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https://hdl.handle.net/2440/43996
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Type: | Journal article |
Title: | Measurement of in vivo BCR-ABL kinase inhibition to monitor imatinib-induced target blockade and predict response in chronic myeloid leukemia |
Author: | White, D. Saunders, V. Grigg, A. Arthur, C. Filshie, R. Leahy, M. Lynch, K. To, L. Hughes, T. |
Citation: | Journal of Clinical Oncology, 2007; 25(28):4445-4451 |
Publisher: | Amer Soc Clinical Oncology |
Issue Date: | 2007 |
ISSN: | 0732-183X 1527-7755 |
Abstract: | <h4>Purpose</h4>Intrinsic sensitivity to imatinib, based on measurement of inhibitory concentration 50% for imatinib, is variable in untreated patients with chronic myeloid leukemia (CML). This suggests that patient-tailored dosing may be more rational than a fixed dose for all. Dose optimization potentially could be based on accurate measurement of the level of BCR-ABL kinase inhibition achieved in vivo.<h4>Patients and methods</h4>In vivo kinase inhibition was measured by calculating the reduction in protein (p)--Crkl level in mononuclear blood cells taken from 49 CML patients at weekly intervals after imatinib therapy was commenced.<h4>Results</h4>Greater than 50% inhibition (> 50% reduction in p-Crkl from baseline) was achieved by 21% of patients by days 7 to 14 (and maintained in all patients on days 21 to 28) and an additional 24% of patients achieved more than 50% inhibition by days 21 to 28. Thus, overall 45% of patients achieved more than 50% inhibition. All of these patients achieved major molecular responses by 24 months compared with 56% of the patients who failed to achieve 50% kinase inhibition (P < .001). Patients with less than 50% kinase inhibition were also more likely to have suboptimal responses.<h4>Conclusion</h4>In vivo BCR-ABL kinase inhibition can be assessed in the first month of imatinib therapy and may provide a valuable guide to optimization of dosage. The extent of BCR-ABL kinase inhibition is an excellent predictor of cytogenetic and molecular response. These observations suggest that dose adjustment based on in vivo measurements of drug-induced target inhibition could be applied in settings beyond imatinib and may be a more effective approach than using one dose for all patients in targeted anticancer therapy. |
Keywords: | Leukocytes, Mononuclear Humans Benzamides Piperazines Pyrimidines Adaptor Proteins, Signal Transducing Fusion Proteins, bcr-abl Nuclear Proteins Antineoplastic Agents Drug Monitoring Drug Screening Assays, Antitumor Analysis of Variance Predictive Value of Tests Dose-Response Relationship, Drug Adult Protein-Tyrosine Kinases Leukemia, Myelogenous, Chronic, BCR-ABL Positive Kaplan-Meier Estimate Biomarkers Imatinib Mesylate |
Description: | Copyright © 2007 American Society of Clinical Oncology |
DOI: | 10.1200/JCO.2006.09.9499 |
Published version: | http://dx.doi.org/10.1200/jco.2006.09.9499 |
Appears in Collections: | Aurora harvest Pathology publications |
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