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N Engl J Med. 2017 Aug 3;377(5):454-464. doi: 10.1056/NEJMoa1614359. Epub 2017 Jun 23.

Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation.

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From the Department of Medical Oncology, Dana-Farber Cancer Institute, Boston (R.M.S.); the Division of Biomedical Statistics and Informatics (S.J.M., K.L.) and the Alliance Statistics and Data Center (S.J.M., K.L., S.G.), Mayo Clinic, Rochester, MN; the Alliance Statistics and Data Center, Duke University, Durham, NC (B.L.S.); the Ohio State University Comprehensive Cancer Center, Columbus (S.G., C.D.B., T.W.P., G.M., R.B.K.); Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus der TU Dresden, Dresden (C.T., G.E.), Department of Internal Medicine III, University Hospital of Ulm, Ulm (K.D., R.F.S., H.D.), Hematology and Oncology, University of Leipzig, Leipzig (D.N.), Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover (J.K., A.G.), and Department of Medicine II, Hematology-Oncology, Goethe University Hospital Frankfurt, Frankfurt am Main (H.S.) - all in Germany; the Department of Biomedicine and Prevention, University Tor Vergata, Rome (F.L.-C., S.A.); the Department of Clinical Haematology, Alfred Hospital and Monash University, Melbourne, VIC, Australia (A.W.); Hospital de la Santa Creu i Sant Pau, Hematology Department, Autonomous University of Barcelona, Barcelona (J.S.), and Hospital Universitario la Fe, Hematology Department, Department of Medicine, University of Valencia, Valencia (M.A.S.) - both in Spain; the Department of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto (J.M.B.); Radboud Institute Molecular Studies, Radboud University Medical Center, Nijmegen, the Netherlands (T.W.); the Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle (F.R.A.); the Division of Hematology-Oncology, Stanford Comprehensive Cancer Center, Stanford University, Stanford, CA (B.C.M.); the Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York (M.S.T.); and the Department of Medicine, University of Chicago, Chicago (R.A.L.).



Patients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin - an oral multitargeted kinase inhibitor that is active in patients with a FLT3 mutation - to standard chemotherapy would prolong overall survival in this population.


We screened 3277 patients, 18 to 59 years of age, who had newly diagnosed AML for FLT3 mutations. Patients were randomly assigned to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo; those who were in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo. Randomization was stratified according to subtype of FLT3 mutation: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with either a high ratio (>0.7) or a low ratio (0.05 to 0.7) of mutant to wild-type alleles (ITD [high] and ITD [low], respectively). Allogeneic transplantation was allowed. The primary end point was overall survival.


A total of 717 patients underwent randomization; 360 were assigned to the midostaurin group, and 357 to the placebo group. The FLT3 subtype was ITD (high) in 214 patients, ITD (low) in 341 patients, and TKD in 162 patients. The treatment groups were well balanced with respect to age, race, FLT3 subtype, cytogenetic risk, and blood counts but not with respect to sex (51.7% in the midostaurin group vs. 59.4% in the placebo group were women, P=0.04). Overall survival was significantly longer in the midostaurin group than in the placebo group (hazard ratio for death, 0.78; one-sided P=0.009), as was event-free survival (hazard ratio for event or death, 0.78; one-sided P=0.002). In both the primary analysis and an analysis in which data for patients who underwent transplantation were censored, the benefit of midostaurin was consistent across all FLT3 subtypes. The rate of severe adverse events was similar in the two groups.


The addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy significantly prolonged overall and event-free survival among patients with AML and a FLT3 mutation. (Funded by the National Cancer Institute and Novartis; number, NCT00651261 .).

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