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

Abstract

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 50718.6% for PMs compared to 25.173.7% for EMs (Po0.018) and 22.7 75.6% for IMs (Po0.042), whereas no significant influence for relapse rate, overall survival or incidence of acute graftversus-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.

Genetic Polymorphism of Metabolic Enzymes P450 (CYP) as a Susceptibility Factor for Drug Response, Toxicity, and Cancer Risk

“…The rate of nelfi navir (for HIV treatment) biotransformation to M8 was reduced by 50 % in patients with the CYP2C19*1/*2 or *2/*2 genotype compared to those with the *1/*1 genotype, with consequences of modifi ed short-term effi cacy and toxicity and fi nal virological response (124). Some reports documented that the CYP2C19*2 loss-of-function polymorphism was associated with an increased treatment-related mortality (TRM) in patients undergoing allogenic transplantation (125). Patients genotyped as PMs had a signifi cantly higher rate of hepato-and nephrotoxicities than intermediate or extensive metabolisers.…”

Cytochrome P450 genetic polymorphisms influence the serum concentration of calcineurin inhibitors in allogeneic hematopoietic SCT recipients

“…The selection was based on publicly available databases (dbSNP, International HapMap project) and on Medline publications for selected SNPs. Finally we examined the CYP2C19 SNP (rs4244285), 10,11 CYP3A5 SNPs (rs15524, rs4646450, rs3800959 and rs776746) 4,12,13 and MDR1 SNPs (rs1128503, rs2032582 and rs1045642) 12 by PCR based on suitable methods for each SNP (Table 2 and Supplementary Table 1). …”

Value of preemptive CYP2C19 genotyping in allogeneic stem cell transplant patients considered for pentamidine administration

“…(9) and Elmaagacli et al. (10) and encourage routine use (which we now are pursuing at our institution) of preemptive CYP2C19 genotyping in alloSCT patients considered for pentamidine treatment. Confirmatory prospective research regarding the value of preemptive genotyping of CYP2C19, including economic and clinical sensitivity analyses and use of validated systems for more rigorous assessment of toxicities and attribution of causality, appears warranted.…”