Introduction: Hypomethylating agents (HMA) with Venetoclax (Ven) is the standard of care for patients with acute myeloid leukemia (AML) ≥ 75 yrs of age or not candidates to intensive treatment. Döhner, et al. (ASH 2022) demonstrated that the European LeukemiaNet (ELN) risk classifications do not accurately predict prognosis in HMA-Ven treated patients. A prognostic risk signature classification (PRSc) was proposed, stratifying patients by RAS, FLT3 and TP53 mutations alone. We report a validation of this PRSc in a large cohort of patients treated with HMA-Ven.
Methods: This unicentric analysis included patients older than 60 years old with newly diagnosed treated with HMA-Ven in different treatment protocols. Responses were assessed with the ELN-2022 criteria. The PRSc allocated patients with [ K/N]- RAS or FLT3-ITD mutations in the intermediate benefit group, patients with TP53 in the lower benefit group, whereas patients with AML lacking these mutations were allocated in the higher benefit group. Cumulative incidence (CI) was calculated for pts achieving remission with death and relapse as competing events.
Results: A total of 179 patients were included, diagnosed between 11/2014 and 12/2021. Median age was 74 yrs old (range, 61-89) and 58% were male. 31% of patients had diploid cytogenetics and 35% had complex karyotype. According to the ELN 2022 risk category, 30 (17%), 15 (8%) and 114 (64%) patients were allocated in the favorable, intermediate and adverse risk group, respectively. According to the PRSc, 75 (42%), 31 (17%) and 54 (30%) were allocated in the higher, intermediate and lower benefit group, respectively. In the PRSc intermediate benefit group, 21 patients had NRAS mutations, 9 patients had KRAS mutation and 7 patients had FLT3-ITD. Patients received treatment with decitabine 10 days with Ven (n=89, 50%), decitabine 5 days with Ven (n=69, 38%), oral decitabine 5 days with Ven (n=14, 8%) and Azacitidine 7 days with Ven (n=7, 4%).
The overall response rate (ORR) was 70% (126/179), including 96 pts (54%) achieving complete remission (CR) rate and 30 (17%) having CR with incomplete hematologic recovery (CRi). The ORR for patients allocated in the ELN 2022 favorable, intermediate and adverse risk was 90% (27/30), 93% (14/15) and 63% (72/114). According to the PRSc, the ORR was 87% (65/75), 55% (17/31) and 59% (32/54) for patients of the higher, intermediate and lower benefit group, respectively. The median number of cycles to best response was 1 (1-8), and 22 patients (12%) underwent allogeneic stem cell transplantation.
After a median follow-up of 35 months, the median overall survival (OS) was 11 months. According to the ELN 2022 classification, the mOS was 44, 13 and 8 months (p<0.001, C-index=0.6). When applying the PRSc, the median OS was 30, 12 and 5 months for higher, intermediate and lower benefit group (p<0.001, C-index=0.66). Median event-free survival (EFS) was 8 months, being 30, 8, and 5 months for ELN 2022 favorable, intermediate and adverse group, respectively (p<0.001, C-index=0.62). When applying the PRSc, the median EFS was 18, 8 and 4 months for higher, intermediate and lower benefit group, respectively (p<0.001, C-index=0.65).
The 2-yr CI of relapse and death was 47% and 22%, respectively. By the ELN 2022 subgroups, the 2-yr CI of relapse was 29%, 43% and 55% for favorable, intermediate and adverse groups, respectively (p=0.1). The 2-yr CI of death was 12%, 21% and 25% for favorable, intermediate and adverse groups, respectively (p=0.4). By the PRSc, the 2-yr CI of relapse was 26%, 70% and 60% for higher, intermediate and lower benefit group, respectively (p=0.004). The 2-yr CI of death was 20%, 6% and 33% for higher, intermediate and lower benefit group, respectively (p=0.1).
