C H A P T E R
56 Hematopoietic Agents
HEMATOPOIETIC GROWTH FACTORS, p. 663
self-administered at home, epoetin therapy can spare patients considerable inconvenience. Because epoetin works slowly (the hematocrit may take 2 to 4 weeks to recover), transfu-sions are still indicated when rapid replenishment of RBCs is required. Please note that epoetin is not approved for patients with leukemias and other myeloid malignancies because the drug may stimulate proliferation of these cancers. Furthermore, since ESAs can shorten survival time in all cancer patients, epoetin is indicated only when the goal of cancer therapy is palliation. When the goal is cure, ESAs should not be used.
(It makes no sense to give a potentially lethal drug to a patient who might be cured.) A new clinical guideline—American Society of Hematology/American Society of Clinical Oncology Clinical Practice Guideline Update on the Use of Epoetin and Darbepoetin in Adult Patients with Cancer—provides detailed information on using ESAs in patients with cancer.
HIV-Infected Patients Taking Zidovudine. Epoetin alfa is approved for treating anemia caused by therapy with zi-dovudine (AZT) in patients with AIDS. For these patients, treatment can maintain or elevate erythrocyte counts and reduce the need for transfusions. However, if endogenous levels of erythropoietin are at or above 500 milliunits/mL, raising them further with epoetin is unlikely to help.
Anemia in Patients Facing Surgery. Epoetin may be given to increase erythrocyte levels in anemic patients scheduled for elective surgery. The drug should be used only when significant blood loss is anticipated—but should not be used before cardiac or vascular surgery. For surgical patients, epoetin offers two benefits: (1) it decreases the need for transfusions, and (2) by increasing erythrocyte synthesis, it allows patients to predeposit more blood in anticipation of transfusion needs.
Pharmacokinetics
Epoetin alfa is administered parenterally (IV or subQ). The drug cannot be given orally because, being a glycoprotein, it would be degraded in the GI tract. The plasma half-life is highly variable and unchanged by dialysis.
Adverse Effects and Interactions
Epoetin alfa is generally well tolerated. Although the drug is a protein, no serious allergic reactions have been reported. The most significant adverse effect is hypertension. There are no significant drug interactions. As discussed later under Warnings, improper use of epoetin alfa has been associated with serious cardiovascular events, tumor progression, and deaths.
Hypertension. In patients with CRF, epoetin is frequently associated with an increase in blood pressure. The extent of hypertension is directly related to the rate of rise in the hema-tocrit. To minimize risk, blood pressure should be monitored and, if necessary, controlled with antihypertensive drugs. If hypertension cannot be controlled, epoetin dosage should be reduced. In patients with pre-existing hypertension (a common complication of CRF), it is imperative that blood pressure be under control before epoetin use. About 30% of dialysis patients receiving epoetin require an adjustment in their antihypertensive therapy once the hematocrit has been normalized.
Cardiovascular Events. Epoetin has been associated with an increase in serious cardiovascular events. Among these are cardiac arrest, hypertension, HF, and thrombotic events, includ-ing stroke and MI. Risk is greatest when (1) the hemoglobin level exceeds 11 gm/dL or (2) the rate of rise in hemoglobin exceeds 1 gm/dL in any 2-week interval. Accordingly, dosage Physiology
Erythropoietin is a glycoprotein hormone that stimulates produc-tion of RBCs in the bone marrow. The hormone is produced by peritubular cells in the proximal tubules of the kidney. In response to anemia or hypoxia, circulating levels of erythro-poietin rise dramatically, triggering an increase in erythrocyte synthesis. However, because production of erythrocytes requires iron, folic acid, and vitamin B12, the response to erythropoietin is minimal if any of these is deficient.
Erythropoietin has significant physiologic effects outside the hematopoietic system. Animal studies indicate that eryth-ropoietin is secreted by cells of many organs, including the brain, bone marrow, liver, heart, kidney, uterus, testes, and blood vessels—and that receptors for erythropoietin are present at most of these sites. Actions of the hormone include modula-tion of angiogenesis (blood vessel formamodula-tion) and maintenance of cellular integrity (by inhibiting apoptotic mechanisms of cell injury). In the future, these actions may be exploited to treat a variety of disorders, including stroke, diabetic nephropa-thy, multiple sclerosis, MI, and heart failure (HF).
Therapeutic Uses
Anemia of Chronic Renal Failure. Epoetin alfa can partially reverse anemia associated with CRF, reducing—but not eliminating—the need for transfusions. Benefits accrue to patients on dialysis as well as those who do not yet require dialysis. Initial effects can be seen within 1 to 2 weeks. Hemo-globin reaches maximal acceptable levels (10 to 11 gm/dL) in 2 to 3 months. Unfortunately, although treatment reduces the need for transfusions, it does not improve quality of life, decrease fatigue, or prevent progressive renal deterioration.
For therapy to be effective, iron stores must be adequate.
Transferrin saturation should be at least 20%, and ferritin concentration should be at least 100 ng/mL. If pretreatment assessment indicates these values are low, they must be restored with iron supplements.
