Imetelstat Offers Benefits for Patients With MDS Who Are Red Blood Cell–Transfusion Dependent

New results show that the imetelstat, a telomerase inhibitor, offered significant transfusion independence (TI) for patients with lower-risk myelodysplastic syndromes who are red blood cell transfusion dependent and unable to take erythropoiesis-stimulating agents (ESAs).

Findings from the phase 3 IMerge trial (NCT02598661), published December 1, 2023, in The Lancet, showed that TI for at least 8 weeks was significantly higher for patients taking imetelstat, with patients experiencing freedom from transfusions for a median of nearly a year.1 Patients treated with imetelstat also experienced significantly improved hemoglobin levels compared with patients receiving placebo, investigators reported.

Imetelstat, which is being developed by Geron, is under review by FDA for approval to treat transfusion-dependent anemia in patients with lower risk MDS who cannot have ESAs. The deadline for action by FDA has been set for June 16, 2024. It works by binding to enzymes that contribute to cancer cell proliferation, limiting their activity and contributing to cancer cell death. It is being studied in other conditions besides MDS.

Amer Zeidan, MBBS | Image credit: Yale Medical School

“Deep anemia requiring regular transfusions in patients with lower-risk MDS is a major driver of increased morbidity and mortality for these patients, as well as a compromised quality of life, and increased health care utilization and costs,” senior study author Amer Zeidan, MBBS, associate professor of medicine at Yale School of Medicine and director of hematology early therapeutics research at Yale Cancer Center, said in a statement published by Yale Medicine.

The past year has offered new hope for patients with lower-risk MDS. Earlier this year, FDA approved luspatercept (Reblozyl, Bristol Myers Squibb) for patients as a first-line treatment for adults with lower-risk MDS who may require transfusions. However, luspatercept, an erythoid maturation agent, has a different mechanism of action; it works by boosting the number and quality of red blood cells.

The IMerge Study

IMerge is a double-blind, placebo-controlled trial conducted in 118 sites across 17 countries. Patients had to be at least 18 years of age with ESA-relapsed, ESA-refractory, or ESA-ineligible low-risk MDS, which was defined as low or intermediate-1 risk disease under the International Prognostic Scoring System (IPSS) criteria. Patients were randomly assigned 2:1 to receive imetelstat 7.5 mg/kg or placebo, administered as an intravenous infusion every 4 weeks until disease progression, unacceptable toxicity, or withdrawal of consent.

According to investigators, patients were further stratified by previous red blood cell transfusion burden and by IPSS risk group. Patients, investigators, and data analysts were all blinded to group assignments.

The primary endpoint was 8-week red blood cell TI, which was defined as the proportion of patients who did not require red blood cell transfusions for at least 8 weeks from randomization until the treatment with therapy, if any. Patients in the intention-to-treat population were included in the efficacy analysis, and all patients who received at least 1 dose of the study drug were included in the safety analysis. Results showed the following:

• 178 patients were enrolled between September 2019 and October 2021; 118 were assigned to imetelstat and 60 to placebo. Among those enrolled, 111 (62%) were male and 67 (38%) were female.
• 91 patients (77%) in the imetelstat group had discontinued treatment by data cutoff vs 45 (75%) in the placebo group; 1 patient in the placebo group was not treated.
• Median follow-up was 19.5 months (IQR 12.0-23.4) in the imetelstat group and 17.5 months (IQR 12.1-22.7) in the placebo group.
• Among those treated with imetelstat, 47 patients (40%) had red blood cell TI of at least 8 weeks (95% CI 30.9–49.3) vs 9 patients (15%) in the placebo group (7.1–26.6), for a rate difference of 25% (9.9 to 36.9; P = .0008).

Treatment-related adverse events (AEs) were described as frequent but tolerable. AEs affected 107 (91%) of the 118 patients treated with imetelstat and 28 (47%) of 59 patients who received placebo. The most common treatment-emergent grade 3–4 AEs in those taking imetelstat were neutropenia (68%) and thrombocytopenia (62%). Investigators reported no treatment-related deaths.

“The main adverse events, namely neutropenia and thrombocytopenia, while frequent were generally reversible and tolerable,” Zeidan said in the statement. “It is my hope that the IMerge study results will lead to approval of imetelstat by the regulators, and that the drug would become available in the year 2024 as an important therapeutic option for our patients.”

Reference

Platzbecker U, Santini V, Fenaux P, et al. Imetelstat in patients with lower-risk myelodysplastic syndromes who have relapsed or are refractory to erythropoiesis-stimulating agents (IMerge): a multinational, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. Published online December 01, 2023. DOI: https://doi.org/10.1016/S0140-6736(23)01724-5