Prognostic Significance of hOCT1 and ABCG2 Expression in Chronic Myeloid Leukemia Patients Treated with Imatinib

Abstract

Background: Imatinib mesylate is a substrate for both the drug influx transporter human Organic Cation Transporter 1 (hOCT1; SLCA22) and the efflux transporter ATP-binding cassette transporters (ABCG2; BCRP). The correlation between the expression of these two transporters of imatinib and the clinical outcome of imatinib in chronic myeloid leukemia (CML) patients remain clarified.Methods: hOCT-1 and ABCG2 mRNA levels were determined by performing real-time polymerase chain reaction assays on 83 BM samples obtained at initial diagnosis from the patients with chronic phase CML treated with imatinib (started at 400mg/day).Results: Of patients with higher hOCT-1 mRNA expression than median value (≥ 34.53 a.u.) at diagnosis, 59.5% achieved complete cytogenetic response (CCyR) at 6 months, whereas of patients with no more than a median hOCT-1 expression, 33.3% could achieve CCyR at 6 months (p=0.035). Furthermore, patients with low hOCT-1 showed higher rate of suboptimal response [failed to achieve complete hematologic response (CHR) by 3 months, major cytogenetic response (MCyR) by 6 months, CCyR by 12 months, and major molecular response (MMR) by 18 months] than those with high hOCT-1 expression (55.9% vs. 33.3%. p=0.048). There was no statistical significance in progression-free survival (PFS) or overall survival (OS) according to the hOCT-1 expression levels. Patients with low ABCG2 expression (< 13.53 a.u.) showed higher MMR rate at 18 months (57.1% vs. 35.5 %, p=0.09) and longer PFS (3 yr PFS, 87.2% vs. 64.1%, p=0.07) than those with high ABCG2 expression but there was no statistical significance. The time to achieving MMR was significantly shorter in patients with low ABCG2 expression than in those with high ABCG2 expression (6.9 ± 2.1 ms vs. 12.2 ± 4.2 ms, p=0.09). The patients with high hOCT-1 expression showed shorter time to achieving MMR, but there was no statistical significance (8.1 ± 1.9 vs. 10.5 ± 1.7, p=0.50).Conclusions: This study demonstrates that pretreatment assay of hOCT-1 and ABCG2 expression may help us to identify the treatment outcome in the CML patients treated with imatinib.