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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.

SUBMITTER: Dohner K 

PROVIDER: S-EPMC6993016 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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

Döhner Konstanze K   Thiede Christian C   Jahn Nikolaus N   Panina Ekaterina E   Gambietz Agnes A   Larson Richard A RA   Prior Thomas W TW   Marcucci Guido G   Jones Dan D   Krauter Jürgen J   Heuser Michael M   Voso Maria Teresa MT   Ottone Tiziana T   Nomdedeu Josep F JF   Mandrekar Sumithra J SJ   Klisovic Rebecca B RB   Wei Andrew H AH   Sierra Jorge J   Sanz Miguel A MA   Brandwein Joseph M JM   de Witte Theo T   Jansen Joop H JH   Niederwieser Dietger D   Appelbaum Frederick R FR   Medeiros Bruno C BC   Tallman Martin S MS   Schlenk Richard F RF   Ganser Arnold A   Serve Hubert H   Ehninger Gerhard G   Amadori Sergio S   Gathmann Insa I   Benner Axel A   Pallaud Celine C   Stone Richard M RM   Döhner Hartmut H   Bloomfield Clara D CD  

Blood 20200101 5


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 gr  ...[more]

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