Demographics, Characteristics, Survival and Outcomes in Older, Untreated, Acute Myeloid Leukemia Patients with NPM1 Mutations or KMT2A rearrangements from the Beat AML Master Clinical Trial

Background: Chromosomal rearrangements involving the KMT2A gene and mutations involving the nucleophosmin (NPM1) gene have been associated with response to menin inhibitors in multiple studies of acute myeloid leukemia (AML) patients characterized by these genetic alterations. Both alterations are more common in younger AML patients and those with NPM1 mutations historically perform better. However, the prevalence and outcomes of older (≥60 years) AML patients with these alterations who are treated with current therapies is less well understood. We present results from the Beat AML Master Trial (BAMT) that analyze the outcomes of this large, but less common subset of patients in an older AML population.

Methods: Patients were consented and enrolled on this precision medicine-based Beat AML Master Trial (NCT03013998) from November 2016 to June 2024. Patients were included in this analysis if they harbor either the classic NPM1 mutation or a KMT2A rearrangement (over 10 different gene partners). Additionally, 2 patients with a NUP98 rearrangement were included with the KMT2A cohort as they are known to have similar biology in terms of menin dependence. These patients were treated with the following therapies: a sub-study specific targeted therapy for the dominant clone, venetoclax + hypomethylating agent (Ven/HMA), intensive chemotherapy (IC), alternative non-intensive therapy (NIT), or no therapy. Clinical/genetic characteristics and median overall survival (OS) were analyzed in each group separately. Overall survival (OS) was calculated from master consent and estimated using the Kaplan-Meier method.

Results: Of 1096 AML patients enrolled on the BAMT, 246 patients had either an NPM1 (N=207, 18.9%) or KMT2A (N=39, 3.6%) genetic alteration. The baseline characteristics for the NPM1 cohort were median age 72 years (range: 60-92), 50% female, and ECOG performance status: 0-16%, 1-58%, 2-25% and 3-1%. Additional disease characteristics include treatment related AML at 11% and complex karyotype (≥3 abnormalities) at 3%. Median OS for the entire NPM1 cohort was 18.4 months (95% CI: 14.2-24.7). Patients were treated on a sub-study (35%), Ven/HMA (19%), IC (26%), NIT (8%) or no treatment (9%). Between treatment groups, median OS was 21 months (95% CI: 12.8-31.7) for those treated on a sub-study, 22 months (95% CI: 12.6-not reached (NR)) for Ven/HMA, 41.6 months (95% CI: 18.2-NR) for IC, and 6.3 months (95% CI: 1.3-23) for NIT, which was significantly different (p<0.0001).

The baseline characteristics for the KMT2A cohort were median age 69 years (range: 60-88), 44% female, and ECOG performance status: 0-19%, 1-45%, 2-35% and 3-0%. Treatment related AML occurred in 23% of patients and complex karyotype in 31%. Median OS for the KMT2A cohort was 6.5 months (95% CI: 3.6-31.6). Patients were treated on a sub-study (38%), Ven/HMA (15%), IC (15%), NIT (15%), or no treatment (5%). Between treatment groups, median OS was 31.6 months (95% CI: 3.2-NR) for sub-study, 5.0 months (95% CI: 3.0-NR) for Ven/HMA, 12.7 months (95% CI: 4.9-NR) for IC, and 2.9 months (95% CI: 1.5-NR) for NIT, which was also significantly different (p<0.0001).

Conclusions: In this cohort of older AML patients who possess NPM1 or KMT2A mutations, initial demographics and clinical characteristics upon presentation are as expected. Within each cohort and depending on the type of therapy received, there were interesting differences in survival. Median OS was the highest for the NPM1 cohort that received IC while the KMT2A cohort had the highest median OS when enrolled on a KMT2A targeted sub-study; a finding that supports precision-based medicine for this high-risk KMT2A group characterized by poor outcomes. As menin inhibitor combinations with induction chemotherapy or Ven/HMA move to the frontline setting, we anticipate seeing significant improvement in outcomes for AML patients in both of these genomic subsets. Further multivariable analysis will be performed to validate treatment effect on OS. Our analyses for these two cohorts also provide valuable outcome benchmarks for the design of future precision oncology studies that seek to improve survival in these subsets of older AML patients.

Borate:Novartis: Consultancy; Abbvie: Consultancy; Genentech: Consultancy; Incyte: Consultancy; Daiichi Sankyo: Consultancy; Sumitomo: Consultancy; Rigel: Consultancy; Astellas: Consultancy; BMS: Consultancy; Vincerx Pharma: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: IDMC; Ryvue: Other: IDMC. Swords:Disc Medicine: Consultancy. Traer:Schrödinger: Research Funding; Incyte Corporation: Research Funding; Prelude Therapeutics: Research Funding; Rigel Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Servier Laboratories: Membership on an entity's Board of Directors or advisory committees; 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; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding. Stein:Jazz Pharmaceuticals: Consultancy, Other: consulting fees; AstraZeneca: Consultancy, Other: consulting fees; Agios Pharmaceuticals: Consultancy, Other: consulting fees; Celgene: Consultancy, Other: consulting fees; Daiichi Sankyo, Inc.: Consultancy, Other: consulting fees; Genentech: Consultancy, Other: consulting fees; Astellas Pharmaceuticals: Consultancy, Other: consulting fees; Servier: Consultancy, Other: consulting fees; Abbvie: Consultancy, Other: consulting fees; Gilead: Consultancy, Other: consulting fees. Lin:Aptevo; Bio-Path Holdings; Ciclomed; Cleave; Jazz; Jazz Pharmaceuticals; Leukemia & Lymphoma Society; Kura Oncology; Trovagene: Research Funding; Jazz Pharmaceuticals; Servier: Consultancy. 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:Dava Oncology: Honoraria; Servier: Honoraria; Pfizer: Consultancy; Clincal Care Options: Honoraria; Jazz Pharmaceuticals: Consultancy; Kite Pharmceuticals: Consultancy. Stefanos:Eilean Therapeutics: Consultancy. Levine:Zentalis: Membership on an entity's Board of Directors or advisory committees; Qiagen: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Mana: Membership on an entity's Board of Directors or advisory committees; Kurome: Membership on an entity's Board of Directors or advisory committees; Jubilant: Membership on an entity's Board of Directors or advisory committees; Bridge Medicines: Consultancy; 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; Syndax: Consultancy; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Anovia: Consultancy; Bridge Bio: Consultancy; Auron: Membership on an entity's Board of Directors or advisory committees; Imago: Consultancy; Prelude Therapeutics: Membership on an entity's Board of Directors or advisory committees; Epiphanes: Membership on an entity's Board of Directors or advisory committees; Scorpion: Membership on an entity's Board of Directors or advisory committees; Bakx Therapeutics: 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; Novartis: 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; Daiichi Saynko: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Membership on an entity's Board of Directors or advisory committees. Byrd:Vincerx Pharma, Eilean Therapeutics, and Kurome Therapeutics: Current equity holder in private company; Abbvie, AstraZeneca, and Syndax: Consultancy.