Imetelstat reduces RBC transfusion dependence in patients with lower-risk myelodysplastic syndromes

"Treatment with imetelstat helped heavily transfused patients who failed on erythropoiesis-stimulating agents (ESAs), to achieve significantly higher rates of RBC transfusion independence for at least 8 weeks compared to those treated with a placebo (40% versus 15%)," the researchers reported in the study published in The Lancet.

Additionally, RBC transfusion independence was sustained with imetelstat, with 83% of 8-week responders having a single continuous transfusion independence period versus 56% of responders in the placebo group.

"The prolonged transfusion independence seen in this patient population with imetelstat underscores the potential for this novel agent as a second-line therapy in lower-risk MDS," the study stated.

Currently, ESAs are the standard first-line treatment for symptomatic anaemia in lower-risk MDS patients, however, many patients do not respond to lose response within roughly 2 years. In a phase 2 trial, imetelstat, a competitive telomerase inhibitor, showed promising results; it demonstrated a meaningful durable transfusion independence rate across a broad range of heavily transfused patients.

Prof Uwe Platzbecker, University Hospital Leipzig, Leipzig, Germany, and colleagues aimed to compare the RBC transfusion independence (RBC-TI) rate with imetelstat versus placebo in patients with RBC-TD LR-MDS.

The randomised, multinational, double-blind, placebo-controlled, phase 3 trial was conducted at 118 sites in 17 countries comprising 178 patients. From 2019 to 2021. 118 patients were randomly assigned to imetelstat 7.5 mg/kg every four weeks and 60 patients were assigned to placebo.

The median age of the patients was 72 years and 62% were men. They were heavily transfused with a median previous RBC transfusion burden of 6.0 units over eight weeks. Overall, 90% of patients had previously received an ESA, and 6% had previously received luspatercept.

The primary endpoint was 8-week RBC transfusion independence (RBC-TI), defined as the proportion of patients without RBC transfusions for at least 8 consecutive weeks starting on the day of randomisation until subsequent anti-cancer therapy, if any.

The researchers reported the following findings:

• After a median follow-up of 19.5 months for the imetelstat group and 17.5 months for the placebo group, patients received a median of eight treatment cycles of each, with a median duration of treatment of 33.9 weeks and 28.3 weeks, respectively.
• The primary endpoint of RBC transfusion independence for at least 8 weeks was also reached in 45% and 32% of patients with and without ring sideroblasts in the imetelstat group versus 19% and 9%, respectively, in the placebo group.
• Among patients who had 8-week RBC transfusion independence, the median increase in blood haemoglobin from before treatment to the peak during the longest independence period was 3.55 g/dL in the imetelstat group versus 0.80 g/dL in the placebo group.
• Grade 3 or 4 treatment-emergent adverse events (TEAEs) occurred in 91% of patients receiving imetelstat and 47% of those receiving placebo.
• The most common grade 3/4 TEAEs in patients taking imetelstat were neutropenia (68% vs 3% with placebo) and thrombocytopenia (62% vs 8%). No treatment-related deaths were reported.

"Imetelstat offers a novel mechanism of action with durable transfusion independence (about 1 year) and disease-modifying activity for heavily transfused patients with LR-MDS who are not responding to or are ineligible for ESAs," the researchers concluded.

Reference:

Platzbecker, U., Santini, V., Fenaux, P., Sekeres, M. A., Savona, M. R., Madanat, Y. F., Díez-Campelo, M., Valcárcel, D., Illmer, T., Jonášová, A., Bělohlávková, P., Sherman, L. J., Berry, T., Dougherty, S., Shah, S., Xia, Q., Sun, L., Wan, Y., Huang, F., . . . Zeidan, A. M. (2023). 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. The Lancet. https://doi.org/10.1016/S0140-6736(23)01724-5