Influence of glutathione S-transferase gene polymorphisms on busulfan pharmacokinetics and outcome of hematopoietic stem-cell transplantation in thalassemia pediatric patients

Bone Marrow Transplant. 2016 Mar;51(3):377-83. doi: 10.1038/bmt.2015.321. Epub 2015 Dec 21.

Abstract

Hematopoietic stem-cell transplantation (HSCT) is currently the only curative therapeutic option for the treatment of thalassemia. In spite of the high cure rate, HSCT can lead to life-threatening adverse events in some patients. Busulfan (Bu) is a key component of the conditioning regimen prior to HSCT. Inter-individual differences in Bu pharmacokinetics (PK) are hypothesized to influence Bu efficacy and toxicity. Since Bu is mainly metabolized by glutathione S-transferase (GST), we investigated the relationship of GSTA1 and GSTM1 genotypes with first-dose PK and HSCT outcomes in 44 children with thalassemia intermedia and thalassemia major. All children received a myeloablative conditioning regimen with IV Bu. Association analysis revealed a relationship between GSTA169C>T (or haplotype *A/*B) and first Bu dose PK that was dependent on sex and Pesaro risk classification (PRC). Among female patients and patients with PRC I-II, homozygous individuals for the GSTA1T-69 allele defining haplotype *B, had higher Bu exposure and lower clearance (P⩽0.01). Association with HSCT outcomes showed that patients with the GSTM1 null genotypes had higher occurrence of regimen-related toxicity (P=0.01). These results suggest that GST genotypes could be useful to tailor the first Bu dose accordingly to improve HSCT outcome.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Allografts
  • Busulfan* / administration & dosage
  • Busulfan* / pharmacokinetics
  • Child
  • Female
  • Genotype
  • Glutathione Transferase / genetics*
  • Haplotypes
  • Hematopoietic Stem Cell Transplantation*
  • Humans
  • Male
  • Polymorphism, Genetic*
  • Transplantation Conditioning*
  • beta-Thalassemia* / blood
  • beta-Thalassemia* / genetics
  • beta-Thalassemia* / therapy

Substances

  • GSTA1 protein, human
  • Glutathione Transferase
  • glutathione S-transferase M1
  • Busulfan