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1783 Retrospective Comparison between 12-Gray and 8-Gray Total Body Irradiation (TBI) before Allogeneic Hematopoietic Cell Transplantation in Patients with Acute Lymphoblastic Leukemia in First Complete Remission

Program: Oral and Poster Abstracts
Session: 721. Allogeneic Transplantation: Conditioning Regimens, Engraftment and Acute Toxicities: Poster I
Hematology Disease Topics & Pathways:
Lymphoid Leukemias, ALL, Adults, Non-Biological, Clinical Research, Diseases, Therapies, Registries, Lymphoid Malignancies, Radiation Therapy, Study Population
Saturday, December 11, 2021, 5:30 PM-7:30 PM

Alexandros Spyridonidis1*, Myriam Labopin2*, Bipin Savani, MD3, Sebastian Giebel, MD, PhD4*, Christoph Schmid, MD5*, Zinaida Peric, MD, PhD6*, Gesine Bug7*, Stefan Schönland8*, Nicolaus Kröger, MD9*, Matthias Stelljes, MD10, Thomas Schroeder11, Andrew McDonald, MD12*, Igor Wolfgang Blau, MD13*, Martin Bornhäuser, MD14*, Montserrat Rovira15*, Wolfgang Bethge16*, Andreas Neubauer17, Arnold Ganser, MD18, Jean-Henri Bourhis, MD19*, Matthias Edinger, MD, PhD20*, Bruno Lioure, MD21*, Gerald Wulf, MD22*, Kerstin Schaefer-Eckart23, Mutlu Arat, MD24, Ali Bazarbachi, MD, PhD25, Arnon Nagler, M.D.26 and Mohamad Mohty27

1BMT Unit, University Hospital of Patras, University of Patras, School of Medicine, Patras, Greece
2Acute Leukemia Working Party of EBMT, Paris, France
3Department of Medicine, Division of Hematology-Oncology, Vanderbilt University Medical Center, Houston, TX
4Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland
5Department of Hematology and Oncology, University Hospital Augsburg, Augsburg, Germany
6Department of Internal Medicine, University of Zagreb School of Medicine, Zagreb, Croatia
7Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt, Germany
8Department of Internal Medicine V, University Clinic Heidelberg, Heidelberg, Germany
9University Hospital Eppendorf, Hamburg, Germany
10Department of Medicine A, Hematology, Oncology and Pneumology, University of Muenster, Muenster, Germany
11Department of Hematology, Oncology and Clinical Immunology, University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
12Alberts Cellular Therapy, Pretoria East Hospital, Pretoria, South Africa
13Department of Hematology, Oncology, and Tumor Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
14Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany
15Hospital Clínic De Barcelona, Barcelona, ESP
16University of Tuebingen Medical Center, Tuebingen, Germany
17Klinik für Innere Medizin, Schwerpunkt Hämatologie, Onkologie und Immunologie, Philipps University, Marburg, Germany
18Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
19Département d’Hématologie, Institut Gustave Roussy, Villejuif, France
20Internal Medicine III, University Hospital, Regensburg, Regensburg, Germany
21Département d'Hématologie et d'Oncologie, CHU Strasbourg, Strasbourg, FRA
22Department of Hematology and Oncology, Georg-August-University of Göttingen, Göttingen, Germany
23Medical Clinic V, Hematology and Oncology, Klinikum Nuernberg, Nuernberg, Germany
24Hematopoietic Stem Cell Transplantation Unit, Sisli Florence Nightingale Hospital,, Istanbul, Turkey
25Bone Marrow Transplantation Program, Department of Internal Medicine, American University of Beirut, Beirut, Lebanon
26The Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer , Tel Aviv University, Ramat Gan, Israel
27Hematology Department, Hôpital Saint Antoine, Service d'Hématologie et Thérapie Cellulaire, Paris, France, Paris, FRA

Introduction: Total body irradiation (TBI) continues to be an important part of the conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT) in acute lymphoblastic leukemia (ALL). Previous dose escalation studies showed that higher than 12-Gray (Gy) was toxic and did not provide any apparent survival benefit - at least in patients (pts) transplanted in first complete remission (CR1) - thus establishing 12-Gy as the standard TBI dosage. Whether 8-Gy instead of 12-Gy TBI is sufficient in ALL CR1, as has been prospectively demonstrated for AML CR1 (Lancet Oncol 2012; 13: 1035–1044), has not yet been studied.

