Imetelstat Improves Rate of Durable Transfusion Independence in Patients With Lower-Risk MDS

Treatment with imetelstat, a competitive inhibitor of telomerase enzymatic activity, was associated with a clinically meaningful rate of transfusion independence in heavily transfused patients with lower-risk myelodysplastic syndromes (MDS), according to study results published in the Journal of Clinical Oncology.

In the open-label, phase II IMerge trial, David Steensma, MD, of Dana-Farber Cancer Institute, and colleagues evaluated the efficacy and safety of imetelstat in 57 patients with lower-risk MDS who were red blood cell (RBC) transfusion-dependent and ineligible for or relapsed/refractory to erythropoiesis-stimulating agent treatment. Thirty-eight patients who did not have deletion of chromosome 5q and had never received a hypomethylating agent or lenalidomide comprised a subset population.

Patients received 2-hour intravenous infusions of imetelstat 7.5 mg/kg every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or lack of response. At each clinic visit and every 12 weeks, the investigators assessed transfusion requirements.

The primary endpoint of the trial was the rate of 8-week RBC transfusion independence. Secondary endpoints included the 24-week RBC transfusion independence rate, time to onset and duration of transfusion independence, the hematologic improvement-erythroid response (HI-E) rate, disease response (complete response [CR], marrow CR [mCR], or partial response), and safety.

Median age was 71 years in the overall patient population. Approximately 61% of patients were categorized as having refractory anemia with ring sideroblasts (RARS) or refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS), while the remaining 39% had either refractory amenia (RA), RCMD, or refractory anemia with excess blasts (RAEB).

At the clinical cutoff date, the median follow-up was 16.4 months for the overall population and 15.7 months for the subset population. Imetelstat was administered for a median of 8.2 months, and patients received a median of 8 treatment cycles.

Treatment was ongoing in 14 patients of the overall cohort. Reasons for treatment discontinuation included lack of efficacy (n=16), adverse events (AEs; n=14), withdrawal by patient or patient refusal (n=6), progressive disease (n=3), death (n=2), relapse as a result of recurrent transfusion dependence (n=1), and physician decision (n=1).

In the overall population and subset population, 37% and 42%, respectively, had achieved the primary endpoint of RBC transfusion independence for 8 weeks. The median time to the onset of 8-week RBC transfusion independence was 8.3 weeks in both samples. In addition, the investigators reported a 24-week RBC transfusion independence rate of 23% for the overall sample and 29% for the subset population.

Researchers also found evidence suggestive of disease-modifying activity with imetelstat, demonstrated by cytogenetic and mutational analyses showing reductions of malignant clones.

Imetelstat also led to improvements in the following secondary efficacy endpoints:

  • HI-E rate: 26% in the overall population and 32% in the subset population
  • transfusion reduction: 65% and 68%

The safety results were generally consistent between the two patient groups, with 94% of patients in the subset population experiencing at least one treatment-emergent AE. Cytopenias were the most frequently reported treatment-emergent AEs, including thrombocytopenia (61% in the overall population and 66% in the subgroup population), neutropenia (67% and 56%), and anemia (23% and 26%).

Limitations of this study included the small sample size, as well as the lack of a comparator treatment arm. The study led to an ongoing randomized phase III placebo-controlled trial of imetelstat in lower-risk MDS.

The study authors report interests with Geron Corporation and Janssen, which funded the study.


Steensma DP, Fenaux P, Van Eygen K, et al. Imetelstat achieves meaningful and durable transfusion independence in high transfusion-burden patients with lower-risk myelodysplastic syndromes in a phase II study. J Clin Oncol. 2020 October 27. [Epub ahead of print]