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

Simple item page
dc.contributor.authorWhite, D.
dc.contributor.authorDang, P.
dc.contributor.authorEngler, J.
dc.contributor.authorFrede, A.
dc.contributor.authorOsborn, M.
dc.contributor.authorSaunders, V.
dc.contributor.authorManley, P.
dc.contributor.authorZrim, S.
dc.contributor.authorHughes, T.
dc.date.issued2010
dc.description.abstractPurpose: 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.
dc.description.statementofresponsibilityDeborah L. White, Phuong Dang, Jane Engler, Amity Frede, Stephanie Zrim, Michael Osborn, Verity A. Saunders, Paul W. Manley, and Timothy P. Hughes
dc.identifier.citationJournal of Clinical Oncology, 2010; 28(16):2761-2767
dc.identifier.doi10.1200/JCO.2009.26.5819
dc.identifier.issn0732-183X
dc.identifier.issn1527-7755
dc.identifier.orcidWhite, D. [0000-0003-4844-333X]
dc.identifier.orcidOsborn, M. [0000-0002-1288-9930]
dc.identifier.orcidHughes, T. [0000-0002-0910-3730] [0000-0002-7990-4509]
dc.identifier.urihttp://hdl.handle.net/2440/64539
dc.language.isoen
dc.publisherAmer Soc Clinical Oncology
dc.rights© 2010 by American Society of Clinical Oncology
dc.source.urihttps://doi.org/10.1200/jco.2009.26.5819
dc.subjectHumans
dc.subjectLeukemia, Myeloid, Chronic-Phase
dc.subjectBenzamides
dc.subjectPiperazines
dc.subjectPyrimidines
dc.subjectOrganic Cation Transporter 1
dc.subjectRNA, Messenger
dc.subjectAntineoplastic Agents
dc.subjectDisease-Free Survival
dc.subjectTreatment Outcome
dc.subjectDrug Administration Schedule
dc.subjectAnalysis of Variance
dc.subjectProbability
dc.subjectRisk Assessment
dc.subjectSurvival Analysis
dc.subjectFollow-Up Studies
dc.subjectPredictive Value of Tests
dc.subjectReverse Transcriptase Polymerase Chain Reaction
dc.subjectMaximum Tolerated Dose
dc.subjectGene Expression Regulation, Leukemic
dc.subjectDose-Response Relationship, Drug
dc.subjectTime Factors
dc.subjectAged
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectMale
dc.subjectKaplan-Meier Estimate
dc.subjectImatinib Mesylate
dc.titleFunctional activity of the OCT-1 protein is predictive of long-term outcome in patients with chronic-phase chronic myeloid leukemia treated with Imatinib
dc.typeJournal article
pubs.publication-statusPublished

Files

Collections

Medicine publications