What is the best treatment approach for a 55-year-old male with anemia, elevated lactate dehydrogenase (LDH), dysplastic erythroblasts, and a history of repeated red blood cell (RBC) transfusions, despite normal iron profile, vitamin B12, and folic acid levels, and elevated erythropoietin (EPO) levels?

Treatment Approach for Transfusion-Dependent MDS with Dysplastic Erythropoiesis

This patient has myelodysplastic syndrome (MDS) with suppressed erythropoiesis, significant dysplasia, and transfusion dependence—the elevated EPO >750 U/L predicts poor response to erythropoiesis-stimulating agents (ESAs), making hypomethylating agents like azacitidine the preferred first-line treatment after risk stratification. 1

Diagnostic Classification and Risk Assessment

• The bone marrow findings confirm MDS diagnosis: dysplastic erythroblasts with suppressed erythropoiesis meet WHO criteria requiring ≥10% dysplasia in one or more myeloid lineages 1
• The 1% blast count places this in lower blast category, likely refractory cytopenia with multilineage dysplasia (RCMD), though the myeloid:erythroid ratio of 5:1 and suppressed erythropoiesis are concerning features 1
• Normal karyotype is prognostically intermediate in the IPSS-R scoring system 1
• Calculate complete IPSS-R score immediately using current hemoglobin (7.1 g/dL), platelet count (180,000), and total count (2,860) to determine if this is lower-risk versus higher-risk MDS—this is the critical decision point that determines the entire treatment algorithm 2, 1

Treatment Algorithm Based on Risk Stratification

If Lower-Risk MDS (IPSS Low/Int-1; IPSS-R Very Low/Low/Intermediate):

ESAs are NOT recommended as first-line therapy in this patient because:

• EPO >750 U/L (well above the 500 U/L threshold) predicts very low response rates to ESAs 2, 1
• Guidelines specify ESAs should not be used when endogenous EPO levels exceed 500 mU/mL due to very low erythroid response rates 2
• Even with G-CSF addition, response rates remain poor when baseline EPO is elevated 2

Preferred treatment options for lower-risk MDS with high EPO:

• Imetelstat (category 1) is now FDA-approved specifically for transfusion-dependent lower-risk MDS patients ineligible for ESAs (EPO >500 U/L), with initial dosing of 7.1 mg/kg IV monthly 2
• Luspatercept-aamt may be considered if ring sideroblasts ≥15% or SF3B1 mutation present 2
• Lenalidomide can be considered as an alternative option even without del(5q) in this setting 2
• Immunosuppressive therapy with antithymocyte globulin (ATG) ± cyclosporine should be considered, particularly if HLA-DR15 positive 2, 1

If Higher-Risk MDS (IPSS Int-2/High; IPSS-R Intermediate/High/Very High):

Hypomethylating agents are the preferred first-line treatment:

• Azacitidine 75 mg/m² subcutaneously daily for 7 consecutive days every 28 days is the category 1 preferred recommendation based on superior median survival compared to best supportive care 2, 1
• Allogeneic stem cell transplantation should be evaluated as it represents the only curative option—at age 55, this patient is a reasonable candidate if a suitable donor is available 2, 1
• Hypomethylating agents can serve as a bridge to transplant to reduce blast burden if needed 2

Critical Next Steps Before Treatment Initiation

Complete the following assessments immediately:

• Perform molecular testing by next-generation sequencing to detect clonal mutations (TP53, SF3B1, etc.) which provide prognostic information and guide therapy selection 2, 1
• HLA-DR15 typing if immunosuppressive therapy is being considered 2, 1
• Flow cytometry for PNH clone as small PNH clones can accompany MDS and influence treatment decisions toward immunosuppression 1
• Assess for SF3B1 mutation and quantify ring sideroblasts as this determines eligibility for luspatercept 2
• Verify iron stores before any erythropoietic therapy—though ESAs are unlikely to work, iron repletion must be confirmed if any erythroid-stimulating treatment is attempted 2

Supportive Care Management

Transfusion support and iron chelation:

• Continue RBC transfusions using leukoreduced products to maintain hemoglobin sufficient to minimize symptoms 2
• Initiate iron chelation therapy given 11 units PRBC already transfused—consider deferasirox orally or deferoxamine subcutaneously targeting ferritin <1000 ng/mL 2
• Iron overload is a particular concern with frequent transfusions over several years, causing excess iron deposition in liver, heart, skin, and endocrine organs 2

Common Pitfalls to Avoid

• Do not initiate ESA therapy based solely on anemia presence—the EPO >750 U/L makes response extremely unlikely and wastes time and resources 2, 1
• Do not delay risk stratification—treatment differs dramatically between lower-risk and higher-risk MDS 2, 1
• Do not overlook the increased plasma cells on biopsy—while M-protein is negative now, this requires monitoring as plasma cell dyscrasia can occasionally accompany MDS 1
• Do not assume normal cytogenetics means favorable prognosis—molecular mutations (particularly TP53) may confer poor prognosis despite normal karyotype 2, 1
• Do not continue transfusions indefinitely without addressing iron overload—chelation should begin after 20 units or when ferritin exceeds 1000 ng/mL 2