Abstract
Existing treatments for lower-risk myelodysplastic syndromes/neoplasms (LR-MDS) focus on symptom relief. Until recently, altering the disease course was rarely considered a therapeutic objective. The first-in-class, direct, competitive telomerase inhibitor, imetelstat, demonstrated significantly higher rates of red blood cell (RBC) transfusion independence (TI) versus placebo in patients with non-del(5q), RBC transfusion-dependent LR-MDS who were relapsed/refractory to or ineligible for erythropoiesis-stimulating agents in the Phase 3 IMerge study (NCT02598661). In this exploratory analysis of IMerge, patients treated with imetelstat had greater sustained reductions in variant allele frequency of multiple mutations versus placebo recipients, which was positively associated with RBC-TI duration. Subsequent analyses showed that 70% of patients with a cytogenetic response with imetelstat achieved >= 1-year RBC-TI. Additionally, higher rates of >= 1-year RBC-TI were observed in patients with maximum variant allele frequency reduction of >= 50% in SF3B1 (58% vs. 7%), TET2 (90% vs. 9%), DNMT3A (100% vs. 13%), or ASXL1 (50% vs. 0%) and patients with >= 50% bone marrow ring sideroblast reduction (46% vs. 0%) versus patients who did not. Lastly, 60% of patients with >= 1-year RBC-TI had >= 50% reduction in telomerase activity/human telomerase reverse transcriptase RNA. These results suggest that imetelstat targets clonal progenitor cells and may modify LR-MDS biology.