What is the best management approach for a patient with anemia, elevated erythropoietin (EPO) levels, and bone marrow showing dysplastic erythropoiesis?

Management of Anemia with Elevated EPO and Dysplastic Erythropoiesis

This patient should NOT receive erythropoiesis-stimulating agents (ESAs) given the markedly elevated endogenous EPO level of >750 mU/mL, which predicts treatment failure, and instead requires comprehensive evaluation for myelodysplastic syndrome (MDS) with consideration for disease-modifying therapy or supportive transfusions. 1

Why ESAs Are Contraindicated in This Case

The endogenous EPO level exceeding 750 mU/mL is a critical threshold that makes ESA therapy futile:

• ESA treatment is explicitly not recommended when endogenous serum EPO levels exceed 500 mU/mL due to very low erythroid response rates, as this indicates erythropoietin resistance rather than deficiency 1
• The NCCN guidelines specifically state that cytokine treatment with ESAs should not be used in patients with endogenous EPO levels greater than 500 mU/mL because of the very low erythroid response rate 1
• This elevated EPO reflects the body's already maximal attempt to stimulate erythropoiesis, and adding exogenous EPO will not overcome the underlying bone marrow dysfunction 1

Understanding the Bone Marrow Findings

The bone marrow picture reveals dysplastic erythropoiesis with suppressed red cell production:

• Dysplastic erythroblasts with suppressed erythropoiesis strongly suggests MDS, particularly given the patient's age (55 years) and the myeloid:erythroid ratio of 1:1 (normally should favor erythroid lineage) 2
• The 1% blast count and 2% plasma cells rule out acute leukemia and plasma cell disorders, but the dysplasia itself is the key pathologic finding 1
• The absence of M-band on SPEP and normal kappa/lambda ratio effectively excludes multiple myeloma as a cause 1

Recommended Management Algorithm

Step 1: Complete MDS Diagnostic Workup

• Obtain cytogenetic analysis and molecular testing (particularly for del(5q), SF3B1, TP53 mutations) as these determine specific treatment options 1
• Check for HLA-DR15 typing, which may predict response to immunosuppressive therapy in certain MDS subtypes 1
• Assess IPSS-R (Revised International Prognostic Scoring System) risk category to guide treatment intensity 1

Step 2: Risk-Stratified Treatment Approach

For Lower-Risk MDS (if confirmed):

• If del(5q) is present: Lenalidomide 10 mg daily, 3 weeks out of 4, is the treatment of choice with 60-65% response rates and median transfusion independence of 2-2.5 years 1
• If del(5q) is absent and EPO >500 mU/mL: ESAs are not indicated; consider immunosuppressive therapy with anti-thymocyte globulin (ATG) if HLA-DR15 positive, or proceed directly to clinical trials or supportive care 1
• Supportive transfusions with leukoreduced RBC products remain the standard of care for symptomatic anemia 1

For Higher-Risk MDS (if confirmed):

• Consider hypomethylating agents (azacitidine or decitabine) or allogeneic hematopoietic stem cell transplantation if eligible 1

Step 3: Supportive Care Measures

• Monitor and manage iron overload if chronic transfusions become necessary, as transfusion-dependent patients accumulate iron 1
• Use CMV-negative and irradiated blood products if the patient is a potential transplant candidate 1
• Ensure adequate iron stores (ferritin >100 ng/mL, transferrin saturation >20%) before any future consideration of growth factors, though this is unlikely to be relevant given the high EPO 1

Critical Pitfalls to Avoid

Do not initiate ESA therapy based solely on anemia and dysplasia without checking endogenous EPO levels first - this wastes time, exposes patients to unnecessary risks (thromboembolism, hypertension), and delays appropriate MDS-directed therapy 1, 3

Do not assume all dysplastic anemia will respond to ESAs - the bone marrow findings of dysplastic erythropoiesis with suppressed production indicate intrinsic marrow failure, not simply inadequate EPO stimulation 2

Do not overlook cytogenetic testing - specific chromosomal abnormalities like del(5q) completely change the treatment approach from futile ESA therapy to highly effective lenalidomide 1

Why This Patient's EPO is Elevated

The markedly elevated EPO (>750 mU/mL) with persistent anemia indicates:

• Erythropoietin resistance at the bone marrow level due to dysplastic erythropoiesis, where erythroid precursors cannot respond appropriately to EPO signaling 2
• The kidney is appropriately sensing anemia and producing maximal EPO, but the dysfunctional bone marrow cannot execute effective erythropoiesis 4
• This pattern is characteristic of MDS with dyserythropoiesis, where immature erythroblasts accumulate but fail to mature due to differentiation arrest and apoptosis 2