Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia

Author:

Döhner Konstanze1,Thiede Christian2,Jahn Nikolaus1,Panina Ekaterina1,Gambietz Agnes3,Larson Richard A.4ORCID,Prior Thomas W.5,Marcucci Guido5,Jones Dan5,Krauter Jürgen6,Heuser Michael6,Voso Maria Teresa7ORCID,Ottone Tiziana7,Nomdedeu Josep F.8ORCID,Mandrekar Sumithra J.9,Klisovic Rebecca B.5ORCID,Wei Andrew H.10,Sierra Jorge8,Sanz Miguel A.1112ORCID,Brandwein Joseph M.13,de Witte Theo14,Jansen Joop H.15,Niederwieser Dietger16,Appelbaum Frederick R.17,Medeiros Bruno C.18,Tallman Martin S.19,Schlenk Richard F.1ORCID,Ganser Arnold6,Serve Hubert20ORCID,Ehninger Gerhard2,Amadori Sergio7,Gathmann Insa21,Benner Axel3,Pallaud Celine21,Stone Richard M.22,Döhner Hartmut1ORCID,Bloomfield Clara D.5

Affiliation:

1. Department of Internal Medicine III, University of Ulm, Ulm, Germany;

2. Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany;

3. Division of Biostatistics, German Cancer Research Center Heidelberg, Heidelberg, Germany;

4. Department of Medicine and Comprehensive Cancer Research Center, University of Chicago, Chicago, IL;

5. The Ohio State University Comprehensive Cancer Center, Columbus, OH;

6. Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany;

7. Department of Biomedicine and Prevention, Università di Roma “Tor Vergata,” Rome, Italy;

8. Hematology Department, Hospital de la Santa Creu i Sant Pau, IIB-Santpau and Jose Carreras Leukemia Research Institutes, Autonomus University of Barcelona, Barcelona, Spain;

9. Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN;

10. Department of Clinical Hematology, The Alfred Hospital and Monash University, Melbourne, VIC, Australia;

11. Instituto de Investigación Sanitaria La Fe, University of Valencia, Valencia, Spain;

12. Centro de Investigación Biomédica en Red de Cáncer, Instituto Carlos III, Madrid, Spain;

13. Department of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto, ON, Canada;

14. Radboud University Medical Centre, Nijmegen, The Netherlands;

15. Laboratory Hematology, Deptartment of Laboratory Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands;

16. Department of Hematology, Oncology, and Hemostasis, University of Leipzig, Leipzig, Germany;

17. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;

18. Division of Hematology, Stanford Comprehensive Cancer Center, Stanford University, Stanford, CA;

19. Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY;

20. Department of Medicine, Hematology/Oncology, Goethe University, Frankfurt, Germany;

21. Novartis Pharmaceuticals, Basel, Switzerland; and

22. Department of Medical Oncology, Dana-Farber/Partners CancerCare, Boston, MA

Abstract

Abstract Patients with acute myeloid leukemia (AML) harboring FLT3 internal tandem duplications (ITDs) have poor outcomes, in particular AML with a high (≥0.5) mutant/wild-type allelic ratio (AR). The 2017 European LeukemiaNet (ELN) recommendations defined 4 distinct FLT3-ITD genotypes based on the ITD AR and the NPM1 mutational status. In this retrospective exploratory study, we investigated the prognostic and predictive impact of the NPM1/FLT3-ITD genotypes categorized according to the 2017 ELN risk groups in patients randomized within the RATIFY trial, which evaluated the addition of midostaurin to standard chemotherapy. The 4 NPM1/FLT3-ITD genotypes differed significantly with regard to clinical and concurrent genetic features. Complete ELN risk categorization could be done in 318 of 549 trial patients with FLT3-ITD AML. Significant factors for response after 1 or 2 induction cycles were ELN risk group and white blood cell (WBC) counts; treatment with midostaurin had no influence. Overall survival (OS) differed significantly among ELN risk groups, with estimated 5-year OS probabilities of 0.63, 0.43, and 0.33 for favorable-, intermediate-, and adverse-risk groups, respectively (P < .001). A multivariate Cox model for OS using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable revealed treatment with midostaurin, allogeneic HCT, ELN favorable-risk group, and lower WBC counts as significant favorable factors. In this model, there was a consistent beneficial effect of midostaurin across ELN risk groups.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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