LeukemiaJournal Article
09 May 2025
Acute myeloid leukemia (AML) with KMT2A rearrangement (KMT2Ar) has poor outcomes. We analyzed 1,611 patients with AML and 4. 3% demonstrated rearrangements in KMT2A. Signaling-related genes (NRAS 30%, KRAS 23% and FLT3-TKD 16%) were the most frequently mutated in patients with KMT2Ar AML.
Patients treated with intensive chemotherapy (IT) achieved a complete remission (CR)/CR with incomplete blood count recovery (CRi) rate of 81%, and when combined with venetoclax, the CR/CRi rate increased to 100%.
Patients treated with low intensity treatment (LIT) achieved an CR/CRi rate of 33%, and when combined with venetoclax, the CR/CRi rate was 61%.
For patients treated with IT, the 5-year overall survival (OS) and event-free survival (EFS) rates were 66% and 64%, respectively, compared with 7% in those treated with LIT. Thirty-nine patients (57%) underwent allogeneic stem cell transplantation after achieving CR/CRi.
For patients treated with LIT, multivariate analysis demonstrated that N/KRAS mutations were predictive for OS (HR 2. 93, 95% CI 1. 18-7. 29, P = 0. 021) and EFS (HR 3. 51, 95% CI 1. 35-9. 24, P = 0. 01).
In summary, outcomes in KMT2Ar AML have improved over years in patients treated with IT, whereas those treated with LIT continue to show poor survival, highlighting the need for novel combinations.
Competing interests: Ghayas C. Issa reports consulting or advisory role for Novartis, Kura Oncology, Syndax, NuProbe, AbbVie and Sanofi, and research funding from Novartis, Syndax, Kura Oncology, Merck, Cullinan Oncology, Astex Pharmaceuticals and NuProbe. Courtney D. DiNardo has been a board of directors or advisory committee member for Genmab, GSK, Kura Oncology, and Notable Labs; has received honoraria from Kura, Astellas Pharma, Bluebird Bio, Bristol-Myers Squibb, Foghorn Therapeutics, Immune-Onc Therapeutics, Novartis, Takeda Oncology, Gilead Sciences, and Jazz Pharmaceuticals; is a current holder of stock options for Notable Labs; has been a consultant for AbbVie and Servier; and has received research funding from Servier, Bristol-Myers Squibb, Foghorn, Immune-Onc Therapeutics, Loxo Oncology, Astex Pharmaceuticals, Cleave, and Forma. Naval G. Daver has received research funding from Astellas Pharma, AbbVie, Genentech, Daiichi Sankyo, Gilead Sciences, ImmunoGen, Pfizer, Bristol Myers Squibb, Trovagene, Servier, Novimmune, Incyte, Hanmi Pharm, Fate Therapeutics, Amgen, Kite Pharma, Novartis, Astex Pharmaceuticals, KAHR, Shattuck, Sobi, GlycoMimetics, and Trillium; has been an advisor for Astellas Pharma, AbbVie, Genentech, Daiichi Sankyo, Novartis, Jazz Pharmaceuticals, Amgen, Servier, Karyopharm Therapeutics, Trovagene, Trillium, Syndax, Gilead Sciences, Pfizer, Bristol Myers Squibb, Kite Pharma, Actinium Pharmaceuticals, Arog Pharmaceuticals, ImmunoGen, Arcellx, and Shattuck; has been a data monitoring committee member for Kartos Therapeutics and Jazz Pharmaceuticals; has been a consultant or board of directors or advisory committee member for Agios, Celgene, Sobi, and STAR Therapeutics; and has received research funding from Karyopham Therapeutics and Newave Pharmaceutical. Tapan M. Kadia has been a consultant for AbbVie, Agios, BMS, Genentech, Jazz Pharmaceuticals, Novartis, Servier, and PinotBio; has received research funding from AbbVie, BMS, Genentech, Jazz Pharmaceuticals, Pfizer, Cellenkos, Ascentage Pharma, GenFleet Therapeutics, Astellas Pharma, AstraZeneca, Amgen, Cyclacel Pharmaceuticals, Delta-Fly Pharma, Iterion Therapeutics, GlycoMimetics, and Regeneron Pharmaceuticals; and has received honoraria from Astex Pharmaceuticals. Gautam Borthakur has received research funding from Astex Pharmaceuticals, Ryvu Therapeutics, and PTC Therapeutics; has been a board of directors or advisory committee member for Pacyclex Pharmaceuticals, Novartis, CytomX, and Bio Ascend; and has been a consultant for Catamaran Bio, AbbVie, PPD Development, Protagonist Therapeutics, and Janssen. Koji Sasaki reports fees for professional activities from Amgen, Chugai Pharmaceutical, Daiichi Sankyo Company, Novartis, Otsuka Pharmaceutical Co., Ltd., and Pfizer. Kelly Chien declares honoraria from Otsuka Pharma, and consultancy fee from Pfizer Japan. Nicholas J. Short has been a consultant for Takeda Oncology, AstraZeneca, Amgen, Novartis, and Pfizer and received research funding from Takeda Oncology, Astellas, and Stemline Therapeutics as well as honoraria from Amgen. Musa Yilmaz has received research funding from Daiichi-Sankyo and Pfizer. Guillermo Garcia-Manero has received research funding from Astex Pharmaceuticals, Novartis, AbbVie, BMS, Genentech, Aprea Therapeutics, Curis, and Gilead Sciences; has been a consultant for Astex Pharmaceuticals, Acceleron Pharma, and BMS; and has received honoraria from Astex Pharmaceuticals, Acceleron Pharma, AbbVie, Novartis, Gilead Sciences, Curis, Genentech, and BMS. Farhad Ravandi has received research funding from Amgen, Astex Pharmaceuticals/Taiho Oncology, BMS/Celgene, Syos, AbbVie, Prelude, Xencor, Astellas Pharma, and Biomea Fusion as well as honoraria from Amgen, BMS/Celgene, Syos, AbbVie, and Astellas Pharma; has been a board of directors or advisory committee member for Astex Pharmaceuticals/Taiho Oncology; and has been a consultant forBMS/Celgene, Syos, Novartis, AbbVie, AstraZeneca, and Astellas Pharma. Hagop M. Kantarjian has received research funding from AbbVie, Amgen, Ascentage Pharma, BMS, Daiichi Sankyo, ImmunoGen, Jazz Pharmaceuticals, and Novartis as well as honoraria from AbbVie, Amgen, Amphista Therapeutics, Ascentage Pharma, Astellas Pharma, Biologix, Curis, Ipsen, KAHR, Novartis, Pfizer, Precision Biosciences, Shenzhen TargetRx, and Takeda Oncology. Elias Jabbour has been a consultant for AbbVie, Adaptive Biotechnologies, Amgen, Bristol-Myers Squibb, Novartis, Pfizer Canada Inc, and Takeda Onc.
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