AUTHORS
Joshua F. Zeidner, MD, Rina Welkie, MPH2, Tara L. Lin, MD3, Emily Curran, MD4, Shivani Handa, MD5, Wendy Stock, MD6, Olatoyosi Odenike Jr, MD7, Yazan F. Madanat, MD8, Ronan Swords, MD9, Maria R. Baer, MD10, William Blum, MD11, Eytan M Stein I, MD12, Rebecca L Olin, MD13, Gary J. Schiller, MD14, Angela Nichols, NP15, Lacey Williams, MD16, Elie Traer, MD, PhD17, Curtis Lachowiez, MD18, Vu Duong, MD19, Michael Jamie Hochman, MD20, Sheng F. Cai, MD, PhD21, Catherine Smith, MD22, Mona Stefanos, MD, MBChB23, Molly Martycz24, Ying Huang, MA, MS25, Sonja Marcus, MPH26, Timothy Chen, PhD27, Ashley Yocum, PhD28, John Byrd, MD29, Brian Druker, MD30, Ross L. Levine, Prof. Dr.31, Uma Borate, MBBS, MSc32, Alice Scott Mims, MD33
AFFILIATIONS
1 University of North Carolina, Chapel Hill, North Carolina, United States
2 The Ohio State University, Columbus, Ohio, United States
3 University of Kansas Medical Center, Kansas City, Kansas, United States
4 University of Cincinnati, Cincinnati, Ohio, United States
5 The Ohio State University, Columbus, Ohio, United States
6 University of Chicago Comprehensive Cancer Center, Chicago, Illinois, United States
7 University of Chicago Comprehensive Cancer Center, Chicago, Illinois, United States
8 University of Texas Southwestern Medical Center, Dallas, Texas, United States
9 Oregon Health & Science University, Portland, Oregon, United States
10 University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, Maryland, United States
11 Winship Cancer Institute of Emory University, Atlanta, Georgia, United States
12 Memorial Sloan Kettering Cancer Center, New York City, New York, United States
13 University of California San Francisco, San Francisco, California, United States
14 David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California, United States
15 University of North Carolina, Chapel Hill, North Carolina, United States
16 University of North Carolina, Chapel Hill, North Carolina, United States
17 Oregon Health & Science University, Portland, Oregon, United States
18 Oregon Health & Science University, Portland, Oregon, United States
19 University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, Maryland, United States
20 Winship Cancer Institute of Emory University, Atlanta, Georgia, United States
21 Memorial Sloan Kettering Cancer Center, New York City, New York, United States
22 University of California San Francisco, San Francisco, California, United States
23 The Ohio State University, Columbus, Ohio, United States
24 The Ohio State University, Columbus, Ohio, United States
25 The Ohio State University, Columbus, Ohio, United States
26 Blood Cancer United, Washington, District of Columbia, United States
27 The Ohio State University, Columbus, Ohio, United States
28 Blood Cancer United, Washington, District of Columbia, United States
29 University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
30 Oregon Health & Science University, Portland, Oregon, United States
31 Memorial Sloan Kettering Cancer Center, New York City, New York, United States
32 The Ohio State University, Columbus, Ohio, United States
33 The Ohio State University, Columbus, Ohio, United States
ABSTRACT
Introduction: Despite the advancement of azacitidine and venetoclax (Aza/Ven) for newly diagnosed (ND) older/unfit AML patients (pts), overall outcomes remain poor. We previously reported the results of 43 ND NPM1m or KMT2Ar AML pts >60 years treated with Aza/Ven/revumenib (AVR) (Zeidner et al, J Clin Oncol 2025). Herein, we report the updated final analysis, including an expansion cohort of an additional 39 pts.
Methods: ND AML pts >60 years were screened and assigned if they had NPM1m (centrally confirmed) or KMT2Ar (local testing). Dose escalation (cohort 1) and expansion (cohort 2) were previously published. An expansion cohort (cohort 3) randomized pts to revumenib DL1 (220 mg PO BID days (D)1-28) or DL2 (270 mg PO BID D1-28) in combination with Aza 75 mg/m2 D1-7 and Ven 400 mg dose-adjusted D1-28. Strong CYP3A4 inhibitor azoles were not permitted in cycle (C) 1 in cohort 3. After a marrow remission was achieved, Ven was reduced to D1-14 each continuation phase C in cohort 3.
Results: A total of 82 pts (NPM1m: n=66; KMT2Ar: n=16) were enrolled (DL1: n=40; DL2: n=42). Median age was 71 years (range: 60-92) and 25 (31%) were >75 years. Based on ELN-2024 risk classification, 46 (56%), 35 (43%) and 1 (1%) had favorable-risk, intermediate-risk, and adverse-risk, respectively.
Non-hematologic Grade (G)>3 treatment-related adverse events were rare. Differentiation Syndrome occurred in 13 (16%) pts (G>3: 6%), was similar in KMT2Ar vs. NPM1m: (19% vs. 15%), and higher in DL1 vs. DL2 (23% vs. 10%). All-cause QTcF prolongation (QTP) occurred in 33 (42%) pts (G>3: 11%). Overall QTP was higher in DL2 vs. DL1 (50% vs. 30%) but G>3 QTP was similar between DL2 and DL1 (12% vs. 10%). Overall 30-D, 60-D and 100-D mortality rates were 6%, 7%, and 13%, respectively. Causes of 100-D mortality included sepsis/infection (n=4), unknown causes (n=2), AML (n=2), respiratory failure (n=1), stroke (n=1), and recurrent gastrointestinal bleed (n=1).
