remain the strongest predictor of worse RI, NRM, LFS and OS. A better performance status was associated with lower NRM, which translated into better LFS, OS and GRFS. BM as stem cell source was associated with higher RI and lower LFS and OS. BM was not associated with less severe acute or chronic GvHD.

Conclusions: Based on this retrospective study, old MSD or young HID led to similar outcomes after allo-HCT in a elderly AML population in CR1. Old MSD should therefore not be excluded only based on their age and conversely, the availability of a young haploidentical donor should be considered as a valid option.

Disclosure: Nothing to declare

10: Stem Cell Donor

O154 ALTERNATIVE DONORS IN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR ACUTE MYELOID LEUKEMIA IN ADOLESCENT AND YOUNG ADULTS: A REPORT FROM THE SFGM-TC

Aude-Marie Fourmont 1,2, Ibrahim Yakoub-Agha3, Hélène Labussière-Vallet4, Johan Maertens5, Edouard Forcade6, Anne Huynh7, Xavier Poiré8, Raynier Devillier9, Cristina Castilla-Llorente10, Patrice Chevallier2, Marie-Thérèse Rubio11, Etienne Daguindau12, Philippe Lewalle13, Claude-Eric Bulabois14, Mohamad Mothy15, Nicole Raus16, Stéphanie Nguyen17, Loic Vasseur1, Nathalie Dhedin1

1Saint Louis Hospital, Assistance Publique des Hôpitaux de Paris, Paris, France, 2Nantes University Hospital, Hotel Dieu, Nantes, France, 3Lille University Hospital, Claude Hurriet, Lille, France, 4Lyon Sud University Hospital, Hospice civil de Lyon, Pierre Benite, France, 5Universitaire Ziekenhuizen Leuven, Ku Leuven, Belgium, 6Bordeaux University Hospital, Bordeaux, France, 7Toulouse University Hospital, Toulouse, France, 8Cliniques Universitaires Saint-Luc, Bruxelles, Belgium, 9Institut Paoli-Calmettes, Marseilles, France, 10Institut Gustave Roussy, Villejuif, France, 11Nancy University Hospital, Nancy, France, 12Besançon University Hospital, Besançon, France, 13Jules Bordet Institute, Bruxelles, Belgium, 14Grenoble university Hospital, Grenoble, France, 15Saint Antoine Hospital, Assistance Publique des Hôpitaux de Paris, Paris, France, 16Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC), Lyon Sud University Hospital, Pierre Benite, France, 17La Pitié Salpétrière Hospital, Assistance Publique des Hôpitaux de Paris, Paris, France

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) in children results in a low risk of transplant-related mortality (Peters JCO 2021, Pochon BBMT 2021), even with alternative donors (Shaw blood 2010, Locatelli BMT 2015, Srinivasan Transplant Cell therapy 2022, Saglio BMT 2021). In adults, alternative donor transplants are considered to be associated with higher risk of toxicity and are therefore reserved for diseases with a high risk of relapse. To date, impact of alternative donors in adolescent and young adult (AYA) population remains unclear. In this study, we compared alternative donor transplants (haplo-identical transplant [HRT] with post-transplant cyclophosphamide (PCTY) and mismatched unrelated donor [MMUT]) with matched unrelated transplant [MUT] in AYA with acute m