IS DETECTION OF CYP3A5*3 ALLELE IN CHRONIC MYELOID LEUKEMIA PATIENTS PRIOR TO TREATMENT WITH IMATINIB MESYLATE RELEVANT?

Sborník

Background. Imatinib mesylate (IM) is known to be metabolized by CYP3A subfamily members of cytochrome P450 family. When expressed, CYP3A5 can represent up to 50% of CYP3A protein and its inactivation can lead to significant variation of CYP3A mediated IM metabolism. Inactive allele CYP3A5*3 is predominant in Caucasian population. This single nucleotide polymorphism (SNP) A6986G (rs776746) forms cryptic splicing site and leads to incorporation of intron into mRNA, premature termination of translation and expression of truncated protein. Active allele CYP3A5*1 is very rare in Caucasian population, but there are significant differences in distribution of CYP3A5 allelic variants in different ethnic groups. Aims. To determine frequency of CYP3A5*3 allele in our cohort of IM-treated patients and assess the relevance of CYP3A5*3 allele detection prior to IM treatment. Methods. We retrospectively analyzed therapeutical response to IM (400 mg /day) according to European LeukemiaNet (ELN) recommendations in a cohort of 64 patients diagnosed in chronic phase of CML. Patients with treatment failure due to mutations in kinase domain of ABL were not included. CYP3A5*3 was detected by TaqMan SNP genotyping assay. IM plasma levels were detected by liquid chromatography from samples taken 24 hours (+/- 2 hours) after the last imatinib dose. Results. Our cohort consisted of 58 CYP3A5*3 homozygotes, 5 heterozygotes and 1 wild type homozygote, leading to the frequency of allele different than CYP3A5*3 5.7%. Major molecular response at 18 months after diagnosis was not associated with CYP3A5*3/*3 genotype (n = 63, p = 0.191) but heterozygous or wild type individuals for CYP3A5*3 allele showed a trend towards failure of complete cytogenetical response at 12 months (n = 64, p = 0.053). Plasma levels of IM were not altered by CYP3A5*3/*3 genotype (n = 56, p = 0.656). Conclusions. Our study did not confirm any association of heterozygous or wild type genotype for CYP3A5*3 allele and suboptimal response or failure of IM treatment according to ELN but heterozygous or wild type individuals for CYP3A5*3 allele displayed a trend towards failure of complete cytogenetical response at 12 months after diagnosis. Thus, cheap and fast genotyping of CYP3A5*3 in Caucasian population could be relevant but further study with larger patient cohorts are needed to confirm our findings. This study was supported by research project MZO 00179906 from Ministry of Health, Czech Republic. haematologica

Haematologica, 2012; 97(s1):  71