Background: The BeatAML Master Trial (BAMT) began in 2016 with a goal of determining the feasibility of a precision-medicine approach in treating acute myeloid leukemia (AML) in older adults ≥ 60 years of age where outcomes are poor. At the time, standard of care (SOC) for older patients with AML was intensive 7+3 chemotherapy (cytarabine + daunorubicin) if fit and hypomethylating agents (HMA: azacitidine or decitabine) if unfit. Besides confirming the feasibility, the early results (2019) from the Master Trial suggested that patients who received therapy on one of the sub-studies had a lower early death rate and superior overall survival compared to patients receiving off-protocol SOC, which was primarily single-agent HMA at the time. Since then, the 2019 approval of venetoclax (ven) + azacitidine for older unfit AML patients has been transformative and emerged as the SOC. Using data from the BAMT from 2016-2024, we suggest that knowing the comprehensive genomic profile of AML at the time of diagnosis is still beneficial in determining therapy that would lead to the optimal outcome and that development of targeted therapies and combination regimens with ven/HMA is still needed.

Methods: This is a retrospective analysis of 1096 patients who consented and enrolled on the BAMT (NCT03013998) from Nov 2016 through Jun 2024. Patients ≥ 60 years with newly diagnosed AML were included. Patients underwent therapy on a BeatAML sub-study based on their genetics (N=433) or treatment off-protocol (N=663). We divided the patients according to what therapy they received: (1) Non-Intensive (Off-Protocol, N=121), (2) Ven/HMA (Off-Protocol, N=234), (3) Non-Intensive (Sub-Study, N=407), (4) Intensive (Sub-Study, N=26), and (5) Intensive (Off-Protocol, N=155). 94 patients received no treatment and 59 were unknown. Non-intensive therapies included primarily targeted agents or non-ven combinations. We analyzed baseline characteristics and demographics, overall survival (OS), and the impact of allogenic stem cell transplant (SCT). OS, using Kaplan-Meier method, was measured from the start of therapy to all-cause death, censoring patients at last follow-up.

Results: Characteristics and demographics were similar between Groups 1, 2 and 3. Group 4 and 5 were treated with intensive chemotherapy and their characteristics are reflective of younger/fit patients appropriate for the intensive regimen. Groups 4 and 5 also had the longest median OS (mOS) of 40.2 months (95% CI: 13.9-not reached (NR)) and 42.3 months (95% CI: 25.1-NR) respectively. Group 3, which included patients treated with a non-intensive, targeted therapy on a sub-study, had an mOS of 14.0 months (95% CI: 12.3-16.7), which was similar to Group 2, treated with Ven/HMA, that had an mOS of 13.2 months (95% CI: 10.9-16.3). Lastly, patients in Group 1, who were treated primarily with HMA monotherapy, did poorly in comparison, with an mOS of 6.0 months (95% CI: 3.3-10.1).

Additionally, we looked at the cumulative incidence rate (CIR) of SCT. The CIR in 12 months of Group 1 was 9.8% (95% CI: 6.9-13.4), Group 2: 5.4% (95% CI: 2.2-10.7), Group 3 and 4 combined: 35.0% (95% CI: 628.1-42.1), and Group 5: 13.1% (95% CI: 6.9-13.4). In a multi-variable analysis, after adjusting for typical favorable risk factors like NPM1 mutations and core binding factor, SCT was highly significant (p<0.0001) in improving OS with a hazard ratio of 0.23 (95% CI: 0.16-0.32), and Group 3 performed similarly to Group 2 (p=0.20).

Conclusions: First, our results suggest that it is clinically relevant to correctly identify whether an intensive chemotherapy, targeted-therapy, or ven/HMA regimen is best suited for older AML patients, for which a precision-medicine trial is ideal for. Secondly, in this group of patients, our results show that patients treated with a non-intensive targeted therapy (Group 3) has a similar mOS to those treated with ven/HMA (Group 2). Especially after controlling for patient characteristics, patients in Group 2 performed similar to those in Group 3 (p=0.20). Patients in Group 3 were treated on Beat AML sub-studies which included targeted therapy alone or with non-venetoclax combinations, which is a strong rationale for continued development of targeted agents to optimize toxicity and quality of life with similar survival. Lastly, this data also supports the need to improve the ven/HMA SOC by developing combination regimens with targeted agents to further improve outcomes.

