Bone Marrow Modulators: Colony-Stimulating Factors and Erythrocyte-Stimulating Agents

ABSTRACT: The most common dose-limiting toxicities of cancer chemotherapy include febrile neutropenia (FN) and its subsequent infectious complications—anemia and thrombocytopenia. FN is a serious medical problem that is associated with high morbidity, mortality, and cost. Colony-stimulating factors (CSFs) are commonly used in clinical practice to treat either primary or secondary neutropenia. Benefits of CSFs include reduced incidence of life-threatening bacterial and/or fungal infections, reduced hospital stays, and fewer delays in chemotherapy. Exogenous erythrocyte-stimulating agents (ESAs) are often required to treat more severe types of anemia resulting from cancer treatment (chemotherapy or radiation), chronic kidney failure, and certain drugs used to treat HIV infection, and to reduce the number of blood transfusions during and after major surgeries.

Bone marrow suppression represents the most serious toxic effect of antineoplastic induction therapy. Bone marrow modulators, such as colony-stimulating factors (CSFs) and erythrocyte-stimulating agents (ESAs), are used to treat toxicities of cancer chemotherapy.¹ The most common major dose-limiting toxicities of cancer chemotherapy include febrile neutropenia (FN) and its subsequent infectious complications—anemia and thrombocytopenia. These conditions occur with common chemotherapy regimens in 25% to 40% of treatment-naïve patients.¹

Marrow hypoplasia from myelosuppressive regimens usually reaches its lowest point (nadir) after 1 to 2 weeks of therapy. Its severity depends on a number of factors, including the dose intensity of the chemotherapy regimen, the patient’s prior history of either radiation therapy or use of cytotoxic treatment, and comorbidities.¹ It may also lengthen the hospital stay; increase monitoring, diagnostic, and treatment costs; and reduce patient quality of life (QOL).

FEBRILE NEUTROPENIA

Exogenous CSFs are often administered to patients who are undergoing chemotherapy that may cause low white blood cell (WBC) counts (i.e., neutropenia) and to patients with hematologic conditions that predispose them to a greater risk of infection. Neutropenia is defined as an absolute neutrophil count (ANC) of <500/mcL or an ANC of <1,000/mcL with an expected decline to ≤500/mcL in 48 hours. Fever is defined as a single temperature of 38.3°C or a temperature of 38.0°C sustained for 1 hour without an obvious cause.² Despite improvements in clinical treatments, FN is a serious medical problem for patients that is associated with high morbidity, mortality, and cost.^3,4

When patients develop FN, they are usually admitted to the hospital for initiation of appropriate antibiotic therapy.⁴ The diagnosis of infection in neutropenic patients is complicated because there is generally a lack of elevated WBCs, or left shift. Usual signs and symptoms of infection in typical patients are pus, abscesses, and infiltrates on chest x-rays, which depend on the presence of WBCs and a healthy immune system response. However, in FN patients the most reliable indication of infection is elevated temperature. Definitive cultures may take days, and a septic neutropenic cancer patient may die in a few hours if not treated. Therefore, the basic approach to the management of the FN cancer patient is hospitalization and prompt initiation of empiric antibiotics. The most common source of infection in these patients is often self-infection with normal body flora, which may include gram-negative or gram-positive bacteria and/or fungi.⁴

COLONY-STIMULATING FACTOR THERAPY

CSFs or granulocyte CSFs (G-CSFs) are secreted glycoproteins that bind on the surfaces of receptor proteins, thereby activating intracellular signaling pathways that stimulate proliferation, differentiation, and activation of the targeted (granulocyte) cell lines.¹ CSFs are commonly used in clinical practice as either primary or secondary prophylaxis of neutropenia. Primary prophylaxis refers to the use of CSFs to prevent neutropenia with the first cycle of chemotherapy. Secondary prophylaxis refers to the use of CSFs to prevent recurrence of neutropenia in patients who experienced neutropenia with the prior cycle of chemotherapy.^1,5-7

Endogenous CSF is produced by monocytes, fibroblasts, and endothelial cells to regulate neutrophil production in the bone marrow. The neutrophils produced are involved in the following physiological processes: 1) phagocytosis, 2) respiratory burst, 3) antibody-dependent killing, and 4) increased expression of surface antigens.⁷ When patients develop an infection, the immune system responds by releasing G-CSF into the bloodstream. The bone marrow responds by stimulating the growth and maturation of stem cells into neutrophils that enhance the immune system and increase phagocytosis of infectious bacteria.⁷

