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

Dose intensification of Busulfan in the preparative regimen is associated with improved outcomes: A Phase I/II Controlled, Randomized Study.

Dose intensity is important for disease control in allogeneic stem cell transplant (AlloSCT). There is no prospective data to determine the ideal dose for intravenous busulfan to be used in reduced intensity AlloSCT.  We conducted a phase I/II controlled randomized study to determine the optimal dosing schedule of intravenous busulfan. Patients with advanced hematologic malignancies, ≤75 years with HLA-compatible donor were eligible. In the phase 1 portion, seven dose levels were explored. All patients received fludarabine at 30mg/m²/d for 4 days. Dose level 5 (11.2mg/kg) was chosen to be tested for phase II cohort. Eighty patients with a median age of 56 years were enrolled with 40% having relapsed/refractory disease. Engraftment occurred in 91% and complete response was documented in 79% patients after undergoing transplant. At a median follow up of 91 months, no significant difference was seen  in terms of non-relapse mortality of 34% for dose level 5 (11.2mg/kg) vs. 23% for all other dose levels (p=0.4). Significant improvement in cumulative incidence of relapse of 43% vs. 68% (p=0.02); relapse-free-survival of 25% vs. 9% (p=0.017) and overall-survival of 27% vs. 9% (p=0.037) (Figure 1) was demonstrated with the dose intensification of busulfan. We conclude that optimizing intravenous busulfan dose intensity in the preparative regimen leads to improvement in PFS and OS of patients with advanced hematologic malignancies and may overcome disease associated poor prognostic factors.

Figure 1