Treatment with Imetelstat Provides Durable Transfusion Independence (TI) in Heavily Transfused Non-Del(5q) Lower Risk MDS (LR-MDS) Relapsed/Refractory (R/R) to Erythropoiesis Stimulating Agents (ESAs)

Background: Patients (pts) with LR-MDS who are red blood cell (RBC) transfusion dependent (TD) and have ESA-R/R disease have limited treatment options. Imetelstat is a first-in-class telomerase inhibitor that targets cells with short telomeres and active telomerase, characteristics observed in MDS pts across all disease stages. IMerge (MDS3001; NCT02598661) is a Phase 2/3 global study of imetelstat for TD pts with ESA-R/R LR-MDS. Phase 2 results indicate that imetelstat achieves durable TI in induces durable TI in LR-MDS pts (Steensma ASH 2018, Fenaux EHA 2019).

Aims: We report long term efficacy, safety, and biomarker updates in 38 LR non-del(5q) TD ESA R/R MDS pts, all lenalidomide and hypomethylating agent naïve, from the open-label, single-arm Phase 2 portion of IMerge.

Methods: During Phase 2, pts received imetelstat 7.5 mg/kg IV every 4 weeks (w). Long term efficacy includes ≥8-w RBC TI rate, ≥24-w TI rate, ≥1-year (y) TI rate, longest and cumulative duration of ≥8-w TI, duration of hematologic improvement-erythroid (HI-E), and major/minor response per updated International Working Group (IWG) 2018 guidelines. Exploratory biomarker evaluations were performed.

Results: Per IWG 2018, all pts had high transfusion burden (≥8 units [u] RBCs/16 w, ≥4 u/8 w) and 84% had ≥6 u/8 w with a median of 8 u/8 w. 89% received prior ESAs and 32% had EPO level >500 U/L; 71% had ringed sideroblasts (RS) World Health Organization subtypes.

As of 4 Feb 2020, median follow-up was 24 months (mo) for the 38 pts. In these pts, 16 (42%) had ≥8-w TI, of whom 12 showed a hemoglobin rise ≥3.0 g/dL during the transfusion-free interval vs the pretreatment level. Furthermore, 12 (32%) pts achieved ≥24-w TI, and 11 (29%) pts, who had a median transfusion burden of 6 u/8 w, were transfusion free for ≥ 1 y. Kaplan–Meier (KM) median TI duration was 88 w (20 mo) and the longest TI is 2.7 y. KM median cumulative duration of ≥8 w TI (sum of all periods of TI ≥8 w) was 92 w (21 mo). Per IWG 2018, clinically meaningful major (16-w TI) and minor response (50% transfusion reduction/16 w) was achieved by 37% and 55% of pts, respectively. HI-E was achieved by 26 (68%) pts, with KM median duration of 93 w (21 mo). Most frequently reported adverse events were manageable and reversible grade ≥3 cytopenias.

Five of 6 pts (83%) with IPSS-R intermediate or poor cytogenetic risk achieved ≥8-w TI, all with RS WHO subtypes; 3 had ≥1-y TI. Cytogenetic and mutational malignant clone reduction in some pts indicates disease modifying activity of imetelstat. On-target imetelstat activity was demonstrated by ≥50% reduction of telomerase activity post imetelstat dosing in 23.1% (3/13) of pts and of human telomerase reverse transcriptase (hTERT) RNA level in 54.3% (19/35) of pts. Compared to pts without TI, a significantly higher proportion of pts had ≥50% hTERT expression reduction when achieving ≥8-w TI (80% [12/15] vs 35% [7/20]; p=0.0155) and ≥24-w TI (91.7% [11/12] vs 34.8% [8/23]; p=0.0016), indicating a correlation between inhibiting the telomerase target with imetelstat and clinical benefit.

Conclusion: Imetelstat achieved an 8-w TI rate of 42% for a median duration of 20 mo, the longest so far reported with any agent in non-del 5q LR-MDS, and 29% of pts achieved TI ≥ 1 y. Furthermore, a high and durable HI-E rate (68% for median of 21 mo) was also achieved in this population of heavily RBC TD, ESA-R/R LR-MDS. Enrollment is ongoing in the Phase 3 portion of IMerge, a placebo-controlled trial of the efficacy and safety of imetelstat, including potential predictive biomarkers of response.