TY - JOUR
T1 - Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia
AU - Döhner, Konstanze
AU - Thiede, Christian
AU - Jahn, Nikolaus
AU - Panina, Ekaterina
AU - Gambietz, Agnes
AU - Larson, Richard A.
AU - Prior, Thomas W.
AU - Marcucci, Guido
AU - Jones, Dan
AU - Krauter, Jürgen
AU - Heuser, Michael
AU - Voso, Maria Teresa
AU - Ottone, Tiziana
AU - Nomdedeu, Josep F.
AU - Mandrekar, Sumithra J.
AU - Klisovic, Rebecca B.
AU - Wei, Andrew H.
AU - Sierra, Jorge
AU - Sanz, Miguel A.
AU - Brandwein, Joseph M.
AU - De Witte, Theo
AU - Jansen, Joop H.
AU - Niederwieser, Dietger
AU - Appelbaum, Frederick R.
AU - Medeiros, Bruno C.
AU - Tallman, Martin S.
AU - Schlenk, Richard F.
AU - Ganser, Arnold
AU - Serve, Hubert
AU - Ehninger, Gerhard
AU - Amadori, Sergio
AU - Gathmann, Insa
AU - Benner, Axel
AU - Pallaud, Celine
AU - Stone, Richard M.
AU - Döhner, Hartmut
AU - Bloomfield, Clara D.
N1 - Publisher Copyright:
© 2020 by The American Society of Hematology.
PY - 2020/1/30
Y1 - 2020/1/30
N2 - 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.
AB - 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.
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U2 - 10.1182/blood.2019002697
DO - 10.1182/blood.2019002697
M3 - Article
C2 - 31826241
AN - SCOPUS:85078814998
SN - 0006-4971
VL - 135
SP - 371
EP - 380
JO - Blood
JF - Blood
IS - 5
ER -