The Venetoclax Revolution in AML, and Its Limits in MDS: What the PARADIGM and VERONA Trials Mean for Practice

The Venetoclax Revolution in AML, and Its Limits in MDS: What the PARADIGM and VERONA Trials Mean for Practice

Venetoclax dominated the myeloid malignancy conversation at ASH 2025 — but not with a single story. The PARADIGM trial positions ven+aza as a viable alternative to intensive induction chemotherapy in fit younger adults with AML, while the VERONA trial finds the same combination adds nothing meaningful in higher-risk MDS. Dr. Bart L. Scott breaks down both results and their implications for clinical practice.

Introduction: Two Trials, Two Very Different Stories

The biggest story in myeloid malignancies coming out of ASH this year was venetoclax; or more precisely, venetoclax's expanding role in AML and its disappointing performance in MDS. Two abstracts define the moment: the PARADIGM trial, presented at the ASH plenary session, and the VERONA trial, presented as an oral abstract. Together, they tell a nuanced story about where the field is going and where it still has significant limits.

The headline summary: venetoclax plus azacitidine (ven+aza) appears to be a viable alternative to intensive induction chemotherapy for fit younger adults with AML, but ven+aza adds nothing meaningful to azacitidine alone in MDS, and arguably makes it harder to deliver.

The PARADIGM Trial: Ven+Aza Challenges Induction Chemotherapy in AML

Background

The VIALE-A trial established ven+aza as a standard for older, unfit AML patients, demonstrating superiority over azacitidine alone. But for decades, no one seriously proposed extending ven+aza to younger, fit patients who could tolerate intensive induction chemotherapy. The assumption was that a more toxic regimen must be more effective, which the PARADIGM trial directly challenged.

PARADIGM was a phase 2 randomized multicenter study comparing ven+aza to conventional induction chemotherapy (7+3 or CPX-351, center's choice) in newly diagnosed, fit adults with AML who were eligible for induction. Several important groups were excluded: APL patients (cured with ATRA/arsenic trioxide), FLT3-positive patients (who should receive a FLT3 inhibitor with induction), core binding factor leukemias (ETO t(8;21) and inv(16), curable with chemotherapy alone), NPM1-positive AML with normal karyotype and no high-risk mutations (also highly favorable), and mixed phenotype AML (who should undergo transplant). These exclusions reflect the current understanding that chemotherapy still offers optimal outcomes for biologically favorable disease.

Results

The trial enrolled 172 patients, 86 per arm, with a median follow-up of 21.9 months. Key findings:

In favor of ven+aza:

• Superior event-free survival (the primary endpoint), reaching statistical significance
• Higher overall response rates and composite CR rates
• More patients bridged to allogeneic stem cell transplant
• Significantly lower rates of infectious complications and bleeding events
• Lower 60-day mortality (approximately 0% vs. approximately 5%, though not quite statistically significant at p=0.08)
• Better quality of life scores
• Fewer hospital days and ICU admissions
• More favorable cost profile

In favor of chemotherapy:

• No difference in overall survival

The Methodological Caveat

This trial has a significant methodological issue that must be acknowledged. The induction chemotherapy arm was evaluated with a day-14 bone marrow biopsy, an assessment point that is widely considered to be too early and no longer routinely performed in modern practice precisely because it is not informative at that stage. Persistent disease on a day-14 marrow was counted as an "event" in the event-free survival analysis. This means patients in the chemotherapy arm were more likely to be assessed for (and counted as having) an event before their therapy had a reasonable opportunity to work. How much of the EFS difference is driven by this design flaw is unknown.

This is likely why overall survival was identical despite the EFS difference: if those day-14 events were truly progressive disease, one would expect a survival signal. The absence of that signal raises legitimate questions about the primary endpoint.

What This Means in Practice

Despite the methodological concerns, PARADIGM tells us something important: ven+aza is tolerable in younger fit patients, produces high response rates, gets more patients to transplant, and is substantially less toxic than induction chemotherapy. Many centers are already adopting ven+aza for fit patients with non-favorable-risk AML. It is not unreasonable to do so, with the important caveat that ven+aza is not a gentle regimen — cytopenias are real, the day-1 bone marrow after the first cycle remains essential for response assessment, and keeping patients on schedule matters for outcomes.

For patients requiring emergency cytoreduction (white count greater than 100,000 with peripheral blasts ≥50%, or patients with stroke, heart attack, or pulmonary congestion from leukostasis), cytarabine is still needed for rapid count reduction while insurance authorization for venetoclax is pursued.

Favorable-risk AML — core binding factor, NPM1-positive with normal karyotype and no high-risk co-mutations, APL, and FLT3-positive disease (which warrants a FLT3 inhibitor) — should still receive standard intensive induction chemotherapy. Patients with favorable risk AML can be cured with chemotherapy alone and the current standard of care for FLT3-3 positive AML is to add a FLT-3 inhibitor to induction chemotherapy followed by allogeneic transplant in suitable candidates.

The VERONA Trial: Ven+Aza Falls Short in MDS

Why Everyone Expected This to Work

Given ven+aza's success in AML, the field widely anticipated that the same combination would improve outcomes in higher-risk MDS. VERONA randomized 509 patients (256 to ven+aza, 253 to placebo+aza) in a design modeled closely on VIALE-A. The results were sobering.

