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Blood, 23 April 2009, Vol. 113, No. 17, pp. 3938-3946. Prepublished online as a Blood First Edition Paper on November 24, 2008; DOI 10.1182/blood-2008-09-177030. This Article Full Text (PDF) All Versions of this Article: blood-2008-09-177030v1 113/17/3938    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 Pratz, K. W Articles by Levis, M. Search for Related Content PubMed PubMed Citation Articles by Pratz, K. W Articles by Levis, M. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 8, 2008 Accepted November 9, 2008 A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical response Keith W Pratz, Jorge Cortes, Gail J. Roboz, Niranjan Rao, Omotayo Arowojolu, Adam Stine, Yukimasa Shiotsu, Aiko Shudo, Shiro Akinaga, Donald Small, Judith E Karp, and Mark Levis* Department of Oncology, Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, United States Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX, United States Division of Hematology/Oncology, Weill Medical College of Cornell Medical University and New York Presbyterian Hospital, New York, NY, United States Kyowa Pharmaceutical, Inc., Princeton, NJ, United States Clinical Development Department, Kyowa Hakko Kirin Co Ltd, Tokyo, Japan * Corresponding author; email: levisma{at}jhmi.edu. Internal tandem duplication mutations of FLT3 (FLT3/ITD mutations) are common in acute myeloid leukemia (AML) and confer a poor prognosis. This would suggest that FLT3 is an ideal therapeutic target, but they have produced only modest benefits in clinical trials. Due to technical obstacles, the assessment of target inhibition in patients treated with FLT3 inhibitors has been limited and generally only qualitative. KW-2449 is a novel multi-targeted kinase inhibitor that induces cytotoxicity in Molm14 cells (which harbor a FLT3/ITD mutation). The cytotoxic effect occurs primarily at concentrations sufficient to inhibit FLT3 autophosphorylation to less than 20% of its baseline. We report here correlative data from a phase 1 trial of KW-2449, a trial in which typical transient reductions in the peripheral blast counts were observed. Using quantitative measurement of FLT3 inhibition over time in these patients, we confirmed that FLT3 was inhibited, but only transiently to less than 20% of baseline. Our results suggest that the failure to fully inhibit FLT3 in sustained fashion may be an underlying reason for the minimal success of FLT3 inhibitors to date, and stress the importance of confirming in vivo target inhibition when taking a targeted agent into the clinical setting. The clinical studies are registered on www.clinicaltrials.gov as NCT00346632. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: P. P. Zarrinkar, R. N. Gunawardane, M. D. Cramer, M. F. Gardner, D. Brigham, B. Belli, M. W. Karaman, K. W. Pratz, G. Pallares, Q. Chao, et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML) Blood, October 1, 2009; 114(14): 2984 - 2992. [Abstract] [Full Text] [PDF]

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