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

Marc Ansari, Patricia Huezo Diaz Curtis, Chakradhara Rao S. Uppugunduri, Mohammed Aziz Rezgui, Tiago Nava, Vid Mlakar, Laurence Lesne, Yves Théoret, Yves Chalandon, Lee L. Dupuis, Tao Schechter, Imke H. Bartelink, Jaap J. Boelens, Robbert Bredius, Jean Hugues Dalle, Saba Azarnoush, Petr Sedlacek, Victor Lewis, Martin Champagne, Christina PetersHenrique Bittencourt, Maja Krajinovic

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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 haplotypes (p < 0.001) supporting their importance in capturing PK variability. Four GSTA1 diplotype groups that significantly correlated with clearance (p=0.009) were distinguished. Diplotypes underlying fast and slow metabolizing capacity showed higher and lower BU clearance (ml/min/kg), respectively. GSTA1 diplotypes with slow metabolizing capacity were associated with higher incidence of sinusoidal obstruction syndrome, acute graft versus host disease and combined treatment-related toxicity (p < 0.0005). Among other GST genes investigated, GSTP1 313GG correlated with acute graft versus host disease grade 1-4 (p=0.01) and GSTM1 non-null genotype was associated with hemorrhagic cystitis (p=0.003). This study further strengthens the hypothesis that GST diplotypes/genotypes could be incorporated into already existing population pharmacokinetic models for improving first BU dose prediction and HSCT outcomes. (N° Clinicaltrials.gov identifier: NCT01257854. Registered 8 December 2010, retrospectively registered).

Original languageEnglish
Pages (from-to)90852-90867
Number of pages16
JournalOncotarget
Volume8
Issue number53
DOIs
Publication statusPublished - 2017

Keywords

  • Busulfan
  • Hematopoietic stem cell transplantion
  • Pharmacogenetics
  • Pharmacokinetics
  • Toxicity

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