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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.

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


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.

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