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

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.

[1]  Susan Branford,et al.  Phase III, randomized, open-label study of daily imatinib mesylate 400 mg versus 800 mg in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase using molecular end points: tyrosine kinase inhibitor optimization and selectivity study. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  J. Radich,et al.  Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  J. Burke,et al.  High-dose imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: high rates of rapid cytogenetic and molecular responses. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  Giovanni Martinelli,et al.  Comparison of imatinib 400 mg and 800 mg daily in the front-line treatment of high-risk, Philadelphia-positive chronic myeloid leukemia: a European LeukemiaNet Study. , 2009, Blood.

[5]  K. Rezvani,et al.  Does a rise in the BCR‐ABL1 transcript level identify chronic phase CML patients responding to imatinib who have a high risk of cytogenetic relapse? , 2009, British journal of haematology.

[6]  K. Rezvani,et al.  European LeukemiaNet criteria for failure or suboptimal response reliably identify patients with CML in early chronic phase treated with imatinib whose eventual outcome is poor. , 2008, Blood.

[7]  J. Radich,et al.  CML Patients with Low OCT-1 Activity Achieve Better Molecular Responses on High Dose Imatinib Than on Standard Dose. Those with High OCT-1 Activity Have Excellent Responses on Either Dose: A TOPS Correlative Study , 2008 .

[8]  Deborah L White,et al.  Impact of early dose intensity on cytogenetic and molecular responses in chronic- phase CML patients receiving 600 mg/day of imatinib as initial therapy. , 2008, Blood.

[9]  Martin C. Müller,et al.  Desirable performance characteristics for BCR-ABL measurement on an international reporting scale to allow consistent interpretation of individual patient response and comparison of response rates between clinical trials. , 2008, Blood.

[10]  M. Pirmohamed,et al.  Effective dasatinib uptake may occur without human organic cation transporter 1 (hOCT1): implications for the treatment of imatinib-resistant chronic myeloid leukemia. , 2008, Blood.

[11]  J. Melo,et al.  Dasatinib Cellular Uptake and Efflux in Chronic Myeloid Leukemia Cells: Therapeutic Implications , 2008, Clinical Cancer Research.

[12]  S. Baker,et al.  Interaction of Imatinib with Human Organic Ion Carriers , 2008, Clinical Cancer Research.

[13]  J. Goldman,et al.  International standardisation of quantitative real-time RT-PCR for BCR-ABL. , 2008, Leukemia research.

[14]  M. Pirmohamed,et al.  Expression of the Uptake Drug Transporter hOCT1 is an Important Clinical Determinant of the Response to Imatinib in Chronic Myeloid Leukemia , 2008, Clinical pharmacology and therapeutics.

[15]  M. Pirmohamed,et al.  Pharmacologic markers and predictors of responses to imatinib therapy in patients with chronic myeloid leukemia , 2008, Leukemia & lymphoma.

[16]  Francisco Cervantes,et al.  Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. , 2006, The New England journal of medicine.

[17]  Francisco Cervantes,et al.  Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. , 2006, Blood.

[18]  P. Manley,et al.  OCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib. , 2006, Blood.

[19]  M. Pirmohamed,et al.  hOCT 1 and resistance to imatinib. , 2005, Blood.

[20]  Munir Pirmohamed,et al.  Active transport of imatinib into and out of cells: implications for drug resistance. , 2004, Blood.

[21]  R. Herrmann,et al.  Real-time quantitative PCR analysis can be used as a primary screen to identify patients with CML treated with imatinib who have BCR-ABL kinase domain mutations. , 2004, Blood.

[22]  H. Kantarjian,et al.  High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia. , 2004, Blood.

[23]  Susan Branford,et al.  Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. , 2003, The New England journal of medicine.

[24]  Francisco Cervantes,et al.  Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. , 2003, The New England journal of medicine.

[25]  H. Kantarjian,et al.  Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. , 2003, Blood.

[26]  Heinz Bönisch,et al.  Expression and pharmacological profile of the human organic cation transporters hOCT1, hOCT2 and hOCT3 , 2002, British journal of pharmacology.

[27]  C. Sawyers,et al.  Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. , 2001, The New England journal of medicine.

[28]  C. Sawyers,et al.  Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. , 2001, The New England journal of medicine.

[29]  Alfred Gangl,et al.  bloodjournal.hematologylibrary.org at PENN STATE UNIVERSITY on February 23, 2013. For personal use , 2001 .

[30]  T. Meyer,et al.  Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. , 1996, Cancer research.