Can Erythropoiesis-Stimulating Agents (ESAs) be given to a patient with Aplastic Anemia and Myelodysplastic Syndrome (MDS)?

ESA Use in Aplastic Anemia and Myelodysplastic Syndrome

ESAs may be offered to patients with lower-risk MDS (serum erythropoietin ≤500 IU/L) but should NOT be used in aplastic anemia except in rare circumstances where response has been documented. 1

Myelodysplastic Syndrome: Clear Indication

Patient Selection Criteria

ESAs are recommended as first-line therapy for symptomatic anemia in lower-risk MDS (IPSS low/intermediate-1 or IPSS-R very low/low/intermediate) when specific criteria are met 1, 2:

• Serum erythropoietin level ≤500 IU/L (this is the most critical predictor—patients with levels >500 IU/L have very low response rates and should not receive ESAs) 1, 2
• Transfusion requirement <2 units RBC per month (transfusion-dependent patients are less likely to respond) 2, 3
• Hemoglobin <10 g/dL 1
• Lower marrow blast percentage 2, 4

Expected Outcomes in MDS

• Erythroid response rates of 40-60% in appropriately selected lower-risk MDS patients 1, 2, 5
• Median duration of response: 20-24 months, with some patients responding for more than a decade 1, 6
• Improved survival (HR 0.61; 95% CI 0.44-0.83; P=0.002) compared to untreated controls, particularly in IPSS low-risk patients 2
• No negative impact on AML progression—multiple studies confirm ESAs do not increase leukemic transformation risk 1, 6

Dosing Regimen for MDS

• Initial dose: 40,000-60,000 units subcutaneously 1-3 times per week (or darbepoetin 150-300 mcg weekly) 2
• Assess response at 6-8 weeks—if hemoglobin increase <1 g/dL, consider adding G-CSF or discontinuing 1, 2
• Target hemoglobin ≤12 g/dL (never exceed 12 g/dL due to increased thromboembolism and mortality risk) 1, 2

Aplastic Anemia: Generally NOT Indicated

Critical Distinction

ESAs are NOT recommended for aplastic anemia in major clinical practice guidelines 1, 7. The ASCO/ASH 2019 guidelines explicitly state that ESAs should not be offered to most patients with nonchemotherapy-associated anemia, and aplastic anemia falls into this category 1.

Limited Evidence Base

The evidence for ESA use in aplastic anemia is extremely limited:

• Only one older study (1993) showed any response in aplastic anemia, where 3 of 7 patients (43%) responded to high-dose rhEPO (12,000-24,000 units three times weekly), and these responders had relatively low baseline serum erythropoietin levels 8
• No modern randomized controlled trials support ESA use in aplastic anemia 8
• Aplastic anemia is listed as a "patient-related cause of anemia that must be identified and addressed before considering ESA use" in cancer-associated anemia guidelines 7

When ESAs Might Be Considered in Aplastic Anemia

If ESAs are attempted in aplastic anemia (off-label, not guideline-supported), the following conditions should be met:

• Baseline serum erythropoietin level is relatively low (<500 IU/L, though no validated cutoff exists for aplastic anemia) 8
• Patient has failed or is not a candidate for definitive therapies (immunosuppressive therapy or hematopoietic stem cell transplantation)
• Close monitoring with serial serum erythropoietin measurements—a progressive decline in endogenous EPO during therapy may predict response, while persistently elevated or increasing levels suggest non-response 8
• Trial period of 8-12 weeks maximum—discontinue if no response 8

Critical Pre-Treatment Requirements (Both Conditions)

Before initiating ESAs in either MDS or aplastic anemia, the following must be addressed 1, 2:

• Rule out and correct iron deficiency (functional iron deficiency is a common cause of ESA failure) 1, 2
• Exclude other reversible causes: blood loss, infection, B12/folate deficiency, hemolysis 1
• Baseline cardiovascular risk assessment (ESAs increase thromboembolism risk by 67%) 9, 7

Safety Considerations

Thromboembolism Risk

ESAs increase thromboembolism risk by 67% compared to placebo 9, 7. This risk is particularly concerning in:

• Patients with baseline cardiovascular disease 9
• When hemoglobin exceeds 12 g/dL 1, 2
• Patients receiving curative-intent chemotherapy (contraindicated) 1

Monitoring Requirements

• Weekly CBC during initial treatment to assess response and prevent hemoglobin >12 g/dL 2
• Reduce dose by 25-50% if hemoglobin rises >2 g/dL within 4 weeks 9
• Withhold treatment if hemoglobin exceeds 13 g/dL until it falls below 12 g/dL, then restart at 25% lower dose 9

Common Pitfalls to Avoid

• Do not continue ESAs beyond 6-8 weeks in non-responders—this exposes patients to unnecessary thromboembolism risk without benefit 9, 2
• Do not use ESAs when serum erythropoietin >500 IU/L in MDS—response rates are extremely low 1, 2
• Do not target hemoglobin >12 g/dL—multiple studies demonstrate increased mortality and thromboembolism 1, 9, 2
• Do not assume ESAs work in aplastic anemia—the evidence base is minimal and guidelines do not support this use 1, 7