Debate Round 1: Treatment Choices for RS-, EPO < 200 mU/mL LR-MDS (1L Luspatercept or ESA)
Panelists discuss how to choose between first-line (1L) luspatercept vs erythropoiesis-stimulating agent (ESA) therapy for SF3B1-negative patients with lower-risk MDS (LR-MDS) with erythropoietin (EPO) levels under 200 mU/mL. Team Whataburger argues that luspatercept’s superior response rates (60% vs 40%) and survival benefits make it the clear frontline choice, while Team In-and-Out counters that ESA remains viable for minimally transfusion-dependent patients due to cost considerations and potential for sequential therapy approaches.
EP: 1.Long-Term Update on Efficacy and Safety in Phase 3 COMMANDS Trial
EP: 2.Expert Perspectives on Long-Term COMMANDS Findings
EP: 3.Real-World Outcomes From 1L ESA vs Luspatercept Use in LR-MDS
EP: 4.Long-Term Updates From Phase 3 MEDALIST Trial
EP: 5.Clinical Efficacy and Patient-Reported Outcomes from Phase 3 IMerge Trial
EP: 6.Debate Round 1: Treatment Choices for RS-, EPO < 200 mU/mL LR-MDS (1L Luspatercept or ESA)
Debate Round 1: Treatment Choices for RS-, EPO <200 mU/mL LR-MDS (1L Luspatercept or ESA)
The debate centers on frontline treatment for patients with LR-MDS with ring sideroblast–negative disease and EPO levels less than200 mU/mL. Traditionally, ESAs have been 1L therapy, but emerging evidence suggests luspatercept may offer superior outcomes in this subgroup. Recent updates from clinical trials demonstrate higher response rates with luspatercept—approximately 60% compared with approximately 40% for ESAs. Importantly, patients treated with luspatercept also showed prolonged overall survival, with median OS not yet reached, compared with the expected 4 years for this population. These findings are shaping the argument that luspatercept should become the preferred 1L choice for these patients.
Counterarguments emphasize that ESAs still hold value, particularly for certain subgroups. Patients who are minimally transfusion-dependent or symptomatic with EPO levels below 200 mU/mL may still achieve durable responses, with studies showing up to 50% response rates in these select populations. Furthermore, ESAs remain more accessible, often easier to initiate in real-world practice, and significantly less costly. Questions remain regarding the optimal cutoff of 200 mU/mL for EPO levels, as this threshold is somewhat arbitrary and based on prior trial design rather than definitive biologic rationale. Some clinicians argue that a trial of ESA therapy followed by transition to luspatercept if inadequate response occurs remains a pragmatic approach.
Cost-effectiveness, patient quality of life, and real-world feasibility remain important considerations. Luspatercept, while effective, carries a higher up-front cost, and widespread adoption may be limited without strong health economic justification. There is also discussion about sequencing and combination approaches, as both agents act at different stages of erythropoiesis, raising the possibility of synergistic benefit. Early real-world experience suggests that patients who transitioned from ESAs to luspatercept may still achieve meaningful responses, supporting a flexible, individualized approach. Ongoing comparative studies and cost analyses will be critical in defining whether luspatercept should replace or complement ESAs in this LR-MDS setting.