Chemotherapy-Induced Anemia. Epoetin alfa is used to treat chemotherapy-induced anemia in patients with nonmyeloid malignancies, reducing the need for periodic transfusions. Since transfusions require hospitalization, whereas epoetin can be
Biologic Name
Pharmacologic Names Generic Name Brand Name ERYTHROPOIETIC GROWTH FACTORS
Erythropoietin Darbepoetin alfa Aranesp
Epoetin alfa Epogen, Procrit, Eprex LEUKOPOIETIC GROWTH FACTORS
Granulocyte colony- stimulating factor (G-CSF)
Filgrastim Neupogen
Pegfilgrastim Neulasta Granulocyte-macrophage
colony-stimulating factor (GM-CSF)
Sargramostim Leukine
THROMBOPOIETIC GROWTH FACTOR
Interleukin-11 Oprelvekin Generic only
TABLE 56.1 ■ Nomenclature for Hematopoietic Growth Factors
CHAPTER 56 Hematopoietic Agents
The guide also informs patients about what they can do to minimize risk.
Cancer Patients. The ESA APPRISE Oncology Programa sets additional requirements for using ESAs in cancer patients.
Prescribers must enroll in ESA APPRISE, complete a brief training module, discuss the risks and benefits of ESAs with the patient, and sign a form acknowledging that the discussion took place. Hospitals that dispense ESAs must be enrolled in ESA APPRISE and must ensure that all ESA prescribers are enrolled as well. Prescribers who use ESAs for patients who do not have cancer are not required to enroll in ESA APPRISE.
should be reduced when hemoglobin approaches 11 gm/dL or when the rate of rise exceeds 1 gm/dL in 2 weeks—and, in most patients, dosing should be temporarily stopped if hemo-globin rises to 11 gm/dL or more. To prevent clotting in the dialysis machine, CRF patients on dialysis may need increased anticoagulation with heparin.
Autoimmune Pure Red-Cell Aplasia. Very, very rarely, treatment with epoetin leads to pure red-cell aplasia (PRCA), a condition characterized by severe anemia and a complete absence of erythrocyte precursor cells in bone marrow. The cause is production of neutralizing antibodies directed against epoetin itself, as well as any native erythropoietin the body is still able to produce. In the absence of epoetin and erythropoietin, production of RBCs ceases. Because patients can no longer make erythrocytes, transfusions are required for survival. If evidence of PRCA develops, epoetin should be discontinued and blood should be assessed for neutralizing antibodies.
Safety Alert
DOSAGES
To minimize the risk of serious adverse events, the dosage of epoetin alfa and all other ESAs should be the lowest needed to gradually raise hemoglobin content to the lowest level sufficient to reduce the need for RBC transfusions. In most cases, hemoglobin level should not exceed 11 gm/dL. When ESAs are administered in doses sufficient to raise hemoglobin above this level, risk of serious cardiovascular events and death is increased.
Hematopoietic Agents
Life Stage Patient Care Concerns
Infants See “Breast-feeding women,” below.
Children/
adolescents Many hematopoietics can be used safely in children, just in smaller doses. Side effect profiles are similar to those of adults.
Pregnant
women Animal studies indicate that hematopoietics can cause fetal harm, and they are classified in FDA Pregnancy Risk Category C.a Risks and benefits must be considered for administration during pregnancy.
Breast-feeding
women Colony-stimulating factors are normal components of human breast milk. Infant harm has not been demonstrated. No special precautions are required during breast-feeding.
Older adults Hematopoietic agents do not lower mortality or cardiovascular risk in older adults. However, recent studies have shown improved quality of life in older adults with more physiologically normal hemoglobin. Hematopoietic agents can help achieve this.
PATIENT-CENTERED CARE ACROSS THE LIFE SPAN
aAs of 2020, the FDA will no longer use Pregnancy Risk Categories.
Please refer to Chapter 9 for more information.
aESA (erythropoiesis stimulating agent) APPRISE (Assisting Providers and Cancer Patients with Risk Information for the Safe Use of ESAs) Oncology Program.
Warnings
Cancer Patients. Postmarketing reports indicate that ESAs can accelerate tumor progression and shorten life in certain cancer patients—especially when hemoglobin has been driven above 12 gm/dL. In patients with advanced head and neck cancer who are undergoing radiation therapy, ESAs have shortened the time to tumor progression. In patients with metastatic breast cancer who are receiving chemotherapy, ESAs have shortened overall survival and increased deaths from tumor progression. Also, ESAs have increased the risk of death in patients with active malignant disease who are not receiving either radiation or chemotherapy, so ESAs are contraindicated for this group.
Renal Failure Patients. In patients with anemia of chronic renal failure, ESAs can increase the risk of serious cardiovas-cular events and death if hemoglobin levels are driven too high. Accordingly, dosage should be individualized to produce hemoglobin levels no higher than 10 to 11 gm/dL.
Preoperative Patients. When given to preoperative patients to reduce the need for RBC transfusion, ESAs have increased the risk of deep vein thrombosis—but only in patients who were not given an anticoagulant. Accordingly, anticoagulant therapy should be considered for all preoperative patients receiving an ESA.
