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

Article Article scientifique Article Glutathione S-transferase gene variations influence BU pharmacokinetics and outcome of hematopoietic SCT in pediatric patients eng 2013 author Ansari Djaberi Marc Georges 61572 author Rezgui MA author Théoret Y author Uppugunduri Satyanarayana Chakradhara Rao 0000-0002-8928-7049 740772 author Mezziani S author Vachon MF author Desjean C author Rousseau Jeremie 646475 author Labuda M author Przybyla C author Duval M author Champagne M author Peters C author Bittencourt H author Krajinovic M 939-946 10.1038/bmt.2012.265 23292236 0268-3369 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. Adult Age Factors Allografts Busulfan/administration & dosage/pharmacokinetics Child Child, Preschool Female Gene Dosage Glutathione Transferase/genetics/metabolism Haplotypes Hematopoietic Stem Cell Transplantation Humans Infant Male Myeloablative Agonists/administration & dosage/pharmacokinetics Transplantation Conditioning Dewey 618 58 Département de pédiatrie, gynécologie et obstétrique 223 false 564 Oncologie et hématologie pédiatrique 907 Bone marrow transplantation 48 7 2140b2f3-7e42-4a93-8c76-a0966621cf22 Article (Published version) Restricted 939-946.pdf 698444 application/pdf restrictedAccess Faculté de médecine / Section de médecine clinique / Département de pédiatrie, gynécologie et obstétrique

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Glutathione S-transferase gene variations influence BU pharmacokinetics and outcome of hematopoietic SCT in pediatric patients	Bone marrow transplantation			2013	598	5

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Rousseau, Jeremie