Background. Acute myeloid leukemia (AML) is a heterogenous disease that occurs primarily in older adults with a median age of 69 years at diagnosis. Most studies that characterize the genomic landscape of AML include younger adults with the majority of patients being younger than 60 years of age. We aimed to study the mutational landscape of newly diagnosed AML patients aged 60 years or older.

Methods.Samples were collected from the multi-center Beat AML Master Trial (Burd, Nat Med 2020). Patients were enrolled between 2016 and 2023. Informed consent was obtained according to the Declaration of Helsinki. Patients diagnosed with non-APL AML and who were aged ā‰„ 60 years old were included. Patients underwent bone marrow aspiration and biopsy, cytogenetic analysis, FLT3-ITD ratio assessment (LeukoStrat CDx FLT3 Mutation Assay, Invivoscribe) and next generation sequencing (NGS) using FoundationOneĀ®Heme(Foundation Medicine) to interrogate the entire coding region of 406 genes and select introns of 31 genes involved in rearrangements, as well as RNA sequencing to interrogate 265 genes known to be somatically altered in human hematological malignancies. The presence of multiple hotspot mutations within one gene in an individual patient was counted as one gene mutation. Patterns of co-occurrence between gene mutations were calculated using the Phi correlation coefficient. Statistical analyses were performed using R statistical software. P<0.01 was considered statistically significant.

Results. A total of 1088 newly diagnosed AML patients were identified, of whom 1032 were 60 years or older. Patients had a median age of 72 years at time of diagnosis (range 60-92 years). Forty-two percent of the patients were female, most patients were non-Hispanic and 79% were Caucasian. NGS data were available for 1024 patients and mutations were identified in 461 different genes. Patients had a median number of 11.0 mutations (range 3.0 to 28.0). The most frequently mutated genes were DNMT3A (n=257; 25.1%), TP53(n=255; 24.9%), TET2 (n=243; 23.7%), RUNX1 (n=225; 22.0%), SRSF2 (n=221; 21.6%), ASXL1 (n=216; 21.1%), NPM1 (n=206; 20.1%), FLT3 (n=205; 20.0%), IDH2 (n=190; 18.6%), NRAS (n=208; 16.9%), PTPN11(n=104; 10.2%), STAG2 (n=101, 9.9% and IDH1 (n=99; 9.7%) (Figure 1A). FLT3-ITD was present in 98 (12.1%) of the 810 patients who were tested. Strongest significant co-occurrence was found between FLT3and NPM1 (n=103), STAG2 and ASXL1 (n=63), ASXL1 and RUNX1 (n=92), ASXL1 and SRSF2 (n=88), RUNX1 and SRSF2 (n=94), STAG2 and SRSF2 (n=51) and DNMT3A and NPM1 (n=92) (p<0.01). Pairwise negative correlations were observed between TP53 and NPM1 (n=6), TP53 and SRSF2 (n=17), and between NPM1 and RUNX1 (n=6) (p<0.01) (Figure 1B). The cytogenetic profiles and the full genomic landscape will be presented during the ASH meeting.

Discussion. This is the largest study investigating the mutational profile in older adults with AML aged 60 years and older. Due to the 7-day screening period of the Beat AML study, patient selection was biased towards less-rapidly proliferative AML. We showed that the pattern of gene mutations was markedly different from other studies in AML that mainly included younger AML patients (Papaemmanuil, NEJM 2016; TCGA, NEJM 2013 ). The frequency of mutated TP53 was substantially higher in older AML patients, as was the occurrence of myelodysplasia-related gene mutations (e.g., SRSF2, RUNX1, ASXL1, STAG2, U2AF1, and SF3B1) and gene mutations in IDH1, IDH2 and TET2. In contrast, NPM1 mutation was less frequently mutated in older AML patients. Furthermore, we demonstrated that a large proportion (46%) of the AML patients older than 60 years of age do have a mutation that is potentially targetable for treatment ( FLT3 IDH1 IDH2 and NPM1). The high incidence of mutated TP53 and MDS-related gene mutations underscores the increased incidence of high-risk AML and the need for innovative personalized therapies in this older age group.

Figure 1. A. Co-occurrence of the 15 most frequently mutated genes, and B. co-correlation between the 15 most frequently mutated genes. Blue indicates positive correlation, red indicated negative correlation. Only significant correlations (p<0.01) are shown.