Risk Evaluation and Mitigation Strategy
All Patients. Because ESAs can cause serious adverse effects, these drugs must be prescribed and used under a Risk Evaluation and Mitigation Strategy (REMS), mandated by the U.S. Food and Drug Administration (FDA). Under the REMS, all patients must receive a Medication Guide that explains the risks and benefits of ESAs. The goal is to help patients make an informed decision when use of an ESA is under consideration.
Monitoring
Hemoglobin level should be measured at baseline and twice weekly thereafter until the target level has been reached and a maintenance dose established. Complete blood counts with a differential should be done routinely. Blood chemistry—blood urea nitrogen (BUN), uric acid, creatinine, phosphorus, and potassium—should be monitored. Iron should be measured periodically and maintained at an adequate level.
Preparations, Dosage, and Administration
Preparations. Epoetin alfa [Epogen, Procrit, Eprex ] is supplied in 1-mL single-dose vials (2000, 3000, 4000, 10,000, and 40,000 units) and in 1- and 2-mL multidose vials (10,000 and 20,000 units). Vials should not be shaken (because epoetin is a protein that can be denatured by agitation). Don’t mix epoetin with other drugs. Store at 2°C to 8°C (36°F to 46°F); don’t freeze.
General Dosing Guidelines. Use the lowest dosage needed to gradually increase the hemoglobin concentration to the lowest level suf-ficient to reduce the need for RBC transfusion. For most patients, the target
cancer itself. Furthermore, since darbepoetin may increase the risk of cancer-related death, it should be used only when the objective of cancer therapy is palliation, not when the objective is cure.
Adverse Effects and Warnings
Darbepoetin is generally well tolerated. As with epoetin, the most common problem is hypertension. The risk can be mini-mized by ensuring that the rate of rise in hemoglobin does not exceed 1 gm/dL every 2 weeks. If hypertension develops, it should be controlled with antihypertensive drugs. Patients already taking antihypertensive drugs may need to increase their dosage.
Like epoetin alfa, darbepoetin increases the risk of PRCA, MI, HF, stroke, cardiac arrest, and other cardiovascular events, especially when the hemoglobin level exceeds 11 gm/dL or when the rate of rise in hemoglobin exceeds 1 gm/dL in 2 weeks.
Like epoetin alfa, darbepoetin can promote tumor progression and shorten survival in some cancer patients, and thus should not be used when the objective of chemotherapy is cure.
Monitoring
When initiating darbepoetin or changing dosage, the hemoglobin level should be measured weekly until it stabilizes. Thereafter, hemoglobin should be measured at least once a month.
Preparations, Dosage, and Administration
Preparations and Storage. Darbepoetin alfa [Aranesp] is available in 1-mL single-dose vials (25, 40, 60, 100, 200, and 300 mcg/mL and 150 mcg/0.75 mL) and pre-filled single-dose syringes and auto-injectors (10 mcg/0.4 mL, 25 mcg/0.42 mL to 500 mcg/mL). Administration is by subQ and IV injection. Don’t dilute darbepoetin or mix it with other drugs. Because darbepoetin is a protein that can be denatured by agitation, do not shake the drug. Discard preparations that are discolored or contain particles. Store at 2°C to 8°C (36°F to 46°F); don’t freeze.
General Dosing Guidelines. The treatment goal is to reduce the need for transfusions. Dosage should be reduced when hemoglobin approaches 11 gm/dL or when hemoglobin increases by more than 1 gm/dL in any 2-week interval. If hemoglobin rises to 11 gm/dL or higher, withhold treatment until hemoglobin drops below 11 gm/dL. When treatment resumes, decrease the dose by 25%, and then titrate upward as needed.
Dosing in Patients With Chronic Renal Failure. The initial dosage is 0.45 mcg/kg, given either IV or subQ once a week. If hemoglobin rises above 11 gm/dL (for patients on dialysis) or 10 gm/dL (for patents not on dialysis), treatment should be temporarily withheld. Because responses develop gradually, dosage should be adjusted no more than once every 4 weeks. Quite often, the maintenance dosage is less than the initial dosage.
When switching from epoetin to darbepoetin, the new dosage and dosing frequency are based on the existing epoetin usage. For example, patients receiving 5000 to 11,000 units of epoetin each week should receive 25 mcg of darbepoetin each week. If the epoetin dosing frequency was 2 to 3 times a week, darbepoetin should be given once a week; if epoetin was given once a week, darbepoetin should be given once every 2 weeks.
Dosing in Patients Undergoing Cancer Chemotherapy. The initial dosage is 2.25 mcg/kg subQ once a week or 500 mcg subQ every 3 weeks.
If the increase in hemoglobin is less than 1 gm/dL after 6 weeks, dosage should be increased to 4.5 mcg once a week. If the increase in hemoglobin exceeds 1 gm/dL in 2 weeks, or if hemoglobin rises high enough to avoid transfusions, dosage should be reduced by 40%. Dosing should cease when chemotherapy stops.