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Blood, 3 September 2009, Vol. 114, No. 10, pp. 2037-2043. Prepublished online as a Blood First Edition Paper on June 30, 2009; DOI 10.1182/blood-2009-01-197715. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2009-01-197715v1 114/10/2037    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Jabbour, E. Articles by Cortes, J. PubMed PubMed Citation Articles by Jabbour, E. Articles by Cortes, J. Related Collections Free Research Articles Myeloid Neoplasia Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CLINICAL TRIALS AND OBSERVATIONS Long-term outcome of patients with chronic myeloid leukemia treated with second-generation tyrosine kinase inhibitors after imatinib failure is predicted by the in vitro sensitivity of BCR-ABL kinase domain mutations Elias Jabbour1,*, Daniel Jones2,*, Hagop M. Kantarjian1, Susan O'Brien1, Constantine Tam1, Charles Koller1, Jan A. Burger1, Gautam Borthakur1, William G. Wierda1, and Jorge Cortes1 Departments of 1 Leukemia and 2 Hematopathology, University of Texas M. D. Anderson Cancer Center, Houston Secondary imatinib resistance in chronic myeloid leukemia (CML) is associated in approximately 50% of cases with mutations in the BCR-ABL kinase domain, necessitating switch to one of several new tyrosine kinase inhibitors (TKIs) that act differentially on mutated BCR-ABL. We assess here whether scoring mutation based on in vitro inhibitory concentration of each TKI-mutation pair can predict long-term clinical outcome. Among 169 patients with CML after imatinib failure, mutations were detected before TKI switch in 41 (48%) treated with dasatinib and 45 (52%) treated with nilotinib. Inhibitory concentration values for each TKI-mutation pair were stratified into high (n = 42), intermediate (n = 25), low (T315I, n = 9), or unknown sensitivity (n = 10). Hematologic and cytogenetic response rates were similar for patients with or without mutations. For patients in chronic phase, hematologic and cytogenetic responses correlated with mutation score; tumors with low and intermediate scores had lower response rates than those with highly sensitive mutations, and worse event-free and overall survival. These correlations with overall survival were not seen for advanced phases. Mutation scoring can predict outcome in CML-chronic phase with imatinib failure treated with second-generation TKIs and can help in therapy selection. More complex prognostic models will be required for advanced stages of disease. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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