Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia
作者： R M Stone , T Fischer , R Paquette , G Schiller , C A Schiffer
DOI: 10.1038/LEU.2012.115
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摘要: This phase 1b trial investigated several doses and schedules of midostaurin in combination with daunorubicin cytarabine induction high-dose post-remission therapy newly diagnosed patients acute myeloid leukemia (AML). The discontinuation rate on the 50-mg twice-daily dose schedule was lower than 100 mg twice daily, no grade 3/4 nausea or vomiting seen. complete remission for 80% (FMS-like tyrosine kinase 3 receptor (FLT3)–wild-type: 20 27 (74%), FLT3-mutant: 12 13 (92%)). Overall survival (OS) probabilities FLT3-mutant AML at 1 2 years (0.85 0.62, respectively) were similar to FLT3–wild-type population (0.78 0.52, respectively). Midostaurin standard chemotherapy demonstrated high response OS rates younger adults AML, generally well tolerated 50 mg daily 14 days. A III prospective is ongoing (CALGB 10603, NCT00651261).
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Ellen Weisberg, Christina Boulton, Louise M Kelly, Paul Manley, Doriano Fabbro, Thomas Meyer, D.Gary Gilliland, James D Griffin, Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell. ,vol. 1, pp. 433- 443 ,(2002) , 10.1016/S1535-6108(02)00069-7
Adam J. Mead, David C. Linch, Robert K. Hills, Keith Wheatley, Alan K. Burnett, Rosemary E. Gale, FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients with acute myeloid leukemia. Blood. ,vol. 110, pp. 1262- 1270 ,(2007) , 10.1182/BLOOD-2006-04-015826
Frank Breitenbuecher, Boyka Markova, Stefan Kasper, Birgit Carius, Torsten Stauder, Frank D. Böhmer, Kristina Masson, Lars Rönnstrand, Christoph Huber, Thomas Kindler, Thomas Fischer, A novel molecular mechanism of primary resistance to FLT3-kinase inhibitors in AML Blood. ,vol. 113, pp. 4063- 4073 ,(2009) , 10.1182/BLOOD-2007-11-126664
Susan P. Whitman, Amy S. Ruppert, Michael D. Radmacher, Krzysztof Mrózek, Peter Paschka, Christian Langer, Claudia D. Baldus, Jing Wen, Frederick Racke, Bayard L. Powell, Jonathan E. Kolitz, Richard A. Larson, Michael A. Caligiuri, Guido Marcucci, Clara D. Bloomfield, FLT3 D835/I836 mutations are associated with poor disease-free survival and a distinct gene-expression signature among younger adults with de novo cytogenetically normal acute myeloid leukemia lacking FLT3 internal tandem duplications Blood. ,vol. 111, pp. 1552- 1559 ,(2008) , 10.1182/BLOOD-2007-08-107946
Mark Levis, Patrick Brown, B. Douglas Smith, Adam Stine, Rosalyn Pham, Richard Stone, Daniel DeAngelo, Ilene Galinsky, Frank Giles, Elihu Estey, Hagop Kantarjian, Pamela Cohen, Yanfeng Wang, Johannes Roesel, Judith E. Karp, Donald Small, Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors Blood. ,vol. 108, pp. 3477- 3483 ,(2006) , 10.1182/BLOOD-2006-04-015743
Ellen Weisberg, Rosemary Barrett, Qingsong Liu, Richard Stone, Nathanael Gray, James D. Griffin, FLT3 inhibition and mechanisms of drug resistance in mutant FLT3-positive AML Drug Resistance Updates. ,vol. 12, pp. 81- 89 ,(2009) , 10.1016/J.DRUP.2009.04.001
Daniel J. DeAngelo, Richard M. Stone, Mark L. Heaney, Stephen D. Nimer, Ronald L. Paquette, Rebecca B. Klisovic, Michael A. Caligiuri, Michael R. Cooper, Jean-Michel Lecerf, Michael D. Karol, Shihong Sheng, Nick Holford, Peter T. Curtin, Brian J. Druker, Michael C. Heinrich, Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics. Blood. ,vol. 108, pp. 3674- 3681 ,(2006) , 10.1182/BLOOD-2006-02-005702
Mark Levis, Rosalyn Pham, B. Douglas Smith, Donald Small, In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of administration is important to achieve synergistic cytotoxic effects Blood. ,vol. 104, pp. 1145- 1150 ,(2004) , 10.1182/BLOOD-2004-01-0388
Sabine Kayser, Richard F. Schlenk, Martina Correa Londono, Frank Breitenbuecher, Kerstin Wittke, Juan Du, Silja Groner, Daniela Späth, Jürgen Krauter, Arnold Ganser, Hartmut Döhner, Thomas Fischer, Konstanze Döhner, , Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood. ,vol. 114, pp. 2386- 2392 ,(2009) , 10.1182/BLOOD-2009-03-209999
Jonathan E. Kolitz, Krzysztof Mrózek, James W. Vardiman, Michael A. Caligiuri, Clara D. Bloomfield, Kellie J. Archer, Richard A. Larson, Susan P. Whitman, Andrew J. Carroll, Brian Becknell, Lan Feng, Stephen L. George, Brian D. Carlson, Claudia Baldus, Absence of the Wild-Type Allele Predicts Poor Prognosis in Adult de Novo Acute Myeloid Leukemia with Normal Cytogenetics and the Internal Tandem Duplication of FLT3 A Cancer and Leukemia Group B Study Cancer Research. ,vol. 61, pp. 7233- 7239 ,(2001)