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

Abstract

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 with advanced hematologic malignancies, ≤ 75 years with HLA-compatible donor were eligible. All patients received fludarabine at 30mg/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 utilized 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 transplant. Engraftment occurred in 91% and a complete response was achieved in 79% of patients post-transplant. 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 vs. other doses were: non-relapse mortality: 34% vs. 23% (p=0.4); cumulative incidence of relapse: 43% vs. 68% (p=0.02); relapse-free-survival (RFS): 25% vs. 9% (p=0.017); overall-survival (OS): 27% vs. 9% (p=0.02). We conclude that optimizing intravenous busulfan dose intensity in the preparative regimen may overcome disease associated poor prognostic factors.

Personalizing Busulfan-Based Conditioning: Considerations from the American Society for Blood and Marrow Transplantation Practice Guidelines Committee

“…However, outside of this patient population, weight-based BU dosing without TDM has been predominantly used in RIC [29][30][31][32]. In the interest of trying to determine whether BU dosing in the FLU/BU regimen had any effect on disease control, 1 group evaluated 6 different BU dose cohorts, ranging from 3.2 mg/ kg to 12.8 mg/kg, and found that the 11.2 mg/kg dose cohort, compared with all other predominantly lower dose cohorts, had improved overall survival (OS) and relapse-free survival [50]. However, another group compared 3.2 mg/kg daily to 6.4 mg/kg daily and found no difference in OS, diseasefree survival, GVHD, or NRM [29].…”

Safety and Efficacy of Once-Daily Intravenous Busulfan in Allogeneic Transplantation: A Matched-Pair Analysis

“…This difference was probably due to the less frequent use of G-CSF in our institutions due to a preference for avoiding the use of G-CSF for myeloid malignancy. Actually, previous studies reported the faster engraftment of neutrophils with the use of G-CSF in patients with ivBU1 [7,9,17]. The incidence of VOD in the ivBU4 group was significantly higher than that in the ivBU1 group.…”

Allogeneic Hematopoietic Stem Cell Transplantation after Conditioning Regimens with Fludarabine/melphalan or Fludarabine/busulfan for Patients with Hematological Malignancies: A Single-center Analysis

“…On the other hand, dose finding studies of busulfan (16) and melphalan (17) have been conducted, and the reported optimal dose were 11.2 mg/kg and 135 mg/m 2 , respectively. Therefore, the antitumor effect of busulfan may be lower than that of melphalan in the RIC allo-HSCT setting.…”

“…Fludarabinebased regimens have been used as conditioning regimens for allo-HSCT in patients who must avoid cyclophosphamide toxicity or high-dose total body irradiation (TBI). Although fludarabine-based regimens with melphalan or busulfan have been widely used (2)(3)(4)(5)(6)(7)(8), and there have been several retrospective reports comparing the two regimens (9)(10)(11), there have been no randomized, controlled trials to compare these two regimens. We believed that an understanding of the current status is important to conduct prospective trials in the future.…”