Imetelstat Achieved Prolonged, Continuous Transfusion Independence (TI) in Patients with Heavily Transfused Non-Del(5q) Lower-Risk Myelodysplastic Syndrome (LR-MDS) Relapsed/Refractory (R/R) to Erythropoiesis Stimulating Agents (ESAs) within the IMerge Phase 2 Study

Background: Novel treatments that are both efficacious and safe are needed for patients with LR-MDS who are red blood cell (RBC) transfusion dependent (TD) and R/R to ESAs, especially for those with MDS with ring sideroblasts (RS), as primary resistance to ESAs is more frequent. Imetelstat is a first-in-class telomerase inhibitor that targets cells with high telomerase activity and human telomerase reverse transcriptase expression, both of which have been reported in MDS. In the phase 2 part of the IMerge study in patients with RBC TD, ESA-R/R LR-MDS, imetelstat led to a prolonged, durable TI rate (median TI duration, 65 weeks) across a broad range of heavily transfused patients; longer TI duration (median, 86 weeks) was seen in patients with non-del(5q) and lenalidomide/hypomethylating agent (HMA)-naive disease (Steensma. J Clin Oncol. 2021). Here, we describe the characteristics and clinical benefit for patients who were non-del(5q) and lenalidomide/HMA naive and had continued TI for >1 year while on imetelstat.

Methods: IMerge (MDS3001; NCT02598661) is a global, phase 2/3 study of imetelstat in RBC TD, ESA-R/R LR-MDS. After an initial analysis, the phase 2 study was expanded to include patients with no prior HMA or lenalidomide and a non-del(5q) MDS subtype. Imetelstat was administered as a 2-hour intravenous infusion every 4 weeks at 7.5 mg/kg. The primary end point was 8-week TI rate. Secondary end points included safety, 24-week TI rate, MDS response, overall survival (OS), progression free survival (PFS), and time to progression (TTP) to acute myeloid leukemia (AML). The proportion of patients with 8-week, 24-week, and 1-year TI, and other binary end points, were summarized with percentage and 95% 2-sided exact Clopper-Pearson CI. The Kaplan-Meier (KM) method was used to estimate the distribution of duration of TI, OS, PFS, and TTP to AML.

Results: Of 57 patients enrolled and treated in the phase 2 study, 38 patients were in the non-del(5q) and lenalidomide/HMA-naive subset. Of these 38, 11 (29%) achieved >1-year sustained TI, representing 69% of the ≥8-week TI responders (n = 16) and 92% of the ≥24-week TI responders (n = 12). Furthermore, 27 of the 38 patients were MDS-RS, and of these, 10 (37%) achieved TI for >1 year. The prior RBC transfusion burden for the 11 patients who achieved >1 year of sustained TI was 6 units over 8 weeks, and additional baseline characteristics can be found in the table. These 11 patients were treated with imetelstat for a median of 126.1 weeks (range, 70.1-168.1) for a median of 27 cycles (range, 18-40). The median duration of TI was 92.4 weeks (95% CI, 69.6-140.9; Figure). After a median follow-up of 51.5 months, median PFS was 34.2 months (95% CI, 25.1-39.2), median OS was 57.0 months (95% CI, 29.4 to NE), and none of the 11 patients progressed to AML. Of the patients with TI duration >1 year, 9 had mutation data available; 8 (89%) demonstrated a reduction in SF3B1 variant allele frequency (VAF), and 5 (56%) achieved ≥50% VAF reduction. Reduction in VAF correlated with longer TI duration (median, >20 months) and shorter time to onset of TI (<10 weeks). Safety findings were consistent with those of the overall population; the most frequent adverse events were reversible thrombocytopenia and neutropenia.

Conclusions: Treatment with imetelstat achieved >1 year sustained, continuous TI in 29% of RBC TD, ESA-R/R LR-MDS patients who were non-del(5q) and lenalidomide/HMA-naïve and was safe and well tolerated. Of the overall population, attainment of 24-week TI was indicative of a likelihood to achieve TI >1 year. In this ESA-R/R population with a high transfusion burden prior to treatment, a decrease to zero RBC transfusions for a period >1 year represents relief from iron overload and other transfusion-associated complications, and decreased demand on health care resources. Furthermore, durable TI, meaningful reduction in mutational burden, and good survival post-ESA suggest imetelstat may have disease-modifying activity not expected with currently available therapies. Enrollment is complete for the phase 3 part of IMerge, a randomized (2:1) double-blind, placebo-controlled trial to compare efficacy of imetelstat versus placebo in TD, ESA-R/R, non-del(5q), lenalidomide/HMA-naive LR-MDS; results from the primary analysis are expected in early January 2023.