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2853 Clinical Outcomes Associated with NPM1 Mutations in Newly Diagnosed AML

Program: Oral and Poster Abstracts
Session: 615. Acute Myeloid Leukemias: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Acute Myeloid Malignancies, AML, Diseases, Myeloid Malignancies
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Aziz Farhat1*, Hagop M. Kantarjian, MD2, Koji Sasaki, MD2, Nicholas J. Short, MD2, Branko Cuglievan, MD3, Sanam Loghavi, MD4, Keyur P. Patel, MBBS, PhD4, Alex Bataller, MD, PhD2*, Musa Yilmaz, MD2*, Guillermo Montalban-Bravo, MD2, Danielle Hammond, MD2, Naveen Pemmaraju, MD2, Naval Daver, MD5, Farhad Ravandi, MBBS6, Elias Jabbour, MD7, Tapan M. Kadia, MD2, Gautam Borthakur, MD8, Guillermo Garcia-Manero, MD2, Courtney D. DiNardo, MD, MSc9 and Ghayas C. Issa, MD2

1The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
3Division of Pediatrics, MD Anderson Cancer Center, Houston, TX
4Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
5MD Anderson Cancer Center, Houston, TX
6Department of Leukemia, University of Texas- MD Anderson Cancer Center, Houston, TX
7Department of Leukemia, University of Texas M.D. Anderson Cancer Ctr., Houston, TX
8Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
9Department of Leukemia, UT MD Anderson Cancer Center, Houston, TX

Background: Mutations of the Nucleophosmin 1 gene (NPM1mt) form the most common alteration in acute myeloid leukemia (AML) detected in 20-30% of cases. Despite the relatively favorable prognosis associated with NPM1mt, long-term outcomes remain suboptimal. Predictors of outcomes have not been fully elucidated. With the advent of menin inhibitors as a targeted therapy for NPM1mt AML, upcoming combination studies with these agents are intended; however expected outcomes with current therapies are largely unknown. Therefore, we conducted a retrospective analysis to delineate predictors of outcomes in patients (pts) with NPM1mt AML.

Methods: We screened adult pts treated at our center for newly diagnosed AML between January 2012 and December 2023. We identified 396 pts (18%) with NPM1mt and 1819 pts (82%) with NPM1wt. The composite complete remission or complete remission with incomplete hematologic recovery (CRc) was identified by subgroup, and MRD was assessed by flow cytometry (sensitivity: 10-4). Event-free survival (EFS) was defined as the duration from the initiation of treatment until the earliest occurrence of disease relapse, disease progression, death from any cause, or failure of achieving a response (FDA Definition, i.e. event at day 0), with overall survival (OS) defined as the duration from therapy start to death or last follow-up. Predictors of survival were identified using Cox regression where factors with P<0.1 on univariate analysis were selected for multivariate analysis (MVA).

Results: Compared with NPM1wt AML, pts with NPM1mt were more commonly female (56% vs 43%; P<0.001) and had significantly higher bone marrow blasts at diagnosis (P<0.001). Those with NPM1mt more commonly had a monocytic phenotype (27% vs 9%, P<0.001), a diploid karyotype (75% vs 24%, P<0.001), and myelofibrosis (MF-1 or higher) (30% vs 23%, P=0.008). Extramedullary disease (EMD) had similar incidence in both groups (3.5% vs 2.4%; P=0.2). Most common co-occurring mutations included DNMT3A (47% vs 18%, P<0.001), FLT3-ITD (42% vs 13%, P<0.001), KRAS/NRAS (29% vs 25%, P=0.2), SRSF2 (23% vs 28%, P=0.4) and TET2 (22% vs 14%, P<0.001). Therapy-related AML was 9% of NPM1mt vs 19% of NPM1wt AML (P<0.001). There were 16 pts (4%) with NPM1mt and an adverse karyotype; 44 pts (11%) had NPM1mt and co-occurring adverse risk mutations.

High intensity chemotherapy (HIC) was given for 190 NPM1mt pts (48%), of which 46 pts (12%) had the addition of venetoclax (HIC+Ven), whereas 66 pts (17%) received a hypomethylating agent + Ven (HMA+Ven), 32 pts (8%) received cladribine with low-dose cytarabine + Ven (Clad LDAC Ven) and 106 pts (27%) received other lower-intensity treatments.

