Role of Erythropoiesis-Stimulating Agents in Chemotherapy-Induced Anemia

Chemotherapy-induced anemia (CIA) is one of the most common adverse effects of myelosuppressive chemotherapy, a treatment designed to suppress cancerous cells in the bone marrow.¹ Because CIA is characterized by a significant reduction in red blood cell count and hemoglobin, which impedes the delivery of oxygen to body tissues, it can significantly impair a patient’s quality of life. Patients with CIA may experience fatigue, drowsiness, dizziness, dyspnea, and tachycardia.¹ Other symptoms may include insomnia, anorexia, cognitive impairment, and depression.²

The severity and range of CIA symptoms differ widely among patients according to the rapidity of disease onset and the patient’s comorbid conditions. CIA has also been independently linked to reduced response to anti-tumor therapy, resulting in poorer outcomes and reduced disease-free and overall survival.³ Increasing evidence suggests that the tumor hypoxia resulting from impaired oxygen delivery contributes to increased progression of disease and metastasis.²           

Etiology of CIA

Patients with cancer can have underlying anemia resulting from a variety of cancer-related, treatment-related, and patient-related causes (Table 1).⁴ Underlying malignancy can lead to chronic inflammation and upregulation of pro-inflammatory cytokines, which in turn suppresses erythropoiesis in the bone marrow and induces iron-restricted erythropoiesis, erythrocyte degradation, and impairment of erythrocyte survival. Independent of inflammation, malignant cells themselves can infiltrate the bone marrow, leading to suppression of hematopoiesis.

Some patients with cancer develop nausea, vomiting, and loss of appetite, all of which can lead to deficiencies in iron, vitamin B-12, and folate, thus impeding erythropoiesis. Additionally, blood loss resulting from cancer surgery, tumor bleeding, and renal insufficiency can induce anemia in patients with cancer.⁴

Myelosuppressive chemotherapy exacerbates this underlying anemia by either directly impairing hematopoiesis in the bone marrow or impeding erythropoietin production in the kidney via nephrotoxicity.⁴

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Diagnosing CIA

Given the multifactorial etiology of CIA, a definitive diagnosis is made on the basis of a comprehensive medical and treatment history and physical examination. To aid in diagnosis, basic blood cell counts are often supplemented with ferrokinetic studies, kidney function tests, bone marrow biopsies and imaging, urinary tests, blood smears, thyroid tests, and immunologic studies.⁵ The Common Terminology Criteria for Adverse Events (CTCAE) proposed by the National Cancer Institute (NCI) classify CIA into 5 grades according to hemoglobin (Hb) concentration (Table 2).⁶

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CIA Incidence

Because patients with cancer may have preexisting anemia, the incidence rate of CIA has proven difficult to determine. A European cancer survey carried out in 2006 reported incidence rates as high as 53%.⁷ In addition, CIA is more common in patients with hematologic malignant tumors. In a recent study that included patients with non-Hodgkin lymphoma, 36.9% of patients receiving myelosuppressive chemotherapy developed moderate CIA, whereas 11.6% developed severe CIA (Figure).¹

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Recombinant ESAs for the Management of CIA

The goal of treatment of CIA is to restore hemoglobin levels and improve overall quality of life. Red blood cell transfusion is an effective strategy for replacing depleted hemoglobin, although higher-quality studies are needed to understand which patients would benefit from transfusion the most.⁸ Furthermore, although the safety of blood transfusions has improved significantly over the years, the procedure continues to be associated with significant risks for thromboembolic events and mortality.⁹ Allogenic blood transfusion (ABT) can also induce an immune-inflammatory response, which can adversely affect the overall prognosis in patients undergoing chemotherapy.¹⁰ Through immunomodulatory effects, ABT can also independently increase the risk for cancer recurrence.^11,12

The cloning of the human erythropoietin gene in 1984 drove the development of erythropoietin-stimulating agents (ESA), which created opportunities for alternative therapeutic modalities in the management of CIA. ESAs are biological analogues of human erythropoietin that function by stimulating the proliferation and differentiation of hematopoietic progenitors. By reducing the need for red blood cell transfusions, ESAs can improve the quality of life of patients with CIA.¹³ Several short- and long-acting ESAs have been approved for use in cancer patients by the US Food and Drug Administration (FDA).

