The Use of Busulphan As Compared to Melphalan in Combination with Fludarabine in the Reduced Intensity Conditioning Improves Overall Survival in Patients with Lymphoma
Authors: Kekre Natasha , Marquez-Malaver Francisco J , Caballero Dolores , Piñana Jl , Esquirol Albert , Soiffer Robert J. , Cabrero Monica , Terol MJ , Martino Rodrigo , Antin Joseph H. , Lopez Corral L , Solano Carlos , Armand Philippe , Perez-Simon Jose A. 
Published: October 2019

Abstract
Background: While many studies have attempted to compare different GVHD prophylaxis within the reduced intensity conditioning allogeneic stem cell transplant setting (RIC SCT), few studies have been performed comparing different conditioning regimens. Due to the lack of evidence on the best RIC, the selection of the conditioning regimen is mainly based on the experience from each institution. In this study, we compared the outcomes of patients undergoing RIC SCT in 2 different settings: the Spanish Group of Transplantation (GETH), where fludarabine + melphalan (FluMel) has been the standard RIC in patients with lymphoid malignancies and Dana-Farber Cancer Institute/Brigham and Women's Hospital (DFCI/BWH), where fludarabine + busulphan (FluBu) is the standard RIC.
Patients and methods: We analyzed the outcomes of 136 patients diagnosed with lymphoma undergoing RIC with either FluBu (n=61) or FluMel (n=75) in the GETH or at DFCI/BWH between 2007 and 2014. Patient characteristics are shown in table 1. The following variables were included into the multivariable analysis: type of conditioning, GVHD prophylaxis, type of donor, age, previous transplant, and disease risk index (DRI) based on diagnosis and disease status at transplant. Median follow-up was 36 months.
Results: The cumulative incidence of grades 2-4 acute GVHD was 13% vs 36% among patients receiving FluBu vs FluMel, respectively (p=0.002). In multivariable analysis only the type of conditioning significantly influenced the risk of grades 2-4 aGVHD [HR with FluMel 7.35, (95% CI= 2.27-23.8), p=0.0008]. The cumulative risk of non-relapse mortality at 1 year was 3.3% vs 31% for FluBu vs FluMel, respectively (p<0.001). In multivariable analysis again only type of conditioning significantly influenced the risk of NRM [HR with FluMel 5.61, (95% CI= 1.57-20.03), p=0.007]. The 1y cumulative incidence of relapse was 29% with FluBu vs 10% with FluMel (p=0.08). In multivariable analysis, only prior transplantation and donor type were associated with the risk of relapse. The 3-year disease-free survival in patients receiving FluBu was 55%, vs 40% for those receiving FluMel (p=0.24). Only donor type was significant in the DFS in multivariable models. Finally, the 3y OS in the BuFlu group was 72% vs 50% for those receiving FluMel (p=0.01) (fig 1). Conditioning regimen was the only factor significantly associated with OS in multivariable analysis, HR with FluMel 2.87, (95% CI= 1.28-6.43), p=0.01].
Conclusion: In this retrospective study of patients who received a RIC SCT for lymphoma, the use of FluBu as compared to FluMel was associated with a significant decrease in non-relapse mortality and an improvement in overall survival. Acknowledging the limitations associated a retrospective study, but in the absence of prospective randomized data, our results lend support to the choice of FluBu as a conditioning regimen in this setting.
Table 1. N= 136 Flu-Bu (n= 61) Flu-Mel (n= 75) P Sex (male) 41 (67.2%) 49 (65.3%) 0.081 Age 42 (SD: 12.3) 48.2 (SD: 12.3) 0.073 Diagnosis:- Hodgkin- NHL 9 (14.8%) 52 (85.2%) 26 (34.7%) 49 (65.3%) 0.008 Type of donor:- Related- Unrelated 25 (41.0%) 36 (59.0%) 36 (48.0%) 39 (52.0%) 0.413 Source of stem cells:-BM-PB -- 61 (100%) 2 (2.7%) 73 (97.3%) 0.502 Dis status at trx:- CR- PR or active dis 31 (50.8%) 30 (49.2%) 38 (50.7%) 37 (49.3%) 0.986 GVHD prophylaxis:- CNI-MTX- SIRO-TKR 42 (68.9%) 19 (31.1%) 34 (45.3%) 41 (54.7%) 0.006 Cause of death:- GvHD- Infection- Relapse- Others 3 (15.8%) 2 (10.5%) 12 (63.2%) 2 (10.5%) 11 (28.9%) 8 (21.1%) 10 (26.3%) 9 (23.7%) 0.114
Figure 1. Figure 1. OVERALL SURVIVAL:

Disclosures
Antin: Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Armand:BMS: Research Funding; Sequenta, Inc.: Research Funding; Merck: Consultancy, Research Funding; Infinity: Consultancy, Research Funding.