Yale Cancer Center's Dr. Amer Zeidan recently provided insights into the evolving landscape of novel therapies for myelodysplastic syndromes (MDS), highlighting both challenges and promising developments in immunotherapy and targeted approaches.
MDS represents a heterogeneous group of hematologic disorders characterized by ineffective hematopoiesis, cytopenias, and risk of progression to acute myeloid leukemia. Despite advances in treatment options, many patients, particularly those with higher-risk disease, continue to face poor outcomes, underscoring the urgent need for innovative therapeutic strategies.
Immunotherapy Approaches Show Mixed Results
Initial efforts to leverage immune checkpoint inhibition in MDS have yielded disappointing results. A phase 1 clinical trial (NCT02117219) evaluating durvalumab (Imfinzi), a PD-L1 inhibitor, failed to demonstrate meaningful therapeutic benefit in MDS patients, according to Dr. Zeidan, who serves as director of Early Therapeutics Research and the Leukemia and Myeloid Malignancies Program at Yale Cancer Center.
More promising has been the development of sabatolimab (MBG453), a novel TIM-3 inhibitor. The randomized phase 2 STIMULUS-MDS1 trial (NCT03946670) in treatment-naive patients with higher-risk MDS showed early signals of efficacy when sabatolimab was combined with hypomethylating agents, including potentially durable responses. However, the combination did not significantly improve progression-free survival or complete response rates.
"The subsequent phase 3 STIMULUS-MDS2 trial assessed sabatolimab plus azacitidine versus azacitidine plus placebo in 530 patients with first-line higher-risk MDS or chronic myelomonocytic leukemia," Dr. Zeidan explained. Data presented at the 2024 European Hematology Association Congress revealed a numerical, though not statistically significant, increase in overall survival with the investigational combination compared to azacitidine plus placebo.
Promising Ongoing Clinical Trials
Several ongoing trials are generating significant interest in the MDS field. The phase 3 VERONA study (NCT04401748) is investigating the combination of azacitidine plus venetoclax (Venclexta) versus azacitidine plus placebo in patients with newly diagnosed, higher-risk MDS. This trial builds on the success of venetoclax combinations in acute myeloid leukemia and aims to determine whether similar benefits can be achieved in MDS.
For patients who are transfusion independent but remain anemic, the phase 3 ELEMENT-MDS trial (NCT05949684) is evaluating luspatercept-aamt (Reblozyl). Luspatercept has already demonstrated efficacy in reducing red blood cell transfusion dependence in lower-risk MDS patients with ring sideroblasts, and this trial seeks to expand its utility to a broader patient population.
Novel Mechanisms Under Investigation
Early-phase research is exploring innovative mechanisms of action. The pyruvate kinase activator tebipivat (AG-946) is being developed for patients with lower-risk MDS with anemia, targeting metabolic pathways that may improve erythropoiesis.
In the immunotherapy space, novel immune checkpoint inhibitors targeting pathways beyond PD-1/PD-L1 are under investigation. These include AK117, which targets CD47, and bexmarilimab, which targets Clever-1, both being evaluated in patients with high-risk MDS.
"I'm quite excited about several of these agents, and hopefully we get to report on the results from the trials [evaluating them] in the near future," Dr. Zeidan remarked.
Clinical Implications and Future Directions
The development of effective therapies for MDS remains challenging due to the heterogeneity of the disease and the complex interplay of genetic and immunologic factors. While some immunotherapy approaches have shown limited efficacy as monotherapies, their potential in rational combinations with hypomethylating agents or other targeted therapies continues to be explored.
The field is increasingly moving toward biomarker-driven approaches to identify patients most likely to benefit from specific interventions. Molecular and immunologic profiling may help guide treatment selection and sequence, potentially improving outcomes in this difficult-to-treat patient population.
As these clinical trials mature and report results, the treatment landscape for MDS is likely to evolve significantly in the coming years. The integration of novel agents targeting diverse pathways offers hope for improved outcomes in both higher-risk and lower-risk MDS patients, addressing the spectrum of clinical needs from disease modification to quality of life enhancement.
Healthcare providers treating MDS patients should remain attentive to emerging data from these trials, as they may soon inform new standards of care and treatment algorithms for this challenging hematologic malignancy.
