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Angenendt, L.1; Röllig, C.2; Montesinos, P.3; Martínez-Cuadrón, D.3; Barragan, E.3; García, R.4; Botella, C.5; Martínez, P.6; Ravandi, F.7; Kadia, T.7; Kantarjian, H. M.7; Cortes, J.7; Juliusson, G.8; Lazarevic, V.8; Höglund, M.9; Lehmann, S.9; Recher, C.10; Pigneux, A.11; Bertoli, S.10; Dumas, P.-Y.11; Dombret, H.12; Preudhomme, C.13; Micol, J.-B.14; Terré, C.15; Ráčil, Z.16; Novák, J.17; Žák, P.18; Wei, A. H.19; Tiong, I. S.19; Wall, M.20; Estey, E.21; Shaw, C.21; Exeler, R.22; Wagenführ, L.2; Stölzel, F.2; Thiede, C.2; Stelljes, M.1; Lenz, G.1; Mikesch, J.-H.1; Serve, H.23; Ehninger, G.2; Berdel, W. E.1; Kramer, M.2; Krug, U.24; Schliemann, C.1

doi: 10.1097/01.HS9.0000564704.06449.f2
Simultaneous Sessions IV: Refining biomarkers for AML outcome

1Department of Medicine A, University Hospital Münster, Münster

2Department of Medicine I, University Hospital of the Technical University Dresden, Dresden, Germany

3Hospital Universitari i Politècnic La Fe, Valencia Spain & CIBERONC, Instituto Carlos III, Valencia

4Department of Haematology, General Hospital Castellón, Castellón

5Departments of Dermatology and Haematology, Hospital General de Alicante, Alicante

6Hospital 12 de Octubre, Madrid, Spain

7University of Texas MD Anderson Cancer Center, Houston, United States

8Department of Hematology, Stem Cell Center, Lund University, Lund

9Department of Medical Sciences, Uppsala University and Division of Hematology, Uppsala University Hospital, Uppsala, Sweden

10Institut Universitaire du Cancer de Toulouse Oncopole, Université de Toulouse III, CHU de Toulouse, Toulouse

11Service d'Hématologie Clinique et de Thérapie Cellulaire, Centre Hospitalier Universitaire de Bordeaux, Hôpital Haut-Lévèque, Bordeaux

12Department of Hematology, Hôpital Saint-Louis, Assistance Publique-Hopitaux de Paris (AP-HP), Paris Diderot University, Paris

13INSERM Lille, University of Lille, Lille

14Department of Hematology, Gustave Roussy, Paris-Saclay University, Villejuif

15Laboratoire de cytogénétique, Centre de transfusion sanguine, Le Chesnay, France

16Department of Internal Medicine, Hematology and Oncology, Masaryk University and University Hospital Brno, Brno

17Department of Internal Medicine and Hematology. University Hospital Kralovske Vinohrady and Third Faculty of Medicine, Charles University

184th Department of Internal Medicine - Hematology, University Hospital Hradec Kralove, Faculty of Medicine in Hradec Králové, Charles University Prague, Prague, Czech Republic

19The Alfred Hospital and Monash University

20Victorian Cytogenetics and Cancer Service, St. Vincent's Hospital, Melbourne, Australia

21Division of Hematology, University of Washington and Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States

22Institute of Human Genetics, University of Münster, Münster

23Department of Haematology and Oncology, University Hospital Frankfurt, Frankfurt

24Department of Medicine 3, Klinikum Leverkusen, Leverkusen, Germany

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Nucleophosmin 1 (NPM1) mutations confer a favorable prognosis in acute myeloid leukemia (AML) when an internal tandem duplication (ITD) in the fms related tyrosine kinase 3 gene (FLT3) with a high allelic ratio is absent (FLT3-ITDneg/low). The prognostic impact is considered to be independent of the karyotype, most influentially in the most recent 2017 ELN genetic risk classification. Here we investigate the validity of this assumption.

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This study investigates the prognostic impact of concomitant cytogenetic abnormalities in NPM1mut/FLT3-ITDneg/low AML.

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We analyzed the impact of karyotype on outcome in intensively treated patients with NPM1mut/FLT3-ITDneg/low AML who were prospectively enrolled in registry databases from nine international study groups or treatment centers. NPM1wt/FLT3-ITDneg/low AML patients with adverse cytogenetic abnormalities from the same cohorts served as comparator for adverse risk.

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We identified 2426 patients with NPM1mut/FLT3-ITDneg/low AML. 2000 (82.4%) of these had a normal and 426 (17.6%) had an abnormal karyotype, including 329 (13.6%) patients with karyotype abnormalities of intermediate risk and 83 (3.4%) patients with karyotype abnormalities of adverse risk. In patients with NPM1mut/FLT3-ITDneg/low AML, adverse cytogenetics were associated with lower complete remission (CR) rates (87.7%, 86.0%, and 66.3% for normal, aberrant intermediate, and adverse karyotype, respectively; P < .0001), inferior overall (5-year OS, 52.4%, 44.8%, 19.5%; P < .0001) and event-free survival (5-year EFS, 40.5%, 35.8%, 18.0%; P < .0001), and a higher cumulative incidence of relapse (5-year CIR, 43.6%, 44.2%, 51.9%; P = .0012). Cytogenetic risk remained independently associated with all endpoints in multivariable mixed-effects regression analyses adjusted for known clinicopathological risk factors (P < .0001 for all endpoints). In patients with adverse risk chromosomal aberrations, we found no significant influence of the NPM1 mutational status on outcome.

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This international collaborative study reveals that cytogenetic abnormalities are important determinants of outcome in NPM1mut/FLT3-ITDneg/low AML. Most importantly, NPM1 mutated patients with the FLT3-ITDneg/low genotype and adverse risk cytogenetics share the same unfavorable prognosis as their NPM1 wildtype counterparts and should be classified accordingly.

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