Venetoclax with azacitidine is the standard of care for patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy; however, uncertainties remain regarding the treatment schedule, accurate prognostication, and outcomes for patients treated outside clinical trials. The option of venetoclax with low-dose cytarabine (LDAC) is also available; however, it is not clear for which patients it may be a useful alternative. Here, we report a large real-world cohort of 654 patients treated in 53 UK hospitals with either venetoclax and azacitidine (n = 587) or LDAC (n = 67). The median age was 73 years, and 59% had de novo AML. Most patients received 100 mg of venetoclax with an azole antifungal. In cycle 1, patients spent a median of 14 days in the hospital, and 85% required red cell transfusion, 59% platelet transfusion, and 63% required IV antibiotics. Supportive care requirements significantly reduced after the first cycle. Patients receiving venetoclax-azacitidine had a complete remission (CR)/CR with incomplete hematological recovery rate of 67%, day 30 and day 60 mortality of 5% and 8%, respectively, and median overall survival of 13.6 months. Mutations in NPM1, RUNX1, STAG2, and IDH2 were associated with improved survival, whereas age, secondary and therapy-related AML, +8, MECOM rearrangements, complex karyotype, ASXL1, and KIT mutations were associated with poorer survival. Prognostic systems derived specifically for patients treated with venetoclax-azacitidine performed better than the European LeukemiaNet and Medical Research Council classifications; however, improved risk classifications are still required. In the 149 patients with NPM1 mutated AML, outcomes were similar for those treated with venetoclax-azacitidine and venetoclax-LDAC.

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