Dr Iyer on the Mechanism of Action of Imetelstat in Lower-Risk MDS

Sunil Iyer, MD, assistant professor, medicine, Columbia University Irving Medical Center, Herbert Irving Pavilion, discusses the mechanism of action of imetelstat in patients with lower-risk myelodysplastic syndrome (MDS) with anemia.

Imetelstat operates uniquely as a telomerase inhibitor, targeting an enzyme crucial for maintaining telomere length in cells, Iyer begins. Telomeres, composed of nucleotide sequences, naturally shorten with each cell division until reaching a critical length that triggers DNA damage signals, leading to cellular senescence and eventual apoptosis, according to Iyer. Although some cells, such as hematopoietic stem cells and certain immune cells, express telomerase to sustain telomere length and avoid apoptosis, most somatic cells lack telomerase expression, limiting their lifespan, he explains; however, in MDS, abnormal cells exhibit telomerase expression, making it a prime target for therapeutic intervention.

Concerns about potential cytopenia arising from telomerase inhibition are mitigated by the differential impact of imetelstat on malignant vs normal cells, Iyer continues, adding that unlike malignant cells in MDS that overexpress telomerase and are more vulnerable to telomerase inhibition, normal cells only transiently express telomerase, leading to less severe cytopenia and transient effects on normal hematopoietic stem cells.

The phase 2/3 IMerge/MDS3001 trial (NCT02598661) evaluated imetelstat, a first-in-class telomerase inhibitor, vs placebo in patients with lower-risk MDS dependent on red blood cell (RBC) transfusions, he expands. Notably, these patients had relapsed on or were refractory to erythropoiesis-stimulating agents (ESAs), lacked deletion 5q, and were naive to lenalidomide (Revlimid) and hypomethylating agents. Unlike the phase 3 COMMANDS trial (NCT03682536), which focused on treatment-naive patients, IMerge enrolled a specific subset of patients with MDS characterized by ESA resistance or intolerance, Iyer reports. The primary end point of IMerge was to assess rates of RBC transfusion independence at 8 weeks, 24 weeks, and 1 year to determine the durability of treatment response and potential benefits of imetelstat in this patient population. This study provided valuable insights into the efficacy and safety of imetelstat as a targeted therapy for patients with MDS who are refractory to standard treatments, he concludes.