Breaking through the azacitidine plateau?—venetoclax in high-risk myelodysplastic syndrome

Myelodysplastic syndromes (MDS) are heterogeneous clonal bone marrow disorders characterized by ineffective hematopoiesis and an increased risk of transformation into acute myeloid leukemia (AML). Forty-three percent (43%) of MDS patients are categorized as high-risk (HR) MDS based on their degree of cytopenias, blasts percentage, cytogenetic and molecular profile (1) and their course is characterized by substantially increased risk of AML transformation and a median survival of 18 months. Allogeneic bone marrow transplantation (AlloBMT) is the only curative-intent treatment for patients with HR MDS (2,3) but most of the patients are not candidates due to advanced age, impaired performance status and comorbidities.

Based on the results of the AZA-001 trial demonstrating prolonged survival of HR MDS patients treated with the hypomethylating agent (HMA) azacitidine (4), this is currently the standard-of-care therapy for individuals with HR MDS providing a path to AlloBMT in a subset of these patients. Of note, subsequent studies failed to reproduce the survival results of the AZA-001 trial showing a median survival of less than 20 months with azacitidine single-agent therapy (5,6). Thus, given that the clinical ceiling of single-agent HMA therapy for HR MDS is well recognized with relatively infrequent and transient complete remissions (CRs), there is an urgent need for effective combinational strategies built into this backbone. Multiple approaches have been pursued including immune-directed strategies and targeted agents (5,7), but several programs have faced challenges in confirmatory testing particularly in phase 3 clinical trials, highlighting the difficulty of moving beyond the HMA plateau (7).

Multiple pre-clinical studies highlighting the dependence of AML blasts on BCL-2 and dissecting the biologic basis of its combination with HMA, led to the introduction of BCL-2 inhibition as a therapeutic strategy for AML patients who are not eligible for intensive chemotherapy (8,9). The VIALE trial demonstrated that combination of venetoclax, a selective BCL-2 inhibitor with azacitidine significantly improved the survival of patients with treatment-naïve AML, who are ineligible for intensive induction therapy (10). Among the patients included in VIALE trial, 25% had secondary AML arising from antecedent myeloid neoplasm (10) providing the rationale for investigating the efficacy of the combination of azacitidine with venetoclax for patients with HR MDS. The phase 1 open-label, multicenter trial by Garcia et al., reports a good safety profile of this combination for HR MDS patients demonstrating positive response rates and encouraging overall survival (OS) (11).

The trial enrolled 107 adults with untreated HR MDS based on International Prognostic Scoring System (IPSS) or Revised International Prognostic Scoring System (IPSS-R) criteria, fewer than 20% marrow blasts and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or better. The median age was 68 years and most patients were in the high or very high IPSS-R categories. Of note, an early protocol redesign was followed in this trial. Fatal sepsis events occurred under an initial plan with longer venetoclax exposure, prompting a shift to a 14-day venetoclax schedule and mandated antimicrobial prophylaxis during cycle 1. The recommended phase 2 dose (RP2D) for expansion was venetoclax 400 mg on days 1–14 of a 28-day cycle combined with azacitidine 75 mg/m² on standard schedules (7 consecutive days or an alternative 5-2-2 schedule).

CR occurred in 29.9% of patients and marrow CR (mCR) in 50.5%, yielding a modified objective response (mOR) rate of 80.4%, with no partial remissions recorded. Of note, some patients converted from an initial mCR to CR over time, and the median duration of CR was 16.6 months. Time-to-event outcomes were also favorable in this nonrandomized setting. Median OS was 26.0 months, with 1- and 2-year survival estimates above 70% and 50%, respectively. Measures of marrow recovery were clinically meaningful. Approximately 41% of transfusion-dependent patients achieved transfusion independence, and nearly half of evaluable patients met criteria for hematologic improvement (HI). AML transformation occurred in 12.3% of evaluable patients, with a median time to transformation of 6 months. A distinctive feature of this cohort is the high rate of AlloBMT. This was the most common primary reason for discontinuation (37.4%), and 39.3% of patients proceeded to AlloBMT as the immediate next therapy, with 3 as a median number of azacitidine/venetoclax cycles before the transplantation. These findings highlight an important role of lower-intensity regimens in HR MDS as a bridge to a curative-intent pathway.

