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

<jats:title>Abstract</jats:title> <jats:p>Abstract 4449</jats:p> <jats:sec> <jats:title>Background:</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Method:</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Result:</jats:title> <jats:p>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%).</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion:</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Disclosures:</jats:title> <jats:p>No relevant conflicts of interest to declare.</jats:p> </jats:sec>