The CRc rate for those with NPM1mt who received HIC without ven was 94% vs 96% for HIC+Ven, with MRD-neg rates of 86% and 82% respectively. Those with NPM1mt who received HMA+Ven had a CRc rate of 86%, whereas Clad LDAC Ven led to a 94% rate (MRD neg of 96% and 97% respectively).

With a median follow-up of 52.6 months, NPM1mt pts treated with HIC had a median EFS and OS of 87.8 and 87.8 months with 2-year rates of 63% and 65%, respectively. NPM1mt pts treated with Clad LDA Ven had a median EFS and OS of 59.6 and 59.6 months with 2-year rates of 73% and 76% respectively. HMA+ven in NPM1mt (all of whom were >60 years) led to a median EFS and OS of 15.4 and 23.6 months, with 2-year rates of 48% and 51% respectively. In those with NPM1mt and age>75 years, the median EFS and OS were 10.3 months and 10.9 months, with 2-year rates of 32% and 32% respectively.

Among pts with NPM1mt who received HIC, predictors of worse EFS and OS in MVA included age [Hazard ratio (HR) for OS: 1.03; P=0.009], FLT3-ITD (HR for OS: 1.92; P=0.014), EMD (HR for OS: 6.03; P=0.001), and a performance status > 2 (HR for OS: 8.01; P=0.001). The addition of venetoclax to HIC did not independently predict for outcomes. Among pts with NPM1mt who received HMA+Ven, the only predictor of worse EFS and OS was age (HR for OS: 1.10; P=0.016). Notably, therapy-related status or adverse risk features by ELN did not predict outcomes.

Conclusion: In conclusion, older age, worse performance status, FLT3-ITD co-mutation, and EMD predicted for worse outcomes in NPM1mt AML treated with HIC whereas older age was the only predictor of outcomes in those receiving HMA + venetoclax.

