Fludarabine with pharmacokinetically guided IV busulfan is superior to fixed-dose delivery in pretransplant conditioning of AML/MDS patients.

Abstract

We hypothesized that IV Busulfan (Bu) dosing could be safely intensified through pharmacokinetic (PK-) dose guidance to minimize the inter-patient variability in systemic exposure (SE) associated with body-sized dosing, and this should improve outcome of AML/MDS patients undergoing allogeneic stem cell transplantation (allo-HSCT). To test this hypothesis, we treated 218 patients (median age 50.7 years, male/female 50/50%) with fludarabine (Flu) 40 mg/m2 once daily ×4, each dose followed by IV Bu, randomized to 130 mg/m2 (N=107) or PK-guided to average daily SE, AUC of 6,000 µM-min (N=111), stratified for remission-status, and allo-grafting from HLA-matched donors. Toxicity and graft vs. host disease (GvHD) rates in the groups were similar; the risk of relapse or treatment-related mortality remained higher in the fixed-dose group throughout the 80-month observation period. Further, PK-guidance yielded safer disease-control, leading to improved overall and progression-free survival, most prominently in MDS-patients and in AML-patients not in remission at allo-HSCT. We conclude that AML/MDS patients receiving pretransplant conditioning treatment with our 4-day regimen may benefit significantly from PK-guided Bu-dosing. This could be considered an alternative to fixed dose delivery since it provides the benefit of precise dose delivery to a predetermined SE without increasing risk(s) of serious toxicity and/or GvHD.