While allogeneic transplantation remains the only curative option for patients with high-risk myelodysplastic syndrome (HR-MDS), research continues to explore novel treatment strategies to improve outcomes for both transplant-eligible and ineligible patients. Despite the lack of improvement over the current standard of hypomethylating agents in monotherapy over the past 15 years, emerging data and ongoing trials offer hope for advancements in the field.
HR-MDS is characterized by a greater risk of progression to acute myeloid leukemia and/or short estimated survival, typically less than three years. This includes patients with a revised International Prognostic Scoring System (IPSS-R) score over 3.5 or those in a moderate-high or higher-risk category, according to the molecular IPSS (IPSS-M). Patients initially considered lower-risk but with high transfusion dependence and failure of available therapies may also be included.
Failed Combination Therapies
Over the past five years, several randomized clinical trials have compared azacitidine monotherapy with combinations involving drugs with different mechanisms of action, such as lenalidomide, vorinostat, pevonedistat, sabatolimab, durvalumab, eprenetapopt, and magrolimab. While these combinations showed promise in phase 1 and 2 trials, they failed to demonstrate a significant survival benefit over azacitidine monotherapy in phase 3 trials. The heterogeneity of MDS, with varying genetic and molecular profiles within the same high-risk group, may contribute to these failures. Trials often overrepresent patients with very high-risk mutations, such as TP53, making it more challenging to demonstrate improvements in the overall patient population. Additionally, the response criteria used may need updating.
Promising Ongoing Trials
Currently, two trials with pending final data are generating significant interest: the combination of azacitidine with venetoclax, which has shown high response rates in preliminary phases and is already approved for acute myeloid leukemia, and the combination of azacitidine with tamibarotene, specifically designed for patients with RAR-A overexpression, who account for approximately 30% to 50% of high-risk MDS patients.
The Role of Transplantation and Post-Transplant Therapies
As transplantation remains the only curative option, research into post-transplant therapies is crucial to address post-transplant relapse. Combining the antitumor effect derived from graft-vs-tumor with low-toxicity molecules can help control the disease, especially in the early months post-transplant.
The Future of MDS Treatment
The incorporation of molecular findings into routine practice will allow for the design of more specific treatments for patients. The favorable results of ivosidenib in patients with IDH1 mutations, demonstrating good responses and survival, particularly when used in the first line, exemplify this approach. While this mutation affects a small proportion of patients, this study indicates the path forward, designing studies for more homogeneous patient populations.