The term colony-stimulating factors, also known as hematopoietic growth factors, is derived from the method by which they were discovered. Hematopoietic stem cells were cultured on a semisolid matrix, which prevents cells from moving around, so that if a single cell starts proliferating, all cells derived from it will remain clustered around the spot in the matrix where the first cell was originally located.⁶ These clusters are referred to as colonies. Therefore, it was possible to add various substances to cultures to see which kinds of colonies were “stimulated.” Currently, the CSF family includes filgrastim (Neupogen), pegfilgrastim (Neulasta), and sargramostim (Leukine).^8-10 Both filgrastim and pegfilgrastim are G-CSFs derived from Escherichia coli, and sargramostim is a granulocyte-macrophage CSF (GM-CSF) derived from Saccharomyces cerevisiae yeast (see TABLE 1 for a comparison). Initially, clinicians feared that because myeloid blast cells carry receptors for G-CSF and GM-CSF, using CSFs might stimulate regrowth of the myeloid leukemia. However, this outcome is not supported by clinical studies.¹¹

Recently, a new CSF, tbo-filgrastim (Neutroval), received FDA approval.¹² XM02 or tbo-filgrastim is the first biosimilar G-CSF, marketed as safe and effective in reducing the duration of severe neutropenia and the incidence of FN in patients with small cell or non-small cell lung cancer receiving platinum-based chemotherapy.^13-15 The drug is a short-acting recombinant G-CSF agent that is marketed as Tevagrastim in Europe, where tbo-filgrastim is classified as biosimilar to Amgen’s G-CSF product Neupogen. Tbo-filgrastim was approved through the standard FDA process for new drugs and some biological agents. Tbo-filgrastim is reported to be superior to placebo and equivalent to filgrastim in reducing the duration of severe neutropenia and the incidence of FN in cycle 1 in breast cancer patients receiving docetaxel-doxorubicin chemotherapy. The manufacturer, Teva Pharmaceuticals, announced that it does not expect to market tbo-filgrastim until November 2013 at the earliest.^12,13

The term biosimilar refers to products that are marketed after expiration of drug patents and are claimed to have very similar properties to existing biological products. But due to the complexity of newer biologics, a biosimilar product can only be made that is close, not identical, to another, and clinical results from the use of biosimilars may vary from those of the original product.¹²

Indications and Potential Uses

Clinically important uses of CSFs in oncology include prevention of FN after chemotherapy treatment of FN episodes, support following bone marrow transplantation, and collection of CSF-mobilized peripheral blood progenitor cells.^1,5,8-10 Other potential uses include combination therapy with stem cell factors and other cytokines to boost progenitor cell development; maintenance of dose intensity of salvage therapy in metastatic cancer patients; and application in patients with pneumonia, Crohn’s fistulas, breast cancer, lung cancer, non-Hodgkin’s lymphoma, Hodgkin’s disease, diabetic foot infections, and a variety of other infectious conditions.

The high cost of CSFs may limit their widespread use.^16,17 Current American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) guidelines recommend primary prophylaxis, or first cycle use, only for patients with a 20% or higher risk of FN; primary prophylaxis with special circumstances, which may include elderly and other high-risk patients; and secondary prophylaxis.^2,5 Clinical risk factors that may increase patient risk for complications include age >65 years; concurrent chemotherapy and radiotherapy; poor nutritional status; advanced cancer; decreased immune function in patients who are already at an increased risk of infection; preexisting neutropenia due to disease, extensive prior chemotherapy, or previous irradiation to the pelvis or other areas containing large bone marrow reserve; infection or open wound; and other comorbidities.^1,2

Toxicities and Adverse Drug Reactions

The most common toxicity and adverse effects of CSFs include musculoskeletal bone pain (25%-45%), particularly in the large bones, thighs, hips, sternum, and lower spine; acidic diarrhea; headache; lethargy; fever; nausea; vomiting; and diarrhea. Other side effects include an increase in lactate dehydrogenase, alkaline phosphatase, and uric acid levels. Serious adverse effects include effects in the hematologic (sickle cell anemia with crisis and bone marrow leukemia), immunologic (anaphylaxis), and respiratory (acute respiratory distress syndrome) systems; alveolar hemorrhage (manifested as pulmonary infiltrates and hemoptysis); rupture of the spleen; and urinary tract infections.^8-10

