Once Daily Busulfan Cyclophosphamide Is Well Tolerated and Effective Prior to Allogeneic Hematopoietic Stem Cell Transplantation.

The development of intravenous busulfan (Bu) allowed for the delivery of a standard daily dose of Bu to be given in one dose instead of dividing 4 times per day. Pharmacokinetic (PK) studies of Bu support the feasibility of once daily dosing and prior clinical studies found no unexpected toxicity of once daily Bu when combined with fludarabine. Based on this data we began an institutional protocol of delivering Bu once daily follwed by standard cyclophosphamide (Cy) and allogeneic hematopoietic stem cell transplantation (HCT). Only limited data in the literature describes toxicity and clinical outcomes of once daily BuCy. We report a retrospective review of our institutional data using once daily BuCy vs 4x daily BuCy and total body irradiation (TBI)/Cy in pts who received allogeneic HCT from January 2000 to December 2006. Bu 3.2mg/kg daily × 4 days followed by Cy 60mg/kg daily × 2 days was given to 42 patients (pts). Bu 0.8mg/kg/dose given 4x daily for 4 days followed by Cy 60mg/kg was given to 15 pts. Cy 60mg/kg daily for 2 days and fractionated TBI 1200 cGy delivered over 3 days was given to 60 pts. All donors were HLA matched at A, B, C, DR, and DQ and were related/unrelated in 23/19, 11/4, and 21/39 in the once daily BuCy, 4x daily BuCy, and TBI/Cy, respectively. Significantly more pts with myeloid leukemias received a BuCy regimen and significantly more pts with lymphoid malignancies received TBI/Cy. Median follow up for all pts was 370 days. VOD developed in 2 pts in the once daily BuCy group, 1 pt in the 4x daily BuCy group, and in no pts in the TBI/Cy group. Acute GVHD grade II-IV occured in 33% of the once daily BuCy pts, 53% of the 4x daily BuCy pts, and 32% of the TBI/Cy pts. Estimated actuarial transplant related mortality (TRM) and survival are described in the table below. There was no statistical difference in TRM or survival between the once daily and 4x daily BuCy groups or the total BuCy group and TBI/Cy group. The once daily BuCy group had significantly less TRM than the TBI/Cy group at 100 days (p=0.04) and at 1 year (p=0.01). The once daily BuCy group also had significantly better survival at one year compared to the TBI/Cy group (p=0.01), but this became non-significant at 3 years. The significant differences in the pt populations treated in the BuCy and TBI/Cy groups, as well as the retrospective nature of this study, limit the ability to draw conclusions comparing the groups. However, this review does demonstrate once daily BuCy and allogeneic HCT is well tolerated with no unexpected TRM, and provides good long term survival in pts with myeloid malignancies.