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 - Funding Information:
This work was supported in part by a grant from the Deutsche For-schungsgemeinschaft (SFB 1074, project B3) (K.D.), by National Institutes of Health, National Cancer Institute grants U10CA180821 (to the Alliance for Clinical Trials in Oncology Operations Center), U10CA180882 (to the Alliance Statistics and Data Management Center), U24CA196171 (to the Alliance NCTN Biorepository and Biospecimen [C.D.B.]), and UG1CA233338 (to ITSC for Leukemia: Novel Molecular strategies for NCTN Individualized Therapies [C.D.B.]), and by a research grant from Novartis.
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 -