Epoetin Alfa. Epoetin alfa is chemically identical to human erythropoietin, with similar amino acid sequences. First approved for use in patients with cancer in 2008, epoetin alfa has since been evaluated in several randomized-controlled, double-blind, open-label studies. A key outcome of the drug is a marked reduction in the need for transfusions in patients with CIA.¹⁴          

Typically, epoetin alfa is administered intravenously at a dosage of 150 units/kg 3 times weekly or 600 units/kg once per week.¹⁵ Nausea, vomiting, myalgia, arthralgia, stomatitis, leukopenia, bone pain, rash, hyperglycemia, and insomnia are the common adverse effects associated with epoetin alfa. The drug has also been associated with some significant adverse events, including increased risk for cardiovascular events, stroke, and thromboembolism.¹⁴ As a result, epoetin alfa is indicated only for patients with cancer who are receiving myelosuppressive chemotherapy in which the anticipated outcome is not cure. Furthermore, in patients with iron deficiency, iron status should be corrected before the start of treatment.¹⁵

Epoetin Beta. Like epoetin alfa, epoetin beta shares a high degree of molecular similarity with human erythropoietin. The molecule binds to erythropoietin receptors to stimulate the proliferation and differentiation of hematopoietic stem cells. Weekly doses of 30,000 IU (450 units/kg) significantly increase Hb levels in addition to improving overall survival and reducing the need for transfusion.¹⁶ The safety of epoetin beta remains contentious, however. Whereas some studies report little to no adverse events with the drug, others indicate a risk for thromboembolic events, increased tumor progression, and reduced survival in patients with certain tumor types.¹⁶ Although similar in function and efficacy to epoetin alfa, epoetin beta has a longer half-life owing to its higher molecular weight and structural distinctions. Since 1990,epoetin beta has been licensed in Europe to treat CIA in patients with cancer.¹⁷

Darbepoetin Alfa. Darbepoetin alfa is a hyperglycosylated derivative of epoetin that binds to and stimulates erythropoietin receptors by the same mechanism as epoetin alfa and beta. However, because darbepoetin alfa contains additional oligosaccharides, its half-life is 3-fold that of epoetin alfa, and it has demonstrated efficacy in increasing Hb levels irrespective of baseline levels.¹⁸          

Currently, darbepoetin alfa is indicated only for nonmyeloid malignancies being treated with palliative myelosuppressive chemotherapy. The recommended starting dose is 2.25 µg/kg. However, patients should receive only the minimum dose necessary for achieving a reduction in transfusion requirement. The drug is contraindicated in patients with uncontrolled hypertension and in those who develop pure red cell aplasia after treatment initiation. Abdominal pain, edema, and thrombovascular events are the most common adverse effects of the drug, but the drug has also been associated with myocardial infarction, stroke, and thromboembolism. Because the drug has been associated with seizures, patients at risk for seizure should be closely monitored.¹⁹

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Biosimilars for the Management of CIA

In the United States, epoetin use accounts for $1.8 billion in drug spending.²⁰ The high cost of ESAs has limited the availability of these drugs to vulnerable populations. Biosimilar medicines, which have been designed to exhibit pharmacokinetics, pharmacodynamics, immunogenicity, safety, and efficacy similar to approved biologics, represent a cost-effective alternative.

The FDA approved the first biosimilar of epoetin alfa, epoetin alfa-epbx, for the treatment of CIA in 2018.²¹Biosimilar epoetin has been used in the European Union since 2007, where it is called epoetin zeta.²⁰

In a study in Europe, biosimilar epoetin demonstrated both efficacy and safety in the treatment of CIA, achieving an increase in Hb levels with a lower-than-expected rate of thromboembolic events.²² Several studies have also investigated the comparative efficacies of epoetin biosimilars with biologic ESAs. Epoetins and biosimilar epoetins can achieve similar hemoglobin outcomes and reductions in transfusion requirements.^23,24

