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Perl, A.1; Martinelli, G.2; Cortes, J.3; Neubauer, A.4; Berman, E.5; Paolini, S.6; Montesinos, P.7; Baer, M.8; Larson, R.9; Ustun, C.10; Fabbiano, F.11; Di Stasi, A.12; Stuart, R.13; Olin, R.14; Kasner, M.15; Ciceri, F.16; Chou, W.-C.17; Podoltsev, N.18; Recher, C.19; Yokoyama, H.20; Hosono, N.21; Yoon, S.-S.22; Lee, J.-H.23; Pardee, T.24; Fathi, A.25; Liu, C.26; Liu, X.26; Bahceci, E.26; Levis, M.27

doi: 10.1097/01.HS9.0000561784.84381.11
Simultaneous Sessions III: New therapies in AML

1Abramson Cancer Center, University of Pennsylvania, Philadelphia, United States

2Instituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRST IRCCS, Medola, Italy

3MD Anderson Cancer Center, University of Texas, Houston, United States

4Universitätsklinikum Giessen und Marburg GmbH, Marburg, Germany

5Memorial Sloan-Kettering Cancer Center, New York, United States

6L. and A. Seràgnoli Institute of Hematology, Bologna University Medical School, Bologna, Italy

7Hospital Universitari i Politècnic La Fe, Valencia & CIBERONC, Instituto Carlos III, Madrid, Spain

8University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore

9University of Chicago, Chicago

10University of Minnesota, Minneapolis, United States

11Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy

12University of Alabama at Birmingham, Birmingham

13Hollings Cancer Center, Medical University of South Carolina, Charleston

14University of California San Francisco, San Francisco

15Thomas Jefferson University, Philadelphia, United States

16IRCCS San Raffaele Scientific Institute, Milano, Italy

17National Taiwan University, Taipei City, Taiwan, Republic of China

18Yale University School of Medicine, New Haven, United States

19Institut Universitaire du Cancer Toulouse - Oncopole, Cedex, France

20Sendai Medical Center, National Hospital Organization, Sendai

21University of Fukui, Fukui, Japan

22Seoul National University

23Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea, Republic Of

24Wake Forest Baptist Medical Center, Winston-Salem

25Massachussetts General Hospital, Harvard Medical School, Boston

26Astellas Pharma Global Development, Northbrook

27Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, United States

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Gilteritinib is a potent/selective oral inhibitor of fms-like tyrosine kinase 3 (FLT3). Based upon interim analysis response rates from the ADMIRAL phase 3 study of gilteritinib vs salvage chemotherapy (SC) in patients with R/R FLT3mut+ AML (NCT02421939), gilteritinib became the first FLT3 inhibitor approved as single-agent therapy in this population.

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We present the final results of the ADMIRAL trial.

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Adults with confirmed FLT3mut+ AML (FLT3-ITD and/or FLT3-TKD D835 or I836 mutations) refractory to induction chemotherapy or in untreated first relapse were randomized (2:1) to receive continuous 28-day cycles of 120 mg/day gilteritinib or pre-randomization selected SC: low-dose cytarabine (LoDAC), azacitidine (AZA), mitoxantrone/etoposide/cytarabine (MEC), or fludarabine/cytarabine/granulocyte colony-stimulating factor/idarubicin (FLAG-IDA). Prior FLT3 inhibitor use, other than midostaurin or sorafenib, was excluded. Overall survival (OS) and the combined rate of complete remission/complete remission with partial hematologic recovery (CR/CRh) were co-primary endpoints. Secondary endpoints were event-free survival (EFS) and CR rate; safety/tolerability was also examined.

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A total of 371 patients were randomized: 247 to gilteritinib and 124 to SC (MEC, 25.7%; FLAG-IDA, 36.7%; LoDAC, 14.7%; AZA, 22.9%). Median age was 62 years (range, 19-85). Baseline FLT3 mutations were: FLT3-ITD, 88.4%; FLT3-TKD, 8.4%; both FLT3-ITD and FLT3-TKD, 1.9%; unconfirmed, 1.3%. Overall, 39.4% of patients had refractory AML and 60.6% had relapsed AML. Patients randomized to gilteritinib had significantly longer OS (9.3 months) than SC (5.6 months; hazard ratio [HR] for death = 0.637; P = 0.0007); 1-year survival rates were 37.1% and 16.7%, respectively. The CR/CRh rates for gilteritinib and SC were 34.0% and 15.3%, respectively (P = 0.0001); CR rates were 21.1% and 10.5% (2-sided P = 0.0106). Median EFS was 2.8 months and 0.7 months in the gilteritinib and SC arms, respectively (HR 0.793, P = 0.0830). Common adverse events (AEs) in all randomized patients were febrile neutropenia (43.7%), anemia (43.4%), and pyrexia (38.6%). Common grade ≥3 AEs related to gilteritinib were anemia (19.5%), febrile neutropenia (15.4%), thrombocytopenia (12.2%), and decreased platelet count (12.2%). Adjusted for exposure duration, serious treatment-emergent AEs per patient year were less common with gilteritinib (7.1%) than SC (9.2%).



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In patients with R/R FLT3mut+ AML, the potent, selective FLT3 inhibitor gilteritinib resulted in significantly longer overall survival and higher response rates compared with chemotherapy and had a favorable safety profile. These results change the treatment paradigm for salvage therapy of R/R FLT3mut+ AML and establish gilteritinib as the new standard of care.

Copyright © 2019 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the European Hematology Association.