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

• Published in: Leukemia Vol. 23; no. 3; pp. 545 - 556
• Main Authors: Rocha, V, Porcher, R, Fernandes, J F, Filion, A, Bittencourt, H, Silva, W, Vilela, G, Zanette, D L, Ferry, C, Larghero, J, Devergie, A, Ribaud, P, Skvortsova, Y, Tamouza, R, Gluckman, E, Socie, G, Zago, M A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-03-2009; Nature Publishing Group
• Subjects: Adolescent; Adult; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Aryl Hydrocarbon Hydroxylases - genetics; ATP Binding Cassette Transporter, Sub-Family B; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; Biological and medical sciences; Biotransformation - genetics; Bone marrow; Cancer Research; Care and treatment; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Critical Care Medicine; Cyclophosphamide; Cytochrome; Cytochrome P-450 CYP2B6; Cytochromes; Cytomegalovirus; Disease prevention; Drug metabolism; Drug resistance; Drugs; Enzymes; Female; Gene polymorphism; Genes; Genes, MDR; Genetic aspects; Genetic engineering; Genetic factors; Genetic polymorphisms; Genetic Predisposition to Disease; Genomics; Glutathione; Glutathione transferase; Glutathione Transferase - genetics; Graft versus host disease; Graft vs Host Disease - genetics; Graft-versus-host reaction; Health aspects; Hematologic and hematopoietic diseases; Hematology; Hematopoietic Stem Cell Transplantation - adverse effects; Hematopoietic stem cells; Hemorrhage; Hemorrhagic cystitis; Histocompatibility antigen HLA; HLA Antigens - genetics; Humans; Immunosuppressive agents; Immunosuppressive Agents - adverse effects; Immunosuppressive Agents - pharmacokinetics; Immunosuppressive Agents - therapeutic use; Inflammation - chemically induced; Inflammation - genetics; Intensive; Internal Medicine; Leukemia; Leukemia - genetics; Leukemia - mortality; Leukemia - surgery; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Liver diseases; Liver Diseases - genetics; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolism; Methylenetetrahydrofolate reductase; Methylenetetrahydrofolate Reductase (NADPH2) - genetics; Middle Aged; Mortality; Mucositis; Myeloablative Agonists - adverse effects; Myeloablative Agonists - pharmacokinetics; Myeloablative Agonists - therapeutic use; Neoplasm Proteins - genetics; Oncology; original-article; Oxidoreductases, N-Demethylating - genetics; Patients; Pharmacology; Polymorphism, Genetic; Prophylaxis; Receptors, Calcitriol - genetics; Reductases; Risk factors; Serology; Siblings; Stem cell transplantation; Stem cells; Survival; Toxic diseases; Toxicity; Transplantation; Transplantation Conditioning - adverse effects; Transplantation, Homologous - mortality; Vitamin D; Vitamin D receptors; Young Adult; France; Paris France; drug metabolism gene polymorphisms; hematopoietic stem cell transplantation; leukemia; Human; Drug; Immunopathology; Graft versus host disease; Genetic variability; Hematology; Toxicity; Stem cell; Leukemia; Hematopoietic cell; Homograft; Genotype; Malignant hemopathy; Sibling; Metabolism; Survival; Graft; Histocompatibility; Cancer
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2008.323

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.