Implications of RAS Mutational Status in Subsets of Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) across Therapy Groups
Authors: Rivera Daniel , Kantarjian Hagop M. , Borthakur Gautam , Konopleva Marina , Kanagal-Shamanna Rashmi , Pemmaraju Naveen , Daver Naval , DiNardo Courtney D. , Takahashi Koichi , Jabbour Elias , Montalban-Bravo Guillermo , Yilmaz Musa , Pierce Sherry A. , Andreeff Michael , Bhalla Kapil N. , Garcia-Manero Guillermo , Ravandi Farhad , Kadia Tapan M. 
Published: November 2020

Introduction
Activating mutations in RAS have been reported in about 10-15% of patients with AML. Previous studies have not identified a prognostic significance for RAS mutations in AML treated with conventional chemotherapy. However, RAS mutations have emerged as a potential mechanism of resistance to treatment with small molecule inhibitors of FLT3, IDH, and BCL2. With broader availability of next generation sequencing, and the identification of wider heterogeneity in AML, we aimed to better characterize the genomic landscape of RAS mutated AML and outcomes within various subsets.
Methods
We conducted a retrospective analysis in 1410 consecutive patients with newly diagnosed (ND) AML) treated at out institution from 12/2011 to 01/2020, who had a baseline genomic testing available. Patients were treated with a variety of therapies, classified as: HMA-alone, HMA+Venetoclax (Ven), Intensive chemotherapy (HiDAC based), Intensive+Ven, low intensity double nucleoside analogue (cladribine+LDAC; Clad/LDAC), and Clad/LDAC + Ven. Response rates and outcomes were analyzed by age, cytogenetic prognostic subgroup (favorable [FAV], diploid [DIP], other intermediate [INT], adverse [ADV]), and type of therapy in the context of mutated (RAS-mut) or wild type RAS (RAS-WT). We sought to characterize the impact of RAS mutations on AML outcomes in the era of targeted therapy.
Results
Baseline patient and disease characteristics are detailed in table 1. Among 1410 patients with ND AML, 273 (20%) were RAS-mut; of these, 196 (72%) had NRAS-mut, 47(17%) had KRAS-mut, and 29(11%) had both. Patients with RAS-mut were younger(median age 62 vs. 66 years; P=0.001) and had higher a median WBC (P=0.02) and platelet count (P=0.01) at diagnosis compared to those with RAS-WT. Among the cytogenetic groups: FAV, INT, DIPLOID, ADV, RAS-mut were present in 39%, 20%, 16%, and 6%, respectively. Patients with RAS-mut were more likely to have concomitant mutations in ASXL1 (13%; P=0.03), , RUNX1 (10%; P=0.03), and less likely to have concomitant mutations in JAK2 (1%; P=0.03) and TP53 (8%; P&lt;0.01). Outcomes by subset and by therapy group are summarized in Table 2. Although there was a trend in favor of RAS-mut, there was no significant difference in OS among pts younger or older than 60 yrs of age by RAS mutation. There was no difference in OS by NRAS or KRAS mutation (median OS 16 vs. 16.5 m; P=0.45). Pts with RAS-mut AML classified as non-secondary/de novo AML (P=0.003), therapy-related AML (P=0.02), and those who received intensive therapy had a significantly better OS compared to RAS-WT. The addition of Ven to each therapy group was associated with higher response rates and median OS but were not statistically significant (Figure 1). Response rates among patients with or without RAS mutations were similar, with a trend for better responses with araC-based therapy, compared to non-araC based. Compared to RAS-WT, RAS-mut was associated higher response among pts with diploid karyotype, de novo AML, and those treated with intensive therapy. Among pts with MLL-rearrangements (P=0.09) and MECOM translocation (P=0.06), RAS-mut was associated with lower response rates compared to RAS-WT. Among patients with TP53 mutated AML, co-mutation with RAS was associated with worse outcomes compared to RAS-WT (CR rates of 4% vs. 16% P&lt;0.001; median OS 3.4 vs. 5.8 months, P=0.77).
Conclusion
RAS mutations are present across AML subsets, with higher representation among pts with FAV cytogenetics and relative underrepresentation among pts with ADV karyotype and TP53-mutations. Among patients with DIP cytogenetics, de novo AML, and those treated with intensive therapy, RAS-mut are associated with higher response rates and more favorable outcomes. Early observations suggest modest improvements in ORR with the addition of Ven to chemotherapy but no OS benefit. Targeting the RAS pathway among specific AML subsets remains an important area of further research.
Figure 1

Disclosures
Kantarjian: Daiichi-Sankyo: Research Funding; AbbVie: Honoraria, Research Funding; Immunogen: Research Funding; BMS: Research Funding; Jazz Pharma: Research Funding; Novartis: Research Funding; Ariad: Research Funding; Amgen: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Research Funding; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; Astex: Research Funding; Takeda: Honoraria. Borthakur:Curio Science LLC: Consultancy; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; Polaris: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; BioLine Rx: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding; PTC Therapeutics: Research Funding; FTC Therapeutics: Consultancy; BioLine Rx: Consultancy; PTC Therapeutics: Consultancy; Argenx: Consultancy; BioTherix: Consultancy; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy. Konopleva:AbbVie: Consultancy, Research Funding; Sanofi: Research Funding; Kisoji: Consultancy; Genentech: Consultancy, Research Funding; Cellectis: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Rafael Pharmaceutical: Research Funding; Amgen: Consultancy; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Agios: Research Funding; Ascentage: Research Funding; Ablynx: Research Funding; AstraZeneca: Research Funding; Calithera: Research Funding. Pemmaraju:Samus Therapeutics: Research Funding; Blueprint Medicines: Honoraria; Daiichi Sankyo: Research Funding; Affymetrix: Other: Grant Support, Research Funding; MustangBio: Honoraria; Celgene: Honoraria; Cellectis: Research Funding; Pacylex Pharmaceuticals: Consultancy; AbbVie: Honoraria, Research Funding; Incyte Corporation: Honoraria; Plexxikon: Research Funding; Novartis: Honoraria, Research Funding; Roche Diagnostics: Honoraria; SagerStrong Foundation: Other: Grant Support; DAVA Oncology: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; LFB Biotechnologies: Honoraria. Daver:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. DiNardo:Novartis: Consultancy; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Syros: Honoraria; Jazz: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; MedImmune: Honoraria; Calithera: Research Funding; ImmuneOnc: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Takeda: Honoraria. Jabbour:Pfizer: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding. Yilmaz:Pint Pharma: Honoraria; Pfizer: Research Funding; Daicho Sankyo: Research Funding. Andreeff:Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Amgen: Research Funding; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees. Garcia-Manero:H3 Biomedicine: Research Funding; AbbVie: Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amphivena Therapeutics: Research Funding; Onconova: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Novartis: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria. Ravandi:Amgen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; AstraZeneca: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding. Kadia:Astra Zeneca: Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Astellas: Research Funding; Novartis: Honoraria; Abbvie: Honoraria, Research Funding; Cyclacel: Research Funding; Genentech: Honoraria, Research Funding; Celgene: Research Funding; Pulmotec: Research Funding; Amgen: Research Funding; Incyte: Research Funding; Ascentage: Research Funding; Cellenkos: Research Funding; JAZZ: Honoraria, Research Funding.