Busulfan Dose Intensity and Outcomes in Reduced-Intensity Allogeneic Stem Cell Transplantation for MDS/AML

Comparisons of myeloablative conditioning versus reduced intensity conditioning (RIC) demonstrate a tradeoff between relapse and more toxicity. Dose intensity across RIC regimens vary and may affect treatment outcomes. In this retrospective analysis, we investigated if IV busulfan dosing (total dose 3.2 mg/kg vs. 6.4 mg/kg) in fludarabine/busulfan (Flu/Bu) RIC regimens would affect outcomes in patients undergoing HCT for MDS or AML.  A total of 217 patients with MDS or AML underwent Flu/Bu RIC PBSCT from well matched related or unrelated donors at our institutions between 2004 and 2009.  135 patients received Bu1 (busulfan 0.8 mg/kg/d x 4 while 82 patients received Bu2 (busulfan 0.8 mg/kg bid x 4), both with daily fludarabine (30 mg/m2/d x 4 days).  The choice of RIC regimens was based on temporal institutional standard, enrollment on protocols, and physician choice. Patients had similar characteristics with a few notable differences: patients receiving Bu1 were younger (median age 61 vs 64, p<0.001), received more single-antigen mismatched unrelated grafts (14.1% vs. 1.2%, p<0.001), received more sirolimus based GVHD prophylaxis regimens (63% vs 45%, p < .0001), received less ATG for GVHD prophylaxis (0% vs. 22%, p < 0.001) and had less enrollment on a post-HCT clinical trial using prophylactic rituximab for the prevention of chronic GVHD (2.2% vs. 11.0%, p=0.011).  Clinical disease status was similar between the two groups.  Median follow-up for survivors was 4.4 years for Bu1 and 3.2 years for Bu2.  Due to the differences in characteristics, the two groups were compared with the adjustment of a propensity score predicting Bu2 to account for measured differences.  The day +200 cumulative incidence of grades II-IV acute GVHD (Bu1 17% vs Bu2 8.5%, HR 0.56 [0.22, 1.41], p=0.22) or grades III-IV acute GVHD (Bu1 6.7% vs. Bu2 4.9%) were not different.  The 2-year cumulative incidence of chronic GVHD (Bu1 41.5% vs Bu2 28%, HR 0.70 [0.42, 1.17], p=0.09) was not significantly different. 2-year non-relapse mortality (NRM) was similar (Bu1 8.9% vs Bu2 9.8%, HR 0.80 [0.29, 2.21], p=0.67). 2-year progression-free survival (Bu1 40.6% vs Bu2 39.3%, HR 0.82 [0.57, 1.30], p=0.33) and overall survival (Bu1 47.4% vs Bu2 48.8%, HR 0.96 [0.64, 1.44], p=0.85) were also non-significant.  Multivariate Cox model with the propensity risk score applied suggest that in a subset of patients with high clinical disease risk and non-adverse cytogenetics, the higher dose busulfan RIC regimen may be of benefit (2-year PFS, HR 0.54 [0.29, 1.03], p=.062).  For the majority of patients with MDS/AML undergoing Bu/Flu RIC PBSCT, however, the dose of busulfan (3.2 mg/kg vs 6.4 mg/kg) is not associated with significant differences in overall outcomes.