Treatment-emergent adverse events (TEAEs) were observed in all patients treated at the RP2D with 94.4% of individuals experiencing ≥1 grade 3/4 TEAE. Most common events were constipation (53.3%), nausea (49.5%), neutropenia (48.6%) and thrombocytopenia (44.9%). Venetoclax dose reductions and TEAE-related interruptions occurred in 52.3% and 67.3% of patients respectively. The majority of grade 3/4 TEAE were hematologic as expected including neutropenia, thrombocytopenia, and anemia 68.2% of patients experienced at least 1 serious AE such as febrile neutropenia, pneumonia and sepsis. Despite the high incidence of grade 3/4 TEAE, only 1 death was associated with TEAE due to venetoclax, while 21.5% of deaths were associated with disease progression.

This phase 1 open-label, multicenter trial investigated the safety and efficacy of combining azacitidine with venetoclax in HR MDS patients attempting to respond to a critical unmet need in the field given the relatively poor and short response of these individuals to single-agent HMA. The median OS of 26.0 months, together with a CR rate near one-third and a high marrow response rate, compares favorably with the range commonly reported in historical azacitidine datasets, including AZA-001. Cross-trial comparisons remain inherently limited, yet the internal consistency of response depth, transfusion outcomes, and survival supports the plausibility of additive activity rather than isolated endpoint inflation. These results also underscore that the deliverability of venetoclax plus azacitidine in higher-risk MDS is closely linked to schedule design and supportive care, rather than dose intensity alone. Importantly, the high rate of transplantation in this cohort suggests that the regimen may be most relevant in transplant-intended care rather than as a universal approach. The combination may serve as a lower-intensity bridge-to-transplant strategy that promotes deeper responses, improves transfusion outcomes, and facilitates access to curative-intent transplantation in selected patients.

Absence of control group is an important limitation of this phase 1 trial and the relatively small sample size precluded comprehensive analysis of combination efficacy in distinct molecular sub-groups including TP53-mutated MDS. This sub-group falls into the highest-risk categories and is characterized by adverse disease biology and resistance to venetoclax (12). Gaining deeper insight into responses within this subgroup is essential, given their pronounced influence on OS.

Recently, the primary analysis of the very much anticipated phase 3 VERONA trial comparing the efficacy of azacitidine + venetoclax combination with single-agent azacitidine in intermediate and HR MDS showed no OS benefit of the combination (13). This outcome was met with disappointment by the MDS community; however, comparing the cohort enrolled in the phase 1 trial by Garcia et al. with that of the VERONA trial offers important insights. In the phase 1 study, 86% of patients had high-risk or very high-risk disease, and 90% presented with excess blasts at diagnosis. In contrast, nearly one third of VERONA participants had intermediate-risk disease, with only 27% exhibiting excess blasts. This difference is critical, as preclinical data indicate that BCL-2 dependence is predominantly associated with leukemic blasts (8,9). Hopefully, subgroup analysis of VERONA trial patients can provide answers to these questions. Moreover, both trials included a substantial proportion of patients with TP53-mutated MDS. Multiple preclinical studies have demonstrated that TP53 loss-of-function mutations or deletions markedly reduce the sensitivity of AML cells to BCL-2 inhibition (12,14). Consistent with these findings, analysis of the VIALE trial data showed that adding venetoclax conferred no benefit to patients harboring TP53 mutations. Therefore, inclusion of this disease subgroup may have underestimated the potential benefit of combining venetoclax with azacitidine compared to azacitidine monotherapy.

In conclusion, subgroup analyses of HR MDS cohorts treated with azacitidine plus venetoclax are urgently needed to identify clinical and molecular characteristics associated with the greatest depth of response. Moreover, defining the optimal role of this combination in relation to AlloBMT—the only curative option—will be critical to improving outcomes for patients with high-risk MDS.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Translational Medicine. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-2026-1-0019/coif). The authors have no conflicts of interest to declare.

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