What is the diagnosis and treatment plan for a 55-year-old male with refractory anemia, elevated erythropoietin (EPO) levels, and bone marrow findings showing suppressed erythropoiesis with dysplastic erythroblasts?

Diagnosis: Myelodysplastic Syndrome with Multilineage Dysplasia

This 55-year-old male has myelodysplastic syndrome (MDS), most consistent with refractory cytopenia with multilineage dysplasia (RCMD) or potentially RAEB-1, requiring immediate IPSS-R risk stratification to determine whether hypomethylating agents or supportive care is appropriate. 1

Diagnostic Confirmation

The diagnosis of MDS is established by the following features:

• Bone marrow dysplasia ≥10% in erythroid lineage with suppressed erythropoiesis and dysplastic erythroblasts meets WHO diagnostic criteria for MDS 2, 1
• Blast count of 1% places this in the lower blast category, though the myeloid:erythroid ratio of 5:1 (normally 3:1) indicates suppressed erythropoiesis 1
• Normal karyotype is prognostically intermediate in the IPSS-R system 1
• Exclusion of other causes: Normal iron studies, B12, folate, and negative paraprotein workup rule out nutritional deficiencies and plasma cell disorders 2
• Increased plasma cells without M-protein can occasionally accompany MDS but does not indicate plasma cell dyscrasia 1

The elevated EPO >750 U/L is an appropriate physiologic response to severe anemia and does not suggest polycythemia vera or other myeloproliferative neoplasm 1.

Critical Next Step: Complete IPSS-R Scoring

You must immediately calculate the IPSS-R score using:

• Bone marrow blast percentage (1%)
• Cytogenetics (normal karyotype = intermediate risk)
• Current hemoglobin (7.1 g/dL)
• Platelet count (180,000/μL)
• Absolute neutrophil count (from total count 2860/μL) 1, 3

This scoring determines whether the patient has lower-risk or higher-risk MDS, which fundamentally changes the treatment approach and goals 2.

Additional Required Testing Before Treatment

• Molecular testing by next-generation sequencing to detect mutations (SF3B1, TP53, ASXL1, RUNX1, etc.) that provide prognostic information and may guide therapy 1, 4
• HLA-DR15 typing if immunosuppressive therapy is being considered 1
• PNH clone by flow cytometry as small PNH clones can accompany MDS and influence treatment decisions 1
• Repeat bone marrow examination may be needed in 6 months if dysplasia is subtle or diagnosis remains equivocal 2, 5

Treatment Algorithm Based on Risk Stratification

If Lower-Risk MDS (IPSS-R Very Low, Low, or Intermediate):

The extremely elevated EPO >750 U/L predicts poor response to erythropoiesis-stimulating agents (ESAs), with expected response rates <10% 2, 1

Given the transfusion dependence (11 units already) and high EPO, treatment options include:

1. Antithymocyte globulin (ATG) ± cyclosporine if favorable features present (younger age, hypocellular marrow, HLA-DR15 positivity, PNH clone) 2, 1

2. Azacitidine if approved for lower-risk MDS in your region, though this is more commonly reserved for higher-risk disease 2

3. Luspatercept if SF3B1 mutation or ring sideroblasts are present (requires molecular testing confirmation), with FDA/EMA approval for transfusion-dependent lower-risk MDS-RS after ESA failure 2

4. Lenalidomide only if del(5q) is present on cytogenetics, which is not the case here with normal karyotype 2

5. Supportive care with RBC transfusions and iron chelation therapy if ferritin >1000 ng/mL to prevent iron overload complications 2, 6

If Higher-Risk MDS (IPSS-R High or Very High):

Hypomethylating agents are first-line therapy:

• Azacitidine 75 mg/m² subcutaneously daily for 7 consecutive days every 28 days is the standard regimen 1, 3
• Alternative: Decitabine or oral decitabine/cedazuridine 3, 4

Allogeneic stem cell transplantation evaluation is mandatory as this represents the only curative option, with cure rates of 30-50% 3, 6

• At age 55 with no mentioned comorbidities, this patient is a potential transplant candidate 2, 6
• Transplant should be considered upfront for higher-risk disease 3

Critical Pitfalls to Avoid

• Do not start ESAs with EPO >500 U/L - response rates are extremely poor and delay effective therapy 2, 1
• Do not use lenalidomide without del(5q) - it is ineffective and potentially harmful in non-del(5q) MDS 2
• Do not delay molecular testing - mutations like TP53 indicate particularly poor prognosis and may change management to more aggressive approaches including transplant 2, 1
• Monitor for iron overload - with 11 units transfused already, check ferritin and consider chelation if >1000 ng/mL 2, 6
• Do not assume stable disease - repeat bone marrow assessment every 3-6 months to monitor for clonal evolution or progression to higher-risk MDS/AML 2

Prognosis Discussion

• Lower-risk MDS: Median survival 3-10 years 3
• Higher-risk MDS: Median survival <3 years 3
• Transfusion dependence is an independent poor prognostic factor 2
• Normal karyotype is intermediate risk, better than complex or chromosome 7 abnormalities but worse than isolated del(5q) 1