Prognostic Significances of ABCG-2 and hOCT-1 Gene Expression in Chronic Phase Chronic Myeloid Leukemia Patients Treated with Imatinib Mesylate.

Imatinib mesylate is a substrate for both drug efflux transporter ATP-binding cassette transporters (ABCG-2; BCRP) and influx transporter human Organic Cation Transporter 1 (hOCT-1; SLCA22). The correlation between the expression of these two transporters of imatinib and the clinical outcome of imatinib in CML patients remain clarified.

ABCG-2 and hOCT-1 mRNA levels were determined by performing real-time polymerase chain reaction assays on seventy eight BM samples obtained at initial diagnosis from the patients with chronic phase CML treated with imatinib (treatment started at 400mg/day).

Median age of the patients was 51 years (16-83 years) and median follow up time from the start of imatinib treatment was 50.8 months (1-95.4 months). Patients with low ABCG-2 mRNA expression (<13.53 a.u.) at diagnosis could achieve higher rates of MCyR by 6 months (74.3% vs. 51.2%, P=0.039), CCyR by 12 months (79.4% vs. 59.0%, P=0.049) and MMR by 18 months (68.8% vs. 26.3%, P=0.000) than those with high ABCG-2 expression (≥13.53 a.u.). Along with these data, patients with high ABCG-2 showed higher rate of suboptimal responses (fail to achieve CHR by 3 months, MCyR by 6 months, CCyR by 12 months and MMR by 18 months) than those with low ABCG-2 expression (69.3% vs. 22.0%, P=0.000). Furthermore, patients with high ABCG-2 also showed higher rate of primary resistance (fail to achieve CHR by 3 months, PCyR by 6 months and MCyR by 12 months) to imatinib than those with low ABCG-2 expression (19% vs. 2.8%, P=0.025). Patients with low ABGC-2 expression are also demonstrated higher rate of MMR achievement during the whole period of treatment (68.3% vs. 46.2%, P=0.043) and the time to MMR achievement was significantly shorter than those with high ABCG-2 expression (10.5 months vs. 21.8 months, P=0.001). However, there was no statistical significance in response and resistance rates to imatinib according to the hOCT-1 expression levels. Although time to achieving MCyR was significantly shorter in patients with high hOCT-1 expression (≥34.53 a.u.) than those with low hOCT-1 expression (<34.53 a.u.)(6.1 months vs. 6.4 months, P=0.029) and they showed a trend of shorter time to achieving CCR or MMR, there was no statistical significance. Fifteen patients were tested their imatinib plasma concentration at 18 months of treatment. There was no significant correlation between imatinib plasma concentration and ABCG-2 or hOCT-1 expression levels. Although patients with primary resistance to imatinib demonstrated lower imatinib plasma concentration than other patients, there was no statistical significance (958 ng/ml vs. 1476.9 ng/ml, P=0.425).

This study demonstrates that pretreatment assay of ABCG-2 gene expression may help us to identify the treatment outcome in the chronic phase CML patients treated with imatinib.

No relevant conflicts of interest to declare.