Harnessing Venetoclax in NPM1-Mutated AML: A Path to Sustained Remission and Beyond

Acute myeloid leukemia (AML) harboring NPM1 mutations constitutes a biologically and clinically distinct subtype, characterized by marked sensitivity to inhibition of the anti-apoptotic protein BCL-2. The introduction of venetoclax, a selective BCL-2 inhibitor, in combination with hypomethylating agents (HMAs), has reshaped the therapeutic paradigm, particularly for patients deemed unfit for intensive chemotherapy.

This review comprehensively analyzes the available scientific evidence-including prospective clinical trials, retrospective cohorts, and real-world studies-to summarize current knowledge on the efficacy, safety, and therapeutic role of venetoclax-based regimens in NPM1-mutated AML.

Accumulating data demonstrate that venetoclax combined with HMAs achieves high rates of deep molecular remission and significantly improves overall survival in patients with NPM1-mutated AML. Despite these advances, important questions remain regarding the optimal duration of therapy, as well as timing and criteria for treatment discontinuation. Minimal residual disease monitoring is emerging as a pivotal tool to guide therapeutic decisions and enable personalized treatment strategies.

Venetoclax-based regimens represent a major advancement in the treatment of NPM1-mutated AML, promoting a shift toward more targeted and less toxic therapeutic approaches. Nonetheless, prospective randomized trials are required to establish standardized clinical algorithms and to refine maintenance and discontinuation strategies, with the ultimate goal of improving patient quality of life and long-term outcomes.