What is the best treatment approach for a patient with severe anemia, elevated Erythropoietin (EPO) levels, and a bone marrow biopsy showing suppressed erythropoiesis and dysplastic erythroblasts, who has already received multiple Packed Red Blood Cell (PRBC) transfusions?

Management of Severe Transfusion-Dependent Anemia with Dysplastic Erythropoiesis and Elevated EPO

Do not use erythropoiesis-stimulating agents (ESAs) in this patient, as the EPO level >750 mU/mL indicates erythropoietin resistance, not deficiency, and ESAs are contraindicated when endogenous EPO exceeds 500 mU/mL due to negligible response rates. 1, 2

Diagnostic Classification

This presentation is consistent with myelodysplastic syndrome (MDS) based on:

• Dysplastic erythropoiesis with suppressed erythropoiesis and myeloid:erythroid ratio of 5:1 2
• Less than 10% blasts (1% in this case), placing this in the lower-risk category 1
• Normal karyotype, which is prognostically intermediate in IPSS-R scoring 3
• Exclusion of multiple myeloma (no M-protein, normal kappa/lambda ratio) 2
• Negative next-generation sequencing, though this should be repeated as molecular mutations provide critical prognostic information 3

The elevated EPO (>750 mU/mL) with severe transfusion dependence (11 units PRBC) confirms ineffective erythropoiesis rather than erythroid hypoproliferation. 4

Treatment Algorithm

Step 1: Confirm Risk Stratification

• Calculate formal IPSS-R score using blast percentage (1%), cytogenetics (normal karyotype), and cytopenias to determine if this is truly lower-risk versus higher-risk MDS 1, 3
• The severe transfusion burden (11 units) despite lower blast count suggests this may behave as higher-risk disease 3

Step 2: First-Line Treatment Based on Risk Category

For Lower-Risk MDS (if IPSS-R confirms):

• Luspatercept is the preferred first-line agent for transfusion-dependent lower-risk MDS patients with EPO >500 mU/mL 2, 3
• Dosing: 1.0 mg/kg subcutaneously every 3 weeks, with dose escalation to 1.33 mg/kg and then 1.75 mg/kg if inadequate response 4
• This TGF-β ligand trap specifically targets ineffective erythropoiesis and has FDA approval for this indication 4
• Response assessment occurs at 8-12 weeks 4

Alternative for Lower-Risk MDS if luspatercept unavailable or fails:

• Immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG) ± cyclosporine should be considered if: 1
  • Age ≤60 years
  • Hypocellular marrow (check if this was noted on biopsy)
  • HLA-DR15 positivity (needs testing) 1, 2
  • PNH clone positivity (needs testing) 1

For Higher-Risk MDS (if IPSS-R indicates):

• Azacitidine 75 mg/m² subcutaneously daily for 7 consecutive days every 28 days is the category 1 preferred recommendation 1, 3
• This hypomethylating agent improves overall survival compared to best supportive care 1
• Alternative: Decitabine if azacitidine is unavailable 1, 3

Step 3: Supportive Care (Mandatory Regardless of Treatment Choice)

Transfusion Management:

• Continue leukoreduced PRBC transfusions to maintain Hb sufficient to minimize symptoms (typically Hb >7-8 g/dL) 3
• Use CMV-negative and irradiated blood products if the patient is a potential transplant candidate 2

Iron Chelation Therapy (Critical):

• Initiate iron chelation immediately given 11 units transfused and ongoing transfusion dependence 1, 3
• Deferasirox (oral): 20 mg/kg/day, adjusted to maintain ferritin <1000 ng/mL 3
• Alternative: Deferoxamine (subcutaneous) if renal function is impaired 1
• Monitor ferritin and transferrin saturation monthly 1

Step 4: Additional Diagnostic Testing Required

Before finalizing treatment, obtain:

• Repeat molecular testing (NGS panel) focusing on SF3B1, TP53, and other MDS-associated mutations, as these guide therapy selection and prognosis 3
• HLA-DR15 typing if considering immunosuppressive therapy 1, 2
• PNH clone testing by flow cytometry 1
• Formal IPSS-R calculation to confirm risk category 1, 3

Step 5: Allogeneic Stem Cell Transplantation Evaluation

• If age <70 years without major comorbidities, refer for allogeneic hematopoietic stem cell transplantation (allo-HCT) evaluation 1
• Allo-HCT is the only curative option for MDS and should be considered early in higher-risk disease 1
• Reducing blast count with hypomethylating agents before transplant may improve outcomes 1

Critical Pitfalls to Avoid

Do not initiate ESA therapy: The EPO >750 mU/mL definitively indicates erythropoietin resistance. ESAs have <10% response rates when endogenous EPO exceeds 500 mU/mL and will only delay appropriate MDS-directed therapy. 1, 2

Do not delay iron chelation: With 11 units transfused and ongoing transfusion dependence, iron overload is inevitable and increases transplant-related mortality if allo-HCT becomes necessary. 1

Do not assume lower-risk based solely on blast count: The severe transfusion burden and dysplastic features warrant formal IPSS-R scoring, as this may represent higher-risk disease requiring hypomethylating agents rather than luspatercept. 3

Do not overlook molecular testing: The negative NGS result is unusual for MDS and should be repeated with a comprehensive MDS-specific panel, as mutations like SF3B1 predict luspatercept response. 3