What is the management approach for a patient with anemia of unknown origin, normal vitamin B12, folic acid, and iron profile, and bone marrow findings suggestive of suppressed erythropoiesis with increased erythroblasts?

Management of Anemia with Suppressed Erythropoiesis and Increased Erythroblasts

This clinical presentation—anemia with suppressed erythropoiesis, increased erythroblasts and plasma cells on bone marrow, and exclusion of monoclonal gammopathy—strongly suggests myelodysplastic syndrome (MDS), and you should proceed with cytogenetic analysis and WHO classification to guide risk stratification and treatment decisions. 1

Complete the Diagnostic Workup

Your patient has already excluded several key differential diagnoses, but critical diagnostic steps remain:

Essential Missing Tests

• Bone marrow cytogenetics are mandatory and represent the single most important missing test, as chromosomal abnormalities are crucial for MDS diagnosis, WHO classification, and prognostic scoring (IPSS/IPSS-R) 1

• Measure serum erythropoietin (EPO) level immediately, as this will guide treatment decisions if MDS is confirmed 1, 2

• Check lactate dehydrogenase (LDH) for prognostic value and to help exclude hemolysis 1

• Obtain reticulocyte count to confirm the hypoproliferative nature of the anemia 1

• Review peripheral blood smear for dysplastic features in all three cell lineages (erythroid, myeloid, megakaryocytic) 1

• Perform flow cytometry to assess for paroxysmal nocturnal hemoglobinuria (PNH) clone and evaluate CD34+ blast percentage 1, 3

Critical Diagnostic Criteria for MDS

The diagnosis requires exclusion of other causes (which you've largely done) PLUS at least one of three decisive criteria 1:

• Dysplasia ≥10% in ≥1 of the 3 major bone marrow lineages
• Blast cell count 5-19%
• MDS-associated karyotype (del(5q), del(20q), +8, -7/del(7q))

Your bone marrow showing "suppressed erythropoiesis with significant increase in erythroblasts" suggests dysplastic erythropoiesis, but you need formal quantification of dysplasia percentage and blast count. 1

Risk Stratification Once MDS is Confirmed

After obtaining cytogenetics, classify the patient using 1:

• WHO classification for subtype determination
• IPSS-R score for prognosis (lower-risk vs higher-risk disease)

This distinction is critical because it completely changes management:

• Lower-risk MDS: Median survival 3-10 years; focus on symptom management and transfusion reduction 4
• Higher-risk MDS: Median survival <3 years; requires hypomethylating agents or transplant consideration 4

Treatment Algorithm Based on Risk Category

If Lower-Risk MDS is Confirmed

The treatment approach depends on specific features 1, 2:

For patients WITH del(5q) ± one other cytogenetic abnormality:

• Lenalidomide is the preferred first-line therapy (Category 1) regardless of EPO level 1
• If no response to lenalidomide, proceed to erythropoiesis-stimulating agents (ESAs) if serum EPO ≤500 mU/mL 1

For patients WITHOUT del(5q) but WITH ring sideroblasts ≥15% (or ≥5% with SF3B1 mutation):

• If serum EPO ≤500 mU/mL: Luspatercept is preferred first-line (Category 1) based on the COMMANDS trial 1, 2
• Consider ESAs (epoetin alfa or darbepoetin alfa) if serum EPO ≤200 mU/mL 1
• If serum EPO >500 mU/mL: Imetelstat is preferred (Category 1) 1

For patients WITHOUT del(5q) and WITHOUT ring sideroblasts:

• If serum EPO ≤500 mU/mL: Consider ESAs (epoetin alfa or darbepoetin alfa) with or without G-CSF 1
• If serum EPO >500 mU/mL: Imetelstat may be considered 1

If Higher-Risk MDS is Confirmed

• Hypomethylating agents (azacitidine, decitabine, or decitabine/cedazuridine) are first-line therapy 4
• Evaluate for hematopoietic cell transplantation, which is the only potentially curative option 4

Important Caveats and Pitfalls

Common Diagnostic Errors to Avoid

• Do not rely on flow cytometry blast percentage for prognostic scoring—only morphologic blast percentage by an experienced hematopathologist is valid for IPSS-R 1

• Bone marrow biopsy with Prussian blue stain is essential to identify ring sideroblasts (≥15% is diagnostic for MDS with ring sideroblasts) 3

• Consider ICUS (Idiopathic Cytopenia of Uncertain Significance) or IDUS (Idiopathic Dysplasia of Unknown Significance) if dysplasia is <10% and cytogenetics are normal—these patients require close monitoring but may not yet meet MDS criteria 1

Additional Considerations

• Screen for secondary MDS risk factors: prior chemotherapy (especially alkylating agents), radiation exposure, benzene exposure 1

• In younger patients with hypoplastic marrow, consider HLA-DR15 typing and PNH screening to identify candidates for immunosuppressive therapy 1

• Assess transfusion burden if patient becomes transfusion-dependent, as this affects treatment decisions and iron overload monitoring 1

Immediate Next Steps

1. Order bone marrow cytogenetics immediately 1
2. Measure serum EPO level 1
3. Obtain formal hematopathology review with quantification of dysplasia percentage and blast count 1
4. Check reticulocyte count and LDH 1
5. Arrange hematology/oncology referral for definitive management once diagnosis is established 1, 4