Background: Unmet needs remain for red blood cell (RBC) TD pts with LR-MDS R/R or ineligible for ESA. In P2 of the IMerge study (NCT02598661), heavily RBC TD ESA R/R non-del(5q) LR-MDS pts naive to lenalidomide and hypomethylating agents (len/HMA) treated with imetelstat, a telomerase inhibitor, achieved durable and continuous transfusion independence (TI). We report primary data from the P3 study of imetelstat in such pts. Methods: Heavily RBC TD ESA R/R non-del(5q) LR-MDS pts naive to len/HMAs were randomized 2:1 to receive imetelstat 7.5 mg/kg or placebo every 4 wks. Primary endpoint was 8-wk TI; subgroup analyses included IPSS risk, prior transfusion burden and ring sideroblast (RS) status. Secondary endpoints included 24-wk TI, TI duration and hematologic improvement-erythroid (HI-E). Variant allele frequency (VAF) changes were explored. Results: As of Oct 2022, 178 pts were randomized. The primary endpoint was met (Table); 39.8% vs 15.0% of pts receiving imetelstat vs placebo, respectively, achieved 8-wk TI. The rate of 8-wk TI was significantly higher with imetelstat vs placebo across subgroups, including RS negative pts. Median TI duration was significantly longer for imetelstat vs placebo, 51.6 vs 13.3 wks, P < 0.001. Pts receiving imetelstat had significantly higher mean hemoglobin (P < 0.001) and fewer transfusions (P = 0.042) over time than those on placebo. In 3 of 4 genes frequently mutated in MDS, VAF reduction was significantly greater in pts treated with imetelstat than placebo: SF3B1 (P < 0.001), TET2 (P = 0.032), DNMT3A (P = 0.019) and ASXL1 (P = NS). SF3B1 VAF reduction correlated with longer TI duration, P < 0.001. No new safety signals were identified. The most common Grade 3/4 AEs were thrombocytopenia and neutropenia, with similar rates of Grade ≥3 bleeding and infections on imetelstat and placebo. In pts treated with imetelstat, cytopenias were manageable, of short duration, and >80% were reversible to Grade ≤2 within 4 wks. Conclusions: For this LR-MDS pt population, imetelstat demonstrated statistically significant and clinically meaningful efficacy with high 8- and 24-wk TI rates, prolonged TI duration and increased hemoglobin. VAF reduction and its correlation to clinical endpoints support imetelstat’s disease-modifying potential. Safety results were consistent with prior reported experience. Clinical trial information: NCT02598661.

^aCochran Mantel Haenszel test stratified by prior transfusion burden and IPSS; ^b8-wk TI, Kaplan-Meier estimate; ^c2018 IWG; ^dStratified log-rank test.