Safety and Efficacy of Aza/Ven in Therapy-Related MDS

Therapy-related myelodysplastic syndrome (tMDS) is a highly aggressive malignancy resulting from prior genotoxic therapies, accounting for 10 to 20% of new MDS cases. Because tMDS is often characterized by complex cytogenetics and adverse-risk mutations, standard hypomethylating agents (HMAs) typically yield a low complete remission (CR) rate of approximately 14%. This phase 2, multicenter study (NCT05379166) evaluated the safety and efficacy of azacitidine in combination with venetoclax (Aza/Ven) specifically for newly diagnosed patients with tMDS, a group notably excluded from the previous phase 3 VERONA trial (NCT04401748).

The study enrolled 23 patients with a median age of 67 who had high-risk disease; 83% possessed TP53 mutations and 81% had a complex karyotype. Patients received 75 mg/m² of azacitidine for 7 days and 400 mg of venetoclax for the first 14 days of a 28-day cycle. The primary endpoint was the CR rate by the end of the fourth cycle.

Interim results showed an overall response rate (ORR) of 56.5%, including a CR rate of 21.7%, which met the planned interim analysis endpoint. While the median overall survival (OS) for all patients was 10 months, it reached 14.75 months for responders. Notably, all patients who achieved CR had biallelic TP53 mutations, and the combination served as a successful bridge to allogeneic stem cell transplant for some patients.

Regarding safety, 91% of patients experienced grade 3 or higher treatment-emergent adverse events (TEAEs), the most common being anemia (52%), neutropenia (52%), and febrile neutropenia (48%). Despite these high rates of hematological toxicity, only 1 patient discontinued treatment due to adverse events. The researchers concluded that Aza/Ven is an effective induction strategy and a feasible bridge to transplant for this exceptionally high-risk population with limited standard care options.

Read the full interview with Dr Borate here.

REFERENCE

Borate U et al. Phase II study of clinical efficacy of venetoclax in combination with azacitidine in patients with therapy related myelodysplastic syndrome (t-MDS). Presented at: 67th Annual ASH Meeting; December 6–9, 2025; Orlando, Florida. Abstract 238.