FLT3 and NPM1 Are Powerful Determinants of Outcome in Acute Myeloid Leukemia Patients Treated with Autologous Stem Cell Transplantation: An Analysis By the Acute Leukemia Working Party of the EBMT
Authors: Shouval Roni , Labopin Myriam , Bomze David , Baerlocher Gabriela M , Foà Robin , Blaise Didier , Haenel Mathias , Forcade Edouard , Huynh Anne , Saccardi Riccardo , Milone Giuseppe , Zuckerman Tsila , Reményi Péter , Esteve Jordi , Gorin Norbert Claude , Mohty Mohamad , Nagler Arnon 
Published: October 2019

Abstract
Background: While intensive consolidation therapy with autologous stem cell transplantation (ASCT) can secure a remission in selected Acute Myeloid Leukemia (AML) patients with intermediate-risk cytogenetics, a substantial proportion will ultimately relapse. Knowledge of the mutational status of FMS like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) and nucleophosmin (NPM) 1 and their possible combinations could further refine a subset of intermediate cytogenetic risk patients who may benefit from ASCT. However, data are limited. We, therefore, set out to evaluate the impact of FLT3-ITD and NPM1 in a large cohort of patients undergoing ASCT.
Methods: This was a retrospective analysis of the Acute Leukemia Working Parity of the European Society for Blood and Marrow Transplantation (EBMT) registry. We included 405 de-novo AML patients, from 51 European centers, with intermediate-risk cytogenetics (Grimwade et al., Blood 2010) and complete data on FLT3-ITD and NPM1 status, receiving an ASCT at first complete remission (CR1), between 2000-2014. Leukemia free survival (LFS) was the primary outcome. Secondary outcomes were overall survival (OS), transplantation-related mortality (TRM), and relapse incidence (RI). The latter two were considered as competing events. Univariate and multivariable Cox regression models, adjusted for recipient sex, age, Karnofsky performance status, FLT3/NPM1 combinations, days from diagnosis to transplantation, stem cell source -bone marrow or peripheral blood (PB), and use of total-body irradiation-based conditioning.
Results: Patients included had a median age of 52 years and received an autograft at median of 5 months from diagnosis. PB-based autograft and non-TBI conditioning were used in the majority of patients (93% and 90%, respectively). FLT3-/NPM1- was the leading molecular combination (50%), followed by FLT3-/NPM1+ (30%), FLT3+/NPM1+ (11%), and FLT3+/NPM1- (9%). Age, time from diagnosis to transplantation, graft source, and use of TBI were similar between the molecular subgroups. The median year of transplantation was earlier in NPM1- patients (FLT3+/NPM1- 2008, FLT3-/NPM1- 2009, FLT3-/NPM1+ 2010, FLT3+/NPM1+ 2011, p<0.001). In the univariate analysis, age, molecular makers, time from diagnosis to transplantation, and use of TBI were associated with the risk for experiencing an LFS event. Patients in the FLT3-/NPM1+ subgroup had the most favorable outcome (5-years LFS [62%] and OS [74%]). Nonetheless, 5 years following ASCT the RI was 35% (Figure). FLT3+/NPM1- were the least likely to survive due to a tendency to relapse: 5-years LFS (21%), OS (33%),and RI (79%). In a Cox multivariable model, the combination of molecular markers were the strongest predictors of LFS: FLT3-/NPM1+ (reference), FLT3-/NPM1- HR 2.39 (1.65-3.46), FLT3+/NPM1+ HR 2.24 (1.33-3.75), FLT3+/NPM1- HR 5.09 (2.94-8.82). We did not find interactions between molecular markers and other covariates in the model.
Conclusions: In this pioneering analysis of CR1-AML patients, with intermediate risk cytogenetics, receiving an ASCT as post-remission therapy, we show that the molecular subgroups of FLT3-ITD and NPM1 are highly prognostic. In line with previous publications in the allogeneic setting, patients with FLT3-/NPM1+ have promising outcomes, while those with FLT3+/NPM1- do poorly. Testing for the role of additional markers, such as isocitrate dehydrogenase (IDH), could further identify populations who may derive the most benefit from ASCT.
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Disclosures
Baerlocher: Novartis: Research Funding. Foà:NOVARTIS: Speakers Bureau; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; CELTRION: Other: ADVISORY BOARD; AMGEN: Other: ADVISORY BOARD; INCYTE: Other: ADVISORY BOARD. Haenel:Novartis: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Roche: Honoraria. Zuckerman:Cellect Biotherapeutics Ltd: Consultancy. Mohty:MaaT Pharma: Consultancy, Honoraria.