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.

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Sunil Iyer, MD, discusses the mechanism of action of imetelstat in patients with lower-risk myelodysplastic syndrome with anemia.

Dr Iyer on the Design of the COMMANDS Trial in Lower-Risk MDS With Anemia

Sunil Iyer, MD, assistant professor, medicine, Columbia University Irving Medical Center, Herbert Irving Pavilion, discusses the mechanism of action of luspatercept-aamt (Reblozyl), 

 (NCT03682536) in patients with lower-risk myelodysplastic syndrome (MDS) with anemia.

Luspatercept operates through a unique mechanism of action to address disease-related anemia in lower-risk MDS, Iyer begins. Traditionally, erythropoiesis-stimulating agents (ESAs) were the standard medication class used in this patient population, Iyer says. In MDS, cytopenia and ineffective erythropoiesis occur due to signaling from the TGFβ cytokine family, he says. Ligands such as activin and myostatin bind to the activin receptor on the surface of red blood cells (RBCs), leading to impaired erythropoiesis, Iyer explains, adding that this impairment results in immature RBCs that struggle to mature properly.

Luspatercept functions by resembling the extracellular domain of the activin receptor and then binding to TGFβ ligands, preventing them from engaging with the receptor, Iyer elucidates. This interference reduces signaling, facilitating RBC maturation and addressing anemia associated with MDS. The COMMANDS trial focused on evaluating luspatercept compared with ESAs in patients with lower-risk MDS and anemia requiring RBC transfusions, particularly those who had not previously received ESAs, he continues. Notably, this study design differed from previous trials that typically included patients who had already been treated with ESAs and were refractory to them, Iyer shares.

Luspatercept previously received FDA approval

 for patients with low-risk MDS with ring sideroblasts with or without the presence of an 

 mutation who had progressed on ESA therapy, he expands. The unique aspect of the COMMANDS study was its examination of the efficacy and safety of luspatercept as a frontline treatment compared with ESAs in a broader patient cohort. This trial sought to provide valuable insights into the role of luspatercept in the initial management of anemia in lower-risk MDS, potentially impacting treatment strategies for this patient population, Iyer concludes.

Sunil Iyer, MD, discusses the design of the phase 3 COMMANDS trial in patients with lower-risk myelodysplastic syndrome with anemia.

Sunil Iyer, MD

Articles

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

Dr Iyer on the Design of the COMMANDS Trial in Lower-Risk MDS With Anemia