Investigating New Therapies for High-Risk Therapy-Related MDS

Uma Borate, MBBS, describes myelodysplastic syndrome (MDS) as a condition where the bone marrow fails to function normally due to dysplasia, a state in which bone marrow cells are structurally and functionally abnormal. Classified as a type of blood cancer, the disease can progress into a stage known as high-risk MDS.

The classification of high-risk disease is determined by several factors:

• Blast Count: The percentage of immature white blood cells in the bone marrow.
• Cytogenetics: Specific chromosomal changes within the cells.
• Mutations: The presence of particular genetic alterations.

For over a decade, the standard of care for high-risk MDS has remained a class of drugs called hypomethylating agents (HMAs). Borate notes that despite their continued use, there has been limited progress in improving outcomes beyond using these agents as monotherapies.

While stem cell or bone marrow transplants represent a cornerstone of curative treatment, many patients are ineligible for transplant at the time of diagnosis. These patients require effective therapies to control the disease and potentially bridge them to a transplant.

Approximately 20% to 30% of high-risk MDS cases are classified as therapy-related MDS (t-MDS). This occurs in patients who previously received treatment—such as chemotherapy or radiation—for other cancers like breast cancer, lung cancer, or melanoma. While the initial cancer treatment may have been successful, an unfortunate late effect is the development of MDS.

Patients with t-MDS face unique clinical hurdles:

1. Lower Response Rates: They generally do not respond as well to conventional treatments, including HMAs.
2. Aggressive Profile: They often have a higher concentration of high-risk features compared to other MDS patients.
3. Clinical Trial Exclusion: Historically, these patients are often excluded from major clinical trials. For example, the VERONA trial—which investigated the combination of azacitidine (an HMA) and venetoclax (a BCL2 inhibitor)—specifically excluded patients with therapy-related disease.

Motivated by the lack of focus on this specific patient population, Borate initiated a study to address this unmet need. The research aims to evaluate whether the combination of azacitidine and venetoclax provides a clinical benefit specifically for patients with therapy-related MDS, ensuring that this vulnerable group receives the same level of scientific investigation and therapeutic attention as those with primary MDS.

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.