Efficacy and Safety of Venetoclax in Combination with Hypomethylating Agents for the Treatment of High-Risk Myelodysplastic Syndromes–Real-World Analyses
Authors: Zhang Jian , Xu Yang , Lin Zhihong , Chen Jun , Liu Limin , Wu Depei , Qiu Huiying 
Published: December 2024

Introduction The combination of venetoclax with hypomethylating agent (HMA) showed synergistic effects and most of the adverse events were manageable in preclinical studies of high-risk myelodysplastic syndromes (HR MDS), which provides a new therapeutic option for intermediate- and high- risk MDS patients. In addition, venetoclax-based combination therapy for MDS has the potential to be a bridging therapy before allogeneic hematopoietic stem cell transplantation (allo-HSCT), thus potentially improving patients' final outcomes. Although the combination of venetoclax with HMA demonstrates potential therapeutic promise, its widespread use in HR MDS requires further observation. This retrospective and observational study aimed to analyze the clinical efficacy and safety of venetoclax in combination with HMA for the treatment of HR MDS, in order to provide additional evidence support.
Methods Clinical data of 30 patients with HR MDS treated with the combination of venetoclax and HMA at the First Affiliated Hospital of Soochow University from March 2019 to November 2022 were included and analyzed. All patients were defined by the Molecular International Prognostic Scoring System score of &gt; 0 with an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. All patients with HR MDS were treated with the combination of venetoclax and HMA with the following regimen: venetoclax 100 mg orally daily on Day 1, 200 mg on Days 2-14 and azacitidine (Aza) 75 mg/m2 subcutaneously on Days 1-7 (n=22) or decitabine (DAC) 25 mg/m2 intravenously on Days 1-5 (n=8). During the treatment period, the dosage of venetoclax was adjusted appropriately based on patients' tolerance and possible adverse events.
The response to treatment was determined according to the MDS criteria of the International Working Group (IWG), the complete remission (CR), marrow CR (mCR), partial remission (PR), overall survival (OS), and adverse events of all included patients were reported.
Results In the high-risk group of MDS patients treated with venetoclax combined with HMA, 4 were male and 16 were female. The median age was 57 years (range, 23-79). 6 cases achieved CR, 18 cases achieved mCR, 2 cases achieved PR, the median OS was 29.3 months, the median follow-up was 24.5 months (95% CI, 15.8-33.2). In addition, patients who achieved CR/mCR after treatment had a significantly longer OS than those who did not (P = 0.002). The median OS was not determined and 5.9 months (95% CI, 2.9-8.9) in the CR/mCR group (n=24) and non-CR/mCR (n=6) group, respectively. Moreover, 12 patients were treated with allo-HSCT. There were grade 3 or higher hematologic adverse events including thrombocytopenia (n=14), neutropenia (n=14), febrile neutropenia (n=10) and anemia (n=7) as well as gastrointestinal adverse events of any grade, such as vomiting (n=7), diarrhea (n=5), and constipation (n=4). Seven of the 30 patients had their venetoclax dose reduced to 50 to 100 mg/day because of their poor blood routine tests. In addition, 18 patients received voriconazole/posaconazole for the prevention of fungal infections due to the development of neutropenia, and the venetoclax dose was reduced to 100 mg/day. Three of these patients developed severe neutropenia with severe infections, and venetoclax was discontinued.
Conclusion Venetoclax in combination with HMA is an effective and safe treatment option in patients with HR MDS. Continuous attention to the monitoring and management of adverse events is essential for patients' safety in this combination therapy.