Venetoclax Combined with Hypomethylating Agents in Newly Diagnosed Elderly AML: A Systematic Review

Abstract

Introduction: Acute myeloid leukemia (AML) in older adults poses therapeutic challenge due to poor tolerance of intensive chemotherapy. Venetoclax, a BCL-2 inhibitor, plus azacitidine or decitabine has emerged as standard-of-care. This review evaluates long-term survival and resistance mechanisms.
Methods: Systematic review of Phase II/III trials and large real-world series (≥50 patients, age ≥60 years, unfit for intensive chemo). Search: ClinicalTrials.gov, PubMed (2018–2024). Primary endpoint: 2-year overall survival (OS). Secondary: composite complete remission (CRc) and minimal residual disease (MRD) negativity.
Results: Twelve studies (n=3,045) included. Pooled CRc 67% (95% CI 62–72). Median OS 14.7 months (range 10.8–18.9). Two-year OS 32%. MRD negativity (flow cytometry) achieved in 42% of responders and predicted longer OS (HR 0.44, p<0.001). Mutational analysis: IDH1/2 and NPM1 mutations conferred best response (CRc >85%); TP53-mutated AML had poor response (CRc 21%).
Discussion: Venetoclax-azacitidine is effective, but resistance emerges via BCL2 mutations or alternative anti-apoptotic proteins (MCL1, BCL-xL). TP53-mutant AML remains a therapeutic gap. Notable limitations: heterogeneity in MRD assessments and response criteria.
Conclusions: Venetoclax combinations improve survival in elderly AML, but outcomes vary by mutation profile. MRD-guided strategies should be investigated.