Introduction: Cytogenetic and molecular aberrations are common at diagnosis in patients with acute myeloid leukemia (AML) and may have significant prognostic impact. Relapse after prior response is associated with a poor outcome. The dynamics of cytogenetic and molecular abnormalities at relapse and their impact on outcome is less well studied.
Methods: This is a retrospective single center study including patients with AML diagnosed from April 2017 to October 2022 who relapsed after achieving a prior response. Mutations were detected using a targeted 81-gene NGS panel and cytogenetics were assessed using conventional karyotyping and FISH testing. To assess disappearance, maintenance or appearance of cytogenetic and molecular aberrations, they were evaluated at diagnosis and relapse and differences in incidence were evaluated with the Chi-square and Fisher test.
Results: The cohort includes164 patients who had relapsed after achieving remission. The median age at diagnosis and relapse was 67 years (range, 20-94) and 68 years (range, 21-95). 53% were male. Patients received intensive treatment (IT; 40% of patients, 41% of whom with the addition of venetoclax) or low intensity therapy (LIT; 60% of patients, 72% with venetoclax). The median time from diagnosis to relapse was 8.9 months (range, 2.2-52). According to the ELN 2022 risk classification, 15%, 15% and 70% had favorable, intermediate and adverse risk, respectively.
At diagnosis, the most frequent mutations were DNMT3A (32%), TP53 (31%), RUNX1 (19%), TET2 (18%), SRSF2 (17%) and NPM1 (17%). At relapse, the most frequent mutations were DNMT3A (35%), TP53 (35%), TET2 (24%), RUNX1 (20%) and SRSF2 (17%). The median number of mutations per patient at diagnosis and relapse was 3 (0-12) and 3 (0-14), respectively (p=0.07). Most frequent karyotypes at diagnosis were diploid (34%), complex (32%), chromosome 5 abnormalities (29%) and chromosome 7 abnormalities (26%). At relapse, the most frequent karyotypes included complex (36%), chromosome 7 abnormalities (31%), chromosome 5 abnormalities (30%) and diploid karyotype (27%).
When analyzing each mutation individually, the rate of mutation clearance from diagnosis to relapse was higher for FLT3-ITD (58%, p=0.01), FLT3-TKD (83%, p<0.001), KIT (88%, p=0.003), NF1 (71%, p=0.004) and WT1 mutations (71%, p=0.004), compared to other remaining mutations (32%). Conversely, ASXL1 (95%, p=0.01), DNMT3A (84%, p=0.006), SRSF2 (89%, p=0.01), TET2 (84%, p=0.02) and TP53 mutations (86%, p=0.002) persisted more frequently at relapse compared to other mutations (66%). At relapse, WT1 mutations were more frequently acquired (77%, p=0.001), compared to other mutations (36%). Diploid karyotype changed more frequently than other cytogenetic abnormalities (33% vs 5%, p <0.001), whereas complex karyotype persisted at relapse (98% vs 87%, p=0.04) more frequently. Chromosome 7 abnormalities were more frequently acquired at relapse (23%), compared to other cytogenetic abnormalities acquired at relapse (11%, p=0.04).
We then compared mutational dynamics from diagnosis to relapse between patients receiving IT and LIT. NRAS mutations disappeared more frequently from diagnosis to relapse in patients treated with IT (73%), compared with patients treated with LIT (27%, p=0.01) whereas TP53 mutations were acquired more frequently in IT treated patients (67% vs 10%). Patients treated with IT acquired chromosome 7 abnormalities more frequently than patient treated with LIT (60% vs 14%, p=0.007). No significant differences were found regarding disappearance, maintenance or appearance of mutations when comparing patients treated with or without Venetoclax.
Conclusion: The number of mutations does not vary significantly from diagnosis to relapse, and most mutations persist, suggesting maintenance of leukemic clones as the cause of relapse. Overall, genes involved in signaling pathways tend to disappear more frequently at relapse whereas chromatin and histone modifiers as well as TP53 mutations tend to persist. NRAS mutations disappear more frequently at relapse with IT, whereas TP53 mutations are acquired more frequently.
