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In vitro sensitivity to imatinib-induced inhibition of ABL kinase activity is predictive of molecular response in patients with de novo CML

Citation

White, DL and Saunders, VA and Lyons, AB and Branford, S and Hughes, TP, In vitro sensitivity to imatinib-induced inhibition of ABL kinase activity is predictive of molecular response in patients with de novo CML, Blood, 106, (7) pp. 2520-2526. ISSN 0006-4971 (2005) [Refereed Article]

DOI: doi:10.1182/blood-2005-03-1103

Abstract

Most patients with de novo chronic myeloid leukemia (CML) achieve good responses to imatinib, but the rate and degree of molecular response is variable. We assessed the inhibitory concentration 50% for imatinib (IC50imatinib) in 62 patients with de novo chronic-phase CML as a predictor of molecular response. IC50imatinib was determined in pretherapy blood samples by measuring the in vitro imatinib-induced reduction of the phosphorylated form of the adaptor protein Crkl (CT10 regulator of kinase like). There was marked variability between patients, with IC50imatinib ranging from 0.375 to 1.8 microM (median, 0.6 microM). Patients with low IC50imatinib (IC50 < or = 0.6 microM; n = 36) had a 36% probability of achieving 2-log reduction in BCR-ABL (breakpoint cluster region-abelson) by 3 months compared with 8% in patients with high IC50imatinib (n = 26) (P = .01). The IC50imatinib was also predictive of molecular response at 12 months, with 47% of patients in the low IC50imatinib group achieving 3-log reduction and 23% in the high IC50imatinib group (P = .03). The predictive power of IC50imatinib was particularly strong in patients with low Sokal scores. These data provide strong evidence that intrinsic sensitivity to imatinib is variable in previously untreated patients with CML, and the actual level of BCR-ABL kinase inhibition achieved is critical to imatinib response. The IC50imatinib potentially provides a new prognostic indicator for molecular response in patients treated with imatinib.

Item Details

Item Type:Refereed Article
Research Division:Medical and Health Sciences
Research Group:Oncology and Carcinogenesis
Research Field:Molecular Targets
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Blood Disorders
Author:Lyons, AB (Dr Bruce Lyons)
ID Code:73623
Year Published:2005
Web of Science® Times Cited:92
Deposited By:Medicine (Discipline)
Deposited On:2011-10-19
Last Modified:2011-10-19
Downloads:0

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