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Pediatric Transplants

Glutathione S-transferase gene variations influence BU pharmacokinetics and outcome of hematopoietic SCT in pediatric patients

Bone Marrow Transplantation volume 48, pages 939–946 (2013)Cite this article

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Abstract

BU is a key compound of conditioning regimens in children undergoing hematopoietic SCT (HSCT). Inter-individual differences in BU pharmacokinetics (PKs) might affect BU efficacy and toxicity. As BU is mainly metabolized by glutathione S-transferase (GST), we investigated the relationship between GSTA1, GSTM1 and GSTP1 genotypes with first-dose BU PKs, and the relationship with HSCT outcomes in 69 children receiving myeloablative conditioning regimen. GSTM1 null genotype correlated with higher BU exposure and lower clearance in patients older than 4 years (P⩽0.04). In accordance with the suggested functional role, GSTA1*A2 haplotype was associated with lower drug levels and higher drug clearance (P⩽0.03). Gene-dosage effect was also observed (P⩽0.007). GSTA1 haplotypes were associated with HSCT outcomes. Patients with two copies of haplotype *A2 had better event free survival (P=0.03). In contrast, homozygous individuals for haplotypes *B and *B1 had higher occurrence of veno-occlusive disease (P=0.009). GSTM1 null individuals older than 4 years had more frequently graft versus host disease (P=0.03). In conclusion, we showed that GST gene variants influence BU PK and outcomes of HSCT in children. A model for the dosage adjustment with the inclusion of genetic and non-genetic factors should be evaluated in a future prospective validation cohort.

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Acknowledgements

We are thankful to all patients and their parents for consenting to participate in this study. This investigation was supported by grants provided by the Geneva Cancer League, CANSEARCH, Hans Wilsdorf, Telemaque and Charles Bruneau foundations. We thank the Swiss Oncology Group as our sponsor and the European Blood and Marrow Transplantation Pediatric (EBMT) working disease group for their support and for labeling this study as an EBMT trial. This study has been fully registered in a public trials registry as part of an ongoing prospective EBMT multicentric study (register at Clinical Trials.gov, NCT01257854). It is submitted on behalf of the Pediatric Disease Working Parties of the European Blood and Marrow Transplant group and is an EBMT label study (EudraCT number: 2009-018105-41).

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Authors and Affiliations

  1. Department of Pediatrics, Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada

    M Ansari, M A Rezgui, S Mezziani, M-F Vachon, C Desjean, J Rousseau, M Labuda, C Przybyla, M Duval, H Bittencourt & M Krajinovic

  2. Department of Pediatrics, CANSEARCH Research Laboratory, Faculty of Medicine, Geneva, Switzerland

    M Ansari & C R S Uppugunduri

  3. Department of Pediatrics, Onco-Hematology Unit, Geneva University Hospital, Geneva University, Geneva, Switzerland

    M Ansari & C R S Uppugunduri

  4. Department of Pharmacology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada

    M A Rezgui, Y Théoret & M Krajinovic

  5. Department of Pediatrics, Clinical Pharmacology Unit, CHU Sainte-Justine, Montreal, Quebec, Canada

    Y Théoret & M Krajinovic

  6. Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada

    Y Théoret, M Duval & H Bittencourt

  7. Department of Hematology, Hospital Verdun, Montreal, Quebec, Canada

    M Champagne

  8. Department of Pediatrics, Stem Cell Transplantation Unit, St Anna Children’s Hospital, Vienna, Austria

    C Peters

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on behalf of the Pediatric Disease Working Parties of the European Blood and Marrow Transplant Group

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Ansari, M., Rezgui, M., Théoret, Y. et al. Glutathione S-transferase gene variations influence BU pharmacokinetics and outcome of hematopoietic SCT in pediatric patients. Bone Marrow Transplant 48, 939–946 (2013). https://doi.org/10.1038/bmt.2012.265

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