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Pharmacogenomics

Association of drug metabolism gene polymorphisms with toxicities, graft-versus-host disease and survival after HLA-identical sibling hematopoietic stem cell transplantation for patients with leukemia

Leukemia volume 23, pages 545–556 (2009)Cite this article

Abstract

Individual differences in drug efficacy or toxicity can be influenced by genetic factors. We investigated whether polymorphisms of pharmacogenes that interfere with metabolism of drugs used in conditioning regimen and graft-versus-host disease (GvHD) prophylaxis could be associated with outcomes after HLA-identical hematopoietic stem cell transplantation (HSCT). Pharmacogenes and their polymorphisms were studied in 107 donors and patients with leukemia receiving HSCT. Candidate genes were: P450 cytochrome family (CYP2B6), glutathione-S-transferase family (GST), multidrug-resistance gene, methylenetetrahydrofolate reductase (MTHFR) and vitamin D receptor (VDR). The end points studied were oral mucositis (OM), hemorrhagic cystitis (HC), toxicity and venoocclusive disease of the liver (VOD), GvHD, transplantation-related mortality (TRM) and survival. Multivariate analyses, using death as a competing event, were performed adjusting for clinical factors. Among other clinical and genetic factors, polymorphisms of CYP2B6 genes that interfere with cyclophosphamide metabolism were associated with OM (recipient CYP2B6*4; P=0.0067), HC (recipient CYP2B6*2; P=0.03) and VOD (donor CYP2B6*6; P=0.03). Recipient MTHFR polymorphisms (C677T) were associated with acute GvHD (P=0.03), and recipient VDR TaqI with TRM and overall survival (P=0.006 and P=0.04, respectively).Genetic factors that interfere with drug metabolisms are associated with treatment-related toxicities, GvHD and survival after HLA-identical HSCT in patients with leukemia and should be investigated prospectively.

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Acknowledgements

We thank MH Tavela, AG Araujo for the technical assistance and V Bons for updating the database. This study has been supported by Assistance Publique-Hopitaux de Paris, IFR Saint Louis, Association pour la Recherche sur les Transplantations Médullaires (ARTM) and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Brazil.

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Authors and Affiliations

  1. Department of Hematology and Bone Marrow Transplant Unit, University of Paris 7, Hôpital Saint Louis, Paris, France

    V Rocha, J F Fernandes, A Filion, H Bittencourt, G Vilela, C Ferry, J Larghero, A Devergie, P Ribaud, Y Skvortsova, E Gluckman & G Socie

  2. Biostatistics Department (INSERM Erm 321), University of Paris 7, Hôpital Saint Louis, Paris, France,

    R Porcher

  3. Center for Cell Therapy and Immunogenetics, Faculty of Medicine of Ribeir,

    W Silva Jr, D L Zanette & M A Zago

  4. ã,

    W Silva Jr, D L Zanette & M A Zago

  5. o Preto, University of Sao Paulo, Sao Paulo, Brazil

    W Silva Jr, D L Zanette & M A Zago

  6. Immunology department, University of Paris 7, Hôpital Saint Louis, Paris, France

    R Tamouza

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Rocha, V., Porcher, R., Fernandes, J. et al. Association of drug metabolism gene polymorphisms with toxicities, graft-versus-host disease and survival after HLA-identical sibling hematopoietic stem cell transplantation for patients with leukemia. Leukemia 23, 545–556 (2009). https://doi.org/10.1038/leu.2008.323

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