Comparison of Fixed Dose, Reduced-Intensity Conditioning with Busulfan and Fludarabine to Reduced PK-Guided Busulfan AUC Conditioning in Patients Undergoing Hematopoietic Stem Cell Transplant for AML/MDS

Introduction The development of reduced-intensity conditioning (RIC) regimens has allowed more patients to receive allogeneic hematopoietic stem cell transplant (HSCT) by reducing toxicities associated with myeloablative conditioning (MAC). Key in reducing conditioning regimen intensity is modification of busulfan exposure, expressed as an area under the curve (AUC). Prior studies (including BMT CTN 0901) have demonstrated RIC regimens were associated with less toxicity at the cost of potentially decreased survival relative to weight-based MAC regimens. At OSU, we have utilized an AUC target of 4,000 μmol-min/L per day × 4 days in a subset of patients to balance toxicity with risk of relapse. Here we compare outcomes of AUC 4,000 to weight-based RIC Flu/Bu2. Objectives The objectives of this study were to assess differences in safety and efficacy in patients receiving different busulfan dosing strategies. Methods To compare regimens, a retrospective cohort study was conducted of patients undergoing HSCT for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). In the AUC 4,000 group, the target busulfan exposure was 16,000 μmol-min/L divided over 4 daily doses. In the RIC group, patents received busulfan 0.8 mg/kg/dose for 8 doses (Flu/Bu2). The primary outcome was relapse free survival (RFS). Secondary outcomes included overall survival (OS); time to count recovery; incidence of acute and chronic graft vs host disease (GVHD); key adverse effects. Results Seventy-four patients were eligible. There were no differences in disease risk status, rate of AML with myelodysplastic changes, or therapy-related AML/MDS. The percent of patients with HCT-Comorbidity Index score of ≥ 3 was 52.9% for AUC 4,000 and 77.5% for RIC. At 18 months, RFS was not significantly different (p=0.37) (A). Eighteen-month overall survival was also not significantly different (p=0.63) (B). Cumulative incidence of acute and chronic GVHD were not also significantly different (p=0.82, p=0.18, respectively). There was a significant difference in the 18-month cumulative incidence of relapse in favor of AUC 4,000 (hazard ratio 4.08, 95% CI 1.15-14.5) (C). Grade 2-4 mucositis was more common in the AUC 4,000 group (p Conclusion Though no difference existed in disease risk between groups, regimen choice was driven by physician judgement, perceived fitness, and ability to tolerate toxicity. Thus, the results of this study indicate that with patient selection, there is no significant RFS or OS difference, or risk of acute or chronic GVHD between targeted AUC 4,000 and RIC. However, AUC 4,000 was associated with a significantly lower incidence of relapse. Toxicities other than mucositis were not significantly different between groups. In order to definitively compare these two conditioning regimens, a prospective study is needed.