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

M. Ansari, P. Huezo-Diaz, M. A. Rezgui, S. Marktel, M. Duval, H. Bittencourt, B. Cappelli, M. Krajinovic

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)377-383
Number of pages7
JournalBone Marrow Transplantation
Volume51
Issue number3
DOIs
Publication statusPublished - Mar 1 2016

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Busulfan
Thalassemia
Hematopoietic Stem Cell Transplantation
Glutathione Transferase
Pharmacokinetics
Pediatrics
Genes
beta-Thalassemia
Genotype
Haplotypes
Individuality
Alleles
Therapeutics

ASJC Scopus subject areas

  • Hematology
  • Transplantation

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Influence of glutathione S-transferase gene polymorphisms on busulfan pharmacokinetics and outcome of hematopoietic stem-cell transplantation in thalassemia pediatric patients. / Ansari, M.; Huezo-Diaz, P.; Rezgui, M. A.; Marktel, S.; Duval, M.; Bittencourt, H.; Cappelli, B.; Krajinovic, M.

In: Bone Marrow Transplantation, Vol. 51, No. 3, 01.03.2016, p. 377-383.

Research output: Contribution to journalArticle

Ansari, M. ; Huezo-Diaz, P. ; Rezgui, M. A. ; Marktel, S. ; Duval, M. ; Bittencourt, H. ; Cappelli, B. ; Krajinovic, M. / Influence of glutathione S-transferase gene polymorphisms on busulfan pharmacokinetics and outcome of hematopoietic stem-cell transplantation in thalassemia pediatric patients. In: Bone Marrow Transplantation. 2016 ; Vol. 51, No. 3. pp. 377-383.
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