What is the best course of treatment for a 55-year-old male with refractory anemia, elevated Erythropoietin (EPO) levels, and bone marrow biopsy showing dysplastic erythroblasts and suppressed erythropoiesis?

Diagnosis and Treatment Recommendation for Refractory Anemia with Dysplastic Features

This 55-year-old male has myelodysplastic syndrome (MDS), most consistent with refractory cytopenia with multilineage dysplasia (RCMD) or refractory anemia with excess blasts-1 (RAEB-1), and requires risk stratification using IPSS-R scoring followed by erythropoiesis-stimulating agents (ESAs) if lower-risk disease, or hypomethylating agents like azacitidine if higher-risk disease. 1

Diagnostic Classification

The bone marrow findings confirm MDS diagnosis:

• Dysplastic erythroblasts with suppressed erythropoiesis meet the WHO criteria for MDS, requiring ≥10% dysplasia in one or more myeloid lineages 1
• 1% blasts in bone marrow places this case in the lower blast count category, likely RCMD (if multilineage dysplasia confirmed) or potentially RAEB-1 if blasts are between 5-9% on repeat assessment 1
• Increased plasma cells on biopsy without M-protein or paraprotein excludes plasma cell dyscrasia but warrants monitoring, as this can occasionally accompany MDS 1
• Normal karyotype is prognostically intermediate in the IPSS-R scoring system 1
• Elevated EPO >750 U/L indicates endogenous erythropoietin response to anemia and predicts poor response to ESA therapy 1

Risk Stratification Required

You must calculate the IPSS-R score to determine treatment approach: 1

• Bone marrow blast percentage: 1% (very low risk component)
• Cytogenetics: Normal karyotype (intermediate risk component)
• Hemoglobin, platelet, and absolute neutrophil count values are needed to complete scoring 1
• The myeloid:erythroid ratio of 5:1 (elevated from normal 3:1) confirms suppressed erythropoiesis 1

Treatment Algorithm Based on Risk Category

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

First-line treatment for symptomatic anemia:

• ESAs (erythropoietin or darbepoetin) are first-line therapy for anemia in lower-risk MDS without del(5q), with expected response rates of ~60% when baseline EPO is low and transfusion requirement is limited 1
• However, this patient's EPO >750 U/L predicts poor response to ESA therapy (response rates drop significantly when EPO >500 U/L) 1
• ESA dosing: 30,000-80,000 units of EPO weekly or 150-300 μg darbepoetin weekly, with response assessment at 8-12 weeks 1
• Addition of G-CSF to ESA can improve response rates and should be considered 1

Second-line options if ESA fails or EPO too elevated:

• Antithymocyte globulin (ATG) with or without cyclosporine yields erythroid response in 25-40% of patients, particularly effective in younger patients (<65 years), normal karyotype, transfusion history <2 years, HLA-DR15 genotype, and presence of thrombocytopenia 1
• Lenalidomide (without del(5q)) achieves RBC transfusion independence in 25-30% of ESA-resistant patients 1
• Azacitidine (if approved in your region for lower-risk MDS) yields RBC transfusion independence in 30-40% of patients 1

If Higher-Risk MDS (IPSS-R Intermediate, 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 2
• Minimum 6 cycles required before assessing efficacy, as most patients only respond after several courses 2
• Alternative 5-2-2 regimen (5 days on, 2 days off, 2 days on) is acceptable for practical reasons but has not demonstrated survival advantage over 7-day regimen in higher-risk MDS 2
• Hematological improvement by IWG 2006 criteria should be considered indicative of response and is associated with prolonged survival 2

Allogeneic stem cell transplantation consideration:

• If patient is fit and age ≤65-70 years with available donor, allogeneic SCT should be considered as it represents the only curative option 1, 3
• 2-6 cycles of azacitidine are commonly used before transplantation to reduce bone marrow blasts 2

Critical Next Steps for This Patient

Immediate actions required:

1. Complete IPSS-R scoring with current hemoglobin, platelet count, and absolute neutrophil count 1
2. Assess transfusion requirements (number of RBC units per month) as this impacts treatment selection 1
3. Consider HLA-DR15 typing if immunosuppressive therapy is being considered 1
4. Evaluate for PNH clone by flow cytometry as small PNH clones can accompany MDS and influence treatment decisions 1
5. Molecular testing by next-generation sequencing to detect clonal mutations (particularly TP53, SF3B1, ASXL1) which provide prognostic information and may guide therapy 1

Common Pitfalls to Avoid

• Do not start ESA therapy without checking baseline EPO level, as levels >500 U/L predict poor response 1
• Do not discontinue azacitidine before 6 cycles unless clear disease progression, as delayed responses are common 2
• Do not overlook the increased plasma cells on biopsy—while no paraprotein is detected now, serial monitoring is warranted as plasma cell disorders can evolve 1
• Do not assume normal karyotype means favorable prognosis—molecular mutations may confer higher risk despite normal cytogenetics 1
• Do not delay allogeneic SCT evaluation in younger, fit patients with higher-risk disease, as this is the only curative option 1, 3