S165: continuous tranfusion independence with imetelstat in heavily transfused non-del(5q) lower-risk myelodysplastic syndromes relapsed/refractory to erythropoiesis stimulating agents in imerge phase 3

Background: Unmet need remains for novel therapies after failure of erythropoiesis stimulating agents (ESAs) in red blood cell (RBC) transfusion dependent (TD) lower-risk myelodysplastic syndromes (LR-MDS). In IMerge Phase 2 (NCT02598661), treatment with imetelstat, a telomerase inhibitor, resulted in prolonged, durable transfusion independence (TI) across a broad range of heavily RBC TD ESA relapsed/refractory non-del(5q) LR-MDS patients (pts) naive to lenalidomide and hypomethylating agents (len/HMA). Aims: Evaluate the efficacy and safety of imetelstat vs placebo in this pt population in IMerge Phase 3. Methods: Heavily RBC TD ESA relapsed/refractory/ineligible (R/R) non-del(5q) LR-MDS pts naive to len/HMA were randomized 2:1 to receive imetelstat 7.5 mg/kg (N=118) or placebo (N=60) every 4 wks. The primary endpoint was 8-wk TI rate; subgroup analyses included IPSS risk, prior transfusion burden, and ring sideroblasts (RS) status. Secondary endpoints included 24-wk TI rate, TI duration, and hematologic improvement-erythroid (HI-E) rate. Change in mutation burden (variant allele frequency [VAF]) was exploratory. The primary analysis cutoff was Oct 2022; cutoff for ≥1-yr TI was Jan 2023. The primary and key secondary endpoints were compared using a Cochran-Mantel-Haenszel test stratified by prior transfusion burden and IPSS category. TI duration was calculated by Kaplan-Meier method and compared by stratified log-rank test. Results: The primary endpoint was met; 47 pts (39.8%) vs 9 pts (15.0%) receiving imetelstat vs placebo achieved 8-wk TI, P < 0.001. The rate of 8-wk TI was also significantly higher with imetelstat vs placebo across subgroups, including in RS negative pts. Median TI duration (95% CI) was 51.6 (26.9–83.9) wks with imetelstat vs 13.3 (8.0–24.9) wks with placebo, P < 0.001. Twenty-four-wk TI was achieved in 33 pts (28.0%) vs 2 pts (3.3%) receiving imetelstat vs placebo, P < 0.001. With 3 months’ additional follow-up, 21 pts (17.8%) on imetelstat vs 1 pt (1.7%) on placebo achieved ≥1-yr TI, P = 0.002, representing 63.6% of ≥24-wk TI imetelstat responders (Figure). HI-E rates (2018 IWG, emphasizing >16-wk response) were 42.4% with imetelstat vs 13.3% with placebo, 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. VAF reduction in 3 genes frequently mutated in MDS 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 in imetelstat-treated pts, P < 0.001. No new safety signals were identified in IMerge P3. The most common Grade 3/4 AEs with imetelstat were thrombocytopenia and neutropenia; similar rates of Grade ≥3 bleeding and infections were observed on imetelstat and placebo. Cytopenias with imetelstat were of short duration, and >80% resolved to Grade ≤2 within 4 wks. Summary/Conclusion: Imetelstat demonstrated statistically significant and clinically meaningful efficacy with robust 8-wk, 24-wk, and 1-yr TI rates and durable continuous TI. For this LR-MDS patient population, almost one fifth of imetelstat-treated pts achieved continuous TI for ≥1 yr, representing substantial relief from transfusion-associated complications. VAF reduction and its correlation to clinical endpoints, including durable TI, support imetelstat’s disease-modifying potential. Safety results were consistent with prior reports. Imetelstat treatment provides significant clinical benefit to a heavily TD LR MDS pt population in need of novel therapy.Keywords: Therapy, Clinical trial, Myelodysplastic syndrome, Telomerase activity