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Leukemia (2012) 26, 20612068& 2012 Macmillan Publishers Limited All rights reserved 0887-6924/12
http://www.nature.com/LEU
Web End =www.nature.com/leu
ORIGINAL ARTICLE
Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia
RM Stone1, T Fischer2, R Paquette3, G Schiller3, CA Schiffer4, G Ehninger5, J Cortes6, HM Kantarjian6, DJ DeAngelo1, A Huntsman-Labed7, C Dutreix7, A del Corral8 and F Giles9
This phase 1b trial investigated several doses and schedules of midostaurin in combination with daunorubicin and cytarabine induction and high-dose cytarabine post-remission therapy in newly diagnosed patients with acute myeloid leukemia (AML). The discontinuation rate on the 50-mg twice-daily dose schedule was lower than 100 mg twice daily, and no grade 3/4 nausea or vomiting was seen. The complete remission rate for the midostaurin 50-mg twice-daily dose schedule was 80% (FMS-like tyrosine kinase 3 receptor (FLT3)wild-type: 20 of 27 (74%), FLT3-mutant: 12 of 13 (92%)). Overall survival (OS) probabilities of patients with FLT3-mutant AML at 1 and 2 years (0.85 and 0.62, respectively) were similar to the FLT3wild-type population (0.78 and 0.52, respectively). Midostaurin in combination with standard chemotherapy demonstrated high complete response and OS rates in newly diagnosed younger adults with AML, and was generally well tolerated at 50 mg twice daily for 14 days. A phase III prospective trial is ongoing (CALGB 10603, NCT00651261).
Leukemia (2012) 26, 20612068; doi:http://dx.doi.org/10.1038/leu.2012.115
Web End =10.1038/leu.2012.115
Keywords: FMS-like tyrosine kinase 3 receptor; acute myeloid leukemia; midostaurin; PKC412; newly diagnosed
INTRODUCTIONMutations in the FMS-like tyrosine kinase 3 receptor (FLT3) occur in B25% of patients with acute myeloid leukemia (AML), cause constitutive activation, and are associated with poor prognosis.13
Cytogenetically normal patients with AML whose leukemia is characterized by the presence of internal tandem duplication (ITD) mutations in FLT3 (FLT3-ITD) have a signicantly shorter disease-free survival (DFS) and overall survival (OS) than patients without the mutation.2,4
The prognostic signicance of the FLT3 mutation has led to the pursuit of FLT3 inhibitors for the treatment of AML. Midostaurin (PKC412) is a potent kinase inhibitor of FLT3, c-KIT, PDGFR-b,
VEGFR-2 and protein kinase C, with demonstrated activity against cell lines containing mutant FLT3 and against FLT3-induced myeloproliferative disease in a mouse model.5 Midostaurins two major metabolites, CGP62221 and CGP52421, are also capable of inhibiting...