MDS Subtype Shows Poor Response to Venetoclax, Needs New Therapies

Erythroid-Predominant Form Driven by BCL-XL, Not BCL2

A specific subtype of myelodysplastic neoplasms (MDS), known as erythroid-predominant MDS (EP MDS), demonstrates unique genetic markers and dismal outcomes with standard venetoclax treatments. Researchers are urging the development of alternative therapeutic strategies for these patients.

EP MDS Distinct Genomic Profile Revealed

EP MDS, accounting for 18% of newly diagnosed cases, frequently carries TP53 mutations. These patients exhibited a significantly higher incidence of multi-hit TP53 mutations (36% versus 17%), alongside increased rates of BCOR and WT1 mutations compared to non-EP MDS cases.

Researchers analyzed 371 patients with newly diagnosed MDS and a separate group of 112 higher-risk MDS patients receiving hypomethylating agents plus venetoclax. Strict criteria excluded samples with hemodilution to ensure accuracy.

Three Genetic Subgroups Impact Survival

Within EP MDS, three distinct genetic subgroups emerged, each displaying notably different survival durations. Patients with TP53 mutations had a median survival of 11.4 months, while those with splicing mutations had an unreached median survival. The “not otherwise specifiable” group survived a median of 19.5 months, highlighting significant variations.

Venetoclax Therapy Proves Ineffective for EP MDS

In patients treated with hypomethylating agents and venetoclax, EP cases showed a higher rate of leukemic transformation (32% versus 12%) and markedly worse survival (8.3 months compared to an unreached median for others). This poorer performance is linked to the cancer cells’ dependence on BCL-XL, rather than the targeted BCL2 protein.

“Overall, our findings provide a detailed characterization of EP MDS and demonstrate its distinct molecular and clinical profile compared to NEP MDS. Notably, we demonstrate that although EP MDS comprises distinct genomic subsets with diverging clinical behavior, a group of these patients experience poor outcomes with currently available therapies.”

—The Study Authors

Analysis revealed that EP MDS cases had a substantially higher frequency of BCL-XL-positive cells (62.5% versus 10%), with concurrent lower levels of BCL2-positive cells (5% versus 30%). This points to a potential therapeutic vulnerability.

Future Directions Focus on BCL-XL Inhibitors

The study, led by Alexandre Bazinet, MD, Sanam Loghavi, MD, and Guillermo Montalban-Bravo, MD, at The University of Texas MD Anderson Cancer Center, suggests that BCL-XL inhibitors may offer a promising avenue for treatment. Current therapies, like venetoclax, may not be effective due to EP MDS’s cellular reliance on BCL-XL.

The research team acknowledges limitations, including its single-center nature and the low prevalence of EP MDS, which made definitive subgroup identification challenging. Further studies are needed to validate increased BCL-XL expression and its functional impact, and to determine if TP53 mutations or erythroid differentiation drive the poor response to venetoclax-based treatments.

The study was supported by grants from The University of Texas MD Anderson Cancer Center and its Moon Shot initiatives. Several authors disclosed financial ties to pharmaceutical companies, including Amgen, Astellas, and AbbVie.

The incidence of MDS globally is estimated to be between 1 to 5 cases per 100,000 people annually, with the disease becoming more common with age. (Source: National Cancer Institute, 2024)