P0223 CYP3A4∗18 and CYP3A5∗3 gene polymorphisms and imatinib resistance in Malaysian patients with chronic myeloid leukaemia

Abstract

Background Although imatinib mesylate (IM) has shown excellent efficacy as first-line therapy for treatment of chronic myeloid leukaemia (CML), resistance to IM has emerged as a daunting clinical problem. Enhanced drug metabolism has been proposed as a host-dependent mechanism of drug resistance. IM is a substrate of CYP3A4 and CYP3A5 metabolism enzymes. CYP3A4 ∗ 18 and CYP3A5 ∗ 3 polymorphisms exhibit inter-individual differences in mRNA expression levels; however, the clinical significance of these polymorphisms on IM resistance remains unclear. We investigated the association between CYP3A4 ∗ 18 and CYP3A5 ∗ 3 polymorphisms in mediating IM response in Malaysian patients with CML. Methods One hundred and one CML patients (48 IM good response, 53 IM resistant) initially treated with 400 mg IM daily for a minimum of 18 months were enrolled in this case–control study. Response criteria were based on European Leukemia Net recommendations. Genotyping was carried out for CYP3A4 ∗ 18 (rs28371759) and CYP3A5 ∗ 3 (rs776746) polymorphisms by polymerase chain reaction–restriction fragment-length polymorphisms (PCR–RFLP). Logistic regression analysis was done to calculate risk association using Epi-Info 7.0 software. Findings The distribution of CYP3A5 ∗ 3 genotype was 41.5% (GG), 37.7% (GA), and 20.8% (AA) among the IM-resistant group, compared with 45.8% (GG), 33.3% (GA), and 20.9% (AA) among the IM-good-response group. There was no significant difference in genotype frequencies between the two groups ( p = 0.91). On evaluating the risk of IM resistance, the frequencies of homozygous TT genotype and heterozygous TC variant of CYP3A4 ∗ 18 were insignificantly associated with IM response ( p = 0.25). Odds ratio was 0.34 (95% confidence interval [CI] 0.062–1.827, p = 0.19) for the CYP3A4 ∗ 18 heterozygous variant, 1.25 (95% CI 0.516–3.026, p = 0.69) for the CYP3A5 ∗ 3 heterozygous variant, and 1.10 (95% CI 0.389–3.114, p = 0.86) for the CYP3A5 ∗ 3 homozygous variant. Interpretation Our preliminary results suggest a lack of association between CYP3A4 ∗ 18 and CYP3A5 ∗ 3 gene polymorphisms and IM resistance. This study is being continued with a larger number of patients.