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Imetelstat provides durable transfusion independence in heavily transfused non-del(5q) lower risk MDS relapsed/refractory to erythropoiesis stimulating agents

In the phase II IMerge trial, the telomerase inhibitor imetelstat was shown to provide a meaningful and durable transfusion independence to patients with lower-risk myelodysplastic syndrome (LR-MDS) who relapsed after or were refractory to erythropoiesis stimulating agents (ESAs). In total, 42% of the patients achieved an eight-week transfusion independence with a median transfusion independence time of 20 months. In addition, 29% of patients remained transfusion-free for at least one year and 75% of the responders had a haemoglobin rise of 3 g/dL or more.


Patients with LR-MDS who are red blood cell (RBC) transfusion dependent (TD) and failed on a treatment with ESAs (ESA refractory or relapsed disease; ESA-R/R) have limited treatment options. Imetelstat is a first-in-class telomerase inhibitor that targets cells with short telomeres and active telomerase, a characteristic finding in MDS patients across all disease stages. Imetelstat selective kills malignant stem and progenitor cells, enabling a normal blood cell production. IMerge is a phase II/III global study of imetelstat for TD patients with ESA-R/R LR-MDS.

Phase II of the IMerge trial is a single arm, open label study including 38 patients with LR-MDS, relapsed or refractory to ESA. In order to be eligible for the trial, patients had to be transfusion dependent, defined as having received at least four units of RBCs within eight weeks over a 16-week pre-study period. All patients received 7.5 mg/kg intravenous imetelstat once every four weeks. After a median follow-up of 24 months, the median treatment duration was 8.5 months (median of 9 treatment cycles) with a median dose intensity of 100%. In total, 84% had at least 6 units of RBC transfusions within 8 weeks with a median of 8 units in 8 weeks, 89% received prior ESAs and 32% had a serum erythropoietin level >500 U/L. After 24 months of follow-up, 29% of patients terminated study participation, mostly because of death (21%).


Out of the 38 enrolled patients, 16 (42%) became transfusion independent for at least eight weeks. Of them, 12 patients showed a haemoglobin rise ≥3.0 g/dL during the transfusion-free interval compared to the pre-treatment level. Furthermore, 12 (32%) patients achieved transfusion independence for at least 24 weeks, and 11 (29%) patients, who had a median transfusion burden of 6 units within 8 weeks, were transfusion-free for one year or more. Kaplan–Meier (KM) median transfusion independence duration was 88 weeks and the longest observed transfusion independence was as long as 2.7 years. KM median cumulative duration of ≥8 weeks of transfusion independence, defined as the sum of all periods of transfusion independence ≥8 weeks during the treatment, was 92.3 weeks. A clinically meaningful major (16-week transfusion independence) and minor response (≥ 50% transfusion reduction within 16 weeks) was obtained by 37% and 55% of the patients, respectively. Hematologic improvement – erythroid (HI-E) was achieved by 26 (68%) patients, with a median duration of 92.7 weeks (21 months).

The most frequently reported adverse events were manageable and reversible grade ≥3 cytopenias. With respect to frequently reported non-hematologic adverse events, no new clinically significant events occurred. On-target imetelstat activity correlated with transfusion independence and was demonstrated by a ≥50% reduction of telomerase activity post imetelstat dosing in 23.1% (3/13) of patients and of human telomerase reverse transcriptase (hTERT) RNA level in 54.3% (19/35) of patients. Compared to patients without transfusion independence, a significantly higher proportion of patients had a ≥50% reduced hTERT expression when they achieved ≥ 8-weeks transfusion independence (80% vs. 35%; p=0.016). A similar relationship was reported for the ≥ 24-weeks transfusion independence (91.7% vs. 34.8%; p=0.002). As such, these findings indicate a correlation between inhibiting the telomerase target with imetelstat and a clinical benefit for the patients.

Finally, the cytogenetic and mutational malignant clone reduction in some patients indicates that imetelstat might also have disease modifying activity. For example, a reduction in SF3B1 mutations correlated with shorter onset time to achieve transfusion independence.


Imetelstat induced a meaningful and durable transfusion independence across multiple patient subtypes in lower risk-MDS patients who are RBC transfusion dependent and have ESA-R/R disease. A double-blind, placebo-controlled phase III trial with (2:1) randomisation is currently ongoing.


Platzbecker U, Fenaux P, Steensma DP, et al. 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 (ESA). Presented at EHA 2020; Abstract S183.

Speaker Uwe Platzbecker

Uwe Platzbecker

Uwe Platzbecker, MD, PhD, Department of Hematology and Cell therapy, University Clinic Leipzig, Germany


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