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Cytochrome P450 2C19 Loss-Of-Function Polymorphism Is Associated with an Increased Treatment-Related Mortality in Patients Undergoing Allogeneic Transplantation

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Cytochrome P450 2C19 Loss-Of-Function Polymorphism Is Associated with an Increased Treatment-Related Mortality in Patients Undergoing Allogeneic Transplantation Bone Marrow Transplantation (2007) 40, 659–664 & 2007 Nature Publishing Group All rights reserved 0268-3369/07 $30.00 www.nature.com/bmt ORIGINAL ARTICLE Cytochrome P450 2C19 loss-of-function polymorphism is associated with an increased treatment-related mortality in patients undergoing allogeneic transplantation AH Elmaagacli, M Koldehoff, NK Steckel, R Trenschel, H Ottinger and DW Beelen Department of Bone Marrow Transplantation, University Hospital of Essen, Essen, Germany The polymorphic gene expression of CYP2C19 causes characterized enzymes with a large number of genetic individual variability in drug metabolism and thereby in polymorphisms is cytochrome P450 (CYP) 2C19.1 Pre- pharmacologic and toxicologic responses. We genotyped vious studies on CYP2C19 using probe drugs such as 286 patients and their donors for the CYP2C19 gene who S-mephenytoin showed that individuals could be classified underwent allogeneic transplantation for various diseases into three different groups: poor metabolizers (PMs), and analyzed their outcome. Patients were classified as: intermediate metabolizers (IMs) and extensive metabolizers poor metabolizers (PMs; 3.1%), intermediate metaboli- (EMs). PMs have a genetically determined absence of active zers (IMs; 24.5%) and extensive metabolizers (EMs; enzymes, which is the cause for a slower metabolism of 72.5%). Patients genotyped as PMs had significant higher active drugs and is associated with prolonged side effects.1 hepato- and nephrotoxicities compared to IMs or EMs. If prodrugs are applied, the metabolism in their active form Maximum bilirubin and serum creatinine levels measured is delayed and reduced effectiveness may occur. Among the after transplant were approximately twofold higher than drugs which are metabolized by CYP2C19 enzymes are those of EMs or IMs. The increased toxicity resulted in an cytostatics, proton pump inhibitors, antidepressants, seda- increased 4-year estimate for transplant-related mortality tive, beta blockers, antiviral and anti-fungal agents.2–9 (TRM) with 50718.6% for PMs compared to Recently, it was demonstrated that PMs of CYP2C19 25.173.7% for EMs (Po0.018) and 22.7 75.6% for showed a decrease in platelet responsiveness to clopido- IMs (Po0.042), whereas no significant influence for grel.10 In another study, it was reported that patients relapse rate, overall survival or incidence of acute graft- treated with antidepressants and genotyped as PMs for versus-host disease grade 2–4 were found between the CYP2D6 and CYP2C19, remained in hospital for longer groups. Multivariate analysis including all potential (median 57.5 versus 40.0 days) compared to IMs.8 factors that might influence TRM confirmed that the Patients undergoing allogeneic transplantation are trea- genotype of CYP2C19 is an independent factor, which ted with more drugs, that is, immunosuppressives, chemo- influenced TRM significantly. These results suggest that therapeutical agents or anti-infectious medication, each of genotyping for CYP450 2C19 can helpto identify patients them pivotal for the outcome of transplant. However, we with higher risk for TRM. hypothesized that altered drug metabolism in patients who Bone Marrow Transplantation (2007) 40, 659–664; underwent allogeneic transplantation might influence doi:10.1038/sj.bmt.1705786; published online 6 August 2007 transplant outcome. In a retrospective single-center study, Keywords: CYP2C19; poor metabolizers; transplant this paper evaluates whether gene polymorphisms of CYP2C19 enzyme influence the incidence of acute graft- versus-host disease (GVHD) after transplant, and/or influence treatment-related mortality (TRM) and thereby Introduction the outcome of allogeneic stem cell transplantation. The polymorphic expression of drug-metabolizing enzymes Patients and methods is one of the major factors, which cause individual variability in drug metabolism and thereby in pharma- Patients cologic and toxicologic responses. One of the best We included a total of 286 patients (and donors) for the CYP2C19 gene polymorphism analysis, who were trans- planted at the University Hospital of Essen between Correspondence: Dr AH Elmaagacli, Department of Bone Marrow October 1998 and December 2004. Genotyping was Transplantation, University Hospital of Essen, Hufelandstr. 