Pharmacogenetics of intravenous and oral busulfan in hematopoietic cell transplant recipients

Abstract

Kinetics-based dose targeting is often conducted in hematopoietic cell transplant (HCT) patients conditioned with intravenous (IV) or oral busulfan to lower rates of rejection, nonrelapse mortality, and relapse. Using the candidate gene approach, the authors evaluated whether busulfan clearance was associated with polymorphisms in the genes regulating the predominant metabolizing enzymes involved in busulfan conjugation, specifically glutathione S-transferase (GST) isoenzymes A1 (GSTA1) and M1 (GSTM1). Busulfan clearance was estimated after the morning dose on days 1, 2, and 3; each patient's average clearance was used for analyses. The average (± standard deviation) busulfan clearance was 3.2 ± 0.56 mL/min/kg in the separate population of 95 patients who received oral busulfan and 103 ± 24 ml/min/m(2) in the 57 patients who received IV busulfan. Oral busulfan clearance was associated with GSTA1 (P = .008) but not GSTM1 (P = .57) genotypes. However, among the GSTA1 haplotypes (ie, *A*A, *A*B, *B*B), there was significant overlap in the observed oral busulfan clearance and similar rates of achieving the target busulfan exposure. Clearance of IV busulfan was not associated with GSTA1 (P = .21) or GSTM1 (P = .99). These data suggest that personalizing either IV or oral busulfan dosing cannot be simplified on the basis of GSTA1 or GSTM1 genotype.

Figure 1

Figure 1a (top) and 1b (bottom) Association of Age with IV Busulfan Clearance Standardized by Body Weight (panel A) or by Body Surface Area (panel B)

Figure 2

Figure 2a (top) & 2b (bottom) Lack of Association of IV Busulfan Clearance with GSTA1 (panel 2A, p=0.208) and GSTM1 (panel 2B, p=0.986). Bars indicate mean values for each category.

Figure 3

Figure 3a (top) & 3b (bottom) Association of Oral Busulfan Clearance with GSTA1 (panel 3A, P=0.008) but not GSTM1 (panel 3B, p=0.57). Bars indicate mean values for each category.