Exploring the Efficacy and Risks of Imetelstat in Lower-Risk MDS Patients

In a randomized IMerge trial, patients with lower-risk myelodysplastic syndromes (MDS) who relapsed or were refractory to standard treatment achieved improved rates of red blood cell (RBC) transfusion independence with an investigational, first-in-class telomerase inhibitor called imetelstat. This breakthrough therapy showed promising results in achieving sustained transfusion independence and potentially serving as a second-line treatment for lower-risk MDS.

The IMerge trial revealed that heavily transfused patients who failed on erythropoiesis-stimulating agents (ESAs) and were treated with imetelstat had significantly higher rates of RBC transfusion independence for at least 8 weeks compared to those treated with placebo. The data showcased a remarkable improvement, with 40% of imetelstat-treated patients achieving independence compared to only 15% in the placebo group. Furthermore, the study demonstrated that imetelstat sustained transfusion independence, with 83% of the 8-week responders experiencing a single continuous transfusion independence period.

The prolonged transfusion independence observed with imetelstat in lower-risk MDS patients highlights its potential as a second-line therapy. While ESAs currently serve as the standard first-line treatment, a substantial proportion of patients fail to respond or lose response within 2 years. Imetelstat could offer an alternative treatment option for these patients and improve their quality of life.

In a recent phase II study, imetelstat demonstrated a meaningful durable transfusion independence rate across a range of heavily transfused patients. The positive results prompted Geron to submit a new drug application to the FDA, seeking approval for imetelstat as a treatment for transfusion-dependent anemia in low-to-intermediate-1 risk MDS patients. A decision from the FDA is expected by June 2024.

Additionally, the FDA recently approved luspatercept for the front-line management of anemia in patients with lower-risk MDS. As a result, there is a need to investigate if patients treated with luspatercept respond to imetelstat or not. It is essential to gather data in an expedited manner to determine the role of imetelstat in conjunction with luspatercept.

Although imetelstat poses a significant advancement in the treatment of RBC transfusion-dependent MDS, it does come with certain considerations. Substantial thrombocytopenia and neutropenia have been associated with the use of imetelstat, requiring practitioners to optimize supportive care measures. To ensure the safe and appropriate use of this novel therapy, healthcare professionals should adapt their supportive care measures accordingly. The importance of balancing the potential benefits of imetelstat with the burdensome side effects cannot be overlooked.

The double-blind IMerge trial included 178 patients across 118 sites in 17 countries. Of these, 118 patients were assigned to the imetelstat group, receiving 7.5 mg/kg every 4 weeks, while 60 patients were assigned to the placebo group. The patients had a median age of 72, with the majority being men. They were heavily transfused, with a median previous RBC transfusion burden of 6.0 units over 8 weeks.

After a median follow-up of approximately 19.5 months for the imetelstat group and 17.5 months for the placebo group, the patients received a median of eight treatment cycles each. The primary endpoint of RBC transfusion independence for at least 8 weeks was successfully achieved in both patients with and without ring sideroblasts in the imetelstat group, with higher response rates compared to the placebo group.

Improved Patient-Reported Outcomes

In addition to the objective measures of transfusion independence, imetelstat also demonstrated notable improvements in patient-reported fatigue. Patients in the imetelstat group experienced sustained meaningful improvements in fatigue, with a shorter median time to improvement compared to those in the placebo group. These findings emphasize the potential for imetelstat to enhance the overall well-being of patients by reducing the burden of anemia-related fatigue.

Grade 3 or 4 treatment-emergent adverse events (TEAEs) occurred in a higher percentage of patients receiving imetelstat compared to the placebo group. The most common grade 3/4 TEAEs were neutropenia and thrombocytopenia, further highlighting the importance of monitoring and managing these side effects. It is crucial to strike a balance between the therapeutic benefits and the associated risks to ensure patient safety during treatment. Fortunately, no treatment-related deaths were reported during the IMerge trial.

Imetelstat holds significant promise as a second-line therapy for lower-risk MDS patients who relapse or are refractory to standard treatments. Its ability to achieve and sustain RBC transfusion independence, along with improvements in patient-reported outcomes, demonstrates its potential as a valuable addition to the treatment armamentarium. Careful consideration, optimization of supportive care measures, and expedited data gathering in conjunction with other therapies are vital for maximizing the safe and effective use of imetelstat in MDS patients.


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