Disclosures
Kantarjian:Ipsen: Honoraria; Immunogen (Inst): Honoraria, Research Funding; Daiichih-Sankyo (Inst): Honoraria, Research Funding; AstraZeneca/MedImmune: Honoraria; Ascentage Pharma Group: Honoraria; Abbvie: Consultancy, Honoraria; Astellas Pharma: Honoraria; Jazz Pharmaceuticals (Inst): Honoraria, Research Funding; KAHR Medical: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Precision Biosciences: Honoraria; Shenzhen Target Rx: Honoraria; Taiho Pharmaceutical: Honoraria; Abbvie (Inst): Research Funding; Amgen (Inst): Research Funding; Ascentage Pharma (Inst): Research Funding; Bristol-Myers Squibb (Inst): Research Funding; Novartis (Inst): Research Funding; Amgen: Honoraria. Kadia:Agios: Consultancy; GenFleet Therapeutics: Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Research Funding; Celgene: Research Funding; Ascentage Pharma Group: Research Funding; Astellas Pharma Global Development: Research Funding; Daiichi Sankyo, Genentech, Inc., Genzyme, Jazz Pharmaceuticals, Liberum, Novartis, Pfizer, PinotBio, Inc, Pulmotect, Inc, Sanofi-Aventis, Servier: Consultancy; Liberum: Consultancy; Amgen, Inc.: Research Funding; Pulmotect, Inc.: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cure: Speakers Bureau; Jazz Pharmaceuticals, Pfizer, Pulmotect, Inc, Regeneron Pharmaceuticals, SELLAS Life Sciences Group: Research Funding; Cellenkos Inc.: Research Funding; Novartis: Consultancy; Regeneron Pharmaceuticals: Research Funding; Genzyme: Honoraria; 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; Cyclacel: Research Funding; Delta-Fly Pharma, Inc.: Research Funding; Sanofi-Aventis: Consultancy; Biologix, Cure, Hikma Pharmaceuticals: Speakers Bureau; Janssen Research and Development: Research Funding; Glycomimetics: Research Funding; Hikma Pharmaceuticals: Speakers Bureau; Iterion: Research Funding; SELLAS Life Sciences Group: Research Funding; Servier: Consultancy; Pinotb-Bio: Consultancy; BMS: Consultancy, Research Funding; Astex: Honoraria. Daver:Novimmune: Research Funding; Gilead: Consultancy, Research Funding; Glycomimetics: Research Funding; Astellas: Consultancy, Research Funding; Shattuck Labs: Consultancy; Novartis: Consultancy; Hanmi: Research Funding; AbbVie: Consultancy, Research Funding; Celgene: Consultancy; Jazz: Consultancy; AROG: Consultancy; Trovagene: Research Funding; Trillium: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Agios: Consultancy; Genentech: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Servier: Consultancy, Research Funding; FATE: Research Funding; ImmunoGen: Consultancy, Research Funding; Syndax: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Kite, a Gilead company: Consultancy, Research Funding; Kronos Bio: Research Funding. DiNardo:AbbVie/Genentech: Honoraria; Takeda: Honoraria; Notable Labs: Honoraria; Servier: Honoraria; Novartis: Honoraria; ImmuniOnc: Honoraria; Fogham: Honoraria; Astellas: Honoraria; BMS: Honoraria; Schrödinger: Consultancy. Borthakur:Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding; 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. Short:Amgen: Honoraria; Stemline therapeutics: Research Funding; AstraZeneca: Consultancy; Takeda: Consultancy, Research Funding; Astellas: Research Funding; Novartis: Consultancy; Pfizer: Consultancy. Yilmaz:Pfizer: Research Funding; Daiichi-Sankyo: Research Funding. Issa:Novartis: Consultancy, Research Funding; Syndax: Research Funding; Celgene: Research Funding; Kura Oncology: Consultancy, Research Funding; NuProbe: Consultancy; Merck: Research Funding. Alvarado Valero:Daiichi-Sankyo: Research Funding; CytomX Therapeutics: Consultancy; BerGenBio: Research Funding; Astex: Research Funding; FibroGen: Research Funding; Jazz: Research Funding; Sun Pharma: Consultancy, Research Funding; MEI Pharma: Research Funding. Montalban-Bravo:Takeda: Research Funding; Rigel: Research Funding. Maiti:Lin BioScience: Research Funding; Celgene: Research Funding. Jabbour:Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Ascentage Pharma Group: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Hikma Pharmaceuticals: Consultancy, Honoraria, Research Funding. Wierda:Loxo Oncology, Inc./Lilly: Research Funding; GlaxoSmithKline: Research Funding; Janssens Biotech Inc: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Juno Therapeutics: Research Funding; Numab THerapeutics: Research Funding; Miragen: Research Funding; Janssens Biotech: Research Funding; Nurix THerapeutics: Research Funding; Accutar Biotechnology: Research Funding; NIH P30 CA016672/MDACC Cancer Center Support Grant: Research Funding; AbbVie: Consultancy, Research Funding; GSK/Novartis: Research Funding; Cyclacel: Consultancy, Research Funding; Bristol Myers Squibb (Juno & Celgene): Consultancy, Research Funding; Gilead Sciences: Research Funding; AstraZeneca/Acerta Pharma: Consultancy, Research Funding; Pharmacyclics LLC: Research Funding; Sunesis: Research Funding; KITE Pharma: Research Funding; Genentech: Research Funding; 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. 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; Amgen: Honoraria, Research Funding; Biomea fusion: Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Syros: Consultancy, Honoraria, Research Funding; Xencor: Research Funding; Astex/taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Research Funding.
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