Measurement of In Vivo BCR-ABL Kinase Inhibition to Monitor Imatinib-Induced Target Blockade and Predict Response in Chronic Myeloid Leukemia

• Published in: Journal of clinical oncology Vol. 25; no. 28; pp. 4445 - 4451
• Main Authors: WHITE, Deborah, SAUNDERS, Verity, GRIGG, Andrew, ARTHUR, Chris, FILSHIE, Robin, LEAHY, Michael F, LYNCH, Kevin, BIK TO, L, HUGHES, Timothy
• Format: Journal Article
• Language: English
• Published: Baltimore, MD American Society of Clinical Oncology 01-10-2007; Lippincott Williams & Wilkins
• Subjects: Adaptor Proteins, Signal Transducing - antagonists & inhibitors; Adult; Analysis of Variance; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Benzamides; Biological and medical sciences; Biomarkers - metabolism; Chromosome aberrations; Dose-Response Relationship, Drug; Drug Monitoring - methods; Drug Screening Assays, Antitumor - methods; Fusion Proteins, bcr-abl; Humans; Imatinib Mesylate; Kaplan-Meier Estimate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - metabolism; Medical genetics; Medical sciences; Nuclear Proteins - antagonists & inhibitors; Piperazines - administration & dosage; Piperazines - pharmacology; Predictive Value of Tests; Protein-Tyrosine Kinases - antagonists & inhibitors; Pyrimidines - administration & dosage; Pyrimidines - pharmacology; Tumors; Chromosomal aberration; Antineoplastic agent; Imatinib; Targeting; Enzyme; Transferases; Enzyme inhibitor; Chronic myelogenous leukemia; Malignant hemopathy; Philadelphia chromosome; Myeloproliferative syndrome; Abnormal chromosome C9; In vivo; Cancerology; Kinase; Protein kinase; Bcr-abl protein; C-Onc gene; Abnormal chromosome G22; Abnormal chromosome; Predictive factor; Protein-tyrosine kinase; Hybrid gene; Chromosome translocation
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2006.09.9499

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.
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.
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.
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.