# 15-Day Duration of Venetoclax Combined with Azacitidine in Treatment-Naive Higher-Risk Myelodysplastic Syndromes: A Prospective Multicenter Study

## TL;DR

A 15-day treatment combining venetoclax and azacitidine showed high effectiveness and manageable side effects in patients with high-risk myelodysplastic syndromes.

## Contribution

Demonstrates a 15-day venetoclax-azacitidine regimen's high response rates and safety in treatment-naive high-risk MDS patients.

## Key findings

- The regimen achieved an 85.7% overall response rate and 35.7% complete remission rate.
- Responses were consistent across molecular and risk subgroups with manageable toxicity.
- High neutrophil count and adverse cytogenetics were favorable factors for response.

## Abstract

This study evaluated the efficacy and safety of a 15-day venetoclax combined with azacitidine regimen in 28 untreated high-risk myelodysplastic syndromes patients. Results demonstrated that the regimen was highly effective, with an overall response rate of 85.7% and a complete remission rate of 35.7%. Consistent responses were observed across molecular and risk subgroups. The most common severe hematologic toxicity was neutropenia. The study confirmed that this combination regimen yields high response rates with manageable safety, and it may be particularly beneficial for patients with high neutrophil counts, adverse cytogenetics, or those eligible for hematopoietic stem cell transplantation, warranting further validation in larger trials.

Background: Higher-risk myelodysplastic syndromes (HR-MDS) carry a high risk of progression to acute myeloid leukemia and poor overall survival. Hypomethylating agents (HMAs), such as azacitidine, remain the standard of care but have limited efficacy. A 15-day venetoclax-azacitidine regimen has shown promising objective response rates (ORR) and potential as a bridge to allogeneic hematopoietic stem cell transplantation (HSCT) in relapsed/refractory HR-MDS. We conducted a prospective multicenter trial to evaluate its efficacy and safety in previously untreated patients. Methods: This multicenter prospective study enrolled treatment-naïve HR-MDS patients (IPSS-R > 3.5). Venetoclax was administered on days 1–15 (escalated from 100 to 400 mg), combined with azacitidine (75 mg/m2) on days 1–7 of each 28-day cycle. The primary endpoint was ORR (2006 IWG criteria); secondary endpoints included complete remission (CR), overall survival (OS), and AML progression. Results: Twenty-eight patients (median age: 63 years) were enrolled, with a median follow-up of 8.5 months. ORR was 85.7% per 2006 IWG (CR: 35.7%, marrow CR: 50.0%), and 78.6% per 2023 IWG (CR: 35.7%). Responses were consistent across molecular and IPSS-R subgroups. Median OS was not reached. High neutrophil count and high cytogenetic risk were favorable factors; TP53 mutation/deletion was an adverse prognostic marker. Grade 3–4 hematologic toxicities included neutropenia (96.4%), anemia (71.4%), and thrombocytopenia (64.3%). Serious adverse events (35.7%) were mainly infections. No dose-limiting or unexpected toxicities were observed. Conclusions: The 15-day venetoclax plus azacitidine regimen demonstrated high efficacy and manageable toxicity in treatment-naïve HR-MDS. It may be particularly beneficial for patients with high neutrophil counts, adverse cytogenetics, or those eligible for HSCT, supporting further investigation in larger trials.