Evolving Treatment Paradigms in Lower-Risk MDS: Current Therapeutic Options and Mechanistic Approaches

Erythropoiesis-stimulating agents (ESAs) have long been a foundational treatment for anemia in lower-risk myelodysplastic syndrome (MDS). They work by binding to erythropoietin receptors on hematopoietic stem cells, stimulating early-stage red blood cell production and leading to increased hemoglobin levels. Their mechanism is well understood, and they remain a standard option for many patients, particularly those with lower endogenous erythropoietin levels.

Luspatercept, by contrast, targets a different stage of red blood cell development. Rather than stimulating early erythropoiesis, it enhances late-stage erythroid maturation by inhibiting the TGF-beta superfamily of ligands that normally suppress red blood cell formation. This distinct mechanism allows it to complement or even surpass the activity of ESAs in certain patients, particularly those who may not respond well to early-stage stimulation alone.

A third option, imetelstat, also takes a unique approach. As a telomerase inhibitor, it promotes apoptosis of malignant MDS cells by shortening telomeres, thereby reducing the expansion of abnormal clones. This mechanism may support restoration of healthy hematopoiesis. With these mechanistically distinct therapies now available, clinicians have more options to tailor anemia treatment in MDS based on the patient's disease characteristics and response history.