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N Engl J Med. 2019 Oct 31;381(18):1728-1740. doi: 10.1056/NEJMoa1902688.

Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML.

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From the Abramson Cancer Center, University of Pennsylvania (A.E.P.), and Thomas Jefferson University (M.K.) - both in Philadelphia; Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Meldola (G.M.), L. and A. Seràgnoli Institute of Hematology, Bologna University Medical School, Bologna (S.P.), Ospedali Riuniti Villa Sofia-Cervello, Palermo (F.F.), and IRCCS San Raffaele Scientific Institute, Milan (F.C.) - all in Italy; University of Texas M.D. Anderson Cancer Center, Houston (J.E.C.); Universitätsklinikum Giessen und Marburg, Marburg, Germany (A.N.); Memorial Sloan Kettering Cancer Center, New York (E. Berman); Hospital Universitari i Politècnic La Fe, Valencia, and Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Instituto Carlos III, Madrid - both in Spain (P.M.); University of Maryland Greenebaum Comprehensive Cancer Center (M.R.B.) and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University (M.J.L.) - both in Baltimore; University of Chicago, Chicago (R.A.L.), and Astellas Pharma, Northbrook (C.L., N. Hasabou, X.L., E. Bahceci) - both in Illinois; University of Minnesota, Minneapolis (C.U.); University of Alabama at Birmingham, Birmingham (H.P.E., A.D.S.); Hollings Cancer Center, Medical University of South Carolina, Charleston (R.S.); University of California, San Francisco, San Francisco (R.O.); National Taiwan University, Taipei City, Taiwan (W.-C.C.); Yale University School of Medicine, New Haven, CT (N.P.); Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Université Toulouse III Paul Sabatier, Toulouse, France (C.R.); Sendai Medical Center, National Hospital Organization, Sendai (H.Y.), and University of Fukui, Fukui (N. Hosono) - both in Japan; Seoul National University (S.-S.Y.) and Asan Medical Center, University of Ulsan College of Medicine (J.-H.L.) - both in Seoul, South Korea; Wake Forest Baptist Medical Center, Winston-Salem, NC (T.P.); and Massachusetts General Hospital, Harvard Medical School, Boston (A.T.F.).



Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene (FLT3) infrequently have a response to salvage chemotherapy. Gilteritinib is an oral, potent, selective FLT3 inhibitor with single-agent activity in relapsed or refractory FLT3-mutated AML.


In a phase 3 trial, we randomly assigned adults with relapsed or refractory FLT3-mutated AML in a 2:1 ratio to receive either gilteritinib (at a dose of 120 mg per day) or salvage chemotherapy. The two primary end points were overall survival and the percentage of patients who had complete remission with full or partial hematologic recovery. Secondary end points included event-free survival (freedom from treatment failure [i.e., relapse or lack of remission] or death) and the percentage of patients who had complete remission.


Of 371 eligible patients, 247 were randomly assigned to the gilteritinib group and 124 to the salvage chemotherapy group. The median overall survival in the gilteritinib group was significantly longer than that in the chemotherapy group (9.3 months vs. 5.6 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P<0.001). The median event-free survival was 2.8 months in the gilteritinib group and 0.7 months in the chemotherapy group (hazard ratio for treatment failure or death, 0.79; 95% CI, 0.58 to 1.09). The percentage of patients who had complete remission with full or partial hematologic recovery was 34.0% in the gilteritinib group and 15.3% in the chemotherapy group (risk difference, 18.6 percentage points; 95% CI, 9.8 to 27.4); the percentages with complete remission were 21.1% and 10.5%, respectively (risk difference, 10.6 percentage points; 95% CI, 2.8 to 18.4). In an analysis that was adjusted for therapy duration, adverse events of grade 3 or higher and serious adverse events occurred less frequently in the gilteritinib group than in the chemotherapy group; the most common adverse events of grade 3 or higher in the gilteritinib group were febrile neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%).


Gilteritinib resulted in significantly longer survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory FLT3-mutated AML. (Funded by Astellas Pharma; ADMIRAL number, NCT02421939.).

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