Impact of CYP3A4*18 and CYP3A5*3 Polymorphisms on Imatinib Mesylate Response Among Chronic Myeloid Leukemia Patients in Malaysia

Abstract

Imatinib mesylate (IM), a selective inhibitor of the BCR-ABL tyrosine kinase, is a well-established first-line treatment for chronic myeloid leukemia (CML). IM is metabolized mainly by cytochrome P450 (CYP) in the liver, specifically the CYP3A4 and CYP3A5 enzymes. Polymorphisms in these genes can alter the enzyme activity of IM and may affect its response. In this study, the impact of two single-nucleotide polymorphisms (SNPs), CYP3A5*3 (6986A>G) and CYP3A4*18 (878T>C), on IM treatment response in CML patients (n = 270; 139 IM resistant and 131 IM good responders) was investigated. Genotyping of CYP3A4*18 and CYP3A5*3 was performed using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technique. The association between allelic variants and treatment response was assessed by means of odds ratio (OR) with 95% confidence intervals calculated by logistic regression. Our results indicated that CML patients carrying the heterozygous (AG) and homozygous variant (GG) genotype of CYP3A5*3 were associated with a significantly lower risk of acquiring resistance with OR 0.171; 95% CI: 0.090–0.324, p < 0.001 and OR 0.257; 95% CI: 0.126–0.525, p < 0.001, respectively. Although CML patients carrying the heterozygous (TC) genotype of CYP3A4*18 showed a lower risk of acquiring resistance toward IM (OR 0.648; 95% CI: 0.277–1.515), the association was not statistically significant (p = 0.316). No homozygous variant (CC) genotype of CYP3A4*18 was detected among the CML patients. It is concluded that polymorphism of CYP3A5*3 is associated with IM treatment response in Malaysian CML patients with carriers of CYP3A5*1/*3 and CYP3A5*3/*3 genotypes posing lower risk for development of resistance to IM.