Impact of Polymorphisms in Cyp3a5 and Cyp2d6 Genes and Smoking on Imatinib Response, Cytogenetic Relapse in Patients With Chronic Myeloid Leukemia on Imatinib

Background and aim: despite supreme results of imatinib (im), almost 40% of cml patients do not achieve favorite response and some, who response well, afterwards may develop resistance to imatinib leading to recurrence or progression of the disease. little is known about the impact of polymorphisms in the genes coding for imatinib (im) metabolizing enzymes on predicting imatinib response and also cytogenetic relapse in patients with cml.methods: the study protocol was approved by pasteur institute of iran ethics committee (ir.pii.rec.1397.56). in this study, 115 cml patients (57 im resistant and 58 im good responders; including 28 patients with cytogenetic relapse and 30 patients without cytogenetic relapse) were involved. the median duration of follow-up after commencing imatinib was 50 months. the molecular response assessment was carried out by qrt-pcr according to log reduction international scale (si) as the ratio of bcr-abl1 transcripts to abl1 transcripts ≤ 0.1% indicated major molecular response (mmr). cytogenetic relapse was defined as the existence of ph+ chromosome metaphases or loss ofcomplete cytogenetic response (ccyr) in patients who had previously acquired ccyr based on their clinical files. the genotyping of cyp3a5*3 (a6986g), cyp3a5*6 (g14690a) and cyp2d6*4 (g1934a) polymorphisms were done using pcr-rflp method.results: the cyp3a5*6, cyp3a5*3 and cyp2d6*4 mutant genotypes frequency significantly were different between non- responder and responder patients as the achieving of molecular response was lower in patients with mutant allele than to wild types (p= 0.03; p= 0.01, p= 0.009 and or= 3.1, or= 11 respectivly). none of cyp3a5*6 and cyp3a5*3 genotypes were related with cytogenetic relapse but ga+aa genotype (dominant model) for cyp2d6*4 (g1934a) polymorphism significantly were associated with cytogenetic relapse (or= 3.2; 95% ci 1.35- 7.2, p= 0.02). the cigarettes smoke increased imatinib resistance in non- responders than to responders but had not impact on cytogenetic relapse.conclusion: in the all of polymorphisms the patients with mutant genotype had lower rate in achieving of molecular response. cyp2d6*4 polymorphism significantly increased the risk of cytogenetic relapse (3 fold). the smoke as synergestic factor increased im resistance.