Targeting Telomerase in Lower-risk Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) are heterogeneous myeloid malignancies characterized by ineffective hematopoiesis and cytopenias with a highly variable risk of progression to acute myeloid leukemia.¹  In patients with lower-risk MDS, anemia is the most common cytopenia. Erythropoiesis-stimulating agents (ESAs) have been used to treat anemia in lower-risk MDS for many years. Luspatercept, which decreases transforming growth factor beta (TGFβ) signaling and was initially approved for the management of anemia in patients with ring sideroblasts after failure of an ESA, is now also approved for use in the frontline setting in patients with lower-risk MDS with or without ring sideroblasts.²  However, neither of these agents is considered disease-modifying, and options are limited in patients with relapsed or refractory disease after these therapies. While hypomethylating agents and transplant can be used in lower-risk MDS when necessary, these treatments carry a significant risk of toxicity. Imetelstat is a novel agent that targets telomerase activity by binding to the telomerase RNA template.³  IMerge (NCT02598661) was an international phase II/III study of imetelstat in patients with lower-risk MDS. The published results of the phase II study highlighted promising reductions in the transfusion burden in patients with lower-risk MDS.⁴ 

Uwe Platzbecker, MD, and colleagues recently published the results of the phase III portion of IMerge, which was a randomized, blinded, placebo-controlled trial that included patients with red blood cell (RBC) transfusion-dependent, lower-risk MDS. Eligible patients had low or intermediate-1-risk MDS based on the International Prognostic Scoring System, required at least four units of RBCs over an eight-week period, and had either relapsed/refractory disease afterward or were ineligible for ESAs. Patients who had previously received a hypomethylating agent or lenalidomide and those with del(5q) MDS were excluded. Patients were randomized at a 2:1 ratio to receive imetelstat versus placebo. Imetelstat was given intravenously once every four weeks at a dose of 7.5 mg/kg, with protocol-defined dose holds and reductions as needed for toxicities. The primary endpoint was RBC transfusion independence (TI) for at least eight weeks. Secondary endpoints included TI for at least 24 weeks, the rate of hematologic improvement–erythroid response (HI-E) per International Working Group (IWG) criteria, and the duration of TI.⁵ 

The study enrolled a total of 178 patients with a median age of 72 years, with 118 patients randomized to receive imetelstat and 60 to placebo. In the imetelstat group, 47 of 118 (40%) patients met the primary endpoint of TI for at least 8 weeks, while only nine of 60 (15%) patients in the placebo group met the primary endpoint (95% CI: 9.9-36.9%; p=0.0008). The number of patients achieving TI for at least 24 weeks and HI-E based on IWG 2018 criteria was also higher in the imetelstat group than in the placebo group. TI for 24 weeks or longer was reported in 33 of 118 (28%) patients who received imetelstat and in two of 60 (3%) patients who received placebo (p=0.0001). HI-E was observed in 50 of 118 (42%) patients in the imetelstat group and eight of 60 patients (13%) in the placebo group. Among patients in the imetelstat group who achieved the primary endpoint, the median duration of TI was 51.6 weeks. The most common grade 3 and 4 adverse events in the imetelstat group were neutropenia (68%) and thrombocytopenia (62%). Other common adverse events of any grade in patients receiving imetelstat were asthenia (19%), peripheral edema (11%), headache (13%), diarrhea (12%), and constipation (8%).