Debate Round 3: Timing of Treatment Initiation in LR-MDS (Earlier vs Delayed)
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.
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)
EP: 7.Debate Round 2: Managing Luspatercept Super Responders (Dose Reduce vs Hold Dose)
EP: 8.Debate Round 3: Timing of Treatment Initiation in LR-MDS (Earlier vs Delayed)
Debate Round 3: Timing of Treatment Initiation in LR-MDS (Earlier vs Delayed)
The debate on timing of treatment initiation for LR-MDS highlights contrasting philosophies. One perspective emphasizes earlier treatment, particularly when patients develop symptoms such as fatigue or exertional intolerance, even before reaching transfusion dependence. Proponents argue that waiting until hemoglobin falls significantly or transfusion dependency develops only worsens quality of life, depletes blood resources, and may reduce long-term benefit. They point to European practices and data from clinical studies suggesting that earlier initiation, even at hemoglobin levels around 9 to 10 g/dL, could improve outcomes and prevent decline. Trials such as the Ultimate Study and Spanish data were cited as supportive of earlier intervention, reinforcing that listening closely to patient-reported symptoms should guide timing.
In contrast, the delayed treatment approach focuses on evidence gaps, drug durability, and individualized patient care. Advocates for waiting argue that many patients with hemoglobin levels above 10 g/dL remain asymptomatic, and even those with levels below 7 g/dL may tolerate anemia without significant impairment. They stress that treatment agents such as luspatercept may have a finite duration of efficacy, and delaying initiation could preserve effectiveness for when transfusion dependence emerges. Additionally, because fatigue is common in older patients with comorbidities, attributing symptoms solely to anemia can be misleading. This team emphasizes that trial eligibility criteria, typically based on transfusion need, should guide real-world practice to maximize long-term benefit.
The discussion also addresses dosing strategies, including whether to start at guideline-based lower doses with stepwise escalation vs beginning at maximum effective doses to achieve quicker responses. Some clinicians advocate for starting high and reducing as needed, while others favor escalation to balance safety with efficacy. Toxicity management, particularly monitoring for cytopenias, was described as essential regardless of timing strategy. Ultimately, the debate underscores the tension between proactive symptom-driven therapy vs reserving treatment for transfusion dependence, with both approaches requiring careful consideration of patient quality of life, drug durability, and individual variability.