Overall survival: no difference. Complete remission rates: nearly identical (18% in the ven+aza arm versus 20% in the placebo arm). Every combination study adding something to azacitidine in MDS has failed to date.

Why MDS Is Different

The core issue is toxicity tolerance. MDS patients are older, frequently with pre-existing cytopenias, and significantly less able to tolerate the additive myelosuppression of venetoclax. When cytopenias worsen, azacitidine doses are held or reduced. The result: patients in the ven+aza arm didn't actually receive azacitidine on the scheduled frequency, because the venetoclax-driven cytopenias forced treatment holidays. The comparison becomes, in effect, well-delivered azacitidine versus azacitidine that cannot be delivered as intended.

The lesson: adding venetoclax to azacitidine in MDS worsens the tolerability of the regimen before any additional benefits can set in. Until we can identify which MDS patients can tolerate the combination (perhaps younger patients with aggressive biology heading toward transplant) ven+aza should not be considered standard in this population.

The Molecular Era: How We Think About These Diseases Is Changing

Beyond the two trial results, the field's conceptual framework for myeloid malignancies is evolving rapidly.

TP53-mutated myeloid malignancy is now a unified entity. Whether a patient's disease meets the blast threshold for MDS or AML matters less than the TP53 mutation status. The WHO 2022 classification already recognized this with a category that transcends the MDS/AML boundary, and the forthcoming merged WHO/ICC classification is expected to rely even more heavily on molecularly defined disease entities. NPM1-positive status, for instance,defines AML regardless of blast count.

Targeted therapy is reshaping the non-curative landscape. For patients who are not candidates for curative intent (transplant), the focus has appropriately shifted from quantity of life toward quality of life. IDH inhibitors, menin inhibitors, FLT3 inhibitors, and ven+aza all offer disease control with substantially less toxicity than intensive chemotherapy. Toxicity and efficacy are not as directly correlated as was once assumed, and the field is increasingly willing to challenge that assumption.

Direct transplant without pre-transplant cytoreduction is an emerging approach for high-risk myeloid malignancies. For AML and MDS patients who are transplant candidates, moving directly to allogeneic stem cell transplant without attempting to achieve remission first is increasingly being considered, particularly when time is of the essence and when cytoreductive therapy would delay or jeopardize the transplant.

For Patients

If you have been diagnosed with AML or MDS, the treatment options and the way clinicians think about your disease have evolved significantly. For AML specifically, a combination of venetoclax and azacitidine is now being used for many patients as an alternative to traditional intensive chemotherapy, and for appropriate patients it appears to offer comparable or better disease control with less time in the hospital and fewer complications. For MDS, the standard remains azacitidine-based therapy; venetoclax is being studied but has not shown survival benefit in this setting. Clinical trials are an important option for both diseases — ask your oncologist whether a trial is available for your specific situation.

Key Takeaways

• PARADIGM trial: ven+aza produced superior event-free survival, higher response rates, more transplant bridging, and lower toxicity versus intensive induction chemotherapy in younger fit AML patients — but no overall survival difference, partly attributable to a methodological flaw (day-14 bone marrow assessment).
• Favorable-risk AML (core binding factor, NPM1-mutated without high-risk co-mutations, ) and FLT3 positive should still receive standard intensive chemotherapy. Many APL patients can be cured with ATRA and arsenic. These patients were excluded from PARADIGM.
• VERONA trial: ven+aza did not improve overall survival versus azacitidine alone in higher-risk MDS; cytopenias forced treatment delays that undermined azacitidine delivery.
• TP53-mutated myeloid malignancy is increasingly treated as a unified entity regardless of MDS vs. AML classification.
• Direct transplant without pre-transplant cytoreduction is an evolving approach for high-risk myeloid malignancies.
• For non-curative patients, targeted therapies (IDH/menin/FLT3 inhibitors, ven+aza) are shifting the focus toward quality of life over treatment intensity.

About the Author

Bart L. Scott, MD, is a Professor of Medicine in the Division of Oncology at the University of Washington School of Medicine and a physician-scientist at Fred Hutchinson Cancer Center in Seattle, Washington. A leading expert in myelodysplastic syndromes, acute myeloid leukemia, and myeloproliferative neoplasms, he has participated in numerous pivotal clinical trials in this space and was a co-author on the first edition of the NCCN guidelines for MPNs. His research and clinical practice focus on molecularly defined myeloid malignancies and the development of less toxic, more effective treatment strategies for patients with AML and MDS.

References

1. PARADIGM trial. Azacitidine plus venetoclax vs intensive induction chemotherapy in younger fit AML patients. Presented at ASH 2025 Plenary Session.
2. VERONA trial. Venetoclax plus azacitidine vs placebo plus azacitidine in higher-risk MDS. Presented at ASH 2025.
3. DiNardo CD, et al. (VIALE-A). Azacitidine and venetoclax in previously untreated AML. New England Journal of Medicine, 2020.
4. Döhner H, et al. ELN 2022 recommendations for the diagnosis and management of AML in adults. Blood, 2022.
5. Scott BL. "MDS/Leukemias." Presented at the 2026 Alaska Hematology Oncology Conference, Anchorage, AK, May 2026.