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Bone Marrow Transplant. 2016 Mar;51(3):377-83. doi: 10.1038/bmt.2015.321. Epub 2015 Dec 21.

Influence of glutathione S-transferase gene polymorphisms on busulfan pharmacokinetics and outcome of hematopoietic stem-cell transplantation in thalassemia pediatric patients.

Author information

1
Department of Pediatrics, Onco-Haematology unit, Geneva University Hospital, Faculty of Medicine, Geneva, Switzerland.
2
Department of Pediatrics, CANSEARCH Research Laboratory, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
3
These authors contributed equally to this work.
4
Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.
5
Stem Cell Programme, IRCCS, San Raffaele Scientific Institute, Milano, Italy.
6
Department of Pediatrics, University of Montreal, Montreal, Quebec, Canada.
7
Pediatric Immuno-Hematology and BMT unit, IRCCS San Raffaele Hospital, Milano, Italy.
8
Eurocord-Monaco, Centre scientifique de Monaco, Monaco, Principality of Monaco.
9
Department of Pharmacology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.

Abstract

Hematopoietic stem-cell transplantation (HSCT) is currently the only curative therapeutic option for the treatment of thalassemia. In spite of the high cure rate, HSCT can lead to life-threatening adverse events in some patients. Busulfan (Bu) is a key component of the conditioning regimen prior to HSCT. Inter-individual differences in Bu pharmacokinetics (PK) are hypothesized to influence Bu efficacy and toxicity. Since Bu is mainly metabolized by glutathione S-transferase (GST), we investigated the relationship of GSTA1 and GSTM1 genotypes with first-dose PK and HSCT outcomes in 44 children with thalassemia intermedia and thalassemia major. All children received a myeloablative conditioning regimen with IV Bu. Association analysis revealed a relationship between GSTA169C>T (or haplotype *A/*B) and first Bu dose PK that was dependent on sex and Pesaro risk classification (PRC). Among female patients and patients with PRC I-II, homozygous individuals for the GSTA1T-69 allele defining haplotype *B, had higher Bu exposure and lower clearance (P⩽0.01). Association with HSCT outcomes showed that patients with the GSTM1 null genotypes had higher occurrence of regimen-related toxicity (P=0.01). These results suggest that GST genotypes could be useful to tailor the first Bu dose accordingly to improve HSCT outcome.

PMID:
26691424
PMCID:
PMC4777888
DOI:
10.1038/bmt.2015.321
[Indexed for MEDLINE]
Free PMC Article

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