Venetoclax and azacitidine in high-risk myelodysplastic syndromes: expectations vs. evidence

The March 13, 2025 issue of Blood contains the much-anticipated results of the Phase Ib study, “Efficacy and safety of venetoclax plus azacitidine for patients with treatment-naive high-risk myelodysplastic syndromes” by Garcia et al., which provides the first assessment of the safety and efficacy of venetoclax and azacitidine (ven-aza) in high-risk myelodysplastic syndromes (HR-MDS), and is the foundation for the randomized phase 3 VERONA study, which was ultimately negative. Thus, the study by Garcia et al. raises more questions than it answers.

HR-MDS is a disease of older adults defined by cytopenias, morphologic dysplasia and clonal genetic abnormalities (1,2). A score of >3.5 on the Revised International Prognostic Scoring System (IPSS-R) defines “high-risk” disease and is associated with a short survival; adding molecular data into the IPSS-M score upstages up to 75% of patients, highlighting the disease’s biological heterogeneity (3). Azacitidine remains the standard of care treatment for HR-MDS and yields a complete response rate of 17% and an overall survival (OS) of ~18 months (4). Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment but is available to only a small subset of patients. Thus, novel therapies are desperately needed in this disease.

The study by Garcia et al. is the first to test venetoclax (5), a selective, oral inhibitor of BCL2 and potent pro-apoptotic agent, in combination with azacitidine in HR-MDS. The combination of ven-aza yields high response rates and improves survival in patients with acute myeloid leukemia (AML) who are not candidates for induction chemotherapy, and it was anticipated to have the same benefit in HR-MDS (6). The study by Garcia et al. included patients with HR-MDS, defined as IPSS-R >3, previously untreated (7). The first patients enrolled experienced marked hematologic toxicity, necessitating a reduction of venetoclax from 28 to 14 days. Among 107 patients treated at the recommended phase 2 dose (RP2D) of 14 days of ven + 7 days of aza, the regimen achieved a modified overall response (mOR) rate of 80.4%, including complete remission (CR) in 29.9%, with a median CR duration of 16.6 months. Median OS was 26 months, which compares favorably to real-world outcomes with azacitidine monotherapy (median OS 14–16 months) (8). Notably, 44.1% of patients with marrow CR without hematologic improvement proceeded to HSCT which was achievable after a median of 3 cycles of ven-aza and the median OS was not reached among transplanted patients. While this appears encouraging and reinforces the role of HSCT for HR-MDS, the devil is in the details. Around half of the patients in the study required ven dose-reductions, nearly 90% required dose-interruptions, and 94% had grade 3 or 4 treatment-emergent adverse events (TEAEs). Nonetheless, this study established the RP2D of 14 days of venetoclax for HR-MDS and provided the foundation for the randomized, double-blind, placebo-controlled, phase 3 VERONA trial.

Preliminary results from VERONA, which compared ven-aza to aza in HR-MDS, were presented in abstract form in late 2025. This study enrolled 509 adult patients with untreated, IPSS-R >3 MDS who were randomized to 14 days of ven (400 mg) or placebo with 7 days of aza (75 mg/m²) (9). Patients with secondary MDS were excluded. The study protocol included dose adjustments for toxicity with reduction of aza preferred before adjustment of ven. The primary endpoint was OS. Median age was 72 years. About 46% of patients had bone marrow blasts 10–20% in both groups at diagnosis and about 25% in the ven/aza group and 20% in the control group had TP53-mutated disease. No difference in OS was found between arms, with a mOS of ~22 months in both groups (HR 0.908; 95% CI: 0.733–1.126) at a 41-month median follow-up. Thus, VERONA did not meet its primary endpoint but a higher proportion of patients treated with ven-aza achieved mOR (76.6% vs. 57.7%, P<0.0001), modified complete response (mCR) (57.8% vs. 37.5%), transfusion independence (TI) and received HSCT, consistent with the phase Ib findings of Garcia et al. Subgroup analyses also showed a positive trend towards mOR benefit in the ven-aza cohort for patients <75 years, with high blasts, high/very high IPSS-R or ASXL1, TP53 and RUNX1 mutations at baseline. Favorable trends in OS were also highlighted. As would have been expected from the phase Ib results, grade 3 or more hematologic toxicities were more common with ven-aza and aza dose-reductions were almost twice as frequent in the ven-aza group (9).

So why didn’t the Garcia et al. study lead to a positive VERONA? These trial results add to the growing discordance between promising pre-clinical and early clinical expectations in the development of combination therapies for HR-MDS and ultimately negative phase 3 studies (10-12). It is possible that inclusion of intermediate-risk patients by IPSS-R and patients with <5% blasts contributed to the good performance of the control arm in VERONA, thereby diminishing the benefit of ven-aza. MDS without excess blasts may be less dependent on BCL2 for survival and thus less sensitive to ven (13)—a subgroup that represented over 50% of patients in the trial. Some patients in the control arm may also have received off-protocol ven if they were in an MDS/AML overlap state, influencing the results. Furthermore, the reporting of “modified” CR in the phase Ib includes “marrow CR”, a criterion which was removed from 2023 international working group definition of response in MDS, thereby potentially lowering the response rates in VERONA (14). Lastly, ven-aza is clearly punctuated by hematologic and infectious toxicities and there were frequent dose reductions in the ven-aza arm that could have compromised its efficacy. The published literature on ven-aza in AML is concordant with the clinical experience that it is challenging but necessary to titrate this regimen to a schedule that limits toxicity, maintains efficacy, and affords a meaningful quality of life for each individual patient (15,16). The same appears to be true in HR-MDS and may be exaggerated in this disease where the pre-leukemic stem cell is already compromised (17). The new classifications [International Consensus Classification (ICC) and World Health Organization (WHO)] add a category of MDS/AML with 10 to 19% blasts; this blurs the lines between AML and MDS because of common molecular drivers and clinical presentation, and if incorporated into trials, could help to carve out a distinct subset of MDS that responds to AML-directed therapies.

An approach to HR-MDS trials that considers the patient and is “goal”-oriented could also break the cycle of failed phase 3 studies. MDS represents a heterogeneous group of biologically defined entities, likely each with unique targetable molecular vulnerabilities. Targeting these vulnerabilities will likely yield the best results but this will not be pertinent to a large majority of patients, and thus, a goal-centred patient stratification could mitigate toxicity, manage expectations and yield more meaningful results. For example, some patients will undoubtedly never be candidates for HSCT, based on their fitness and comorbidities; they should be considered separately in HR-MDS trials. As well, implementation of the IPSS-M, harmonization of the definition of “high-risk” disease and acknowledgment of the MDS/AML overlap state in future trials could help better select patients for trials that offer the possibility of a meaningful therapy for each group.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Blood. The article has undergone external peer review.

Peer Review File: Available at https://aob.amegroups.com/article/view/10.21037/aob-2026-1-0009/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aob.amegroups.com/article/view/10.21037/aob-2026-1-0009/coif). S.A. reports consulting fees and payments for lectures from Roche, and consulting fees from Novartis, Gilead, Janssen, Astra Zeneca and Lilly. She’s on the Advisory Board of Roche, Novartis, Gilead, Janssen, Astra Zeneca and Lilly. The other authors have no conflicts of interest to declare.

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