Impact of polymorphisms in CYP۳A۵ and CYP۲D۶ 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 ۴۰% 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.۱۳۹۷.۵۶). In this study, ۱۱۵ CML patients (۵۷ IM resistant and ۵۸ IM good responders; including ۲۸ patients with cytogenetic relapse and ۳۰ patients without cytogenetic relapse) were involved. The median duration of follow-up after commencing imatinib was ۵۰ months. The molecular response assessment was carried out by qRT-PCR according to log reduction international scale (SI) as the ratio of BCR-ABL۱ transcripts to ABL۱ transcripts ≤ ۰.۱% indicated major molecular response (MMR). Cytogenetic relapse was defined as the existence of Ph+ chromosome metaphases or loss of complete cytogenetic response (CCyR) in patients who had previously acquired CCyR based on their clinical files. The genotyping of CYP۳A۵*۳ (A۶۹۸۶G), CYP۳A۵*۶ (G۱۴۶۹۰A) and CYP۲D۶*۴ (G۱۹۳۴A) polymorphisms were done using PCR-RFLP method.Results: The CYP۳A۵*۶, CYP۳A۵*۳ and CYP۲D۶*۴ 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= ۰.۰۳; P= ۰.۰۱, P= ۰.۰۰۹ and OR= ۳.۱, OR= ۱۱ respectivly). None of CYP۳A۵*۶ and CYP۳A۵*۳ genotypes were related with cytogenetic relapse but GA+AA genotype (Dominant model) for CYP۲D۶*۴ (G۱۹۳۴A) polymorphism significantly were associated with cytogenetic relapse (OR= ۳.۲; ۹۵% CI ۱.۳۵- ۷.۲, P= ۰.۰۲). 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. CYP۲D۶*۴ polymorphism significantly increased the risk of cytogenetic relapse (۳ fold). The smoke as synergestic factor increased IM resistance.

Keywords:

Cytogenetic response , Chronic myeloid leukemia , CYP۳A۵ , CYP۲D۶ , Imatinib