Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic disorders characterized by marked heterogeneity and complex prognosis. While treatment of intermediate- and high-risk disease remains challenging, there is also considerable room to optimize therapeutic strategies for lower-risk MDS.
At the 67th American Society of Hematology (ASH) Annual Meeting, several innovative studies shed new light on the management of low-risk MDS. Oncology Frontier – Hematology Frontier invited Prof. Huaqian Wang from Tianjin Medical University General Hospital to interpret a representative randomized, multicenter trial that evaluated shorter courses of hypomethylating agents (HMAs) in lower-risk MDS, and to discuss the clinical implications of these findings.
Study overview
Publication number: 487 Title: A randomized, multicenter trial of shorter durations of hypomethylating agents in lower-risk Myelodysplastic Syndromes Chinese title: 在低危骨髓增生异常综合征患者中缩短去甲基化药物治疗时间：一项随机、多中心试验
Background
In higher-risk MDS, standard HMA dosing typically consists of azacitidine 75 mg/m² for 7 days or decitabine 20 mg/m² for 5 days per cycle. For lower-risk MDS, the possibility that shorter HMA schedules might remain effective while reducing toxicity and treatment burden has attracted increasing interest. This trial was designed to clarify how reduced-duration HMA therapy influences the natural history of low-risk disease.
Methods
This randomized, multicenter study enrolled patients with low-risk or intermediate-1 MDS, as well as patients with chronic myelomonocytic leukemia. Three HMA regimens were evaluated: 3-day decitabine, 3-day azacitidine, and 5-day azacitidine.
Patients were stratified by transfusion status into transfusion-dependent and transfusion-independent groups. Transfusion dependence was defined as requiring red blood cell or platelet transfusion at any time before study treatment. Transfusion-independent patients were also randomized to a best supportive care (BSC) arm.
Treatment allocation used Bayesian adaptive randomization, favoring regimens associated with better event-free survival (EFS).
The primary endpoint was EFS, defined as the time from randomization to the first occurrence of any of the following: lack of response after six cycles, loss of response, increase in bone marrow blast percentage, or discontinuation due to adverse events. Key secondary endpoints included overall survival (OS), achievement of transfusion independence, and responses according to 2006 International Working Group (IWG) criteria.
Overall response rate (ORR) was defined as the proportion of evaluable patients achieving complete remission, hematologic improvement, or marrow complete remission.
Results
A total of 247 patients were randomized: 151 transfusion-dependent and 96 transfusion-independent. The median age was 70.8 years; 25% were women and 13% were of Black, Asian, Hispanic or Middle Eastern background. Median IPSS score was 0.5, and median IPSS-R score was 3.
Among 230 patients who underwent next-generation sequencing, the most frequent mutations were ASXL1 (31%), SF3B1 (19%), RUNX1 (14%), DNMT3A (13%), and TP53 (8%).
In transfusion-dependent patients, ORR was 53% in the 3-day decitabine arm, 53% with 3-day azacitidine, and 48% with 5-day azacitidine. The proportion of patients converting from red cell or platelet transfusion dependence to independence was 44%, 42%, and 40% in the 3-day decitabine, 3-day azacitidine, and 5-day azacitidine arms, respectively.
In transfusion-independent patients, ORR was 50% with 3-day decitabine, 54% with 3-day azacitidine, 70% with 5-day azacitidine, and 17% with best supportive care. In this subgroup, response duration was longer with 3-day decitabine or 5-day azacitidine than with 3-day azacitidine.
Early mortality was low: the 30-day mortality rate was 1%, and the 60-day mortality rate 2%. Across transfusion strata, decitabine was associated with a higher incidence of grade ≥3 thrombocytopenia than either 3-day or 5-day azacitidine.
In multivariable Cox models adjusted for age, performance status, disease risk, and molecular features, 5-day azacitidine produced superior EFS compared with 3-day azacitidine in transfusion-dependent patients. EFS with 5-day azacitidine and 3-day decitabine did not differ significantly in this group, but 5-day azacitidine was associated with better OS than 3-day decitabine.
In transfusion-independent patients, 5-day azacitidine yielded superior EFS compared with 3-day decitabine, 3-day azacitidine and best supportive care, and also improved OS relative to 3-day decitabine and best supportive care.
Conclusion
Shortened HMA courses are safe and effective in lower-risk MDS. Among the regimens tested, 5-day azacitidine offered the most favorable balance between safety and efficacy and provided the most consistent benefits in EFS and OS.
Expert commentary – Prof. Huaqian Wang
The randomized, multicenter trial (NCTOZG9280) presented at ASH 2025 directly addresses a pressing question in daily practice: can we reasonably shorten HMA schedules in low-risk MDS to reduce treatment burden while maintaining efficacy and safety?
This study gives a clear and encouraging answer. In low-/INT-1-risk patients, shortened HMA regimens—3- to 5-day courses instead of classical 7-day azacitidine or 5-day decitabine—still produced meaningful response rates and clinical benefit.
Several points are particularly relevant for clinicians.
First, for transfusion-independent patients, 5-day azacitidine stood out. It not only achieved the highest ORR but also delivered superior EFS and OS compared with 3-day regimens and best supportive care. This strongly supports earlier, proactive intervention in lower-risk patients who already show symptoms or signs of progression, rather than adopting a prolonged “watch and wait” strategy in all cases.
Second, the trial clearly delineates the relative strengths of the tested regimens. Five-day azacitidine emerged as the “winning schedule,” offering the best balance of efficacy and tolerability and the most consistent survival benefit. In contrast, 3-day decitabine was associated with more frequent grade ≥3 thrombocytopenia, reminding us to be cautious in patients with poor marrow reserve or those who urgently need platelet recovery.
Third, for transfusion-dependent patients, shortened HMA schedules effectively reduced transfusion requirements, with similar ORR across the three active arms. In this setting, the superior EFS profile of 5-day azacitidine makes it a reasonable preferred option when choosing a short-course regimen.
Overall, this study helps shift our treatment philosophy in low-risk MDS—from a simple choice between “observation” and “full-length HMA” towards a more nuanced, risk-adapted and burden-conscious approach. Five-day azacitidine can serve as a practical starting platform for active therapy in suitable low-risk patients, reducing treatment intensity without sacrificing outcomes and potentially improving survival.
These findings are likely to influence future guideline updates and will encourage further research into more precise, individualized, low-intensity strategies for low-risk MDS. The ultimate goal is not only to prolong survival but also to improve quality of life by tailoring treatment intensity to disease biology and patient needs.
Expert profile
Prof. Huaqian Wang Tianjin Medical University General Hospital
Prof. Wang is Chief Physician, doctoral supervisor and Deputy Director (administrative) of the Department of Hematology at Tianjin Medical University General Hospital.
He has served as a member and secretary of the Red Cell Disorders (Anemia) Working Group of the 9th–11th Hematology Branch Committees of the Chinese Medical Association, and as Vice-Chair of the 10th Red Cell Disorders Working Group. He is also a member of the Leukemia and Lymphoma Working Group of the 11th Hematology Branch Committee.
Prof. Wang is a member of the 5th Hematology Physicians Committee of the Chinese Medical Doctor Association, a member of the MDS Academic Working Committee of the Hematology Branch of the Chinese Geriatrics Society, and a member of the second MDS/MPN Working Group of the Hematologic Malignancies Committee of the Chinese Anti-Cancer Association.
