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

Deborah White, Verity Saunders, Andrew Grigg, Chris Arthur, Robin Filshie, Michael F. Leahy, Kevin Lynch, L. Bik To, Timothy Hughes

From the Division of Hematology, Institute of Medical and Veterinary Science & Hanson Institute; The University of Adelaide; and Royal Adelaide Hospital, Adelaide, South Australia; Royal Melbourne Hospital, Melbourne; Royal North Shore Hospital, Sydney; St Vincent's Hospital, Melbourne; Fremantle Hospital, Perth; and Novartis Pharmaceuticals Australia Pty Ltd, Sydney, Australia

Address reprint requests to Deborah White, Division of Hematology, Institute of Medical and Veterinary Science & Hanson Institute, PO Box 14, Rundle Mall Post Office, Adelaide, Australia 5001; e-mail: deb.white{at}imvs.sa.gov.au

Purpose 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.

Patients and Methods 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.

Results 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.

Conclusion 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.

Supported in part by a grant from the Cancer Council of Australia, with additional support from Novartis Australia, the Australasian Leukemia Lymphoma Group, Novartis, and Amgen Pharmaceuticals.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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