Cytochrome P450 2C19 loss-of-function polymorphism is associated with an increased treatment-related mortality in patients undergoing allogeneic transplantation

• Published in: Bone marrow transplantation (Basingstoke) Vol. 40; no. 7; pp. 659 - 664
• Main Authors: ELMAAGACLI, A. H, KOLDEHOFF, M, STECKEL, N. K, TRENSCHEL, R, OTTINGER, H, BEELEN, D. W
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.10.2007
• Subjects: Adolescent; Adult; Aged; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Aryl Hydrocarbon Hydroxylases - genetics; Aryl Hydrocarbon Hydroxylases - metabolism; Bilirubin; Biological and medical sciences; Bone marrow; Bone marrow, stem cells transplantation. Graft versus host reaction; Creatinine; Cytochrome; Cytochrome P-450 CYP2C19; Cytochrome P450; Cytochromes P450; Drug metabolism; Female; Gene expression; Gene polymorphism; Genotype; Genotyping; Graft-versus-host reaction; Humans; Leukemia - mortality; Leukemia - therapy; Male; Medical sciences; Middle Aged; Mixed Function Oxygenases - genetics; Mixed Function Oxygenases - metabolism; Mortality; Multiple Myeloma - mortality; Multiple Myeloma - therapy; Multivariate analysis; Myelodysplastic Syndromes - mortality; Myelodysplastic Syndromes - therapy; Neutrophils - transplantation; Patients; Polymorphism; Polymorphism, Genetic; Retrospective Studies; Stem cell transplantation; Survival Analysis; Tissue Donors; Toxicity; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Transplantation; Transplantation Conditioning; Transplantation, Homologous - mortality; Transplants & implants; Human; Genetic variability; Hematology; Enzyme; Cytochrome P450; Mortality; poor metabolizers; Homograft; Genotype; CYP2C19; Treatment; Graft; transplant; Polymorphism
• ISSN: 0268-3369; 1476-5365
• DOI: 10.1038/sj.bmt.1705786

The polymorphic gene expression of CYP2C19 causes individual variability in drug metabolism and thereby in pharmacologic and toxicologic responses. We genotyped 286 patients and their donors for the CYP2C19 gene who underwent allogeneic transplantation for various diseases and analyzed their outcome. Patients were classified as: poor metabolizers (PMs; 3.1%), intermediate metabolizers (IMs; 24.5%) and extensive metabolizers (EMs; 72.5%). Patients genotyped as PMs had significant higher hepato- and nephrotoxicities compared to IMs or EMs. Maximum bilirubin and serum creatinine levels measured after transplant were approximately twofold higher than those of EMs or IMs. The increased toxicity resulted in an increased 4-year estimate for transplant-related mortality (TRM) with 50+/-18.6% for PMs compared to 25.1+/-3.7% for EMs (P<0.018) and 22.7 +/-5.6% for IMs (P<0.042), whereas no significant influence for relapse rate, overall survival or incidence of acute graft-versus-host disease grade 2-4 were found between the groups. Multivariate analysis including all potential factors that might influence TRM confirmed that the genotype of CYP2C19 is an independent factor, which influenced TRM significantly. These results suggest that genotyping for CYP450 2C19 can help to identify patients with higher risk for TRM.