A Comparison of Fractionated Myeloablative Total Body Irradiation Schedules Combined with Chemotherapy As Conditioning for Allograft Bone Marrow Transplantation in Patients with Acute Leukemia: The Sarasin Study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)
Authors: Belkacemi Yazid , Labopin Myriam , Giebel Sebastian , Loganadane Gokoulakrichenane , Miszyk Leszek , Beohou Eric , Michallet Mauricette , Socie Gerard , Schaap Nicolaas PM , Cornelissen Jan J. , Yakoub-Agha Ibrahim , Mohty Mohamad , Nagler Arnon 
Published: October 2019

Abstract
Introduction
Total-body irradiation (TBI) has an historical established role in preparative regimens used before allogeneic transplant in both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). The most popular myeloablative conditioning consists of 12Gy TBI administered in 6 fractions (2Gy twice daily for 3 days) in combination with cyclophosphamide. This schedule of treatment delivery is, however, time-consuming. With limited availability of irradiation equipment, many departments in the world limit the number of patients receiving TBI due to non-medical reasons. Therefore, one of the possible solutions is to reduce the number of fractions for a similar effective dose. The aim of the SARASIN study was to analyze the impact of fractionation on outcome of patients undergoing allotransplant for ALL and AML.
Patients and methods
We retrospectively compared myeloablative TBI regimens of 3126 patients registered in the EBMT database transplanted between 2000 and 2014 for ALL (n=1783) or AML (n=1343). Pre-transplant chemotherapy consisted mainly of cyclophosphamide (Cy) in 92% and 97% of ALL and AML patients, respectively. TBI was delivered as either 12Gy in 6 fractions (group 1; ALL, n=1362 and AML, n=857), or single dose TBI (STBI) (group 2; ALL, n=54 and AML, n=79), or 9-12Gy in 2 fractions (group 3; ALL, n=173 and AML, n=256), or 12Gy in 3-4 fractions (group 4; ALL, n=194 and AML, n=151). The majority (70%-79%)* of ALL and AML (57%-79%) patients were grafted in 1stcomplete remission (CR1). The rate of transplants from unrelated donors was higher in ALL (24%-50%) as compared to AML (20%-37%) of the patients, with similar rates of non-in vitro T-cell depletion that ranged from 25% to 96% in the 4 TBI groups, respectively. Graft versus host disease (GvHD) prevention consisted mainly (75% to 89%) of cyclosporine and methotrexate.
Results
The median follow-up was 61 (1-87) months and 85 (1-192) months in the ALL and AML patients, respectively. At 5 years, leukemia free survival (LFS), overall survival (OS), relapse incidence (RI) and non-relapse mortality (NRM) were 46.5% (44.1% - 49%), 50.4% (47.9% - 52.9%), 29% (26.7% - 31.1%), 24.5% (22.5% - 26.6%) in ALL and 45.7% (43% - 48.5%), 48% (45.3% - 51%), 30.4% (28% - 33%) and 23.8% (21.5% - 26.2%), respectively. LFS at 5y in AML and ALL patients were respectively: 48% and 45%, 32% and 45%, 45% and 53%, 42% and 50% in the 4 TBI groups (p=0.082 for AML and p=0.32 for ALL). Additionally, for both AML and ALL, no statistical significance was found between the 4 TBI groups for OS (p=0.82 in ALL; p=0.11 in AML), RI (p=0.29 in ALL; p=0.23 in AML) and for NRM (p=0.58 in ALL; p=0.12 in AML). In multivariate analyses of TBI schedules, comparing the different schedules to the standard 12Gy in 6 fractions (group 1 vs group 2; group 1 vs group 3; group 1 vs group 4), fractionation was not found as independent prognostic factor neither in ALL nor in AML patients for LFS, OS, RI or NRM.
Conclusion
The SARASIN study showed that using a TBI dose of 12Gy as pre allogeneic transplantation, fractionation has no impact on relapse or survival neither in ALL, nor in AML patients. Furthermore, the reduction of the number of fractions even in this rather high total body radiation dose level is not associated with increased risk of NRM. Altogether, our data suggests that 12Gy could be delivered safely in less than 6 fractions. Late effects analyses are ongoing. Our findings are not only of considerable practical importance for radiotherapy departments but moreover it may lead to increase TBI availability as pre transplantation conditioning for leukemic patients undergoing allogeneic transplantation.

Disclosures
Michallet: Astellas Pharma: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria.