Does Presence of Persistent Molecular Mutations Matter in AML Patients Undergoing Allogeneic Stem Cell Transplant?
Authors: Lee Sangmin , Hsu Jingmei , Tahri Yassine , Chen Zhengming , Shore Tsiporah B. , Ritchie Ellen K. , Gergis Usama , Desai Pinkal , Mayer Sebastian A. , Samuel Michael , Phillips Adrienne A. , Cushing Melissa M. , Roboz Gail J. , Van Besien Koen 
Published: October 2019

Abstract
Introduction: Mutations at diagnosis in acute myeloid leukemia (AML) patients have prognostic implications. For AML patients undergoing allogeneic stem cell transplant (SCT), the prognostic impact of molecular mutations pre-transplant and immediately post-transplant are less well characterized. Here we examine the mutation status of AML patients at different time points in relation to allogeneic SCT and their implications in relapse and survival.
Methods: AML patients who underwent allogeneic SCT after achieving complete remission with available molecular mutation testing at diagnosis, prior to transplant (within 4 weeks), and 28 days post-transplant were included in the analysis. Multivariable cox regression analysis was adjusted for age, gender, CIBMTR disease risk index (DRI), type of transplant, and genetic mutation. Backward selection method was used to select the best combination of genes that is associated with OS and relapse-free survival (RFS).
Results: A total of 110 AML patients with molecular genetic data available from 2014 to2018 at Weill Cornell Medicine were included in the analysis. Clinical characteristics of the patients are summarized in Table 1. The median age was 58 years (20-77). Twenty-three molecular mutations analyzed at baseline, pre-transplant, and at 28 days are listed in Table 2.
With a median follow-up time of 31.6 month, the median overall survival for the cohort was 37.1 months. Eighty-one patients had molecular testing at diagnosis. The presence of mutations in TP53 at diagnosis was associated with worse OS by both univariate (HR 3.67, p=0.0030, CI 1.56-8.68) and multivariate analysis (HR 4.75, p=0.0014, CI 1.82-12.39) with median OS reduced from 49.3 to 19.3 months (p=0.002). High CIBMTR DRI (HR 0.17, p=0.0018, CI 0.05-0.51) predicted reduced RFS, but not OS on multivariate analysis.
Seventy-seven patients had molecular testing prior to transplant and 27 patients had persistent mutations (Table 2). The presence of mutations in ETV6 and FLT3-ITD were independently associated with worse RFS ((HR 49.7, p=0.001, CI 5.0-528) & (HR 36.4, p<0.0001, CI 6.6-200)) and OS ((HR 38.31, p=0.0035, CI 3.31-443.37) & (HR 10.57, p=0.0038, CI 2.14-52.27)). The presence of NRAS mutations was associated with worse RFS (HR 105, p=0.0004, CI 8.1-1350), but not OS. Mutations in TP53 were associated with worse RFS (HR 70.97, p=0.0026 CI 4.44-1135) and OS on univariate (HR 9.82, p=0.0327, CI 1.21-79.82), but not on multivariate analysis.
At 28 days post-transplant, only 9 of the 84 patients had persistent mutations. Persistence of FLT3-ITD conferred worse RFS and OS in both univariate ((HR 11.92, p=0.0218, CI 1.43-98.98) & (HR 25.16, p=0.0052, CI 2.62, 241.92)) and multivariate ((HR 18.13, p=0.0089, CI 2.07-158.86) & (HR 35.47, p=0.0028, CI 3.41-368.81)) analysis.
Conclusions: Persistent presence of mutations in ETV6 and FLT3-ITD prior to stem cell transplant were associated with shorter RFS and OS independent of CIBMTR DRI. Persistent mutations in NRAS and CBL prior to stem cell transplant were associated with poor RFS and OS respectively. This analysis further supports association of adverse outcomes in AML patients with selected persistent mutations prior to stem cell transplant. Utility of serial mutation testing prior to transplant should be further investigated in prospective studies.

Disclosures
Lee: AstraZeneca: Consultancy; Clinipace: Consultancy; Karyopharm Therapeutics Inc: Consultancy; LAM Therapeutics: Research Funding; Amgen: Consultancy. Ritchie:NS Pharma: Research Funding; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; ARIAD Pharmaceuticals: Speakers Bureau; Astellas Pharma: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Consultancy, Research Funding; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau. Desai:Argenx: Consultancy; Cellerant Inc: Consultancy. Roboz:Eisai: Consultancy; Pfizer: Consultancy; AbbVie: Consultancy; Roche/Genentech: Consultancy; Aphivena Therapeutics: Consultancy; Eisai: Consultancy; AbbVie: Consultancy; Daiichi Sankyo: Consultancy; Argenx: Consultancy; Novartis: Consultancy; Janssen Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Orsenix: Consultancy; Celgene Corporation: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Cellectis: Research Funding; Celltrion: Consultancy; Celgene Corporation: Consultancy; Celltrion: Consultancy; Argenx: Consultancy; Astex Pharmaceuticals: Consultancy; Bayer: Consultancy; Cellectis: Research Funding; Sandoz: Consultancy; Astex Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy; Sandoz: Consultancy; Orsenix: Consultancy; Otsuka: Consultancy; Jazz Pharmaceuticals: Consultancy; Roche/Genentech: Consultancy; Otsuka: Consultancy; Bayer: Consultancy; Aphivena Therapeutics: Consultancy; Pfizer: Consultancy.