Methods: In this registry-based retrospective study of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (ALWP-EBMT), we compared outcomes of ALL-CR1 pts who underwent a matched-sibling donor (MSD) or matched-unrelated donor (MUD) allo-HCT (94% peripheral blood stem cells) with TBI-based conditioning at a total dose of 12-Gy vs 8-Gy. Patients included in this analysis had received fludarabine (Flu) as the sole chemotherapy counterpart of TBI (12-Gy vs 8-Gy TBIFlu).

Results: The median follow up for the whole cohort (n=639 pts) was 22.5 months (95% CI, 17.2-24.1) and did not differ between the 8-Gy (n=494) and 12-Gy (n= 145) TBIFlu treated pts. 25% pts had B-precursor ALL, 54% Philadelphia (Ph)-positive ALL and 21% T-ALL (p=0.008 between groups). Patients conditioned with 8-Gy TBIFlu were older than 12-Gy TBIFlu treated pts (median 55.7 vs 40.3 years, IQR 50.2-61.3 vs 27-50.2 years, <0.0001) and more frequently received in vivo T-cell depletion (71% vs 40%, <0.0001). All other characteristics were well balanced between 8-Gy vs 12-Gy groups including time from diagnosis to HCT (5.5 vs 5.8 months), Karnofksy <90% (34% vs 26%), minimal residual disease (MRD) positivity at HCT (37% vs 43%), MUD (72% vs 68%) and type of GvHD prevention. Engraftment failure was low and below 2% in both groups. Overall, 29% and 27% of 8-Gy vs 12-Gy treated patients died, with the main causes of death not differing between groups (relapse 41% vs 44%, infections 26% vs 24%, GVHD 12.6% vs 12.7%, respectively). Both in univariate and in the age-adjusted Cox proportional-hazards analysis, relapse (REL), non-relapse mortality (NRM), leukemia-free survival (LFS), overall survival (OS), and GVHD-free, relapse-free survival (GRFS) were not influenced by TBI dose (Figure 1, Table 1). These results were confirmed when we focused on pts aged <55 years (median age 47 years; 8-Gy 229 pts vs 12-Gy 131 pts). In the multivariate analysis, an incremental age of 10 years was associated with increased NRM risk (hazard ratio [HR] 1.66, 95% CI, 1.25-2.22) and reduced OS (HR 1.32, 1.09-1.59). Ph+ and T-ALL pts had significantly better survival outcomes than Ph- B-ALL pts, mainly due to significantly fewer relapses (Table 1).

Conclusion: Although there were limitations to this study (TBI dose and age were correlated; missing data on TBI fractionation; missing MRD data for nearly one-third of the pts) this retrospective analysis was able to investigate the effect of TBI total dose independently from the chemotherapy counterpart (TBIFlu regimen only) and suggests that 12-Gy and 8-Gy results in similar outcomes in ALL patients transplanted in CR1. Whether this is also true for more advanced disease (>=CR2) and/or young adults) cannot be answered, as our study included only CR1 pts, few of whom were below 25 years of age. The reduced REL risk of Ph+ B-ALL pts is probably due to the increased use of tyrosine kinase inhibitors (TKIs) pre- and post-transplant. Clinically, these results suggest 8-Gy TBI as sufficient for ALL patients transplanted in CR1 with no additional benefit of augmenting the conditioning intensity to 12-Gy, a finding which should be validated in prospective trials.

Disclosures: Spyridonidis: Menarini: Current Employment. Labopin: Jazz Pharmaceuticals: Honoraria. Giebel: Janssen: Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau. Peric: Therakos: Honoraria; servier: Honoraria; MSD: Honoraria; Astellas: Honoraria; NOVARTIS: Honoraria; Abbvie: Honoraria; Pfizer: Honoraria. Schönland: Janssen: Honoraria, Other: Travel grants, Research Funding; Pfizer: Honoraria; Prothena: Honoraria, Other: Travel grants; Takeda: Honoraria, Other: Travel grants; Sanofi: Research Funding. Kröger: Novartis: Research Funding; Riemser: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Gilead/Kite: Honoraria; Celgene: Honoraria, Research Funding; AOP Pharma: Honoraria. Stelljes: Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Kite/Gilead: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Medac: Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau. Schroeder: JAZZ: Honoraria, Research Funding. McDonald: BioCryst Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ganser: Novartis: Honoraria; Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria. Wulf: Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Clinigen: Consultancy, Honoraria. Bazarbachi: Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Hikma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

*signifies non-member of ASH