Real-world outcomes associated with azacitidine and venetoclax in Myelodysplastic Syndromes Free

Introduction: Myelodysplastic syndromes (MDS) are hematologic malignancies characterized by bone marrow failure and risk for progression to acute myeloid leukemia (AML). Treatment for MDS depends on patients' risk of transformation to AML and death, calculated using the International Prognostic Scoring System-Revised (IPSS-R). For patients with higher-risk disease, the NCCN guidelines recommend combination therapy with a hypomethylating agent with or without venetoclax, among other targeted agents. Previous studies included a Phase 1b trial assessing combination therapy with azacitidine and venetoclax in adults with higher-risk MDS. Results included a complete remission rate of 30% and a median overall survival (OS) of 26 months. Furthermore, the Phase 3 VERONA trial did not meet the primary endpoint of OS with a hazard ratio of 0.908. The goal of the current study was to analyze outcomes in patients with higher-risk MDS treated with azacitidine and venetoclax at the Huntsman Cancer Institute.

Methods: This is a single-center, retrospective study including patients with MDS who received at least one dose of azacitidine and venetoclax between January 1, 2022 and July 31, 2024. The primary outcome was overall response rate (ORR). Secondary outcomes included progression free survival (PFS), OS and time to best response. Safety outcomes included incidence of neutropenia, thrombocytopenia, neutropenic fever, sepsis and bacteremia.

Results: Eighteen patients were included. The median age was 67-years-old (range 54-77), median bone marrow blast percentage was 12.2 (range 3-19), 66.7% of patients had not received prior treatment, 72.2% of patients had a TP53 mutation, 94.5% of patients had high or very high risk per IPSS-R. At diagnosis, 55.6% had MDS with biallelic TP53 inactivation and 33.3% had a myeloid neoplasm post cytotoxic therapy per WHO 2022.

Azacitidine was administered at 75 mg/m² IV daily for 5-7 days per cycle. Venetoclax dosing ranged from 100 mg to 400 mg daily adjusted for azole antifungal use. Duration of venetoclax varied with a median of 9 days of therapy across all cycles (range 6-21 days).

Sixteen patients were analyzed for the primary outcome. The ORR was 81.3%, including 12 bone marrow complete responses (CR) and 1 partial response (PR). Of the CRs, 2 had unknown blood counts at the time of marrow assessment, and 4 met IWG 2006 but not IWG 2023 criteria due to the lack of count recovery. All CRs occurred within 1-2 cycles, with a median time to first response of 25 days. Four patients (22.2%) proceeded to allogeneic stem cell transplant (SCT).

All patients (n = 18) were evaluated for survival outcomes. Median PFS was 4.2 months (95% CI 1.3 months-not reached) in the overall population, 3.7 months (95% CI 1-5.8 months) in patients with a TP53 mutation, and 17.3 months (95% CI 1.1 months-not reached) in patients without a TP53 mutation. Median OS was 5.6 months (95% CI 2.6-9.7 months) in the overall population, 4.4 months (95% CI 2.1-8.4 months) in patients with a TP53 mutation, and 17.3 months (95% CI 2.1 months-not reached) in patients without a TP53 mutation. Median time to transformation to AML was 4.2 months (95% CI 2.1 months-not reached). All patients developed Grade 3 or 4 neutropenia with a median time to absolute neutrophil count above 1000 x10⁹ cells/L of 33 days. Fifteen patients (83.3%) developed grade 3-4 thrombocytopenia with a median time to platelet count above 50 x10⁹ cells/L of 23.5 days. Ten patients (55.6%) developed neutropenic fever, and 7 patients (38.9%) developed bacteremia or sepsis.

Discussion: In this population of high and very high risk MDS patients receiving azacitidine and venetoclax, the ORR was high at 81.3%. Due to high response rates, this regimen may be beneficial as a bridge for patients proceeding with allogeneic SCT. PFS and OS were considerably shorter in patients with a TP53 mutation indicating a lack of sustained benefit in this population. There are several limitations to this study including the retrospective nature of the analysis, variability in venetoclax dosing and duration, and inability to access outside records.

Conclusion: Treatment with azacitidine and venetoclax in patients with higher-risk MDS may be helpful to achieve disease control quickly providing benefit in those intending to proceed to SCT. In our population, azacitidine and venetoclax did not provide long term disease control, especially in TP53-mutated disease.