GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study.
- Ansari M Department of Pediatrics, CANSEARCH Research Laboratory, Faculty of Medicine, Geneva, Switzerland.
- Curtis PH Department of Pediatrics, CANSEARCH Research Laboratory, Faculty of Medicine, Geneva, Switzerland.
- Uppugunduri CRS Department of Pediatrics, CANSEARCH Research Laboratory, Faculty of Medicine, Geneva, Switzerland.
- Rezgui MA Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.
- Nava T Department of Pediatrics, CANSEARCH Research Laboratory, Faculty of Medicine, Geneva, Switzerland.
- Mlakar V Department of Pediatrics, CANSEARCH Research Laboratory, Faculty of Medicine, Geneva, Switzerland.
- Lesne L Department of Pediatrics, CANSEARCH Research Laboratory, Faculty of Medicine, Geneva, Switzerland.
- Théoret Y Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.
- Chalandon Y Department of Medical Specialties, Division of Hematology, Geneva University Hospital, Geneva, Switzerland.
- Dupuis LL Department of Haematology/Oncology, Blood and Marrow Transplant Unit, The Hospital for Sick Children, Toronto, Ontario, Canada.
- Schechter T Department of Haematology/Oncology, Blood and Marrow Transplant Unit, The Hospital for Sick Children, Toronto, Ontario, Canada.
- Bartelink IH Pediatric Blood and Marrow Transplantation Program, University Medical Center, Utrecht, The Netherlands.
- Boelens JJ Pediatric Blood and Marrow Transplantation Program, University Medical Center, Utrecht, The Netherlands.
- Bredius R Department of Pediatrics, Center of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
- Dalle JH Pediatric Hematology Department, Robert Debré Hospital, Assistance Publique, Hôpitaux de Paris, Paris, France.
- Azarnoush S Pediatric Hematology Department, Robert Debré Hospital, Assistance Publique, Hôpitaux de Paris, Paris, France.
- Sedlacek P Department of Pediatric Hematology and Oncology Teaching Hospital, 2nd Medical School, Charles University, Prague, Czech Republic.
- Lewis V Department of Pediatrics, Alberta Children's Hospital, Calgary, Alberta, Canada.
- Champagne M Department of Hematology, Hospital Verdun, Montreal, Quebec, Canada.
- Peters C Department of Pediatrics, Stem Cell Transplantation Unit, St Anna Children's Hospital, Vienna, Austria.
- Bittencourt H Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.
- Krajinovic M Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.
- 2017-12-07
Published in:
- Oncotarget. - 2017
English
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. (No Clinicaltrials.gov identifier: NCT01257854. Registered 8 December 2010, retrospectively registered).
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.18632/oncotarget.20310
- PMID 29207608
- Persistent URL
- https://sonar.ch/global/documents/287985
Statistics
Document views: 28
File downloads:
- Full-text: 0