55, 45122 performed without knowledge of GVHD status or outcome Essen, Germany. E-mail: [email protected] of the patients analyzed. All aspects of this study were Received 9 March 2007; revised 6 June 2007; accepted 11 June 2007; approved by the Institutional Review Board on Medical published online 6 August 2007 Ethics at the University Hospital of Essen. Loss-of-function allele of CYP2C19 and transplant-associated mortality AH Elmaagacli et al 660 Pre-transplant histocompatibility testing of patients and Analysis and measurement of blood parameters donors was performed at low-resolution human leukocyte Total bilirubin, g-glutamyl transferase, prothrombin time, antigen (HLA)-A, -B, -C and high-resolution HLA-DRB1, activated partial thromboplastin, fibrinogen and creatinine DQB1 level DNA-based typing according to standard were determined at baseline, and daily thereafter, until methods.11 at least day þ 30 after HSCT. Weight and abdominal circumference were measured daily. Conditioning regimen The conditioning regimen consisted of intravenous cyclo- Isolation of genomic DNA phosphamide in combination with fractioned total body DNA was prepared from peripheral blood mononuclear irradiation (TBI) or oral busulfan (BU), in combination cells obtained from the donor and patient before the with cyclophosphamide or treosulfan in combination with transplant using the phenol/chloroform method.14 cyclophosphamide or fludarabine as published earlier.12 Patients who underwent transplantation of highly enriched CD34 þ cells received a conditioning regimen with frac- Genotyping for CYP2C19 tioned TBI, cyclophosphamide and thiotepa as published Polymorphisms of CYP2C19 were determined by use of the earlier.12 Patients scheduled for peripheral blood stem cell hybridization probe format (LightCycler CYP2C19 Muta- transplantation (PBSCT) with reduced conditioning re- tion Detection Kit with specific primers; Roche Applied ceived BU (1 mg/kg of body weight every 6 h over 2days) in Science; Mannheim, Germany). Following genotypes were combination with fludarabine (30 mg/m2 of body surface determined: CYP2C19*1/*1 (EMs); CYP2C19*1/*2 (IMs), area over 5 days). CYP2C19*1/*3 (IMs), CYP2C19*2/*2 (PMs), CYP2C19*2/ GVHD prophylaxis consisted of methotrexate (MTX) *3 (PMs), CYP2C19*3/*3 (PMs). PCR and subsequent and cyclosporine (CSA) in patients who received an melting curve analysis were performed using the Lightcycler unmanipulated graft.12 In the patients who underwent a device (Roche Applied Science) and software. Control CD34 þ -PBSCT, no further GVHD prophylaxis was given. samples confirmed by sequencing were included in each run. In vivo T-cell depletion was performed using Campath-1 H (10 or 20 mg for 5 days) in combination with CSA or (rabbit) anti T-lymphocyte globuline (ATG-S, Fresenius, Definition of the study groups Bad Homburg, Germany) (10 mg/kg of body weight for Patients with wild type (EMs) of the analyzed gene were 4 days) in combination with CSA and MTX. defined as group 1. Patients with heterozygous mutations Patient demographics are summarized in Table 1. (IMs) of the analyzed gene were designated as group 2, while patients with homozygous mutations (PMs) of the analyzed gene at the donor side only were named group 3. Supportive care Besides these three groups, we also investigated the possible All patients were isolated in reverse isolation rooms influence of donor genotype on patient outcome. equipped with high-efficiency particular filtration systems and received prophylactic metronidazole 400 mg three times daily and oral ciprofloxacin, 750 mg twice daily and Statistics fluconazole, 200 mg once daily. Cumulative estimates (7standard errors) were calculated by the Kaplan–Meier method.15 Differences between time- to-event distribution functions were compared by a log- Clinical study endpoints rank test (Mantel–Haenszel).16 A stepwise proportional Neutrophil engraftment was defined as the first of three hazards general linear model (PHGLM) analysis was used consecutive days with an absolute neutrophil count greater to evaluate interactions of different covariates on the than 0.5 Â 109/l. Acute GVHD was graded according to analytical endpoint of TRM. Covariates in PHGLM standard criteria.13 Chronic GVHD was assessed in patients analyses were stratified according to severe acute GVHD, alive after 100 days. TRM was defined as death with no age ( 40 or 440 years), gender constellation (male relapse. Overall survival (OS) was defined as survival from p patient with female donor or other), PM (mutations at transplantation without death from any cause. patient site) versus others, HLA-constellation between patient and donor, sibling donor versus unrelated donor, Diagnostic criteria for veno-occlusive disease graft-type (PBSC or bone marrow), T-cell depleted graft Veno-occlusive disease (VOD) was suspected clinically versus non T-cell depleted graft, and disease stage according to the modified Seattle criteria which require (advanced versus early disease stages) were analyzed. the presence of at least two of the following three clinical Conditional risk ratios (RR) and their 95% confidence findings before day þ 30 after hematopoietic stem cell intervals (95% CI) were derived from PHGLM analyses transplantation
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