1. Significantly more patients in the imetelstat group achieved RBC transfusion independence at 8 weeks after treatment compared to placebo.

2. Grade 3-4 treatment-related adverse events were greater in the imetelstat group.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Patients with red blood cell transfusion-dependent lower-risk myelodysplastic syndromes (LR-MDS) face unmet medical needs when unresponsive to erythropoiesis-stimulating agents (ESAs). Imetelstat, a telomerase inhibitor, showed promise in a phase 2 trial; however, limited evidence exists surrounding its therapeutic efficacy. This randomized controlled trial aimed to compare imetelstat with placebo in ESA-relapsed, ESA-refractory, and ESA-ineligible LR-MDS patients. The primary outcome was RBC transfusion independence (RBC-TI) at 8 weeks, while key secondary outcomes were the rate of grade 3-4 treatment-emergent adverse events. According to study results, imetelstat demonstrated a higher 8-week RBC-TI rate compared to placebo but was associated with more severe adverse advents. Although this study was well done, it was limited by a high discontinuation rate in both groups.

Click to read the study in The Lancet

Relevant Reading: Telomerase Inhibitor Imetelstat in Patients with Essential Thrombocythemia

In-depth [randomized-controlled trial]: Between Sept 11, 2019, and Oct 13, 2021, 317 patients were screened for eligibility across 118 tertiary sites in 17 countries. Included were patients ≥ 18 years with red blood cell transfusion-dependent LR-MDS ineligible for or unresponsive to ESAs. Altogether, 178 patients (118 in imetelstat and 60 in placebo) were included in the study. The primary outcome of RBC-TI at 8 weeks was significantly higher in imetelstat versus placebo (40% vs. 15%, p=0.0008). However, the secondary outcome of grade 3-4 treatment-emergent adverse events was also higher for imetelstat than placebo (91% vs. 47%), with neutropenia (68%) and thrombocytopenia (62%) being most common. Overall, findings from this study suggest that imetelstat provides a novel mechanism of action, offering durable transfusion independence and disease-modifying activity for heavily transfused LR-MDS patients unresponsive to or ineligible for erythropoiesis-stimulating agents.

Image: PD

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