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

• Published in: Oncotarget Vol. 8; no. 53; pp. 90852 - 90867
• Main Authors: Ansari, Marc, Curtis, Patricia Huezo-Diaz, Uppugunduri, Chakradhara Rao S, Rezgui, Mohammed Aziz, Nava, Tiago, Mlakar, Vid, Lesne, Laurence, Théoret, Yves, Chalandon, Yves, Dupuis, Lee L, Schechter, Tao, Bartelink, Imke H, Boelens, Jaap J, Bredius, Robbert, Dalle, Jean-Hugues, Azarnoush, Saba, Sedlacek, Petr, Lewis, Victor, Champagne, Martin, Peters, Christina, Bittencourt, Henrique, Krajinovic, Maja
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 31.10.2017
• Subjects: Research Paper; busulfan; toxicity; pharmacokinetics; hematopoietic stem cell transplantion; pharmacogenetics
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.20310

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 ( ) were evaluated 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 haplotypes (p<0.001) supporting their importance in capturing PK variability. Four 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. 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 genes investigated, correlated with acute graft versus host disease grade 1-4 (p=0.01) and genotype was associated with hemorrhagic cystitis (p=0.003). This study further strengthens the hypothesis that 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).