Disclosures: Kantarjian: AbbVie, Amgen, Ascentage, Ipsen Biopharmaceuticals, KAHR Medical, Novartis, Pfizer, Shenzhen Target Rx, Stemline,Takeda: Consultancy, Honoraria. Sasaki: Daiichi-Sankyo: Consultancy; Enliven: Research Funding; Otsuka: Other: Lecture fees; Chugai: Other: Lecture fees; Novartis: Consultancy, Research Funding; Pfizer: Consultancy. Short: Novartis: Honoraria; Takeda Oncology: Honoraria, Research Funding; BeiGene: Honoraria; Sanofi: Honoraria; Autolus: Honoraria; GSK: Consultancy, Research Funding; Amgen: Honoraria; Pfizer Inc.: Honoraria; NextCure: Research Funding; Adaptive Biotechnologies: Honoraria; Stemline Therapeutics: Research Funding; Xencor: Research Funding; Astellas Pharma, Inc.: Honoraria, Research Funding. Cuglievan: Kura Oncology: Research Funding; Syndax Pharmaceuticals, Inc.: Other: travel, accommodations, Research Funding; LLS: Research Funding; Octapharma: Other: travel, accommodations, research. Loghavi: Pathology Education Partners; VJ HemeOnc, College of American Pathologists, OncLive, ICCS, MD Education, NCCN, MashUp Media, NCTN, Aptitude Health: Honoraria; Guidepoint; QualWorld; Gerson Lehrman Group, AlphaSight, Arima, Qiagen, Opinion Health: Consultancy; Astellas, Amgen: Research Funding; Abbvie: Current holder of stock options in a privately-held company; Syndx, Servier, BMS: Membership on an entity's Board of Directors or advisory committees; Abbvie, Daiichi Sankyo, BluePrint Medicine, Caris Diagnostics, Recordati, Servier: Consultancy. Yilmaz: daiichi sankyo: Honoraria, Research Funding. Montalban-Bravo: Rigel: Research Funding; Takeda: Research Funding. Pemmaraju: Protagonist Therapeutics: Consultancy; Celgene: Honoraria, Other: Travel Expenses; Cellectis: Research Funding; Incyte: Honoraria; CTI BioPharma: Consultancy; Pacylex: Consultancy; Bristol-Myers Squibb: Consultancy; Aptitude Health: Honoraria; Roche Molecular Diagnostics: Honoraria; Novartis: Honoraria, Research Funding; Immunogen: Consultancy; LFB Biotechnologies: Honoraria; CareDx: Honoraria; Mustang Bio: Honoraria, Other: Travel Expenses, Research Funding; Springer Science + Business Media: Honoraria; Neopharm: Honoraria; ClearView Healthcare Partners: Consultancy; Stemline Therapeutics: Honoraria, Other: Travel Expenses, Research Funding; DAVA Oncology: Honoraria, Other: Travel Expenses; Affymetrix/Thermo Fisher Scientific: Research Funding; Blueprint Medicines: Consultancy, Honoraria; Triptych Health Partners: Consultancy; Daiichi Sankyo: Research Funding; Plexxikon: Research Funding; Samus Therapeutics: Research Funding; Blueprint Medicines OncLive PeerView Institute for Medical Education: Consultancy, Other: advisory board; Astellas: Consultancy; AbbVie: Honoraria, Other: Travel Expenses, Research Funding; ASH Committee on Communications ASCO Cancer.NET Editorial Board: Other: Leadership; Karger Publishers: Other: Licenses; National Institute of Health/National Cancer Institute (NIH/NCI): Research Funding; HemOnc Times/Oncology Times: Other: uncompensated. Daver: Novimmune: Research Funding; Arog: Consultancy; Celgene: Consultancy; Servier: Consultancy, Research Funding; Agios: Consultancy; FATE Therapeutics: Other: Consulting Fees, Research Funding; Trillium: Consultancy, Research Funding; Trovagene: Research Funding; Menarini Group: Consultancy; Shattuck Labs: Consultancy; Gilead: Consultancy, Research Funding; Jazz: Consultancy; Hanmi: Research Funding; KITE: Research Funding; Novartis: Consultancy; Syndax: Consultancy; Astellas: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Glycomimetics: Research Funding. Ravandi: Abbvie: Consultancy, Honoraria; Xencor: Research Funding; Amgen: Research Funding; Syros: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Prelude: Consultancy, Honoraria, Research Funding; Syndax: Honoraria; BMS: Consultancy, Honoraria; Astyex/Taiho: Research Funding. Jabbour: AbbVie, Adaptive Biotechnologies, Amgen, Astellas Pharma, BMS, Genentech, Incyte, Pfizer, Takeda: Consultancy; AbbVie, Adaptive Biotechnologies, Amgen, Ascentage Pharma Group, Pfizer, Takeda: Research Funding. Kadia: Sellas: Consultancy, Research Funding; Amgen: Research Funding; Incyte: Research Funding; ASTEX: Research Funding; Ascentage: Research Funding; DrenBio: Consultancy, Research Funding; Pfizer: Research Funding; Novartis: Honoraria; Abbvie: Consultancy, Research Funding; Rigel: Honoraria; BMS: Consultancy, Research Funding; Regeneron: Research Funding; AstraZeneca: Research Funding; Genentech: Consultancy, Research Funding; JAZZ: Research Funding; Servier: Consultancy; Cellenkos: Research Funding. Borthakur: Catamaran Bio, AbbVie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding; Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees. Garcia-Manero: Bristol Myers Squibb: Other: Personal fees, Research Funding; Curis: Research Funding; Forty Seven: Research Funding; Merck: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Astex: Research Funding; Onconova: Research Funding; AbbVie: Research Funding; Helsinn: Research Funding; Novartis: Research Funding; H3 Biomedicine: Research Funding; Aprea: Research Funding; Astex: Other: Personal fees; Helsinn: Other: Personal fees; Genentech: Other: Personal fees; Amphivena: Research Funding. DiNardo: Loxo: Research Funding; BMS: Consultancy, Honoraria, Research Funding; AstraZeneca: Honoraria; Astex: Research Funding; GSK: Consultancy, Honoraria; GenMab: Consultancy, Honoraria, Other: data safety board; Riegel: Honoraria; Immunogen: Honoraria; Rigel: Research Funding; Amgen: Consultancy; Astellas: Consultancy, Honoraria; Gilead: Consultancy; Genetech: Honoraria; Servier: Consultancy, Honoraria, Other: meetingsupport, Research Funding; Notable Labs: Honoraria; Foghorn: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; ImmuneOnc: Research Funding; Schrodinger: Consultancy, Honoraria; Cleave: Research Funding; Jazz: Consultancy, Honoraria; Stemline: Consultancy. Issa: Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; Syndax Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; NuProbe: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Astex: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; Merck: Research Funding; Celgene: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Kura Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding.

*signifies non-member of ASH