How can I get Reblozyl (luspatercept) approved for a patient with myelodysplastic syndrome (MDS) and anemia who has not responded to erythropoiesis-stimulating agents (ESAs) and has a hemoglobin level below 10 g/dL?

Getting Reblozyl Approved for MDS Patients Who Cannot Achieve Hemoglobin ≥10 g/dL

Reblozyl (luspatercept) can be approved for your MDS patient through two distinct FDA-approved pathways: either as first-line therapy if the patient is ESA-naïve with very low- to intermediate-risk MDS requiring regular transfusions, or as second-line therapy if the patient has failed ESA treatment and requires ≥2 RBC units over 8 weeks with ring sideroblasts (≥15%) or SF3B1 mutation. 1

FDA-Approved Indications for Reblozyl

The FDA label provides three specific approval pathways for MDS-associated anemia 1:

First-Line Option (ESA-Naïve Patients)

• Approved for anemia WITHOUT previous ESA use in adults with very low- to intermediate-risk MDS who may require regular RBC transfusions 1
• This pathway does NOT require ring sideroblasts or SF3B1 mutation 1
• The hemoglobin level being below 10 g/dL is not a barrier—the indication focuses on transfusion requirements, not specific hemoglobin thresholds 1

Second-Line Option (ESA-Failure Patients)

• Approved for anemia FAILING an ESA and requiring ≥2 RBC units over 8 weeks in adults with very low- to intermediate-risk MDS with ring sideroblasts (MDS-RS) OR SF3B1 mutation 1
• Must document ESA failure (defined as lack of response after 8-12 weeks of appropriate ESA dosing) 2
• Requires either ≥15% ring sideroblasts on bone marrow examination OR documented SF3B1 mutation 1

Documentation Requirements for Insurance Approval

For ESA-Naïve Patients (First-Line)

Document the following 1:

• IPSS or IPSS-R risk category (must be very low, low, or intermediate)
• Transfusion history showing regular RBC transfusion requirements
• Reason patient is ESA-naïve (never tried ESAs OR ineligible for ESAs)

For ESA-Failure Patients (Second-Line)

Document the following 2, 1:

• ESA trial details: Specific agent used (epoetin alfa 30,000-80,000 IU weekly OR darbepoetin alfa up to 300 mcg weekly), duration (minimum 8-12 weeks), and lack of response
• Consider adding G-CSF documentation: If ESA alone failed, guidelines recommend adding G-CSF 300 mcg/week for 2-3 doses before declaring ESA failure 2
• Transfusion burden: ≥2 RBC units over any 8-week period 1
• Bone marrow findings: Either ring sideroblasts ≥15% OR SF3B1 mutation status 1
• IPSS/IPSS-R risk: Very low, low, or intermediate risk 1

Critical Pitfalls to Avoid

Do not attempt to get Reblozyl approved by arguing the patient "cannot achieve Hgb 10 g/dL"—this is not how the FDA indication is written. 1 The approval is based on transfusion dependence and ESA status, not on achieving specific hemoglobin targets.

If your patient has already failed ESAs but lacks ring sideroblasts AND lacks SF3B1 mutation, the second-line pathway will NOT work. 1 In this scenario, you must use the first-line ESA-naïve pathway by arguing the patient should be considered for Reblozyl as if ESA-naïve (though this may face insurance challenges).

Ensure proper ESA trial documentation before declaring failure. 2 ESMO guidelines specify ESAs should be given at 30,000-80,000 IU weekly for 8-12 weeks, and if no response, G-CSF should be added at 300 mcg/week before considering the patient a true ESA failure 2. Inadequate ESA dosing or duration may result in denial.

Do not use Reblozyl in higher-risk MDS (IPSS intermediate-2 or high, or IPSS-R high or very high). 1 The FDA indication explicitly limits use to very low- to intermediate-risk disease.

Alternative Strategy: Combination Therapy

Emerging real-world evidence suggests combining luspatercept with erythropoietin alfa may improve response rates 3. In a 2024 Czech study, 60.7% of patients received concomitant epoetin alfa with luspatercept, and 55.2% of all responders benefited from this combination, with 16 patients achieving transfusion independence who had not responded to luspatercept alone 3. While not FDA-approved, this approach may be considered if monotherapy fails, particularly in patients with low transfusion burden 3.

Practical Approval Algorithm

Step 1: Determine if patient is ESA-naïve

• If YES: Use first-line indication—document IPSS/IPSS-R risk and transfusion requirements 1
• If NO: Proceed to Step 2

Step 2: Confirm adequate ESA trial

• If inadequate trial (wrong dose, insufficient duration, no G-CSF added): Complete proper ESA trial first 2
• If adequate trial with failure: Proceed to Step 3

Step 3: Check for ring sideroblasts or SF3B1 mutation

• If present: Use second-line indication—document ESA failure, transfusion burden ≥2 units/8 weeks, and IPSS/IPSS-R risk 1
• If absent: Consider arguing for first-line ESA-naïve pathway or clinical trial enrollment 2