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.
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.
Rocha
V
V
Department of Hematology and Bone Marrow Transplant Unit, University of Paris 7, Hôpital Saint Louis, Paris, France. vanderson.rocha@sls.aphp.fr
Porcher
R
R
Fernandes
J F
JF
Filion
A
A
Bittencourt
H
H
Silva
W
W
Vilela
G
G
Zanette
D L
DL
Ferry
C
C
Larghero
J
J
Devergie
A
A
Ribaud
P
P
Skvortsova
Y
Y
Tamouza
R
R
Gluckman
E
E
Socie
G
G
Zago
M A
MA
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001711:Biotransformation / Q000235:genetics*; D056486:Chemical and Drug Induced Liver Injury; D002648:Child; D002675:Child, Preschool; D065702:Cytochrome P-450 CYP2B6; D005260:Female; D019450:Genes, MDR; D020022:Genetic Predisposition to Disease; D005982:Glutathione Transferase / Q000235:genetics; D006086:Graft vs Host Disease / Q000235:genetics*; D006680:HLA Antigens / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics; D007938:Leukemia / Q000235:genetics / Q000401:mortality / Q000601:surgery*; D008107:Liver Diseases / Q000235:genetics; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D019653:Myeloablative Agonists / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D009363:Neoplasm Proteins / Q000235:genetics; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics; D011110:Polymorphism, Genetic; D018167:Receptors, Calcitriol / Q000235:genetics; D035781:Siblings; D019172:Transplantation Conditioning / Q000009:adverse effects; D014184:Transplantation, Homologous / Q000401:mortality; D055815:Young Adult
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D006680:HLA Antigens; D007166:Immunosuppressive Agents; D019653:Myeloablative Agonists; D009363:Neoplasm Proteins; D018167:Receptors, Calcitriol; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D005982:Glutathione Transferase