US Food and Drug Administration Approval Summary: Imetelstat for Selected Patients With Low- to Intermediate-1 Risk Myelodysplastic Syndromes With Transfusion-Dependent Anemia

On June 6, 2024, the US Food and Drug Administration (FDA) approved imetelstat (RYTELO, Geron) for adults with low- to intermediate-1 risk myelodysplastic syndromes (MDS) with transfusion-dependent anemia requiring ≥4 red blood cell units over 8 weeks who have not responded to or have lost response to or are ineligible for erythropoiesis-stimulating agents. The approval was based on a randomized (2:1), double-blind, placebo-controlled multicenter trial, Study MDS3001. In the protocol-specified primary analysis, the ≥8-week RBC transfusion independence (RBC-TI) rate was 39.8% (95% CI, 30.9 to 49.3) in the imetelstat group versus 15% (95% CI, 7.1 to 26.6) in the placebo group (<i>P</i> < .001). This was supported by the rate of ≥24-week RBC-TI of 28% (95% CI, 20.1 to 37) in the imetelstat group versus 3.3% (95% CI, 0.4 to 11.5) in the placebo group (<i>P</i> < .001). However, there was no major difference between arms regarding the key secondary end point of erythroid response (HI-E) per International Working Group 2006 criteria or secondary end points reflective of a disease-modifying effect such as complete remission rate and overall survival. The most common adverse reactions were thrombocytopenia, leukopenia, neutropenia, increased liver enzymes, fatigue, prolonged partial thromboplastin time, arthralgia/myalgia, COVID-19, and headache. The rate of grade 3 to 4 neutropenia and thrombocytopenia were 72% and 65%, respectively, in the imetelstat arm compared with 7% and 8% in the placebo arm. Despite the high incidence of neutropenia and thrombocytopenia, the FDA determined that the benefits outweighed the risks in this patient population with high unmet need. Postmarketing requirements were issued to evaluate long-term safety and to conduct a randomized trial comparing at least two dosages of imetelstat to potentially minimize risks of imetelstat treatment and improve tolerability.