Swords:Kronos Bio: Research Funding. Traer:Servier: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Research Funding; Schrodinger: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Prelude Therapeutics: Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees. Stein:Eisai: Research Funding; Bristol Myers Squib: Consultancy, Research Funding; Novartis: Consultancy; PinotBio: Consultancy; Janssen: Consultancy; Agios: Consultancy; Jazz: Consultancy; Menarini: Consultancy; Genentech: Consultancy; Genesis: Consultancy; Abbvie: Consultancy; Neoleukin: Consultancy; Gilead: Consultancy; Syndax: Consultancy; OnCusp: Consultancy; CTI Biopharma: Consultancy; Foghorn: Consultancy; Servier: Consultancy; Calithera: Consultancy; Daiichi: Consultancy; Aptose: Consultancy; Syros: Consultancy; Astellas: Consultancy; Ono Pharma: Consultancy; Blueprint: Consultancy. Lin:Bio-path Holdings: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Celyad: Research Funding; Aptevo Therapeutics: Research Funding; Cleave Biosciences: Research Funding; Ciclomed: Research Funding; Jazz Pharmaceuticals: Research Funding. Patel:Servier LLC: Current Employment. Baer:Takeda (Inst): Research Funding; Abbvie (Inst): Research Funding; Kura Oncology (Inst): Research Funding; Kite, a Gilead company (Inst): Research Funding; Ascentage Pharma (Inst): Research Funding; FORMA Therapeutics (Inst): Research Funding. Stock:Newave: Honoraria; Amgen: Honoraria; Servier: Other: Data Safety Monitoring Board/Advisory Board; Kura: Research Funding; Kite: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria; Glaxo Smith Kline: Consultancy. Odenike:BMS/Celgene, Novartis, Rigel, Servier, Taiho ; DSMB-Kymera therapeutics: Membership on an entity's Board of Directors or advisory committees; ABBVIE, Astrazeneca, Agios, Aprea, Astex, BMS/Celgene, CTI, Daiichi, Incyte, Janssen, Kartos, Novartis, NS-Pharma and Oncotherapy Sciences: Research Funding. Kovacsovics:Servier: Consultancy; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Gilead: Research Funding; Novartis: Research Funding; Syndax Pharmaceuticals: Research Funding. Zeidner:AbbVie: Consultancy, Honoraria, Research Funding; Arog: Research Funding; Astex: Research Funding; Daiichi Sankyo: Honoraria; Foghorn: Consultancy; Gilead: Consultancy, Honoraria, Research Funding; Immunogen: Honoraria; Jazz: Research Funding; Merck: Research Funding; Novartis: Consultancy; Sellas: Consultancy; Servier: Consultancy, Honoraria; Shattuck Labs: Honoraria, Research Funding; Stemline: Research Funding; Sumitomo Dainippon Pharma: Research Funding; Takeda: Research Funding. 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Schiller:Agios: Consultancy; Ono Pharmaceutical: Consultancy; Novartis: Consultancy, Research Funding; Stemline Therapeutics: Speakers Bureau; Incyte: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; Bristol Myers Squibb: Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Karyopharm Therapeutics: Research Funding, Speakers Bureau; Sanofi: Research Funding, Speakers Bureau; Kite: Research Funding, Speakers Bureau; Astellas Pharma: Consultancy, Research Funding, Speakers Bureau; AbbVie: Consultancy, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Amgen: Current equity holder in publicly-traded company, Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Actinium Pharmaceuticals: Research Funding; Actuate Therapeutics: Research Funding; Arog: Research Funding; Celator: Research Funding; Constellation Pharmaceuticals: Research Funding; Daiichi Sankyo: Research Funding; Deciphera: Research Funding; Delta-Fly Pharma: Research Funding; FORMA Therapeutics: Research Funding; Fujifilm: Research Funding; Gamida Cell: Research Funding; Genentech/Roche: Research Funding; Geron: Research Funding; Mateon Therapeutics: Research Funding; Onconova Therapeutics: Research Funding; Pfizer: Research Funding; Precog: Research Funding; REGiMMUNE: Research Funding; Samus Therapeutics: Research Funding; Sangamo Bioscience: Research Funding; Sellas Life Sciences: Research Funding; Stemline Therapeutics: Research Funding; Takeda: Research Funding; Tolero Pharmaceuticals: Research Funding; Trovagene: Research Funding; Agios: Research Funding; ElevateBio: Research Funding; Ono Pharmaceutical: Research Funding; AVM Biotechnology: Research Funding; Syros Pharmaceuticals: Research Funding; Kronos Bio: Research Funding. 