Conclusion: The PRSc classification can stratify 3 different groups of patients with distinct outcomes. In the present study the 3 categories defined by the PRSc have very similar survival than the median OS previously reported (27, 12 and 5 months for higher, intermediate and lower benefit group), with a better performance according to the C-index. Signaling mutations ( RAS or FLT3-ITD) as well as TP53 mutations represent a challenge with HMA-Ven, in which novel treatments or combinations are warranted to improve outcomes.
Disclosures
DiNardo:Astellas: Honoraria; AbbVie/Genentech: Honoraria; BMS: Honoraria; Schrödinger: Consultancy; Notable Labs: Honoraria; Fogham: Honoraria; Takeda: Honoraria; Servier: Honoraria; ImmuniOnc: Honoraria; Novartis: Honoraria. Borthakur:Catamaran Bio, Abbvie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy; Pacylex, Novartis, Cytomx, Bio Ascend:: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding. Short:Novartis: Consultancy; AstraZeneca: Consultancy; Stemline therapeutics: Research Funding; Takeda: Consultancy, Research Funding; Amgen: Honoraria; Astellas: Research Funding; Pfizer: Consultancy. Jabbour:Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Ascentage Pharma Group: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Hikma Pharmaceuticals: Consultancy, Honoraria, Research Funding. Daver:AbbVie: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Jazz: Consultancy; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novimmune: Research Funding; Trillium: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Agios: Consultancy; Glycomimetics: Research Funding; AROG: Consultancy; Novartis: Consultancy; Hanmi: Research Funding; ImmunoGen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Trovagene: Research Funding; FATE: Research Funding; Celgene: Consultancy; Gilead: Consultancy, Research Funding; Shattuck Labs: Consultancy; Syndax: Consultancy; Servier: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Kite, a Gilead company: Consultancy, Research Funding; Kronos Bio: Research Funding. Issa:Syndax: Research Funding; Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding; NuProbe: Consultancy; Celgene: Research Funding; Merck: Research Funding. Pemmaraju:EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dava Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Patient Power: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CareDx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; United States Department of Defense (DOD): Research Funding; Harborside Press: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Menarini Group: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Magdalen Medical Publishing: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pacylex: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Imedex: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medscape: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; OncLive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PeerView Institute for Medical Education: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ASCO Cancer.Net Editorial Board: Other: Leadership; CancerNet: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Cimeio Therapeutics AG: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karger Publishers: Other: Licenses; Stemline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Intellisphere: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Curio Science: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ClearView Healthcare Partners: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Protagonist Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Neopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ASH Committee on Communications: Other: Leadership; CTI BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Aplastic Anemia & MDS International Foundation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ImmunoGen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Physician Education Resource (PER): Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Aptitude Health: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; National Institute of Health/National Cancer Institute (NIH/NCI): Research Funding; HemOnc Times/Oncology Times: Other: Uncompensated; Bristol Myers Squibb Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jain:Medisix: Research Funding; CareDX: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Loxo Oncology: Research Funding; ADC Therapeutics: Research Funding; Incyte: Research Funding; Servier: Research Funding; Ipsen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; BMS: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Genentech: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Pfizer: