Leukemia Advances at ASH 2025: Expert Insights and Future Directions

Niranjan Khaire, MBBS, MD, DM MD Anderson Cancer Center

Key Points

• The PARADIGM trial showed that for young, fit patients with acute myeloid leukemia (AML) who have intermediate- to adverse-risk disease and require an allogeneic stem cell transplant (allo-SCT) in first complete remission (CR1), achieving transplant with azacitidine plus venetoclax appears to be as effective as the traditional 7+3 regimen.

• FLT3 inhibitors continue to improve outcomes; menin inhibitors should be used based on specific genomic subtypes.

• Delivering safe and effective AML therapy relies on careful personalization—assessing patient fitness, optimizing venetoclax duration, using growth factors appropriately, and adjusting doses during continuation cycles.

• While the VERONA trial did not meet its overall survival (OS) endpoint, it revealed important clinical insights for future practice in the treatment of myelodysplastic syndromes (MDS).

The 2025 ASH Annual Meeting (ASH 2025) showcased exciting developments in leukemia research, setting the stage for more precise and effective therapies. An expert panel featuring Uma Borate, MBBS, of The Ohio State University, and Jorge Cortes, MD, of Georgia Cancer Center, moderated by Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, unpacked the most meaningful updates.

Is it Time for a PARADIGM Shift in AML?

The much-anticipated PARADIGM study, comparing standard 7+3 versus azacitidine plus venetoclax in frontline AML, was presented at the plenary session and sparked lively discussion. Dr. Borate, a co-investigator, highlighted that the key takeaway for patients with intermediate- to adverse-risk of AML aiming for allo-SCT in CR1 is to reach transplant safely more than the intensity of induction therapy. Both approaches appear equivalent in achieving this goal. Dr. Borate also cautioned that the study population excluded CBF, FLT3 ITD/TKD, or NPM1-mutated cases, where intensive therapy or targeted agents may still be appropriate.  

Targeted Therapies in AML

The panelists also discussed several updates on FLT3 inhibitor triplets and menin inhibitors presented at ASH 2025. FLT3 inhibitors continue to improve outcomes, with momentum building toward their use in frontline therapy rather than being limited to relapse settings.

Menin inhibitors also showed promise, although Dr. Cortes predicts their role will likely be given in combination therapies in the future, considering their modest single-agent activity. He also explained that their use requires careful consideration of pharmacological differences within the drug class and attention to distinct toxicities such as differentiation syndrome and hyperinflammatory syndromes. 

The Art of Managing AML

Closing out the AML discussion, the panelists emphasized that despite rapid innovation, a patient-tailored approach is needed to avoid hematological and other toxicities. One key intervention is reducing venetoclax dosing, with shorter courses of 14 or 21 days appearing as effective as the VIALE-A regimen. Other important strategies include appropriate assessment of patient fitness, use of growth factor support, utility of day 14 marrow to decide duration of venetoclax when used as a triplet combination, among other considerations. These refinements help balance efficacy with safety in complex regimens.

Treatment of CML in 2026

The panel then turned to the growing number of treatment options for patients with chronic lymphocytic leukemia. Dr. Cortes described these options as “good versus better.” In his practice, he chooses a tyrosine kinase inhibitor (TKI) after a discussion with the patient on goals of therapy. Imatinib remains a good option, offering near-normal survival, an excellent cardiac toxicity profile, and affordability. However, if a deeper and faster response with the intention of treatment-free remission is desired, next-generation TKIs, such as asciminib, may be the better choice. 

Lessons From VERONA

The panel concluded with thoughts on lessons from the much-awaited VERONA study.  The trial randomized patients with high-risk MDS to single-agent azacitidine versus azacitidine plus venetoclax. Although the trial failed to meet its primary endpoint of OS, the detailed analysis showed better responses with addition of venetoclax in certain molecular subgroups. Factors such as allo-SCT consolidation and cross-over therapy likely influenced outcomes and led to lack of survival benefit. 

ASH 2025 reaffirmed that while novel agents and combinations are transforming leukemia care, success hinges on precision, patient fitness, and pragmatic clinical judgment.