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

Konstanze Döhner, Christian Thiede, Nikolaus Jahn, Ekaterina Panina, Agnes Gambietz, Richard A. Larson, Thomas W. Prior, Guido Marcucci, Dan Jones, Jürgen Krauter, Michael Heuser, Maria Teresa Voso, Tiziana Ottone, Josep F. Nomdedeu, Sumithra J. Mandrekar, Rebecca B. Klisovic, Andrew H. Wei, Jorge Sierra, Miguel A. Sanz, Joseph M. BrandweinTheo De Witte, Joop H. Jansen, Dietger Niederwieser, Frederick R. Appelbaum, Bruno C. Medeiros, Martin S. Tallman, Richard F. Schlenk, Arnold Ganser, Hubert Serve, Gerhard Ehninger, Sergio Amadori, Insa Gathmann, Axel Benner, Celine Pallaud, Richard M. Stone, Hartmut Döhner, Clara D. Bloomfield

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)371-380
Number of pages10
JournalBlood
Volume135
Issue number5
DOIs
StatePublished - Jan 30 2020

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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