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


Authors: Döhner, K.; Thiede, C.; Jahn, N.; Panina, E.; Gambietz, A.; Larson, R. A.; Prior, T. W.; Marcucci, G.; Jones, D.; Krauter, J.; Heuser, M.; Voso, M. T.; Ottone, T.; Nomdedeu, J. F.; Mandrekar, S. J.; Klisovic, R. B.; Wei, A. H.; Sierra, J.; Sanz, M. A.; Brandwein, J. M.; de Witte, T.; Jansen, J. H.; Niederwieser, D.; Appelbaum, F. R.; Medeiros, B. C.; Tallman, M. S.; Schlenk, R. F.; Ganser, A.; Serve, H.; Ehninger, G.; Amadori, S.; Gathmann, I.; Benner, A.; Pallaud, C.; Stone, R. M.; Döhner, H.; Bloomfield, C. D.
Article Title: Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia
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. © 2020 by The American Society of Hematology.
Keywords: adult; cancer survival; controlled study; treatment response; middle aged; major clinical study; overall survival; placebo; cancer combination chemotherapy; cohort analysis; genotype; retrospective study; protein p53; gene duplication; allogeneic hematopoietic stem cell transplantation; leukocyte count; high risk population; flt3 ligand; leukemia remission; transcription factor runx1; nucleophosmin; midostaurin; acute myeloid leukemia; cancer prognosis; human; male; female; priority journal; article
Journal Title: Blood
Volume: 135
Issue: 5
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2020-01-30
Start Page: 371
End Page: 380
Language: English
DOI: 10.1182/blood.2019002697
PUBMED: 31826241
PROVIDER: scopus
PMCID: PMC6993016
DOI/URL:
Notes: Article -- Export Date: 2 March 2020 -- Source: Scopus
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  1. Martin Stuart Tallman
    486 Tallman