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  • 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 MF, Lynch K, To LB, Hughes T.
    Journal: J Clin Oncol; 2007 Oct 01; 25(28):4445-51. PubMed ID: 17906206.
    Abstract:
    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.
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