Counseling Considerations for Patients Taking CSFs^8-10:

• Do not shake prefilled syringe/vial before using.
• Do not freeze but refrigerate syringes/vials (2°-8°C or 36°-45°F) in original carton.
• Discard unused syringes stored at room temperature for longer than 48 hours. Protect from light.
• Allow the CSF product to reach room temperature (this takes about 30 minutes) before administering.
• Rotate subcutaneous (SC) injection sites. Use a different place on your arms, stomach, hips, or legs each time you give the injection. Do not inject into the same place two times in a row.
• Do not use the medication if it has changed colors or has particles in it.
• The needle cover on the single-use prefilled syringe contains dry natural rubber (latex), which should not be handled by persons sensitive to this substance.
• Treatment for bone pain can usually be managed by acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs).
• If a dose is missed, use it as soon as you remember, but not within the 24-hour period before or after you receive chemotherapy. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.

Generally, CSF therapy should not begin sooner that 24 hours after the last dose of chemotherapy and should be continued until the ANC exceeds a safe level following the expected chemotherapy nadir. To avoid the potential risks of excessive leukocytosis (WBC >50,000 cells/mm³; ANC >20,000 cells/mm³), CSF therapy may be discontinued if the ANC surpasses 10‚000/mm³ after the chemotherapy-induced ANC nadir has occurred. Administering doses of CSF when the ANC exceeds 10‚000/mm³ may not result in any additional clinical benefit. CBCs will be routinely conducted to monitor CSF therapy results.^8-10

Patients may have delays or dose reductions in chemotherapy treatment, which have the potential to impact their QOL, as well as their survival. The occurrence of FN often causes subsequent chemotherapy delays or dose reductions. It may also lengthen hospital stay, increase monitoring, diagnostic, and treatment costs, and reduce patient QOL.^8-10

Information Specific to Sargramostim: The first dose of sargramostim may cause difficulty breathing, flushing, fainting, dizziness, or fast or irregular heartbeat. These signs usually resolve and usually do not occur again. This effect may get worse if the drug is taken with alcohol or certain medications. Patients should not drive or perform other possibly unsafe tasks until they know how they will react to sargramostim.¹⁰

For patients with diabetes, sargramostim may affect blood glucose levels, so blood glucose should be checked regularly. Patients should be advised to discuss any dosing changes to their diabetes medications with their physician. Laboratory tests, including liver function, kidney function, blood counts, body weight, and fluid and serum electrolyte levels, may be performed while using sargramostim. These tests may be used to monitor the condition or check for side effects. Adverse drug effects such as edema, capillary leak syndrome, and pleural and/or pericardial effusions have been reported in patients after administration of the drug.¹⁰

ERYTHROCYTE-STIMULATING AGENT THERAPY

Conventional therapy (e.g., iron, folic acid, vitamin B₁₂) is often effective in treating common types of anemia. For more severe types of anemia, exogenous ESAs are often required. Anemias requiring ESAs include those from cancer treatment (chemotherapy or radiation), chronic kidney failure, and the use of antiretroviral agents; ESAs are also used to reduce the number of blood transfusions during and after major surgeries.¹⁸ In addition, preexisting anemia may be exacerbated by myelosuppressive cancer treatment, particularly in patients who undergo intensive chemotherapy or combined modality treatment with both chemotherapy and radiation therapy. Erythropoiesis is the development process by which new red blood cells (RBCs), or erythrocytes, are produced. Erythropoietin (EPO) is a naturally occurring substance, and about 90% is produced by the kidneys.^19,20 Kidneys can detect low oxygen levels in blood or tissue and respond by releasing EPO into the plasma, which travels to the red bone marrow to stimulate stem cells to differentiate into proerythroblasts, increase the rate of mitosis, increase the release of reticulocytes, and induce hemoglobin formation.

