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RATIFY: PROGNOSTIC IMPACT OF FLT3 TYROSINE KINASE DOMAIN (TKD) AND NPM1 MUTATION STATUS IN PATIENTS WITH NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA (AML) TREATED WITH MIDOSTAURIN + STANDARD CHEMOTHERAPY

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Voso, M. T.1; Larson, R. A.2; Prior, T.3; Marcucci, G.3; Jones, D.3; Krauter, J.4; Heuser, M.5; Lavorgna, S.1; Nomdedeu, J.6; Geyer, S. M.7; Klisovic, R.3; Wei, A. H.8; Sierra, J.6; Sanz, M. A.9; Brandwein, J. M.10; de Witte, T. M.11; Jansen, J. H.11; Niederweiser, D.12; Appelbaum, F. R.13; Medeiros, B. C.14; Tallman, M. S.15; Schlenk, R. F.16; Ganser, A.5; Amadori, S.1; Cheng, Y.17; Chen, Y.17; Tiecke, E.18; Du, L.17; Ehninger, G.19; Thiede, C.19; Döhner, K.16; Döhner, H.16; Stone, R. M.20; Bloomfield, C. D.3; Lo-Coco, F.1

doi: 10.1097/01.HS9.0000559236.73191.39
Poster Session I: Acute myeloid leukemia - Clinical
Free

1Department of Biomedicine and Prevention, University Tor Vergata, Rome, Italy

2University of Chicago, Chicago

3Comprehensive Cancer Center, The Ohio State University, Columbus, United States

4Department of Hematology and Oncology, Klinikum Braunschweig, Braunschweig

5Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany

6Hematology Department, Hospital de la Santa Creu i Sant Pau and José Carreras Leukemia Research Institute, Autonomous University of Barcelona, Barcelona, Spain

7Alliance Statistics and Data Center, Mayo Clinic, Rochester, United States

8Department of Clinical Haematology, Alfred Hospital and Monash University, Melbourne, Australia

9Department of Medicine, Hospital Universitari i Politecnic La Fe and Centro de Investigación Biomédica en Red de Cáncer, University of Valencia and Instituto Carlos III, Madrid, Spain

10Department of Medicine, University of Alberta, Edmonton, Canada

11Radboud University Medical Centre, Nijmegen, Netherlands

12Department of Hematology, University of Leipzig, Leipzig, Germany

13Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle

14Division of Hematology, Stanford Comprehensive Cancer Center, Stanford University, Stanford

15Division of Hematologic Oncology, Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, United States

16Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany

17Novartis Pharmaceuticals Corporation, East Hanover, United States

18Novaremed AG, Basel, Switzerland

19Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus der TU Dresden, Dresden, Germany

20Department of Medical Oncology, Dana-Farber/Partners CancerCare, Boston, United States

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Background:

Mutations localized in the tyrosine kinase domain activation loop of FLT3 (FLT3-TKD), induce constitutive tyrosine phosphorylation, and activation of the receptor tyrosine kinase similarly to FLT3 internal tandem duplication (ITD) mutations. However, the prognostic role of FLT3-TKD in AML is not well established. In the phase 3 RATIFY trial [CALGB 10603/Alliance; NCT00651261; Stone et al. N Engl J Med. 2017] midostaurin, in combination with standard chemotherapy, improved survival outcomes across all three FLT3 stratification subgroups (ITD high allelic ratio (AR) [≥ 0.7], ITD low AR [< 0.7] and TKD) vs placebo.

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Aims:

Here, a post hoc analysis was used to establish the efficacy of midostaurin in patients (pts) in the RATIFY trial stratified by FLT3-TKD AR and NPM1 mutational status.

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Methods:

In RATIFY, newly diagnosed pts with AML 18-60 years (y) old were randomly assigned to receive midostaurin or placebo together with standard induction and consolidation therapy followed by twelve 28-day cycles of maintenance therapy with midostaurin or placebo. FLT3-TKD mutation was detected by PCR and capillary electrophoresis at nine reference laboratories. The FLT3-TKD AR was calculated as the ratio between the areas under the curve of mutant to wild-type allele. Pts were categorized as NPM1 mutated (mut) or NPM1 wild-type (WT) using PCR. Efficacy outcomes included complete remission (CR), overall survival (OS), event-free survival (EFS) and disease-free survival (DFS). EFS and DFS analyses were performed considering CR within a 60-day window. P values presented were not adjusted for multiplicity.

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Results:

Of 163 FLT3-TKD pts, 134 with available NPM1 data had consented for exploratory analysis and were included in this study. Overall, 58.9% of pts had NPM1-mut, 47.8% were male and the median age was 49 y (range: 19.3-59.9 y). The median white blood cell (WBC) count was higher in pts with NPM1-mut than in pts with NPM1-WT (34.1 vs 15.5 × 109 /L). The median FLT3-TKD AR was 0.4 (range: 0-2.7). Overall CR rate (regardless of NPM1 genotype) was 64% for midostaurin and 56% for placebo in FLT3-TKD pts. Pts with FLT3-TKD AR ≥ 0.4 treated with midostaurin showed a trend towards improved OS and reduced cumulative incidence of relapse (CIR) (Figure). In FLT3-TKD AR ≥ 0.4 pts, the presence of a NPM1 mutation had a significant prognostic effect for all endpoints consistently with hazard ratios (HRs) around 0.50 or lower. Regardless of treatment OS, EFS, and DFS estimates at 3 y were 73% vs 52%, 48% vs 25%, and 74% vs 47%, respectively, for the 45 pts with FLT3-TKD/NPM1-mut vs the 25 pts with FLT3-TKD/NPM1-WT. It should be noted that the number of pts in each subgroup was small. Multivariate analyses in these FLT3-TKD pts revealed that NPM1 genotype was an independent prognostic factor for OS and EFS (2-sided P < 0.05), whereas study drug, age, sex, TKD AR, WBC at baseline and stem cell transplantation (SCT) (no/yes) did not reach this level of significance in the Cox model.

Figure

Figure

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Summary/Conclusion:

This post hoc analysis of the subset of FLT3-TKD pts in the RATIFY trial showed the high prognostic value of NPM1 mutational status. Midostaurin showed an overall benefit in the FLT3-TKD pts for OS, EFS, CR and DFS, with the impact of treatment on outcome for NPM1-mut pts being greatest in those with higher FLT3-TKD allelic burden. U10CA180821, U10CA180882, U24CA196171, U10CA180861; Novartis; htt***ps://acknowledgments.alliancefound.org

Copyright © 2019 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the European Hematology Association.