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Blood, 1 October 2005, Vol. 106, No. 7, pp. 2520-2526. Prepublished online as a Blood First Edition Paper on June 14, 2005; DOI 10.1182/blood-2005-03-1103. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-03-1103v1 106/7/2520    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by White, D. Articles by Hughes, T. Search for Related Content PubMed PubMed Citation Articles by White, D. Articles by Hughes, T. Related Collections Neoplasia Oncogenes and Tumor Suppressors Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA In vitro sensitivity to imatinib-induced inhibition of ABL kinase activity is predictive of molecular response in patients with de novo CML Deborah White, Verity Saunders, A. Bruce Lyons, Susan Branford, Andrew Grigg, L. Bik To, and Timothy Hughes From the Division of Haematology, Institute of Medical and Veterinary Science (IMVS) and Hanson Institute, Adelaide, Australia; the University of Adelaide, Adelaide, Australia; the Division of Molecular Pathology, IMVS, Adelaide, Australia; and the Royal Melbourne Hospital, Melbourne, Australia. 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 µM (median, 0.6 µM). Patients with low IC50imatinib (IC50 0.6 µM; 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. (Blood. 2005; 106:2520-2526) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. K. Hiwase, V. Saunders, D. Hewett, A. Frede, S. Zrim, P. Dang, L. Eadie, L. B. To, J. Melo, S. Kumar, et al. Dasatinib Cellular Uptake and Efflux in Chronic Myeloid Leukemia Cells: Therapeutic Implications Clin. Cancer Res., June 15, 2008; 14(12): 3881 - 3888. [Abstract] [Full Text] [PDF] J. S. Khorashad, D. Milojkovic, P. Mehta, M. Anand, S. Ghorashian, A. G. Reid, V. De Melo, A. Babb, H. de Lavallade, E. Olavarria, et al. In vivo kinetics of kinase domain mutations in CML patients treated with dasatinib after failing imatinib Blood, February 15, 2008; 111(4): 2378 - 2381. [Abstract] [Full Text] [PDF] D. L. White, V. A. Saunders, P. Dang, J. Engler, A. Venables, S. Zrim, A. Zannettino, K. Lynch, P. W. Manley, and T. Hughes Most CML patients who have a suboptimal response to imatinib have low OCT-1 activity: higher doses of imatinib may overcome the negative impact of low OCT-1 activity Blood, December 1, 2007; 110(12): 4064 - 4072. [Abstract] [Full Text] [PDF] J. M. Goldman How I treat chronic myeloid leukemia in the imatinib era Blood, October 15, 2007; 110(8): 2828 - 2837. [Abstract] [Full Text] [PDF] D. White, V. Saunders, A. Grigg, C. Arthur, R. Filshie, M. F. Leahy, K. Lynch, L. B. To, and T. Hughes Measurement of In Vivo BCR-ABL Kinase Inhibition to Monitor Imatinib-Induced Target Blockade and Predict Response in Chronic Myeloid Leukemia J. Clin. Oncol., October 1, 2007; 25(28): 4445 - 4451. [Abstract] [Full Text] [PDF] M. Mohty, A. S. M. Yong, R. M. Szydlo, J. F. Apperley, and J. V. Melo The polycomb group BMI1 gene is a molecular marker for predicting prognosis of chronic myeloid leukemia Blood, July 1, 2007; 110(1): 380 - 383. [Abstract] [Full Text] [PDF] M. Baccarani, G. Saglio, J. Goldman, A. Hochhaus, B. Simonsson, F. Appelbaum, J. Apperley, F. Cervantes, J. Cortes, M. Deininger, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet Blood, September 15, 2006; 108(6): 1809 - 1820. [Abstract] [Full Text] [PDF] D. L. White, V. A. Saunders, P. Dang, J. Engler, A. C. W. Zannettino, A. C. Cambareri, S. R. Quinn, P. W. Manley, and T. P. Hughes OCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib Blood, July 15, 2006; 108(2): 697 - 704. [Abstract] [Full Text] [PDF] T. Hughes ABL Kinase Inhibitor Therapy for CML: Baseline Assessments and Response Monitoring Hematology, January 1, 2006; 2006(1): 211 - 218. [Abstract] [Full Text] [PDF] A. S. M. Yong, R. M. Szydlo, J. M. Goldman, J. F. Apperley, and J. V. Melo Molecular profiling of CD34+ cells identifies low expression of CD7, along with high expression of proteinase 3 or elastase, as predictors of longer survival in patients with CML Blood, January 1, 2006; 107(1): 205 - 212. [Abstract] [Full Text] [PDF]

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