Alexander E. Perl, University of Pennsylvania
Giovanni Martinelli, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS)
Jorge E. Cortes, University of Texas M.D. Anderson Cancer Center
Andreas Neubauer, Universitätsklinikum Giessen und Marburg
Ellin Berman, Memorial Sloan Kettering Cancer Center
Stefania Paolini, Bologna University Medical School
Pau Montesinos, Hospital Universitari i Politècnic La Fe; Centro de Investigación Biomédica en Red Cáncer (CIBERONC)
Maria R. Baer, University of Maryland Greenebaum Comprehensive Cancer Center
Richard A. Larson, University of Chicago
Celalettin Ustun, University of Minnesota
Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello
Harry P. Erba, University of Alabama at Birmingham
Antonio Di Stasi, University of Alabama at Birmingham
Robert Stuart, Medical University of South Carolina
Rebecca Olin, University of California, San Francisco
Margaret Kasner, Thomas Jefferson UniversityFollow
Fabio Ciceri, IRCCS San Raffaele Scientific Institute
Wen-Chien Chou, National Taiwan University
Nikolai Podoltsev, Yale University
Christian Recher, Université Toulouse III Paul Sabatier
Hisayuki Yokoyama, Sendai Medical Center, National Hospital Organization
Naoko Hosono, University of Fukui
Sung-Soo Yoon, Seoul National University
Je-Hwan Lee, University of Ulsan College of Medicine
Timothy Pardee, Wake Forest Baptist Medical Center
Amir T. Fathi, Harvard Medical School
Chaofeng Liu, Astellas Pharma
Nahla Hasabou, Astellas Pharma
Xuan Liu, Astellas Pharma
Erkut Bahceci, Astellas Pharma
Mark J. Levis, Johns Hopkins University

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From the New England Journal of Medicine, Perl, A. E., Martinelli, G., Cortes, J. E., Neubauer, A., Berman, E., Paolini, S., Montesinos, P.; Baer, M.R., Larson, R.A., Uston, C., Fabbiano, F., Erba, H.P., Di Stasi, A., Stuart, R., Olin, R., Kasner, M., Ciceri, F., Chou, W.C., Podoltsev, N., Recher, C., Yokoyama, H., Hosono, N., Yoon, S.S., Lee, J.H., Pardee, T., Fathi, A.T., Liu, C., Hasabou, N., Liu, X., Bahceci, E., & Levis, M. J., Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML, Volume No. 381(18), Pages 1728-1740. Copyright © 2019 Massachusetts Medical Society. Reprinted with permission.


BACKGROUND: 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.

METHODS: 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.

RESULTS: 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%).

CONCLUSIONS: 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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