Disclosures

Borate:Beigene: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharma: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Astellas: Consultancy; Rigel: Consultancy; Sumitomo: Consultancy; Daiichi Sankyo: Consultancy; Incyte: Consultancy; Genentech: Consultancy; Abbvie: Consultancy; Novartis: Consultancy; Takeda: Other: IDMC; Ryvue: Other: IDMC. Swords:Disc Medicine: Consultancy. Traer:Prelude Therapeutics: Research Funding; Daiichi Sankyo, Inc.: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Servier Laboratories: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Research Funding; Rigel Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Schrödinger: Research Funding. Stein:Genentech: Consultancy, Other: consulting fees; Gilead: Consultancy, Other: consulting fees; Servier: Consultancy, Other: consulting fees; Astellas Pharmaceuticals: Consultancy, Other: consulting fees; Jazz Pharmaceuticals: Consultancy, Other: consulting fees; Daiichi Sankyo, Inc.: Consultancy, Other: consulting fees; Agios Pharmaceuticals: Consultancy, Other: consulting fees; Celgene: Consultancy, Other: consulting fees; AstraZeneca: Consultancy, Other: consulting fees; Abbvie: Consultancy, Other: consulting fees. Lin:Jazz Pharmaceuticals; Servier: Consultancy; Aptevo; Bio-Path Holdings; Ciclomed; Cleave; Jazz; Jazz Pharmaceuticals; Leukemia & Lymphoma Society; Kura Oncology; Trovagene: Research Funding. Madanat:Taiho Oncology, Rigel Pharmaceuticals, Novartis: Consultancy; OncLive, MD Education, Sierra Oncology, Stemline, MorphoSys: Consultancy; Sierra Oncology, Stemline Therapeutics, Blueprint Medicines, Morphosys, Taiho Oncology, SOBI, Rigel Pharmaceuticals, Geron, Cogent Biosciences and Novartis: Other: Advisory Board; Blueprint Medicines, MD Education, and Morphosys: Other: travel; BMS, Kura Oncology, BluePrint Medicines, Geron: Consultancy. Patel:Servier: Current Employment. Arellano:Syndax Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board meeting 5/31/24, Syndax pharmaceuticals, role of menin inhibition in treatment of acute leukemias. Stock:Adaptive: Consultancy, Honoraria; Kura: Research Funding; Kura, Servier, Newave, Adaptive, Jazz, Asofarma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Odenike:AbbVie; Blueprint Medicines; BMS; Bristol-Myers Squibb/Celgene (Inst); Celgene; CTI; Impact Biomedicines; Kymera; Novartis; SERVIER; Taiho Pharmaceutical; Treadwell Therapeutics: Honoraria; AbbVie (Inst); Agios (Inst); Aprea AB (Inst); Astex Pharmaceuticals (Inst); AstraZeneca (Inst); Bristol-Myers Squibb (Inst); Celgene (Inst); CTI BioPharma Corp (Inst); Daiichi Sankyo (Inst); Incyte (Inst); Janssen Oncology (Inst); Kartos Therapeutics (Ins: Research Funding. Deininger:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Grants, travel, clinical trial support, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Grants, Travel, Research Funding; Blueprint Medicines Corporation: Consultancy, Honoraria, Other: Part of a study management committee, Research Funding; Incyte: Honoraria, Research Funding; Medscape: Honoraria, Other: Case Author ; Sangamo: Consultancy, Honoraria; Takeda: Honoraria, Other: Part of a study management committee, Research Funding; DisperSol: Consultancy; Fusion Pharma: Consultancy; Leukemia & Lymphoma Society: Research Funding; SPARC: Research Funding. Olin:Cellectis: Research Funding; Servicer: Consultancy; Riger: Consultancy. Smith:Cellgene: Other: Clinical Trial Funding; Abbvie: Honoraria, Research Funding; Genentech: Honoraria; Biomea: Other: Clinical Trial Funding; ERASCA: Research Funding; Revolution Medicines: Research Funding. Curran:Clincal Care Options: Honoraria; Jazz Pharmaceuticals: Consultancy; Kite Pharmceuticals: Consultancy; Pfizer: Consultancy; Servier: Honoraria; Dava Oncology: Honoraria. Stefanos:Eilean Therapeutics: Consultancy. Levine:Imago: Consultancy; Mana: Membership on an entity's Board of Directors or advisory committees; Epiphanes: Membership on an entity's Board of Directors or advisory committees; Auron: Membership on an entity's Board of Directors or advisory committees; Mission Bio: Membership on an entity's Board of Directors or advisory committees; Kurome: Membership on an entity's Board of Directors or advisory committees; Qiagen: Membership on an entity's Board of Directors or advisory committees; Anovia: Consultancy; Prelude Therapeutics: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Ajax: Membership on an entity's Board of Directors or advisory committees; Bridge Medicines: Consultancy; Syndax: Consultancy; Zentalis: Membership on an entity's Board of Directors or advisory committees; Bridge Bio: Consultancy; Bakx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Scorpion: Membership on an entity's Board of Directors or advisory committees; Jubilant: Membership on an entity's Board of Directors or advisory committees. Burd:Eilean Therapeutics: Current Employment. Mims:Treadwell Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society Beat AML Study: Other: Senior Medical Director; Foghorn Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Daiichi Saynko: Membership on an entity's Board of Directors or advisory committees. Byrd:Abbvie, AstraZeneca, and Syndax: Consultancy; Vincerx Pharma, Eilean Therapeutics, and Kurome Therapeutics: Current equity holder in private company.

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