BACKGROUND: The combination of venetoclax + azacitidine (VenAza) has become the standard frontline treatment for older unfit AML patients. METHODS: We analyzed outcomes using VenAza for previously untreated unfit AML patients at a single center between 2020-2024. RESULTS: The overall response rate (ORR) was 69/105 (66%), was highest for patients with NPM1 (78%) and IDH1/2 (82%) mutations and lowest with TP53 mutations (40%). The median overall survival (OS) was 9.6 months, and 16.3 months for those achieving CR/CRi. There was no significant difference in OS between those achieving CR and CRi (p = 0.077). Patients treated between 2022-24 had a lower early death rate (8% vs. 22%) and better OS (median 10.4 vs 5.8 mos, p = 0.033) than those treated between 2020-21. There was no difference in OS between by age grouping or for patients with prior hypomethylating agent exposure. Patients with FLT3-ITD/RAS or TP53 mutations had an inferior OS compared with the other patients (median OS 8.1, 1.7 and 16 months, respectively). On multivariate analysis, achievement of CR/CRi was associated with better OS (p <
0.002), and FLT3-ITS/RAS/TP53 mutations were associated with inferior OS (p = 0.003), while ELN2022 risk group was not associated with OS. The median DFS for patients achieving CR/CRi was 7.1, 4.9 and 21 mos, for those with FLT3-ITD/RAS, TP53 and others, respectively (p = 0.003). CONCLUSIONS: This real-world analysis confirmed the prognostic importance of the mutational risk classification with VenAza treatment. OS was inferior to that reported in the VIALE A study but did improve over time.