Epoetin alfa-epbx is currently indicated for use in the treatment of CIA in patients with solid tumors, malignant lymphoma, and multiple myeloma receiving palliative chemotherapy. Like other epoetins, epoetin alfa-epbx has been associated with both mild adverse events (nausea, vomiting, myalgia, arthralgia, stomatitis, leukopenia, bone pain, rash, hyperglycemia, insomnia, and depression) and severe adverse events (thromboembolism, myocardial infarction, and stroke). A recommended starting dose of 150 units/kg is administered subcutaneously 3 times weekly. When Hb levels increase by 1 g/dL, a dose reduction of 25% is recommended.²⁵

Supplementation of ESAs with Iron

Patients with CIA treated with ESAs exhibit a marked increase in erythron iron requirements, in addition to erythrocyte suppression in the bone marrow. As a result, iron supplementation has been explored as an adjunct treatment. ²⁶ The findings relating to the efficacy of iron supplementation are contradictory, however. Some studies have shown that patients receiving iron supplementation therapy require lower doses of ESAs to achieve Hb targets, whereas others have shown no significant effect on blood transfusion, Hb levels, ESA use, or patient quality of life.²⁶

Currently, iron supplements are indicated for patients with CIA exhibiting functional iron deficiency with ferritin levels between 30 and 500 ng/mL. Typically, in patients with CIA, 100 to 200 mg of iron is administered orally or intravenously. Intravenous iron can deliver higher doses rapidly.⁵

Several iron salts, including ferrous sulfate, ferrous gluconate, ferrous fumarate, iron dextran, iron ferric gluconates, iron sucrose, and ferumoxytol, have been approved for the treatment of CIA. Most iron supplements are associated with only mild adverse effects such as gastrointestinal effects and allergic reactions, although some iron preparations can increase the risk for abdominal bleeding and inflammation.²⁷

Risk Evaluation and Mitigation Strategies

ESAs have been consistently associated with a spectrum of significant adverse events, including thromboembolism, cardiovascular events, stroke, tumor recurrence, and reduced survival. In response to the increasing evidence of these significant and life-threatening adverse events, in 2010 the FDA announced a Risk Evaluation and Mitigation Strategy (REMS) called ESA APPRISE, which included safety and monitoring procedures.

After the establishment of ESA APPRISE, the prescription of ESAs for the treatment of CIA decreased significantly over the next decade. Even among patients with advanced grade 4 CIA, the use of ESAs was significantly restricted. Conversely, the proportion of patients with CIA receiving blood transfusions increased.²⁸

In 2017, the FDA announced that the REMS was no longer essential in facilitating the safe administration of epoetin alfa and epoetin alfa-epbx. The agency determined that health care providers understood the risks with use of these agents and were prescribing them appropriately.²⁹

Current ASCO Guidelines

In 2019, the American Society of Clinical Oncology (ASCO) carried out a meta-analysis of evidence pertaining to the safety and efficacy of ESAs. Given the evidence, the ASCO revised their guidelines for prescriptions related to CIA management.³⁰ The recommendations include the following:

• ESAs may be offered to patients with CIA whose cancer treatment is not curative in intent;
• ESAs should not be offered to most patients with non-chemotherapy-associated anemia;
• In patients with myeloma, non-Hodgkin lymphoma, and chronic lymphocytic leukemia, hematologic response to cancer treatment should be monitored before ESAs are administered to minimize thromboembolic complications;
• ESA prescriptions should be made only after history, physical examination, and diagnostic testing are carried out to identify alternative causes of anemia;
• The ASCO panel considers epoetin beta, epoetin alfa, darbepoetin alfa, and biosimilar epoetin alfa to be of similar efficacy and safety;
• Because ESAs increase the risk for thromboembolism, they should be prescribed only after careful consideration of risks and benefits;
• Starting doses and modifications should follow FDA recommendations;
• Doses should be reduced to the lowest concentration that achieves a reduction in transfusion requirements;
• ESAs should be discontinued in patients who demonstrate no improvement within 6 to 8 weeks; and
• Iron-replacement therapy may be used to improve the efficacy of ESAs and reduce the need for transfusions. Periodic monitoring of iron levels is recommended during treatment.

Given the morbid implications of untreated CIA, the newly proposed ASCO guidelines may finally lead to a paradigm shift in ESA prescription in the United States.

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Cancer Therapy Advisor had no role in this content’s preparation.

                                                                                                                          Reviewed July 2022