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Harnessing Venetoclax in NPM1-Mutated AML: A Path to Sustained Remission and Beyond
by
, , and
Matteo Molica
1,*
,
Claudia Simio
1,
Laura De Fazio
1,
Caterina Alati
2,
Massimo Martino
2 and
Marco Rossi
1 1
Division of Hematology-Oncology, Azienda Universitaria Ospedaliera Renato Dulbecco, 88100 Catanzaro, Italy
2
Hematology and Stem Cell Transplantation and Cellular Rerapies Unit (CTMO), Department of Hemato-Oncology and Radiotherapy, Grande Ospedale Metropolitano “Bianchi-Melacrino-Morelli”, Presidio Morelli, 89128 Reggio Calabria, Italy
*
Author to whom correspondence should be addressed.
Cancers 2025, 17(23), 3733; https://doi.org/10.3390/cancers17233733
Submission received: 22 October 2025
/
Revised: 19 November 2025
/
Accepted: 20 November 2025
/
Published: 21 November 2025
(This article belongs to the Special Issue From Bench to Bedside: Novel Molecular Targets and Therapeutic Strategies in AML)
Simple Summary
Acute myeloid leukemia (AML) with nucleophosmin 1 (NPM1) mutation represents a distinctive subpopulation with unique molecular and clinical features. The introduction of venetoclax in combination with hypomethylating agents has revolutionized the treatment of this setting, especially in patients unfit for intensive chemotherapy. This review analyses the most recent evidence on the efficacy and safety of venetoclax in patients with NPM1-mutated AML, exploring the biological mechanisms underlying sensitivity, post-remission strategies, and therapeutic discontinuation options. Key unresolved clinical questions and future perspectives are also discussed, focusing on ongoing trials and the potential for personalized management based on minimal residual disease monitoring. The aim is to provide an updated and critical overview to support clinicians in therapeutic decisions and to promote further targeted research.
Abstract
Background: 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. Materials and Methods: 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. Results and Discussion: 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. Conclusions: 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.
