TY - JOUR
T1 - GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation
T2 - A multicenter study
AU - Ansari, Marc
AU - Curtis, Patricia Huezo Diaz
AU - Uppugunduri, Chakradhara Rao S.
AU - Rezgui, Mohammed Aziz
AU - Nava, Tiago
AU - Mlakar, Vid
AU - Lesne, Laurence
AU - Théoret, Yves
AU - Chalandon, Yves
AU - Dupuis, Lee L.
AU - Schechter, Tao
AU - Bartelink, Imke H.
AU - Boelens, Jaap J.
AU - Bredius, Robbert
AU - Dalle, Jean Hugues
AU - Azarnoush, Saba
AU - Sedlacek, Petr
AU - Lewis, Victor
AU - Champagne, Martin
AU - Peters, Christina
AU - Bittencourt, Henrique
AU - Krajinovic, Maja
N1 - Funding Information: This study was performed under the supervision of the Swiss National Science Foundation and CANSEARCH foundation. We warmly thank the patients and their parents for consenting to participate in this study. We also thank R. Lo Piccolo, S. Mezziani, M-F.Vachon, and M. Cortier for the help in this study as well as N. Von Der Weid and the Swiss Pediatric Oncology Group for being the sponsors of this study. This study was supported by grants from the Swiss National Science Foundation (Grant number153389), CANSEARCH Foundation, the Geneva Cancer League, the Dr. Henri Dubois-Ferri?re Dinu Lipatti Foundation, and Foundation of Charles-Bruneau Cancer Center. Publisher Copyright: © Ansari et al. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2017
Y1 - 2017
N2 - 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).
AB - 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).
KW - Busulfan
KW - Hematopoietic stem cell transplantion
KW - Pharmacogenetics
KW - Pharmacokinetics
KW - Toxicity
UR - http://www.scopus.com/inward/record.url?scp=85032656495&partnerID=8YFLogxK
U2 - https://doi.org/10.18632/oncotarget.20310
DO - https://doi.org/10.18632/oncotarget.20310
M3 - Article
SN - 1949-2553
VL - 8
SP - 90852
EP - 90867
JO - Oncotarget
JF - Oncotarget
IS - 53
ER -