What are Erythropoiesis-Stimulating Agents (ESAs)?

Erythropoiesis-Stimulating Agents (ESAs): Definition and Clinical Use

Erythropoiesis-stimulating agents (ESAs) are medications designed to stimulate red blood cell production in the bone marrow to treat anemia, primarily indicated for chemotherapy-induced anemia in cancer patients and anemia associated with chronic kidney disease. 1

Types of ESAs

• ESAs currently available include epoetin alfa, epoetin beta, darbepoetin alfa, and continuous erythropoietin receptor activator (CERA) 2
• Short-acting ESAs include epoetin alfa and epoetin beta, which typically require more frequent dosing (1-3 times weekly) 3
• Long-acting ESAs include darbepoetin alfa (administered every 2 weeks) and methoxy polyethylene glycol-epoetin beta/CERA (administered every 4 weeks) 3, 4
• Biosimilar ESAs have been developed following patent expiration of original ESAs 2, 3

Mechanism of Action

• ESAs mimic the action of endogenous erythropoietin, a hormone naturally produced by the kidneys 1
• They stimulate erythropoiesis (red blood cell production) in the bone marrow by binding to erythropoietin receptors on erythroid progenitor cells 2, 4
• Chemical modifications like glycosylation and polyethylene glycosylation determine the half-life, receptor affinity, and immunogenicity of different ESAs 4

Clinical Indications

• Treatment of anemia due to Chronic Kidney Disease (CKD) in patients on dialysis and not on dialysis 5, 6
• Treatment of chemotherapy-induced anemia in adult patients with non-myeloid malignancies 1
• ESAs are not indicated for patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure 5
• ESAs are not indicated for patients not receiving chemotherapy or for those receiving only radiotherapy, hormonal therapy, or biological products 5, 6

Dosing Considerations

• Initial dosing depends on the specific ESA and indication:
  • For cancer patients: Epoetin alfa (150 IU/kg subcutaneously three times weekly), epoetin beta (30,000 IU subcutaneously weekly), or darbepoetin (2.25 μg/kg subcutaneously weekly) 1
  • For CKD patients: Dosing varies by ESA and whether patient is on dialysis 5
• Dose adjustments are made based on hemoglobin response:
  • Increase dose if hemoglobin rise is <1 g/dL after 4 weeks 1
  • Reduce dose by 25-50% if hemoglobin rises >2 g/dL in 4 weeks or exceeds 12 g/dL 1
  • Withhold dose if hemoglobin exceeds 13 g/dL until it falls below 12 g/dL 1

Efficacy

• ESAs increase hemoglobin levels with an overall weighted mean difference of 1.63 g/dL compared to controls in chemotherapy-induced anemia 1
• They reduce the need for red blood cell transfusions by approximately 36% in cancer patients 1
• Different ESAs have comparable efficacy when used according to approved dosing regimens 7

Safety Concerns and Risks

• ESAs carry a boxed warning regarding increased risks of death, myocardial infarction, stroke, venous thromboembolism, and tumor progression or recurrence 5
• The relative risk of thromboembolic events is increased by 67% in patients treated with ESAs compared with placebo 1
• ESAs should be used with caution in patients with:
  • Uncontrolled hypertension 5
  • History of thromboembolic events 1
  • Multiple myeloma treated with thalidomide or lenalidomide 1
• Pure red cell aplasia (PRCA) is a rare but serious adverse effect associated with ESA use, particularly with certain biosimilars 3

Monitoring and Management

• Regular monitoring of hemoglobin levels is essential during ESA therapy 1
• Target hemoglobin should generally be <12 g/dL for cancer patients 1
• For CKD patients, a target hemoglobin of 10-12 g/dL is generally recommended 1
• Treatment should be discontinued 4 weeks after completion of chemotherapy in cancer patients 1
• If no response is observed after 8-9 weeks of therapy, treatment should be discontinued 1

Common Pitfalls in ESA Use

• Targeting hemoglobin levels >12 g/dL increases cardiovascular risks without providing additional benefits 1, 5
• Using ESAs in cancer patients not receiving chemotherapy increases mortality risk 1, 5
• Failure to correct iron deficiency before initiating ESA therapy can lead to poor response 1
• Using ESAs as a substitute for immediate correction of anemia instead of blood transfusion when rapid correction is needed 5, 6