FACE-OFF: Low-Risk MDS SOHO 2025

Panelists discuss how the COMMANDS phase 3 trial data demonstrate long-term efficacy and safety benefits of a newer drug compared with ESA in patients with low-risk myelodysplastic syndromes (MDS), with improved 5-year overall survival rates (54% vs 42%) and sustained transfusion independence lasting over 6 months, while maintaining a well-tolerated safety profile with no new safety signals identified in extended follow-up.

Panelists discuss how the long-term COMMANDS data reveal impressive survival benefits and durable transfusion independence responses, particularly in patients with SF3B1 mutations, while debating whether the observed survival advantage stems from transfusion independence alone or represents true disease modification through broader systemic effects beyond just bone marrow changes.

Panelists discuss how real-world retrospective data comparing first-line (1L) erythropoiesis-stimulating agents (ESAs) vs luspatercept in patients with low-risk MDS (LR-MDS) validate clinical trial findings, showing doubled response rates with luspatercept (particularly in SF3B1-positive patients). They debate optimal response end points, hemoglobin targets, and the need to incorporate quality-of-life measures beyond traditional transfusion independence criteria.

Panelists discuss how long-term MEDALIST trial data demonstrate the sustained efficacy of luspatercept in transfusion-dependent patients with lower-risk MDS, with median response duration exceeding 2 years and manageable safety profiles. They address concerns about cardiac events in this elderly population and the need for multidisciplinary care coordination including cardio-oncology consultation and optimization of cardiovascular risk factors.

Panelists discuss how the IMerge trial data demonstrate imetelstat’s efficacy in SF3B1-negative patients with lower-risk MDS who failed ESA therapy, achieving substantial hemoglobin improvements (averaging 4-5 g/dL in responders) with meaningful transfusion independence rates. They debate the clinical significance of modest patient-reported quality-of-life improvements and question whether historical hemoglobin ceiling limits should be reconsidered given robust treatment responses.

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.

Panelists discuss how to manage luspatercept “super responders” with hemoglobin levels above 12 g/dL, with Team Whataburger advocating for dose reduction to maintain stable responses and avoid hemoglobin fluctuations that disrupt patients’ quality of life, while Team In-and-Out argues for holding doses due to lack of safety data at very high hemoglobin levels and cost considerations. However, both teams acknowledge the need for individualized approaches and question whether current hemoglobin ceiling limits are appropriate for patients with MDS.

Panelists discuss how the timing of treatment initiation in lower-risk MDS (LR-MDS) should be approached. Team Whataburger advocates for earlier intervention based on symptoms and hemoglobin levels around 9 to 10 g/dL (citing European practices and the upcoming ULTIMATE study), while Team In-and-Out argues for delayed treatment until transfusion dependence develops to maximize the therapeutic lifespan of drugs such as luspatercept, given that symptomatically reported anemia can be subjective in this older population with multiple comorbidities.