Improving Venetoclax and Other Targeted Therapies in AML

Zachary Braunstein, MD The Ohio State University | Jayastu Senapati, MBBS MD Anderson Cancer Center

December 23, 2025

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Key Points

  • Recent data support the efficacy of azacitidine and venetoclax for acute myeloid leukemia (AML), even in patients otherwise eligible for conventional chemotherapy.

  • Genetic and genomic testing are crucial in patients with AML as more targeted therapies emerge.

  • TP53-mutated AML remains without truly effective targeted therapies, and physicians should pursue rapid transplants for patients in this subgroup.

Optimizing Venetoclax and Other Targeted Therapies in AML

Jayastu Senapati, MBBS, of MD Anderson Cancer Center, and Zachary Braunstein, MD, of The Ohio State University, sat down at the 2025 ASH Annual Meeting (ASH 2025) to discuss the current landscape of targeted therapies and what unmet needs exist. 

Previously, data from the VIALE-A trial showed the value of adding venetoclax to azacitidine in patients ineligible for intensive induction chemotherapy. The phase 2 PARADIGM study compared azacitidine and venetoclax with induction chemotherapy in fit, younger patients with newly diagnosed AML without core binding factor fusions, FLT3 mutations, or NPM1 mutations (unless aged 60 years or older). Azacitidine and venetoclax improved event-free survival, overall response, and composite remission rates. 

Among responders in either arm, a greater proportion of those treated with azacitidine and venetoclax proceeded to hematopoietic cell transplant compared with chemotherapy, according to the ASH 2025 presentation.

The data from PARADIGM support the value of azacitidine and venetoclax in patients with AML, but the next step may be to combine azacitidine and venetoclax with other targeted therapies, said Dr. Senapati. 

As more targeted therapies are developed, genomic and genetic testing are more important than ever to guide treatment decisions. Dr. Senapati suggested community oncologists perform mutational testing as rapidly as possible so patients who carry one of the ever-growing list of targetable alterations can benefit from novel therapies. 

For subgroups in which targeted therapies are less effective, such as secondary AML or TP53-mutated AML, physicians should pursue rapid transplants before patients become ineligible, Dr. Senapati said.