GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study

Abstract

Busulfan (BU) dose adjustment following therapeutic drug monitoring contributes to better outcome of hematopoietic stem cell transplantation (HSCT). Further improvement could be achieved through genotype-guided BU dose adjustments. To investigate this aspect, polymorphism within glutathione S transferase genes were assessed. Particularly, promoter haplotypes of the glutathione S transferase A1 (GSTA1) were evaluated in vitro, with reporter gene assays and clinically, in a pediatric multi-center study (N =138) through association with BU pharmacokinetics (PK) and clinical outcomes. Promoter activity significantly differed between the GSTA1

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

“…The search and selection process ultimately identified 19 studies for the meta‐analysis from the 142 articles obtained by the computerized search (Figure ). The characteristics of the studies are presented in Table . All the studies included in the analysis were assessed as being of high quality.…”

Incorporation ofGSTA1genetic variations into a population pharmacokinetic model for IV busulfan in paediatric hematopoietic stem cell transplantation

“…Despite its wide utilization, Bu presents a narrow therapeutic window. Higher rates of relapse and rejection occur among patients with a low Bu exposure, whereas over‐exposure correlates with transplant‐related toxicities such as acute graft versus host disease (aGVHD), sinusoidal obstruction syndrome (SOS) and death . Pharmacokinetic (PK) studies have demonstrated a high intra‐ and inter‐patient variability despite equivalent doses of Bu .…”

Pharmacokinetic analysis for model‐supported therapeutic drug monitoring of busulfan in Japanese pediatric hematopoietic stem cell transplantation recipients

“…Functional polymorphisms in GST genes have been suggested to play a role interindividual variability in the PKs of busulfan . The influence of GST polymorphisms on busulfan PKs has also been suggested in Japanese children .…”

“…Ethnic variability should be recognized when generalizing the results of studies of busulfan PK. Interestingly, recent pharmacogenetic studies have shown that the effect of GSTA1 haplotype on busulfan clearance is associated with age . There is an obvious need for further research that combines PPK model‐based strategy with the findings on genetic polymorphisms to provide more effective busulfan TDM.…”

“…Busulfan is eliminated via conjugation mainly catalyzed by the hepatic GST enzymes, especially by its isoform α‐1 (GSTA1) isoform . Recent studies have suggested that GST gene variants influence busulfan PKs in SCT recipients …”