Sustained Long-Term MMR to a Reduced Dose of Imatinib in Chronic-Phase CML: A Pilot Study of SLC22A1 Gene Polymorphisms

Recently, The efficacy of reduced dose of imatinib for the patients with small BSA was reported by our group and Japanese group. Also, therapeutic drug monitoring to maintain a plasma threshold level of about 1,000ng/ml would be beneficial during imatinib therapy in practical setting. But, we sometimes see a discrepancy between imatinib trough level and clinical efficacy. Observed inter-patient pharmacokinetic variability may be due to patients' genetics.

We investigated a panel of 9 polymorphisms in 4 genes (ABCG2, SLC22A1, ABCB1, CYP3A5), potentially associated with the pharmacogenetics of imatinib in a subset of 7 patients with sustained MMR. The DNAs from peripheral blood samples were genotyped. Imatinib trough levels were tested between 21 and 27 hours from the last dose of imatinib.

All patients were reduced dose to 300mg/day within six months after starting imatinib therapy with 400mg/day. The main reasons for dose reduction were severe neutropenia or thrombocytopenia (≥ grade 3) (62.9%). They couldn't increase a standard imatnib dose due to severe adverse effect. Although relatively small BSA (mean BSA; 1.53), 4 of seven patients showed lower imatinib trough level than 1,000ng/ml. After median follow-up period of 66.2 months (18.4∼150.7), all patients have sustained MMR. Allele frequencies of rs683369, rs2282143, rs628031and rs2282143 polymorphisms of SLC22A1 gene were 0%, 78.5% and 8.3%, respectively. Interethnic differences in the genotype and allele frequencies of SLC22A1 gene polymorphism were observed when compared with other previous major populations. The SNPs rs2282143, T allele and rs628031, G allele were more common in Asians (5.5–16.8% and 76.2–81%) and African Americans (8.2% and 73.5%) than in Caucasians (0–2% and 57.4–60%).

In our pilot study, we found interethnic differences in the genotype and allele frequencies of SLC22A1 gene in spite of very small cases. These findings might be explained a discrepancy between imatinib trough level and clinical efficacy in practical setting with reduced dose and further studies with larger scale will be needed to clarify the effect of these results.

No relevant conflicts of interest to declare.