IMerge phase III results validate the observations from the phase II part and show that imetelstat, a telomerase inhibitor, provides clinically significant benefit to a patient population with heavily transfusion dependent lower-risk myelodysplastic syndromes (LR-MDS). Treatment with imetelstat showed durable red blood cell (RBC) transfusion independence, reduction in transfusion burden, and increased haemoglobin concentrations in RBC transfusion dependent patients with anaemia and LR-MDS who had relapsed after, were refractory to, or were ineligible for treatment with erythropoiesis-stimulating agents (ESAs).
Durable RBC transfusion independence for 24 weeks and even longer than 1 year has not been previously shown in the study population. Improvement in patient-reported fatigue and cytogenetic responses; the substantial reduction of variant allele frequency (VAF) in SF3B1, TET2, ASXL1, and DNMT3A; and the decline of bone-marrow ring-sideroblast cells and their association with the clinical endpoint of RBC transfusion independence support the disease-modifying potential of imetelstat, according to Prof. Uwe Platzbecker of the Department of Hematology, Cellular Therapy, Infectious Diseases, and Hemostaseology, University Hospital Leipzig in Leipzig, Germany, and colleagues, who published the findings on 1 December 2023 in The Lancet.
Approximately 70% of patients diagnosed with MDS are classified as lower risk. A high proportion of patients with LR-MDS eventually become RBC transfusion dependent, which is associated with reduced quality-of-life (QoL) and increased mortality. Treatment goals include eliminating transfusions, increasing haemoglobin concentrations, and improving QoL and survival rates.
Although ESAs are currently the standard first-line treatment for symptomatic anaemia in patients with LR-MDS, many patients do not respond or lose response within roughly 2 years. Patients with serum erythropoietin concentrations of more than 500 mU/mL are unlikely to respond to ESAs and are considered ineligible. Eventually, with or without ESA treatment, patients develop worsening anaemia and consequently become RBC transfusion dependent. Subsequent treatment options are indicated only for specific subgroups, particularly luspatercept for patients with MDS with ring sideroblasts and lenalidomide for patients with MDS-del(5q).
There is a need for novel therapies with robust efficacy, preferentially disease-modifying potential, and broad activity, directed towards the underlying dysplastic stem and progenitor cells responsible for disease progression. The inhibition of telomerase activity constitutes an attractive treatment approach in MDS. By targeting cells with increased telomerase activity, imetelstat selectively induces apoptosis of malignant haematopoietic progenitor cells while sparing the normal counterparts, enabling the recovery of bone marrow function and erythropoiesis, and leading to clinical benefits.
IMerge is a multinational, phase II/III study assessing the efficacy, safety, and disease-modifying activity of imetelstat in patients with LR-MDS who RBC transfusion are dependent and ineligible for, have relapsed after, or are refractory to, ESAs. In IMerge phase II, imetelstat treatment led to durable, continuous transfusion independence in patients who were heavily transfused. Cytogenetic and mutational data revealed a reduction of the myelodysplastic clones, suggesting imetelstat has disease-modifying activity.
The primary hypothesis of the study was that imetelstat will significantly improve the rate of RBC transfusion independence versus placebo in patients with RBC transfusion dependent LR-MDS. Therefore, in IMerge phase III, the safety, efficacy, and disease-modifying activity of imetelstat versus placebo was evaluated in patients with heavily RBC transfusion dependent, ESA-relapsed, ESA-refractory, or ESA-ineligible, and non-del(5q) LR-MDS, and without previous treatment with lenalidomide or hypomethylating agents.
In phase III of IMerge, a double-blind, placebo-controlled study conducted in 118 sites including university hospitals, cancer centres, and outpatient clinics in 17 countries, patients were randomly assigned 2:1 to receive imetelstat 7.5 mg/kg or placebo, administered as a 2-hour intravenous infusion, every 4 weeks until disease progression, unacceptable side effects, or withdrawal of consent. Randomisation was stratified by previous RBC transfusion burden and risk group. Patients, investigators, and those analysing the data were masked to group assignment.
