What is the thromboembolic event risk in a patient with Myelodysplastic Syndromes (MDS) and anemia, comparing Reblozyl (luspatercept) to Retacrit (epoetin zeta, an erythropoiesis-stimulating agent, ESA)?

Thromboembolic Event Risk: Reblozyl vs Retacrit in MDS

Reblozyl (luspatercept) carries a lower thromboembolic risk compared to Retacrit (epoetin zeta/ESA) in patients with MDS, making it the preferred agent when ESAs have failed or when thromboembolic risk is a concern. However, ESAs remain first-line therapy for lower-risk MDS with appropriate patient selection and hemoglobin targets.

Thromboembolic Risk with ESAs (Retacrit)

ESAs increase thromboembolic event risk by 67% compared to placebo (RR 1.67; 95% CI: 1.35–2.06) in cancer patients 1. This risk is particularly elevated when:

• Hemoglobin targets exceed 12 g/dL 1
• Patients have a history of thrombosis, recent surgery, or prolonged immobilization 1
• Multiple myeloma patients receive concurrent thalidomide or lenalidomide with doxorubicin and corticosteroids 1

The FDA issued strengthened safety warnings in 2007-2008 noting increased mortality, possible tumor promotion, and thromboembolic events when ESAs target hemoglobin levels >12 g/dL 1. Current guidelines mandate a target hemoglobin of ≤12 g/dL to minimize these risks 1, 2.

Thromboembolic Risk with Luspatercept (Reblozyl)

Luspatercept has a generally manageable tolerability profile with thromboembolic events listed as an adverse event of special interest 3, but the incidence appears lower than with ESAs. In the pivotal MEDALIST phase III trial:

• Luspatercept demonstrated "limited toxicity" in phase II studies 1
• The most common adverse events were fatigue, diarrhea, asthenia, nausea, and dizziness—not thromboembolism 4
• Adverse event incidence decreased over time with continued luspatercept therapy 4

Real-world data from 54 MDS patients showed luspatercept was well-tolerated with no adverse events higher than grade II toxicity 5, suggesting a favorable safety profile in clinical practice.

Clinical Decision Algorithm

First-Line Therapy Selection

For newly diagnosed lower-risk MDS with symptomatic anemia:

1. Start with ESAs (epoetin alfa/Retacrit or darbepoetin) if 1, 2:

   • Serum erythropoietin <500 mU/mL
   • <2 RBC units transfused per month
   • Low marrow blast percentage
   • No history of thromboembolic events
   • Target hemoglobin ≤12 g/dL

2. Avoid ESAs and consider luspatercept earlier if 1:

   • Previous thrombosis history
   • Recent surgery or prolonged immobilization
   • Multiple myeloma with concurrent thalidomide/lenalidomide therapy
   • High baseline thromboembolic risk

Second-Line Therapy After ESA Failure

Luspatercept is FDA/EMA approved for lower-risk MDS with ring sideroblasts (MDS-RS) or SF3B1 mutation who are refractory to ESAs 1. This represents the optimal transition point where thromboembolic risk shifts favorably toward luspatercept.

Monitoring Requirements

For ESA therapy 2:

• Weekly CBC monitoring initially
• Monitor for thromboembolic events (leg swelling, chest pain, dyspnea)
• Verify adequate iron stores
• Discontinue if no response after 6-8 weeks

For luspatercept therapy 3, 4:

• Monitor for hypertension and bone pain (other adverse events of special interest)
• Standard thromboembolic surveillance (less intensive than ESAs)

Key Clinical Pitfalls

Common mistake: Continuing ESAs beyond 6-8 weeks without response increases thromboembolic exposure without benefit 1, 2. Discontinue promptly if hemoglobin rise <1-2 g/dL.

Common mistake: Targeting hemoglobin >12 g/dL with ESAs dramatically increases thromboembolic risk 1. Always maintain target ≤12 g/dL.

Emerging strategy: Real-world data suggests combining luspatercept with ESAs in poorly responding patients may improve efficacy 5, 6, though formal thromboembolic risk data for this combination are limited. In one series, 61% of patients received concurrent ESAs with luspatercept without reported thrombotic complications 5.

Bottom Line for Thromboembolic Risk

Luspatercept carries lower thromboembolic risk than ESAs based on adverse event profiles from clinical trials and real-world experience 3, 5, 4. ESAs increase thromboembolic events by 67% 1, particularly when hemoglobin targets exceed 12 g/dL 1. For MDS patients with prior thrombosis or high baseline risk, luspatercept represents a safer option if they meet approval criteria (MDS-RS or SF3B1 mutation, ESA-refractory) 1.