title: Influence of glutathione S-transferase gene polymorphisms on busulfan pharmacokinetics and outcome of hematopoietic stem-cell transplantation in thalassemia pediatric patients.
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.
authors.affiliation: 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.
authors.forename: M
authors.initials: M
authors.lastname: Ansari
authors.affiliation: 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.
authors.forename: P
authors.initials: P
authors.lastname: Huezo-Diaz
authors.affiliation: Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.
authors.forename: M A
authors.initials: MA
authors.lastname: Rezgui
authors.affiliation: Stem Cell Programme, IRCCS, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Marktel
authors.affiliation: Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.|Department of Pediatrics, University of Montreal, Montreal, Quebec, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Duval
authors.affiliation: Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.|Department of Pediatrics, University of Montreal, Montreal, Quebec, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Bittencourt
authors.affiliation: Pediatric Immuno-Hematology and BMT unit, IRCCS San Raffaele Hospital, Milano, Italy.|Eurocord-Monaco, Centre scientifique de Monaco, Monaco, Principality of Monaco.
authors.forename: B
authors.initials: B
authors.lastname: Cappelli
authors.affiliation: Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.|Department of Pediatrics, University of Montreal, Montreal, Quebec, Canada.|Department of Pharmacology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Krajinovic
mesh_terms: D000483:Alleles; D064591:Allografts; D002066:Busulfan / Q000008:administration & dosage / Q000493:pharmacokinetics; D002648:Child; D005260:Female; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006239:Haplotypes; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D019172:Transplantation Conditioning; D017086:beta-Thalassemia / Q000097:blood / Q000235:genetics / Q000628:therapy
chemical_list: D002066:Busulfan; D005982:Glutathione Transferase; C484555:GSTA1 protein, human