As presented at the 2023 ASCO Annual Meeting, the phase III IMerge trial of imetelstat1 and the phase III COMMANDS trial of luspatercept2 met their primary endpoints of transfusion independence. The findings suggest that lower-risk patients with transfusion-dependent, non-del(5q) myelodysplastic syndrome (MDS) will probably be gaining new treatment options, which is a welcomed advance in a group of patients with a high unmet treatment need, according to the studies’ invited discussant Anand Ashwin Patel, MD, Assistant Professor of Medicine at the University of Chicago Medical Center.
Anand Ashwin Patel, MD
“You really do get to a point in lower-risk MDS with anemia, particularly in the second- or third-line setting and beyond, where there is no firm standard of care,” Dr. Patel explained. “You can think about DNA methyltransferase inhibition, or lenalidomide in those who have not already received it,” he added, but one aim should be to reduce transfusion independence. “Reducing transfusion dependence is associated with improved quality of life in lower-risk and high-risk disease.”
IMerge Subgroups of Interest
IMerge examined imetelstat in patients with lower-risk MDS who had high endogenous erythropoietin (EPO) levels or previous exposure to erythropoiesis-stimulating agents (ESAs), without del(5q) and with or without ring sideroblasts. Red blood cell transfusion independence of at least 8 weeks was achieved by 39.8% of the imetelstat arm vs 15.0% of the placebo arm (P < .001), and benefit was largely maintained at 16 and 24 weeks. Furthermore, imetelstat had a clear effect in virtually all subgroups, Dr. Patel pointed out.
“Looking at subgroups of interest, you see improved outcomes—regardless of ring sideroblast status and both in EPO-high patients (> 500 IU/L) and in those with EPO < 500 IU/L,” he continued. Treatment with imetelstat led to transfusion independence in 45% of patients with ring sideroblasts, 32% of those without ring sideroblasts, 45% of patients with an EPO up to 500 IU/L and 27% of those with an EPO greater than 500 IU/L. The responses were approximately double, or better, than those achieved with placebo.
Dr. Patel said he was reassured by the toxicity profile, which showed cytopenias to be typically transient and reversible with dose modification and interruptions. He highlighted the lack of drug-induced liver injury, which was a concern in previous studies that used higher doses.
Although about 90% had prior treatment with ESAs, only about 7% had received luspatercept, which becomes relevant with the findings from COMMANDS. This trial demonstrated the superiority of luspatercept over ESAs as first-line therapy in lower-risk patients with and without ring sideroblasts, he said.
Clinical Implications of Both IMerge and COMMANDS
The efficacy described at the 2023 ASCO Annual Meeting for both luspatercept and imetelstat could signal a coming shift in the first-line treatment algorithm. For non-del(5q) patients who have an EPO less than 500 IU/L, the first-line treatment would be luspatercept; for patients with an EPO greater than 500 IU/L, it would be imetelstat, according to Dr. Patel. “However, it’s a little more complex than that,” he added, and mentioned the following open questions:
- Considering the potential for increased use of luspatercept in the front-line setting, what is the role of imetelstat in patients previously treated with luspatercept?
- For those with lower-risk MDS and previous ESA exposure, how will clinicians choose between luspatercept and imetelstat?
- Will long-term follow-up of COMMANDS show improved clinical endpoints beyond transfusion independence?
- Is there clinical equipoise between luspatercept and ESAs in low-risk MDS without ring sideroblasts?
- What is the quality of life of patients in the IMerge and COMMANDS trials?
- What is the minimum interval of transfusion independence that is meaningful?
DISCLOSURE: Dr. Patel has received honoraria from AbbVie and Bristol Myers Squibb; and has received research funding from Pfizer, Kronos Bio, and Sumitomo.
REFERENCES
1. Zeidan AM, Platzbecker U, Santini V, et al: IMerge: Results from a phase 3, randomized, double-blind, placebo-controlled study of imetelstat in patients with heavily transfusion dependent non-del(5q) lower-risk myelodysplastic syndrome relapsed/refractory to erythropoiesis-stimulating agents. 2023 ASCO Annual Meeting. Abstract 7004. Presented June 2, 2023.
2. Garcia-Manero G, Platzbecker U, Santini V, et al: Efficacy and safety results from the COMMANDS trial: A phase 3 study evaluating luspatercept vs epoetin alfa in erythropoiesis-stimulating agent-naive transfusion-dependent patients with lower-risk myelodysplastic syndromes. 2023 ASCO Annual Meeting. Abstract 7003. Presented at a press briefing May 22, 2023.