The primary endpoint was 8-week RBC transfusion independence, defined as the proportion of patients without RBC transfusions for at least 8 consecutive weeks starting on the day of randomisation until subsequent anticancer treatment, if any. Primary efficacy analyses were performed in the intention-to-treat population, and safety analyses were conducted in patients who received at least one dose of study medication or placebo.
Between 11 September 2019 and 13 October 2021, 178 patients were enrolled and randomly assigned, 118 to imetelstat and 60 to placebo. A total of 111 patients (62%) were male and 67 (38%) were female; 91 of 118 patients (77%) had discontinued treatment by data cut-off in the imetelstat group versus 45 (75%) in the placebo group (one patient in the placebo group did not receive treatment). 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.
In the imetelstat group, 47 patients (40%; 95% confidence interval [CI] 30.9–49.3]) patients had an RBC transfusion independence of at least 8 weeks versus 9 (15%; 95% CI 7.1–26.6) in the placebo group with a rate difference of 25% (95% CI 9.9 to 36.9; p = 0.0008).
Among 8-week RBC transfusion independent responders in the imetelstat group, RBC transfusion independence was durable with a median duration of 51.6 weeks and continuous over time, with 83% of patients having a single continuous RBC transfusion independence period. In the imetelstat group, 28% of patients had RBC transfusion independence for at least 24 weeks and 18% had RBC transfusion independence for at least 1 year. Significant improvement in RBC transfusion independence was observed with imetelstat versus placebo across different LR-MDS subgroups, including patients with or without ring sideroblasts and in patients with very high transfusion burdens.
Patients in the imetelstat group were more likely to have sustained, meaningful improvement in fatigue, with shorter median time to improvement than those in the placebo group. The rates of cytogenetic response and maximum percent reduction in mutation VAF in SF3B1, TET2, ASXL1, and DNMT3A were numerically higher in patients treated with imetelstat compared with patients treated with placebo. Furthermore, most patients with bone marrow ring-sideroblast cell reduction and patients with a cytogenetic response also had 8-week RBC transfusion independence and a reduction in VAF was associated with RBC transfusion independence rates, RBC transfusion independence duration, and haemoglobin increase.
Overall, 107 of 118 patients (91%) receiving imetelstat and 28 of 59 patients (47%) receiving placebo had grade 3-4 treatment-emergent adverse events (TRAEs). The most common grade 3-4 TRAEs) in patients taking imetelstat were neutropenia (68% of patients who received imetelstat versus 3% who received placebo) and thrombocytopenia (62% versus 8%). No treatment-related deaths were reported.
In an accompanied comment, Prof. Mrinal M Patnaik of the Division of Hematology, Department of Internal Medicine, Mayo Clinic in Rochester, MN, US wrote that of the several telomere- and telomerase-targeting therapies being developed, imetelstat, a 13-mer oligonucleotide modified with lipid extensions, is furthest along in development.
However, there are several questions pertaining to its routine use. The drug must be given intravenously for approximately 2 hours every month and is associated with substantial thrombocytopenia and neutropenia. Although no drug-related deaths were reported in this study, practitioners would need to optimise supportive care measures unlike what they normally use for therapies for anaemia-directed, LR-MDS, such as ESA and luspatercept. The IMerge study offers little information on the safety and efficacy of the drug in people of diverse ethnic origins and has no data on patients with telomere biology disorders who often develop MDS, for whom theoretically this drug could cause severe cytopenias.
Reliable and practical biomarkers and patient selection criteria are much needed and, depending on the cost of the drug, one questions whether it would be feasible for patients to avoid getting hypomethylating agents or lenalidomide in the real world before they access imetelstat. With the August, 2023, US Food and Drug Administration approval of luspatercept for the front-line management of anaemia in patients with LR-MDS regardless of ring-sideroblast status, data would be needed in an expedited manner to see if patients treated with luspatercept respond to imetelstat or not.
The study was funded by Janssen Research & Development before 18 April 2019 and Geron Corporation thereafter.
References
- 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, placebocontrolled, phase 3 trial. The Lancet; Published online 1 December 2023. DOI: https://doi.org/10.1016/S0140-6736(23)01724-5
- Patnaik MM. Telomerase inhibition in haematological neoplasms—are we ready for primetime? The Lancet; Published online 1 December 2023. DOI: https://doi.org/10.1016/S0140-6736(23)02187-6