Comparative Effectiveness of Fludarabine and Busulfan Versus Fludarabine and 400 cGy Total Body Irradiation Reduced Intensity Conditioning Regimens for Allogeneic Hematopoietic Cell Transplantation for AML/MDS
Authors: Mustafa Ali Moaath , Abounader Donna M , Rybicki Lisa A. , Yurch Melissa A , Starn Jamie , Ferraro Christina , Winslow Victoria , Hamilton Betty K. , Gerds Aaron T. , Liu Hien , Dean Robert , Hill Brian T. , Pohlman Brad , Andresen Steven , Hanna Rabi , Kalaycio Matt , Bolwell Brian J. , Majhail Navneet S. , Sobecks Ronald 
Published: October 2019

Abstract
Reduced intensity conditioning for allogeneic hematopoietic cell transplantation (alloHCT) has become a standard approach for older patients and for those with co-morbidities that prohibit myeloablative conditioning. The optimal conditioning regimen for patients with AML or MDS undergoing such transplants is not clear. Therefore we performed a single center, retrospective analysis comparing busulfan (100 mg/m2/day on days -5, -4, -3, -2) and fludarabine (40 mg/m2/day on days -5, -4, -3, -2) (BuFlu) versus fludarabine (30 m2/day on days -5, -4, -3) and 400 cGy total body irradiation (200 cGy on days -1 and 0) (FluTBI) conditioning. All of the BuFlu transplants were performed as inpatient hospitalizations while all of those with FluTBI were performed as an outpatient. A total of 71 patients in two cohorts were included. The first study cohort consisted of 38 patients (23 AML, 15 MDS) who received FluTBI from 3/2004-4/2010, and the second included 33 (20 AML, 13 MDS) patients conditioned with FluBu from 6/2010-12/2013. The groups had similar disease risk and HCT comorbidity index scores. The BuFlu patients were older (median age 65 [range, 34-73] vs. 61[range, 44-70] years, P=0.03), but there were no other differences in patient or disease characteristics. All patients received peripheral blood stem cells as the graft source. The donor sources were 53% matched related (MRD) and 47% matched unrelated (MUD) for FluTBI patients and 58% MRD and 42% MUD for BuFlu patients. The BuFlu group received more red blood cell (RBC) transfusions (median 4 vs. 2, P=0.02), but there were no differences in platelet transfusion requirements. Platelet recovery was longer for patients receiving BuFlu than FluTBI (median 16 vs. 12 days, P=0.004), but there was no difference in cumulative incidence of neutrophil recovery. The respective median number of days hospitalized in the first 100 days post-transplant was 22 vs. 10 days (P<0.001) and in the first year was 40 vs. 16 days (P<0.001). Post-transplant outcomes are shown in the Table. The most common causes of death were relapse and infection for both the FluTBI (44% and 13%) and BuFlu (57% and 14%) groups. Quality of life assessments using the FACT-BMT were performed pre-alloHCT, at day 100, 6 months and 1 year. There was no difference in physical, social, emotional, and functional well-beings, additional concerns, trial outcome index or total score between the two groups at baseline or any of the follow-up timepoints. We conclude that alloHCT using FluTBI or BuFlu reduced intensity conditioning regimens results in comparable outcomes in patients with AML/MDS. The greater RBC transfusion requirement and need for inpatient hospitalization with the BuFlu regimen have implications for healthcare resource utilization. Future prospective investigation comparing these regimens with larger patient cohorts and cost-effectiveness analyses are warranted.
Table 1. Patient outcomes Variable FluTBI N (%) BuFlu N (%) P-value T-cell complete donor chimerism 29 (78) 26 (81) 0.83 Graft failure/rejection 3 (8) 3 (9) 0.87 Grade II-IV acute GvHD 13 (34) 17 (52) 0.24 Grade III-IV acute GvHD 3 (8) 6 (18) 0.21 Any Chronic GvHD 16 (42) 14 (42) 0.91 Extensive chronic GvHD 8 (21) 13 (39) 0.06 CMV reactivation 12 (32) 13 (39) 0.66 Fungal Infection 2 (5) 1 (3) 0.83 Relapse (2-years) 20 (53) 17 (52) 0.96 100 day mortality 13 (95% CI 6-29 ) 9 (95% CI 3-26 ) 0.59 Non-relapse mortality (2-years) 29 (95% CI 15-44) 29 (95% CI 14-45) 0.56 Relapse mortality (2-years) 34 (95% CI 20-49) 36 (95% CI 20-53) 0.86 Overall survival (2-years) 37 (95% CI 22-52) 35 (95% CI 19-51) 0.73

Disclosures
Majhail: Gamida Cell Ltd.: Consultancy; Anthem Inc.: Consultancy.