Please use this identifier to cite or link to this item: 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
Appears in Collections:Aurora harvest
Pathology publications

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