VERONA Trial Misses Primary End Point of OS Benefit With Azacitidine/Venetoclax in Higher-Risk MDS

Higher-Risk MDS | Image credit:

© Motion Pics - stock.adobe.com

The combination of venetoclax (Venclexta) and azacitidine (Vidaza) did not provide an overall survival (OS) advantage over placebo plus azacitidine in patients with newly diagnosed higher-risk myelodysplastic syndromes (MDS), failing to meet the primary end point of the phase 3 VERONA trial (NCT04401748).1

The hazard ratio for OS was 0.908 (stratified log-rank P = .3772). The investigators observed no new safety signals, according to a news release.

Findings from the VERONA trial will be presented at a future medical meeting and/or published in a scientific journal. Furthermore, any patients who received venetoclax plus azacitidine through participation in VERONA will be informed of the trial results by their treating physicians.

Notably, these data do not affect any currently approved venetoclax indications.

VERONA Trial Design

VERONA enrolled patients at least 18 years of age with MDS per the 2016 World Health Organization classification who had a presence of less than 20% bone marrow blasts per marrow biopsy/aspirate at screening.2 Patients needed to have an overall revised International Prognostic Scoring System score of greater than 3 (intermediate, high, or very high); an ECOG performance status of 0 to 2; and be eligible for hematopoietic stem cell transplantation (HSCT) with no pre-arranged HSCT at day 1 of the study, or be ineligible for HSCT with no plan for HSCT at day 1 of the study. Patients were excluded if they had received prior therapy for MDS with any hypomethylating agent, chemotherapy, or allogeneic stem cell transplantation; or if they had a pre-diagnosis of therapy-related MDS, MDS evolving from a preexisting myeloproliferative neoplasm (MPN), MDS/MPN including chronic myelomonocytic leukemia, atypical chronic myeloid leukemia, juvenile myelomonocytic leukemia, and unclassifiable MDS/MPN.

Patients were randomly assigned to receive subcutaneous or intravenous azacitidine daily at 75 mg/m2 for 7 of the first 9 days of each 28-day cycle in combination with once-daily oral tablets of either venetoclax or placebo at 400 mg on days 1 to 14 of each cycle.2,3 Patients were planned to receive study treatment until disease progression, unacceptable toxicity, hematopoietic cell transplantation, withdrawal of consent, or study discontinuation.3

Secondary end points of the trial included modified overall response, the percentage of patients achieving overall hematological improvement, complete response (CR), the percentage of patients who were transfusion dependent at baseline who achieved transfusion independence, the time to deterioration in physical functioning as measured by the Physical Functioning domain of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire scale, change in Patient-Reported Outcomes Measurement Information System-Fatigue Short Form 7a Scale score, and overall response.2,3

VERONA Regimen in Context

Previously, a phase 1b study (NCT02942290) showed a favorable efficacy and safety profile of venetoclax plus azacitidine in patients with treatment-naive high-risk MDS.4 Patients received venetoclax plus azacitidine at the same doses and schedule as in VERONA.

At a data cutoff in May 2023, among 107 patients who had received the combination, best responses of CR or marrow CR were seen in 29.9% (95% CI, 21.4%-39.5%) and 50.5% (95% CI, 40.6%-60.3%) of patients, respectively; the median overall response rate was 80.4% (95% CI, 71.6%-87.4%). The median OS was 26.0 months (95% CI, 18.1-51.5), and the estimated 1- and 2-year OS rates were 71.2% (95% CI, 61.4%-78.9%) and 51.3% (95% CI, 41.2%-60.5%), respectively.

Additionally, among patients with baseline red blood cell and/or platelet transfusion dependence (n = 59), 40.7% (95% CI, 28.1%-54.3%) achieved transfusion independence during the study, including 18.6% (95% CI, 9.7%-30.9%) of patients who also achieved CR. Moreover, 49.0% (95% CI, 39.1%-59.0%) of all evaluable patients in the total population (n = 104) achieved hematologic improvement. The median time to next treatment, excluding transplantation, was 13.4 months (95% CI, 9.7-17.7).

The safety findings from this study reflected the known safety profiles for venetoclax and azacitidine. The most common adverse effects included constipation (53.3%), nausea (49.5%), neutropenia (48.6%), thrombocytopenia (44.9%), febrile neutropenia (42.1%), and diarrhea (41.1%).

The VERONA trial was designed to confirm the OS benefit of azacitidine plus venetoclax that was observed in this phase 1b trial.

References

1. AbbVie provides update on VERONA trial for newly diagnosed higher-risk myelodysplastic syndromes. News release. AbbVie. June 16, 2025. Accessed June 17, 2025. https://news.abbvie.com/2025-06-16-AbbVie-Provides-Update-on-VERONA-Trial-for-Newly-Diagnosed-Higher-Risk-Myelodysplastic-Syndromes
2. Study of venetoclax tablet with intravenous or subcutaneous azacitidine to assess change in disease activity in adult participants with newly diagnosed higher-risk myelodysplastic syndrome (Verona). ClinicalTrials.gov. Updated June 20, 2024. Accessed June 17, 2025. https://clinicaltrials.gov/study/NCT04401748
3. Zeidan AM, Garcia JS, Fenaux P, et al. Phase 3 VERONA study of venetoclax with azacitidine to assess change in complete remission and overall survival in treatment-naïve higher-risk myelodysplastic syndromes. J Clin Oncol. 2021;39(suppl_15):TPS7054. doi:10.1200/JCO.2021.39.15_suppl.TPS7054
4. Garcia JS, Platzbecker U, Odenike O, et al. Efficacy and safety of venetoclax plus azacitidine for patients with treatment-naive high-risk myelodysplastic syndromes. Blood. 2025;145(11):1126-1135. doi:10.1182/blood.2024025464