Personalizing Busulfan Therapy for Children Undergoing HSCT

Busulfan in Children Undergoing Hematopoietic Stem Cell Transplantation

Busulfan (BU) has been widely used as a component of conditioning regimens to prepare patients for hematopoietic stem cell transplantation (HSCT) especially in children to avoid deleterious effects of total body irradiation.^[1,2] Nevertheless, BU also holds its own disadvantages mainly due to its narrow therapeutic window, with optimal outcomes when the plasma levels are within this window.^[3,4] To avoid variability in absorption, an intravenous formulation of BU was developed for use instead of oral formulation (associated with higher risks of hepatic veno-occlusive disease or sinusoidal obstruction syndrome, pulmonary toxicity and graft-versus-host disease), which consequently gained popularity, especially in children, as pharmacokinetics (PK) was found to be more predictable after intravenous administration compared with the oral route.^[4] However, important inter-individual variability still persists and several additional factors have been hypothesized to contribute to such findings.^[5,6]

Metabolism by glutathione S-transferase (GST) is the main route of BU biotransformation. GSTA1 is the predominant GST isoform catalyzing BU conjugation with glutathione (GSH), followed by activities of GSTM1 and GSTP1, respectively.^[6] In addition to the weight, age and body surface area of the patients, inter-individual variability in BU clearance may be explained, at least in part, by GST polymorphisms influencing the enzyme activity and several polymorphisms, shown in some studies to be functional, have been identified in the GSTA1 gene.^[7] A significant number of individuals of Caucasian origin lack GSTM1 activity due to the homozygous deletion of the GSTM1 gene.^[8] Two missense variations in GSTP1 (rs1695 and rs1138272) resulting in different catalytic activities, might also alter the metabolic efficiency of this enzyme.^[8] Thus, genotyping patients for relevant polymorphisms in the genes encoding for these enzymes might further help to individualize BU dose based on the metabolic capacity of an individual.

Furthermore, in order to optimize BU treatment to be within therapeutic window, transplant centers follow therapeutic drug monitoring and subsequent dose adjustment.^[5] However, there is no consensus on the optimal therapeutic window of intravenous BU in pediatric patients; although studies have shown improved outcomes at steady-state concentrations (Css) of 600–900 ng/ml, when BU is administered in a 16-dose protocol.^[3,4,9] In our recent study we have shown that if the BU Css is in the lower part of the range (600 ng/ml), it was associated with lower toxicity and better survival, suggesting that the optimal window for BU in children might be different to that of adults.^[10] The relationship between genetic factors and BU PK has been established in few replicative studies, but clear evidence of this relationship is still debatable until this association is validated in a large and more homogeneous pediatric cohort.