Background Only one-third of patients with higher-risk myelodysplastic syndromes (MDS) respond to hypomethylating agents. The overall survival (OS) is short, ranging from 12 to 18 months. Venetoclax, a BCL2 inhibitor, improves response and survival in acute myeloid leukemia (AML) in combination with azacitidine, encouraging the investigation of venetoclax-based combinations in higher-risk MDS. We report the first-line results of the safety and efficacy of azacitidine-venetoclax in high-risk MDS and chronic myelomonocytic leukemia (CMML).

Methods This was a phase 1/2 study involving patients with International Prognostic Scoring System (IPSS) intermediate-2- or high-risk MDS, including CMML and MDS/myeloproliferative neoplasm (MPN) at The University of Texas MD Anderson Cancer Center (NCT04160052). Patients aged ≥18 years with any Eastern Cooperative Oncology Group (ECOG) performance status and bone marrow blasts >5% were eligible. The previously reported phase 1 portion used a 3+3 design to establish the recommended phase 2 dose of venetoclax at 400 mg for 14 days with 75 mg/m2 intravenous azacitidine for 5 days.

The primary objective of the phase 2 portion was to estimate the overall response rate (ORR; complete remission [CR] + marrow CR + HI) by the International Working Group (IWG) 2006 criteria. Key secondary objectives were to estimate OS, event-free survival (EFS), and safety of the regimen. The data cut-off date was July 1, 2025.

Results We enrolled 43 patients between November 2019 and April 2025. The median age was 69 years (range, 51–83), the median ECOG score was 1 (range, 0–2), and the median Charlson comorbidity index score was 4 (range, 2–12). Fourteen (33%) patients were female and 10% were from Black, Asian, or American Indian ethnic backgrounds. Thirty-five patients (81%) had MDS, 6 (14%) had CMML, and 2 (5%) had MDS/MPN. By the World Health Organization 2022 criteria, 32% had MDS-IB1 at the start of treatment, and 68% had MDS-IB2. The median IPSS score was 2, the median IPSS-R score was 6, and the median IPSS-M score was 1.69, all consistent with higher-risk disease. The most common mutations were: 44% ASXL1, 28% SRSF2, 26% TP53, 21% RUNX1, and 19% STAG2. The median TP53 variant allele frequency was high at 44% (range, 4%–84%).

After a median of 3 (range, 1–24) cycles, 13 (30%) patients attained CR and 27 (63%) attained marrow CR by IWG 2006; the ORR was 93% (95% CI, 81%–98%). By IWG 2023, 13 (30%) patients attained CR, 9 (21%) CRbi, 10 (23%) CRuni, and 1 (3%) CRh; the composite complete remission (CRc) rate was 77% (95% CI, 62%–87%). Among responding patients, the median time to the best response was 59 (range, 25–231) days, corresponding to a median of 2 (range, 1–7) cycles of therapy. Among 32 patients who received >1 cycle of treatment, the venetoclax duration was reduced in 16 (50%) patients in subsequent cycles. The most common grade ≥3 non-hematologic adverse events were pneumonia (28%), neutropenic fever (21%), sepsis (14%), hemorrhage (9%), and respiratory failure (7%). There was 1 (2%) death within 30 days and 1 (2%) death within 60 days.

At a median follow-up time of 41 months, the median OS was 16.1 (95% CI, 9.1–46.6) months, the median EFS was 10.1 (95% CI, 5.4–16.6) months, and the 2-year probability of AML was 34% (95% CI, 19%–54%). In a landmark analysis, the OS of patients who underwent stem cell transplant (SCT) was not reached; the 5-year probability of OS was 68%, compared to 9.4 months for patients who did not undergo SCT (P < 0.01). In a multivariate Cox model with SCT as a time-dependent covariate, accounting for age, performance status, IPSS-R scores, and molecular profiles, DDX41mut(hazard ratio [HR], 0.21; 95% CI, 0.06–0.66; P < 0.01), CRc attainment (HR, 0.20; 95% CI, 0.06–0.66; P = 0.01), and SCT (HR, 0.07; 95% CI, 0.01–0.43; P < 0.01) were significantly associated with improved OS. Conversely, ASXL1mut (HR, 2.97; 95% CI, 0.87–10.13; P = 0.08) and TP53mut (HR, 6.52; 95% CI, 0.77–55.4; P = 0.09) were associated with worse OS.

Conclusions Azacitidine-venetoclax produces high response rates in treatment-naïve high-risk MDS and CMML, providing encouraging results in this cohort with a significant burden of TP53mutations. High disease risk, low rates of SCT, and lower doses of therapy compared to the phase 3 VERONA study resulted in an OS of 16.1 months. Remission attainment, SCT, and unique molecular subsets, such as patients with DDX41mut, were associated with improved OS.

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2025
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