Citations 2
Midostaurin in patients with acute myeloid leukemia and FLT3-TKD mutations: a subanalysis from the RATIFY trial
Voso, Maria Teresa , Larson, Richard A. , Marcucci, Guido , Prior, Thomas W., Krauter, Jürgen, Heuser, Michael , Nomdedéu, Josep , Geyer, Susan M. , Wei, Andrew H. , Sierra, Jorge , Sanz, Miguel Á. , Brandwein, Joseph , Witte, Theo M. de, Niederwieser, Dietger , Appelbaum, Frederick R. , Medeiros, Bruno C. , Tallman, Martin S. , Schlenk, Richard F. , Ganser, Arnold , Cheng, Yuan, Chen, Yin-Miao, Pallaud, Céline , Du, Ling, Piciocchi, Alfonso , Ehninger, Gerhard , Byrd, John C. , Thiede, Christian , Döhner, Konstanze , Stone, Richard M. , Bloomfield, Clara D. , Byrd, John C. , Larson, Richard A , Wei, Andrew H , Jones, Dan M. , Lavorgna, Serena , Walker, Alison , Jansen, Joop H. , Amadori, Sergio , Cheng, Yuan, Döhner, Hartmut , Lo‐Coco, Francesco , Voso, Maria Teresa , Byrd, John C
Blood Advances | October 13, 2020 | Volume: 4 | Issue: 19 | Pages: 4945-4954
10.1182/bloodadvances.2020002904
Abstract The results from the RATIFY trial (ClinicalTrials.gov: NCT00651261; CALGB 10603) showed that midostaurin combined with standard chemotherapy significantly improved outcomes in patients with FMS-like tyrosine kinase 3 (FLT3)–mutated acute myeloid leukemia (AML), compared with placebo. In this post hoc subgroup analysis from the trial, we evaluated the impact of midostaurin in 163 patients with FLT3-tyrosine kinase domain (TKD) mutations. At a median follow-up of 60.7 months (95% CI, 55.0-70.8), the 5-year event-free survival (EFS) rate was significantly higher in patients treated with midostaurin than in those treated with placebo (45.2% vs 30.1%; P = .044). A trend toward improved disease-free survival was also observed with midostaurin (67.3% vs 53.4%; P = .089), whereas overall survival (OS) was similar in the 2 groups. Patients with AML and NPM1mut/FLT3-TKDmut or core binding factor (CBF)–rearranged/FLT3-TKDmut genotypes had significantly prolonged OS with or without censoring at hematopoietic cell transplantation (HCT), compared with NPM1WT/CBF-negative AMLs. The multivariable model for OS and EFS adjusted for allogeneic HCT in first complete remission as a time-dependent covariable, revealed NPM1 mutations and CBF rearrangements as significant favorable factors. These data show that NPM1 mutations or CBF rearrangements identify favorable prognostic groups in patients with FLT3-TKD AMLs, independent of other factors, also in the context of midostaurin treatment.
Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia
Döhner, Konstanze , Thiede, Christian , Jahn, Nikolaus , Panina, Ekaterina, Gambietz, Agnes, Larson, Richard A. , Prior, Thomas W., Marcucci, Guido , Krauter, Jürgen, Heuser, Michael , Ottone, Tiziana , Nomdedéu, Josep , Mandrekar, Sumithra J. , Klisovic, Rebecca B. , Wei, Andrew H. , Sierra, Jorge , Sanz, Miguel Á. , Brandwein, Joseph , Witte, Théo de , Niederwieser, Dietger , Appelbaum, Frederick R. , Medeiros, Bruno C. , Tallman, Martin S. , Schlenk, Richard F. , Ganser, Arnold , Ehninger, Gerhard , Gathmann, Insa, Benner, Axel , Pallaud, Céline , Stone, Richard M. , Bloomfield, Clara D. , Larson, Richard A , Wei, Andrew H , Jones, Dan M. , Voso, Maria Teresa , Jansen, Joop H. , Serve, Hubert L. , Amadori, Sergio , Döhner, Hartmut
Blood | December 11, 2019 | Volume: 135 | Issue: 5 | Pages: 371-380
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.