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Blood, 1 December 2007, Vol. 110, No. 12, pp. 4005-4011. Prepublished online as a Blood First Edition Paper on September 4, 2007; DOI 10.1182/blood-2007-03-080838. This Article Full Text (PDF) All Versions of this Article: blood-2007-03-080838v1 110/12/4005    most recent Alert me when this article is cited Alert me if a correction is posted 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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Cortes, J. Articles by Jones, D. Search for Related Content PubMed PubMed Citation Articles by Cortes, J. Articles by Jones, D. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 21, 2007 Accepted August 7, 2007 Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors Jorge Cortes*, Elias Jabbour, Hagop Kantarjian, C. Cameron Yin, Jianqin Shan, Susan O'Brien, Guillermo Garcia-Manero, Francis Giles, Megan Breeden, Nubia Reeves, William G. Wierda, and Dan Jones Department of Leukemia, U.T. M.D. Anderson Cancer Center, Houston, TX, United States Department of Hematopathology, U.T. M.D. Anderson Cancer Center, Houston, TX, United States * Corresponding author; email: jcortes{at}mdanderson.org. Dasatinib and nilotinib are potent tyrosine kinase inhibitors (TKIs) with activity against many imatinib-resistant chronic myeloid leukemia (CML) clones with BCR-ABL kinase domain (KD) mutations, except T315I. We assessed for changes in the BCR-ABL KD mutation status in 112 patients with persistent CML who received a second generation TKI after imatinib failure. Sixty-seven different KD mutations were detected before the start of therapy with a second TKI, with T315I seen in 15%. Equal numbers of patients received nilotinib or dasatinib following imatinib, and 18 received 3 TKIs. Response rates were similar for patients with and without mutations, regardless of mutation site except for T315I. Overall, 29 patients (26%) developed new KD mutations after therapy with a second (n=24) or third (n=5) TKI, but only 4 (4%) developed T315I. In 73% of cases, the KD mutations that persisted or developed following switch to new TKI were at sites also found in prior in vitro TKI mutagenesis assays. Although there is only a mild increase in mutation frequency with sequential TKI treatment, novel mutations do occur and mutation regression/acquisition/persistence generally reflects the in vitro differential sensitivity predicted for each TKI. In this study, there was no marked increase in development of T315I. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. D. Press, S. G. Willis, J. Laudadio, M. J. Mauro, and M. W. N. Deininger Determining the rise in BCR-ABL RNA that optimally predicts a kinase domain mutation in patients with chronic myeloid leukemia on imatinib Blood, September 24, 2009; 114(13): 2598 - 2605. [Abstract] [Full Text] [PDF] E. Jabbour, D. Jones, H. M. Kantarjian, S. O'Brien, C. Tam, C. Koller, J. A. Burger, G. Borthakur, W. G. Wierda, and J. Cortes 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 Blood, September 3, 2009; 114(10): 2037 - 2043. [Abstract] [Full Text] [PDF] S. Soverini, A. Gnani, S. Colarossi, F. Castagnetti, E. Abruzzese, S. Paolini, S. Merante, E. Orlandi, S. de Matteis, A. Gozzini, et al. Philadelphia-positive patients who already harbor imatinib-resistant Bcr-Abl kinase domain mutations have a higher likelihood of developing additional mutations associated with resistance to second- or third-line tyrosine kinase inhibitors Blood, September 3, 2009; 114(10): 2168 - 2171. [Abstract] [Full Text] [PDF] W. W. Zhang, J. E. Cortes, H. Yao, L. Zhang, N. G. Reddy, E. Jabbour, H. M. Kantarjian, and D. Jones Predictors of Primary Imatinib Resistance in Chronic Myelogenous Leukemia Are Distinct From Those in Secondary Imatinib Resistance J. Clin. 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