Venetoclax and Azacitidine Combination Therapy in Unfit Patients with Newly Diagnosed Acute Myeloid Leukemia

Abstract

Adding venetoclax to azacitidine produced the first meaningful survival gain for patients unfit for intensive chemotherapy, and the regimen became standard within two years. Practice has since diverged from the trial protocol, and the modifications appear to work.
Objectives: To review the published evidence on venetoclax combined with azacitidine in newly diagnosed acute myeloid leukaemia in patients unfit for intensive therapy: what the pivotal trial demonstrated, what the toxicity costs, how outcomes compare in routine care, and what the modifications adopted in practice have achieved. Material and Methods: Narrative review of randomised trials, prospective real-world cohorts, retrospective series and consensus recommendations indexed in PubMed and the major haematology journals. Studies were eligible if they reported efficacy, toxicity or outcome of venetoclax-based combination therapy in a defined newly diagnosed acute myeloid leukaemia population unfit for intensive chemotherapy. No new patient data were generated and no patients were recruited; every estimate quoted is one published by the original investigators. Results: In the pivotal randomised trial, median overall survival was 14.7 months with the combination against 9.6 months with azacitidine alone (HR 0.66, 95% CI 0.52-0.85, p < 0.001), composite complete remission 66.4 against 28.3 per cent and complete remission 36.7 against 17.9 per cent. Grade 3 or higher febrile
neutropenia occurred in 42 against 19 per cent, neutropenia in 42 against 29 and thrombocytopenia in 45 against 38 per cent. In a prospective real-world cohort, median survival was 13.0 months (95% CI 11.4-15.7) and matched comparison against the trial population gave 14.8 against 14.9 months (p = 0.6), with 30-day mortality of 2.6 per cent against 7 per cent in the trial. Survival differed by genetic risk group at 24.5, 15.4 and 8.9 months. Shortening venetoclax from 28 days produced comparable remission rates with less febrile neutropenia in several series. Conclusion: The survival benefit is established and the regimen is appropriately standard. Its dominant toxicity is myelosuppression, and routine practice has converged on shortening venetoclax exposure faster than trials have tested it, with early outcomes suggesting the modification is sound. Abbreviations: AML – Acute Myeloid Leukaemia, ND – Newly Diagnosed, VEN – Venetoclax, AZA – Azacitidine, HMA – Hypomethylating Agent, LDAC – Low-Dose Cytarabine, CR – Complete Remission, CRi – Complete Remission with Incomplete Haematological Recovery, CRc – Composite Complete Remission, OS – Overall Survival, ELN – European LeukemiaNet, G-CSF – Granulocyte Colony-Stimulating Factor, HR – Hazard Ratio.