Dose Intensification of Busulfan in the Preparative Regimen is Associated with Improved Survival: A Phase I/II Controlled, Randomized Study

Dose intensity is important for disease control in patients undergoing allogeneic stem cell transplantation. We conducted a phase I/II controlled, adoptive, randomized study to determine the optimal dosing schedule of i.v. busulfan. Patients aged ≤75 years with advanced hematologic malignancies with human leukocyte antigen-compatible donor were eligible. All patients received fludarabine at 30 mg/m²/d for 4 days, and busulfan was administered in different doses in oral or i.v. formulations. As determined by the phase I trial, i.v. busulfan at a dose of 11.2 mg/kg/d was used for the phase II expansion cohort. Altogether, 80 patients with a median age of 56 years were enrolled. Forty percent had active disease at the time of transplantation. Engraftment occurred in 91%, and a complete response was achieved in 79% of patients posttransplantation. At a median follow-up of 91 months in the surviving patients, the outcomes for i.v. busulfan dose of 11.2 mg/kg/d versus other doses were as follows: nonrelapse mortality, 34% versus 23% (P = .4); cumulative incidence of relapse, 43% versus 68% (P = .02); relapse-free survival, 25% versus 9% (P = .017); and overall survival, 27% versus 9% (P = .02). We conclude that optimizing i.v. busulfan dose intensity in the preparative regimen may overcome disease-associated poor prognostic factors.