Functional activity of the OCT-1 protein is predictive of long-term outcome in patients with chronic-phase chronic myeloid leukemia treated with imatinib

Deborah White, Yen Dang, Jane Engler, Amity Frede, Stephanie Zrim, Michael Osborn, Verity Saunders, Paul W. Manley, Timothy Hughes

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    146 Citations (Scopus)

    Abstract

    Purpose: Organic cation transporter-1 (OCT-1) activity (OA), a measure of the OCT-1-mediated influx of imatinib into CML mononuclear cells (MNCs), is predictive of major molecular response (MMR) at 12 and 24 months in patients with untreated CML. We now report the impact of OA on loss of response, disease transformation, and survival after 5 years of imatinib. Patients and Methods: OA is defined as the difference in intracellular concentration of carbon-14-imatinib with and without OCT-1 inhibition. OA was measured in blood from 56 patients with untreated chronic-phase CML. Results: More patients who had high OA (ie, > median OA value) achieved MMR by 60 months compared with patients who had low OA (89% v 55%; P = .007). A low OA was associated with a significantly lower overall survival (87% v 96%; P = .028) and event-free survival (EFS; 48% v 74%; P = .03) as well as a higher kinase domain mutation rate (21% v 4%; P = .047). These differences were highly significant in patients who averaged less than 600 mg/d of imatinib in the first 12 months but were not significant in patients averaging ≥ 600 mg/d. Patients with very low OA (ie, quartile 1) were the only group who developed leukemic transformation (21% in quartile 1 v 0% in all other quartiles; P = .002). Conclusion: Measurement of OA pretherapy is a predictor for the long-term risk of resistance and transformation in patients with imatinib-treated CML. Early dose-intensity may reduce the negative prognostic impact of low OA. We propose that OA could be used to individualize dosage strategies for patients with CML to maximize molecular response and optimize long-term outcome.

    Original languageEnglish
    Pages (from-to)2761-2767
    Number of pages7
    JournalJournal of Clinical Oncology
    Volume28
    Issue number16
    DOIs
    Publication statusPublished - 1 Jun 2010

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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