Research Funding; TransThera Sciences: Research Funding; Takeda: Research Funding; Dialectic Therapeutics: Research Funding; Newave: Research Funding; Novalgen: Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; AstraZeneca: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Fate Therapeutics: Research Funding; Mingsight: Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Aprea Therapeutics: Research Funding; Kite/Gilead: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; MEI Pharma: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Cellectis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Beigene: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Pharmacyclics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Montalban-Bravo:Takeda: Research Funding; Rigel: Research Funding. Wierda:National Comprehensive Cancer Network: Other: Nonrelevant Financial Relationship/Chair, CLL). Supported by the NIH/NCI under award number P30 CA016672 and used MDACC Cancer Center Support Grant (CCSG) shared resources; Accutar Biotechnology: Research Funding; Pharmacyclics LLC: Research Funding; Janssens Biotech Inc: Research Funding; Numab THerapeutics: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; GSK/Novartis: Research Funding; Genentech: Research Funding; AstraZeneca/Acerta Pharma: Consultancy, Research Funding; Cyclacel: Consultancy, Research Funding; Loxo Oncology, Inc./Lilly: Research Funding; AbbVie: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Janssens Biotech: Research Funding; Juno Therapeutics: Research Funding; Nurix THerapeutics: Research Funding; NIH P30 CA016672/MDACC Cancer Center Support Grant: Research Funding; Miragen: Research Funding; Sunesis: Research Funding; KITE Pharma: Research Funding; Bristol Myers Squibb (Juno & Celgene): Consultancy, Research Funding; Gilead Sciences: Research Funding. Garcia-Manero:Bristol Myers Squibb: Other: Medical writing support, Research Funding; Genentech: Research Funding; AbbVie: Research Funding. Ravandi:Abbvie: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Astex/taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Research Funding; Prelude: Research Funding; Amgen: Honoraria, Research Funding; Syros: Consultancy, Honoraria, Research Funding; Biomea fusion: Honoraria, Research Funding. Kantarjian:Amgen (Inst): Research Funding; Ascentage Pharma (Inst): Research Funding; Bristol-Myers Squibb (Inst): Research Funding; Novartis (Inst): Research Funding; Abbvie: Consultancy, Honoraria; Abbvie (Inst): Research Funding; Taiho Pharmaceutical: Honoraria; Shenzhen Target Rx: Honoraria; Precision Biosciences: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; KAHR Medical: Honoraria; Jazz Pharmaceuticals (Inst): Honoraria, Research Funding; Ipsen: Honoraria; Immunogen (Inst): Honoraria, Research Funding; Daiichih-Sankyo (Inst): Honoraria, Research Funding; AstraZeneca/MedImmune: Honoraria; Astellas Pharma: Honoraria; Ascentage Pharma Group: Honoraria; Amgen: Honoraria. Kadia:Pfizer: Consultancy, Research Funding; Delta-Fly Pharma, Inc.: Research Funding; AstraZeneca: Research Funding; Regeneron Pharmaceuticals: Research Funding; Agios: Consultancy; Daiichi Sankyo, Genentech, Inc., Genzyme, Jazz Pharmaceuticals, Liberum, Novartis, Pfizer, PinotBio, Inc, Pulmotect, Inc, Sanofi-Aventis, Servier: Consultancy; Celgene: Research Funding; Cellenkos Inc.: Research Funding; Amgen, Inc.: Research Funding; Sanofi-Aventis: Consultancy; Cyclacel: Research Funding; AbbVie, Amgen, Inc, Ascentage Pharma Group, Astellas Pharma Global Development, Astex, AstraZeneca, BMS, Celgene, Cellenkos Inc, Cyclacel, Delta-Fly Pharma, Inc, Genentech, Inc., Genfleet, Glycomimetics, Iterion, Janssen Research and Development: Research Funding; Janssen Research and Development: Research Funding; Jazz Pharmaceuticals, Pfizer, Pulmotect, Inc, Regeneron Pharmaceuticals, SELLAS Life Sciences Group: Research Funding; Biologix, Cure, Hikma Pharmaceuticals: Speakers Bureau; Genzyme: Honoraria; Astellas Pharma Global Development: Research Funding; Glycomimetics: Research Funding; Hikma Pharmaceuticals: Speakers Bureau; Iterion: Research Funding; Ascentage Pharma Group: Research Funding; Liberum: Consultancy; SELLAS Life Sciences Group: Research Funding; Cure: Speakers Bureau; Novartis: Consultancy; GenFleet Therapeutics: Research Funding; Genentech: Consultancy, Research Funding; Pulmotect, Inc.: Consultancy, Research Funding; Servier: Consultancy; Pinotb-Bio: Consultancy; BMS: Consultancy, Research Funding; Astex: Honoraria.
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