Background: Unmet medical needs remain in patients with red blood cell transfusion red blood cell transfusion: A procedure in which packed red blood cells are given to a person through an intravenous (IV) line into the bloodstream. Transfused red blood cells increase the blood count and help improve symptoms of anemia. Before transfused blood is given, donated blood is typed and crossmatched to the… -dependent (RBC-TD) lower-risk myelodysplastic syndromes myelodysplastic syndromes: (my-eh-lo-diss-PLASS-tik SIN-dromez) A group of disorders where the bone marrow does not work well, and the bone marrow cells fail to make enough healthy blood cells. Myelo refers to the bone marrow. Dysplastic means abnormal growth or development. People with MDS have low blood cell count for at… (LR-MDS) who are not responding to or are ineligible for erythropoiesis-stimulating agents (ESAs). Imetelstat Imetelstat: Who should not take RYTELO? Before taking RYTELO, tell your healthcare provider about all your medical conditions, including if you: are pregnant or plan to become pregnant. RYTELO may harm your unborn baby and may cause loss of pregnancy. Tell your healthcare provider right away if you… , a competitive telomerase inhibitor, showed promising results in a phase 2 trial. We aimed to compare the RBC transfusion independence transfusion independence: No longer needing any type of blood transfusion. (RBC-TI) rate with imetelstat versus placebo placebo: A placebo is an inactive pill, liquid, or powder that has no treatment value. in patients with RBC-TD LR-MDS.
Methods: In phase 3 of IMerge, a double-blind, placebo-controlled trial conducted in 118 sites including university hospitals, cancer centres, and outpatient clinics in 17 countries, patients (aged ≥18 years) with ESA-relapsed, ESA-refractory, or ESA-ineligible LR-MDS (low or intermediate-1 risk disease as per International Prognostic Scoring System International Prognostic Scoring System: A system that turns patient data into a score. The score tells how quickly a myelodysplastic syndrome (MDS) case is progressing and helps predict what may happen with the patient's MDS in the future. Also called IPSS. [IPSS] criteria) were randomly assigned via a computer-generated schedule (2:1) to receive imetelstat 7·5 mg/kg or placebo, administered as a 2-h intravenous infusion intravenous infusion: A method of getting fluids or medicines directly into the bloodstream over a period of time. Also called IV infusion. , every 4 weeks until disease progression, unacceptable toxic effects, or withdrawal of consent. Randomisation was stratified by previous RBC transfusion burden and IPSS risk group. Patients, investigators, and those analysing the data were masked to group assignment. The primary endpoint was 8-week 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. 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 trial medication or placebo. This trial is registered with ClinicalTrials.gov (NCT02598661; substudy active and recruiting).
Findings: Between Sept 11, 2019, and Oct 13, 2021, 178 patients were enrolled and randomly assigned (118 to imetelstat and 60 to placebo). 111 (62%) were male and 67 (38%) were female. 91 (77%) of 118 patients had discontinued treatment by data cutoff in the imetelstat group versus 45 (75%) in the placebo group; a further 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 (12·1-22·7) in the placebo group. In the imetelstat group, 47 (40% [95% CI 30·9-49·3]) patients had an RBC-TI of at least 8 weeks versus nine (15% [7·1-26·6]) in the placebo group (rate difference 25% [9·9 to 36·9]; p=0·0008). Overall, 107 (91%) of 118 patients receiving imetelstat and 28 (47%) of 59 patients receiving placebo had grade 3-4 treatment-emergent adverse events. The most common treatment-emergent grade 3-4 adverse events in patients taking imetelstat were neutropenia neutropenia: (noo-truh-PEE-nee-uh) A condition in which there is a shortage of neutrophils in the bloodstream. Neutrophils are a type of white blood cell. This results in a low white blood cell count. (80 [68%] patients who received imetelstat vs two [3%] who received placebo) and thrombocytopenia thrombocytopenia: (throm-buh-sie-tuh-PEE-nee-uh) A condition in which there is a shortage of platelets in the bloodstream. This results in a low platelet count. Bleeding and bruising often occur with thrombocytopenia. (73 [62%] vs five [8%]). No treatment-related deaths were reported.
Interpretation: Imetelstat offers a novel mechanism of action with durable transfusion independence (approximately 1 year) and disease-modifying activity for heavily transfused patients with LR-MDS who are not responding to or are ineligible for ESAs.
Funding: Janssen Research & Development before April 18, 2019, and Geron Corporation thereafter.