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Druker:The RUNX1 Research Foundation: Membership on an entity's Board of Directors or advisory committees; VB Therapeutics: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharma, Inc.: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Beat AML LLC: Membership on an entity's Board of Directors or advisory committees; Multicancer Early Detection (MCED) Consortium: Membership on an entity's Board of Directors or advisory committees; Aileron Therapeutics: Membership on an entity's Board of Directors or advisory committees; Therapy Architects, LLC: Membership on an entity's Board of Directors or advisory committees; CureOne: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: PI or Co-investigator on clinical trial(s) funded via contract with OHSU., Research Funding; AstraZeneca: Other: PI or Co-investigator on clinical trial(s) funded via contract with OHSU.; Enliven Therapeutics: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oregon Health & Science University: Current Employment, Patents & Royalties: #1518 (exclusive option agreement with CytoImage); #0606/Patent 6958335 (Novartis exclusive license); #2573; #0843; #0996; DNA SEQ: Membership on an entity's Board of Directors or advisory committees; Dana-Farber Cancer Institute: Patents & Royalties: #2063 (licensed exclusively to Merck & Co); and #2524, Research Funding; Bristol Myers Squibb: Other: Co-investigator on clinical trial(s) funded via contract with OHSU.; Celgene: Other: Co-investigator on clinical trial(s) funded via contract with OHSU.; Astellas: Other: Co-investigator on clinical trial(s) funded via contract with OHSU.; Incyte: Other: Co-investigator on clinical trial(s) funded via contract with OHSU.; Tolero: Other: Co-investigator on clinical trial(s) funded via contract with OHSU.; Syndax: Other: Co-investigator on clinical trial(s) funded via contract with OHSU.; Gilead: Other: Co-investigator on clinical trial(s) funded via contract with OHSU.; US Patent and Trademark Office: Patents & Royalties: Patents 6958335 (Novartis exclusive license), 4326534, 7416873, 7592142, 10473667, 10664967, 11049247; Recludix Pharma, Inc.: Consultancy, Current holder of stock options in a privately-held company; Labcorp: Membership on an entity's Board of Directors or advisory committees; Nemucore Medical Innovations, Inc.: Membership on an entity's Board of Directors or advisory committees; Iterion Therapeutics: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; GRAIL: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Cepheid: Membership on an entity's Board of Directors or advisory committees; Burroughs Wellcome Fund: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Aptose Biosciences: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Adela, Inc.: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Amgen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Levine:Novartis: Consultancy; AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy; Qiagen: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Isoplexis: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Prelude: Membership on an entity's Board of Directors or advisory committees; Auron: Membership on an entity's Board of Directors or advisory committees; Zentalis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Mission Bio: Membership on an entity's Board of Directors or advisory committees; Ajax: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria; Lilly: Honoraria; Amgen: Honoraria. Burd:Eilean Theraputics: Current Employment, Current equity holder in private company. Borate:Astellas: Membership on an entity's Board of Directors or advisory committees; Blueprint: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Research; Kura: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Incyte: Other; Genentech: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Research; Jazz: Other: Research; RUNX1 Foundation: Honoraria. Mims:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Byrd:Orbimed: Consultancy, Research Funding; OSU Drug Devel. Inst.: Consultancy; Vincerx: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Kurome: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Newave: Membership on an entity's Board of Directors or advisory committees, Research Funding; Orange Grove Bio: Membership on an entity's Board of Directors or advisory committees; American Cancer: Membership on an entity's Board of Directors or advisory committees; Eilean Therapeutics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Madanat:OncLive: Honoraria; Novartis: Honoraria; Taiho oncology: Honoraria; Stemline therapeutics: Honoraria; Morphosys: Honoraria, Other: travel reimbursement; Sierra Oncology: Honoraria; GERON: Consultancy; Blueprint Medicines: Consultancy, Honoraria, Other: travel reimbursement; MD Education: Honoraria; Rigel Pharmaceuticals: Honoraria.

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2023
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