Addressing the Overlooked: A New Approach to Treatment-Related High-Risk MDS

For patients facing myelodysplastic syndrome (MDS), the diagnostic journey is often complex and daunting.

While MDS is considered a type of blood cancer, the progression to high-risk MDS marks a critical turning point. This classification depends on the number of blasts, or immature white blood cells, in the marrow, chromosomal changes, and specific mutations. For a decade, the standard of care has remained a class of agents called hypomethylating agents (HMAs).

"We haven't really made substantial progress past using these hypomethylating agents by themselves in patients with high-risk MDS," Uma Borate, MBBS, hematologist specialist at The James, The Ohio State Comprehensive Cancer Center, said in an interview with Targeted Oncology.

The Challenge of Treatment-Related MDS

A significant subset of patients—roughly 20% to 30%—suffer from what is known as treatment-related or therapy-related MDS (t-MDS). These patients developed MDS as an effect of prior treatments for other cancers, such as breast cancer, lung cancer, or melanoma.

Borate explained the unique difficulty this group faces.

"We do know from prior studies that treatment-related MDS patients, unfortunately, don't respond as well to our conventional treatments, including hypomethylating agents. They inherently have a higher percentage of patients with high-risk disease, even within high-risk MDS,” she said.

Despite their high-risk status, these patients are frequently excluded or removed from a number of ongoing clinical trials. Driven by a desire to provide answers for this overlooked population, Borate led a specialized phase 2 study (NCT05379166),¹ the findings of which were presented at the 67^th Annual ASH Meeting and Exposition.²

Study Design: A Potent Combination

The single-arm phase 2 study tested a combination of 2 primary agents:

• Azacitidine: The standard-of-care hypomethylating agent.
• Venetoclax (Venclexta): A BCL-2 inhibitor currently approved in acute myeloid leukemia.

The primary goal was to measure complete remission (CR) rates, as these often correlate with long-term patient outcomes. The study also monitored secondary endpoints like overall survival and how many patients could successfully proceed to a stem cell transplant.

Efficacy and the TP53 Factor

The results offered a mix of sobriety and hope. While the safety signals—such as low blood counts and neutropenia—were consistent with previous studies, the efficacy data revealed a significant hurdle: every single patient in the study had a TP53 abnormality or mutation.

"What we have learned is these patients, unfortunately, do not do well with either azacitidine and venetoclax generally, but it didn't prevent any of them from getting into a complete remission at various time points," said Borate.

Key findings included:

• Remission: About a third or more of patients achieved complete remission.
• Transplant Success: Patients who achieved CR and moved to a stem cell transplant "did really, really well,” according to Borate.
• Survival: Those who reached transplant had double the survival rate of those who did not.

The Path Forward

While the combination shows promise, Borate emphasized that the medical community is still searching for the best treatment to improve overall survival for those who cannot reach transplant.

"I’m still hoping that we would get other new, novel agents that may ultimately lead to that goal, because that’s what patients want, right? Everybody wants to live longer, and they want to live with good quality of life," she said.

Reflecting on the trial, Borate shared her pride in focusing on a group of patients that the industry often avoids.

"I think we weren't scared or intimidated by that group, and we wanted to answer a specific question for them. I really wanted to mention how grateful I am to the patients that participate in these studies, because it’s not easy... they’re giving valuable time... to make somebody else's life better,” she concluded.

REFERENCES

1. Venetoclax and azacitidine for treatment of therapy related or secondary myelodysplastic syndrome. ClinicalTrials.gov. Updated December 22, 2025. Accessed February 3, 2026. https://clinicaltrials.gov/study/NCT05379166

2. 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.