Effect of glutathione S‐transferase genetic polymorphisms on busulfan pharmacokinetics and veno‐occlusive disease in hematopoietic stem cell transplantation: A meta‐analysis

Abstract

This meta-analysis was conducted to derive an integrated conclusion about the influence of glutathione S-transferase (GST) genetic polymorphisms on busulfan pharmacokinetic (PK) parameters and veno-occlusive disease (VOD). Studies which analysed the effect of GST genetic polymorphisms on area under the curve (AUC), clearance (CL) or VOD were searched for and selected. A pooled analysis was conducted using Comprehensive Meta-Analysis programme. Nineteen studies were included in this meta-analysis. GSTA1*B and GSTM1 null genotypes significantly decreased CL IV of busulfan (standardized difference in means (SDM) = −1.103; P = 0.019 and SDM = −0.418; P = 0.002, respectively). GSTA1*B significantly increased AUC IV of busulfan (SDM = 0.832; P = 0.046), whereas GSTM1 did not (SDM = 0.155; P = 0.478). The PK parameters of oral busulfan did not differ according to GST genotype. GSTA1, GSTM1 and GSTP1 were not significantly associated with VOD occurrence. GSTA1 and GSTM1 genotypes affected CL IV of busulfan, but only GSTA1 affected AUC IV . There was no significant difference in the PK parameters of oral busulfan (CL PO and AUC PO ) and VOD when only GST genotypes were considered. K E Y W O R D Sbusulfan, genetic polymorphisms, glutathione S-transferase, pharmacokinetics, veno-occlusive disease

Can First-Dose Therapeutic Drug Monitoring Predict the Steady State Area Under the Blood Concentration-Time Curve of Busulfan in Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation?

“…A total of 42 of patients were GSTM1 positive and 27 patients were neither GSTM1 positive or null; these patients could be carrying different alleles that are not detected by the genotyping assay. Previous studies reported that busulfan clearance is reduced among patients carrying GSTA1 *B/*B, GSTM1-null, and GSTP1 *A/*G ( 16 ).…”

Genetic Predictors for Sinusoidal Obstruction Syndrome—A Systematic Review

“…We identified 708 unique citations after the removal of duplicates and excluded 677 manuscripts after the title and abstract screening. After assessment of the full text, two reports on subpopulations [ 29 , 30 ] of larger studies were excluded as well as one that assessed HSCT donor genotypes [ 31 ] and one review without original data [ 23 ]. Finally, we retained 27 manuscripts ( Figure 1 ).…”

“…Possibly, the heterogeneity between these studies in terms of age at HSCT, HSCT conditioning regimen, and underlying disease might have contributed to the varying results. A recent systematic review with a meta-analysis of glutathione S-transferase genes was performed by Kim et al [ 23 ]. The authors included nine studies on GSTA1*A*A versus *B haplotypes, seven studies on GSTM1 “null genotype”, and five studies on GSTP1 .…”

“…They showed an association of the GSTA1*B haplotype with the area under the curve of intravenous busulfan but failed to show an association of glutathione S-transferases with SOS. However, some of the studies we identified were not included in the analysis by Kim et al [ 23 ]. The studies by Ansari et al 2013, 2017 and 2020 [ 30 , 47 , 51 ] were not assessed, while some studies that they included did not meet our inclusion criteria as they reported low patient numbers (<20 participants) or no patients with the outcome of interest.…”

“…Various pathways have been assessed for their association with SOS. A recent systematic review looked at the influence of glutathione S-transferase genes on pharmacokinetic parameters of busulfan and SOS incidence [ 23 ]. To our knowledge, there is no systematic review that summarizes the evidence for all postulated germline genetic predictors for sinusoidal obstruction syndrome.…”