An intent-to-treat analysis revealed ORR, CRc, and CR rates of 90%, 85%, and 68% (DL1: 93%, 90%, and 68% vs. DL2: 88%, 81%, and 69%, respectively). ORR, CRc, and CR rates were 88%, 81%, and 75% in KMT2Ar and 91%, 86%, and 67% in NPM1m, respectively. Eight (10%) pts required 2 C’s of induction therapy. No pt had refractory disease; 8 (10%) were non-evaluable for response due to early death or withdrawal from study prior to disease assessment. Among ELN-2024 intermediate/adverse-risk pts, ORR, CRc and CR were 83%, 78% and 64%, respectively. In NPM1m pts, ORR, CRc, and CR were 95%, 89%, and 68% in ELN-2024 favorable-risk vs. 86%, 83%, and 66% in ELN-2024 intermediate-risk. Twenty-five (30%) pts proceeded to an allogeneic stem cell transplant (NPM1m: n=19; KMT2Ar: n=6).
Measurable residual disease (MRD) was assessed centrally by flow cytometry (Hematologics: sensitivity <0.02%) and NPM1m NGS-PCR (Invivoscribe). All evaluable pts (n= 71) achieved flow-MRD negative remission (95% flow MRD-negative after cycle 1). In evaluable patients with a sensitivity threshold of 0.01% by NPM1m NGS-PCR, 66% (23/35) and 88% (15/17) were MRD-negative after 2 and 6 cycles, respectively.
With a median follow up of 16.8 months (mos), median OS was 24.3 mos (KMT2Ar: 14.7 mos vs. NPM1m: not reached (NR); DL1: 19.5 mos vs. DL2: NR). Two-year OS was 39% and 59% in KMT2Ar and NPM1m, respectively. In NPM1m pts, 2-year OS was 67% vs. 51% in DL2 vs. DL1, respectively; median OS was NR and 19.5 mos in NPM1m ELN-2024 favorable-risk vs. intermediate-risk, respectively. Median EFS was 24.3 mos (KMT2Ar: 12.0 mos vs. NPM1m: NR; DL1: 19.5 mos vs. DL2: 24.3 mos). Median duration of ORR was 38.4 mos (KMT2Ar: 13.8 mos vs. NPM1m: NR).
Conclusion: Updated analyses continue to demonstrate promising clinical activity of Aza/Ven/Revumenib in ND older pts ineligible for intensive chemotherapy with NPM1m or KMT2Ar AML. Overall toxicity was similar between DL1 and DL2 while OS and EFS appeared improved with DL2. With longer follow-up data, NPM1m AML pts appear to have favorable long-term outcomes, particularly in DL2. Additionally, clinical outcomes were particularly encouraging in high-risk pt populations (ie, KMT2Ar and ELN-2024 intermediate-risk NPM1m pts) compared to historical controls. These findings support the ongoing randomized phase 3 study (EVOLVE-2; NCT06652438) of AVR vs. AV-Placebo in ND older NPM1m pts and the RAVEN (Revumenib/Aza/VEN) study (NCT07605949) in ND younger/fit KMT2Ar AML.
DISCLOSURES
Joshua F. Zeidner, MD: Sumitomo Dainippon Pharma - Research Funding; Novartis - Research Funding; Zentalis Pharmaceuticals - Research Funding; Akesobio - Research Funding; Ascentage - Research Funding; Shattuck Labs - Research Funding; Faron - Research Funding; SELLAS Life Sciences - Research Funding; Innocare - Research Funding; Lin Biosciences - Research Funding; Stemline - Research Funding; Arog Pharmaceuticals - Research Funding; Jazz Pharmaceuticals - Research Funding; Aptevo Therapeutics - Research Funding; Auron Therapeutics - Research Funding; AstraZeneca - Research Funding; Daiichi Sankyo - Research Funding; Geron - Consultancy (Includes expert testimony); Johnson & Johnson - Consultancy (Includes expert testimony); Ascentage - Consultancy (Includes expert testimony); AstraZeneca - Consultancy (Includes expert testimony); Shattuck Labs - Consultancy (Includes expert testimony); Servier - Consultancy (Includes expert testimony); NeoGenomics - Consultancy (Includes expert testimony); Sumitomo Dainippon Pharma - Consultancy (Includes expert testimony); Foghorn - Consultancy (Includes expert testimony); Halia Therapeutics - Consultancy (Includes expert testimony); Relmada Therapeutics - Consultancy (Includes expert testimony); SELLAS Life Sciences - Consultancy (Includes expert testimony); AbbVie - Consultancy (Includes expert testimony); Syndax - Consultancy (Includes expert testimony); Cullinan Therapeutics - Consultancy (Includes expert testimony); Ipsen - Consultancy (Includes expert testimony); Daiichi Sankyo - Consultancy (Includes expert testimony); Genentech - Consultancy (Includes expert testimony); Crossbow Therapeutics - Consultancy (Includes expert testimony); Novartis - Consultancy (Includes expert testimony); Kura Oncology - Consultancy (Includes expert testimony); Aveo Pharmaceuticals - Consultancy (Includes expert testimony); Jazz Pharmaceuticals - Consultancy (Includes expert testimony); Genmab - Consultancy (Includes expert testimony); Astellas - Consultancy (Includes expert testimony); Rigel - Consultancy (Includes expert testimony)