Human erythrocytes, are produced through a process termed erythropoiesis, developing from committed stem cells to mature erythrocytes in about 7 days.^21,22 When matured, these cells exist in blood circulation for about 100 to 120 days (80-90 days in a full-term infant). Through this process erythrocytes are continuously produced in the red bone marrow of large bones (the vertebrae, sternum, ribs, and pelvis), at a rate of about 2 million per second in a healthy adult. Just before and after leaving the bone marrow, immature RBCs are known as reticulocytes; these cells constitute about 1% of circulating RBCs.

When the kidneys cannot produce enough EPO to maintain the RBCs and hemoglobin needed, ESAs may be prescribed. ESAs act like natural EPO and can be given to increase RBCs and hemoglobin production.^23-25 ESAs are administered either subcutaneously or intravenously, and are given in many dosing schedules, ranging from once a week to several times a week to once a month, depending on the ESA selected, the dose needed, and the reason it is being given.^23-25 It may take several weeks to raise the RBCs and hemoglobin levels and relieve symptoms. Currently, exogenous EPOs approved by the FDA are produced by recombinant DNA technology in cell culture, and include epoetin alfa (Procrit/Epogen) and darbepoetin alfa (Aranesp) (see TABLE 2 for a comparison). Darbepoetin alfa has a longer duration of action than epoetin alfa and can usually be administered less often.^18,26 ESAs are structurally and biologically similar to naturally occurring EPO, and they stimulate erythropoiesis by the same mechanism as EPO.^18,27-29

Recently, the FDA approved peginesatide (Omontys), a novel ESA for the treatment of anemia due to chronic kidney disease (CKD) in adult patients on dialysis. It is a synthetic peptide that mimics the structure of EPO.¹²

Toxicities and Adverse Drug Effects of ESAs

Side effects that occur most often with ESA use include high blood pressure, swelling, fever, dizziness, nausea, and pain at the site of the injection. These drugs also have black box warnings of increased risk of death, myocardial infarction, stroke, venous thromboembolism, and tumor recurrence.³⁰

Counseling Considerations for Patients Taking ESAs^18,27-29:

• ESAs increase the risk of venous thromboembolism (blood clots in the veins), and a blood clot can break away from one location and travel to the lungs (pulmonary embolism), where it can block circulation.
• Use ESAs with caution in patients who have the following conditions: heart disease; high blood pressure, especially uncontrolled hypertension; porphyria (a group of diseases that are caused by enzyme deficiencies); seizures; and an allergy to epoetin alfa or any other part of this medicine; also in women who are pregnant, planning to become pregnant, or breastfeeding.
• Inform patients that blood transfusions may improve symptoms of anemia right away, but ESAs may take from weeks to months to provide noticeable relief of the symptoms of anemia.
• Determine if the patient is allergic to ESAs or to products containing human albumin, or if the patient has any other allergies.
• Some products may contain inactive ingredients (e.g., polysorbate, latex), which can cause allergic reactions or other problems. The needle cover of prefilled syringes may contain dry natural rubber (a derivative of latex), which can cause allergic reactions.
• Do not shake prefilled syringes or vials. Do not use products that have been shaken or frozen.
• Protect vials and prefilled syringes from light.
• Do not use any vials or prefilled syringes exhibiting particulate matter or discoloration.  
• Discard unused portions of vials or prefilled syringes. Do not re-enter vial.
• Do not dilute darbepoetin alfa and do not administer in conjunction with other drug solutions.

SUMMARY

CSFs help reduce the duration of neutropenia and the incidence of FN episodes in patients receiving myelosuppressive chemotherapy. Since common signs of systemic infections are often not present, unexplained fever and an ANC <500/mcL are considered key indicators of FN. Due to the high morbidity of FN, it is important to begin G-CSF treatment and appropriate antibiotic therapy. Currently, the ASCO and NCCN guidelines recommend the use of G-CSF when patients have a 20% or greater risk of developing FN from chemotherapy.^2,5 Benefits of CSFs include reduced incidence of serious infections, shorter hospital stays, and fewer delays in chemotherapy.

Conventional medications and ESAs are available to help correct anemias and may at times be used concurrently. ESAs have been administered successfully to millions of patients worldwide and are becoming the standard of care for cancer and HIV medication–induced anemias.

REFERENCES

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