Pierre Noel
ERYTHROPOIETIN (EPOIETIN ALFA, PROCRIT™, EPOGEN™)
Epoietin Alfa (EPO) Indications
Anemia of chronic renal failure (CRF) patients (dialysis [+] or dialysis [–]).
Anemia in zidovudine-treated human immunodeficiency virus (HIV)-infected patients.
Anemia in patients undergoing chemotherapy.
Reduction of allogeneic blood transfusions in surgical patients.
In adult patients with CRF, doses of 50 to 100 U/kg three times weekly are required to maintain a hematocrit in the mid- to high thirties. The intravenous (IV) route of administration is recommended in dialysis patients; the IV or subcutaneous (SC) administration routes can be utilized in patients with CRF not undergoing hemodialysis. Patients with CRF treated with erythropoietin (EPO) experienced an increased risk of serious cardiovascular disease when treated with target higher hemoglobin levels. The dose of EPO should be individualized to achieve and maintain hemoglobin levels between 10 and 12 g/dL and should be reduced in patients who respond rapidly (>1 g/dL increase in hemoglobin over a period of 2 weeks) to minimize the risk of serious cardiovascular events. In zidovudine-treated adult patients with HIV with a serum EPO of <500 mU/ mL who are receiving a dose of zidovudine <4,200 mg/week, the recommended starting dose is 100 U/kg as an IV or SC injection three times a week for 8 weeks. The dose of EPO should be titrated to avoid transfusions and not to exceed a hemoglobin level of 12 g/dL. Patients with endogenous EPO levels >500 mU/mL are unlikely to respond to EPO. In adult anemic cancer patients undergoing chemotherapy, the initial recommended dose of EPO is 150 U/kg SC three times a week or 40,000 U SC weekly. Therapy should not be initiated if the hemoglobin is >10 g/dL. Patients with serum EPO levels >200 mU/mL are unlikely to respond to EPO. In some recent clinical studies, erythropoiesis-stimulating agents (ESA) shortened overall survival and/or increased the risk of tumor progression or recurrence in patients with breast, nonsmall cell lung, head and neck, lymphoid, and cervical cancers; because of these findings, EPO use is not recommended in patients receiving myelosuppressive therapy when the anticipated outcome is cure. In adult surgical patients, the reduction of allogeneic transfusion can be achieved with an EPO dose of 300 IU/kg/day for 10 days prior to surgery, on the day of surgery, and for 4 days after surgery. An alternate dose schedule is 600 U/kg SC in once-a-week doses starting 3 weeks prior to surgery plus a fourth dose on the day of surgery. All patients should receive iron supplementation. The preoperative hemoglobin should be between 10 and 13 g/dL. In surgical patients not receiving prophylactic anticoagulation, EPO increased the rate of deep venous thrombosis. Deep venous thrombosis prophylaxis should be considered in this setting.
Prior to and during treatment with EPO, the patient’s iron stores should be evaluated. Most patients require iron supplementation during therapy with EPO. Blood pressure may rise during treatment of anemia with EPO; hypertension should be controlled before initiation of therapy. The hemoglobin levels need to be monitored regularly while patients are being treated with EPO.
Allergic reactions and antibody-mediated pure red cell aplasia have been associated with the use of EPO. EPO contains albumin; it carries a very small risk of transmission of viral diseases.
DARBEPOIETIN ALFA (ARANESP™)
Darbepoietin alfa differs from recombinant human EPO by having sialylated carbohydrate content increasing the molecular weight, prolonging its half-life and increasing its biologic in vivo activity.
Darbepoietin alfa is indicated for the treatment of anemia with CRF and the treatment of anemia associated with nonmyeloid malignancies because of chemotherapy. In adult patients with anemia associated with renal failure, the recommended starting dose is 0.45 μg/kg administered IV or SC once per week. Alternatively, in patients not undergoing hemodialysis an initial dose of 0.75 μg/kg may be administered SC once every 2 weeks.
Darbepoietin alfa has been associated with an increased risk of cardiovascular events in patients with CRF. The risk of cardiovascular events is higher in patients who have target hemoglobin of 14 g/dL compared with patients who have target hemoglobin of 10 g/dL. The dose should be titrated to achieve and maintain target hemoglobin of 10 to 12 g/dL. In patients with nonmyeloid cancer receiving chemotherapy, the recommended doses of darbepoietin alfa are 2.25 μg/kg SC weekly or 500 μg SC every 3 weeks. Therapy should not be initiated at hemoglobin levels >10 g/dL. The goal of darbepoietin alfa treatment in the cancer setting is to avoid transfusions.
Blood pressure may rise during treatment of anemia with darbepoietin alfa; hypertension should be controlled before initiation of therapy.
Seizures and serious cardiovascular events have been reported in patients who had a rapid rate of increase in hemoglobin; the dose of darbepoietin alfa should be reduced if the hemoglobin level increase exceeds 1.0 g/dL in any 2-week period.
Clinical studies in cancer patients treated with ESAs reported shortened overall survival and/or increase in the risk of tumor progression in patients with breast, nonsmall cell lung, head and neck, lymphoid, and cervical cancer; because of these findings, darbepoietin alfa use is not recommended in patients receiving myelosuppressive therapy when the anticipated outcome is cure.
Darbepoietin alfa is supplied in two formulations: one containing polysorbate 80 and another containing albumin. Albumin is associated with a small risk of transmitting viral diseases.
METHOXY POLYETHYLENE GLYCOL-EPOETIN BETA (MIRCERA™)
Methoxy polyethylene glycol-epoetin beta is a continuous erythropoietin receptor activator that can be administered monthly. It has an extended half-life of 130 hours and a low clearance as well as unique receptor-binding properties.
Methoxy polyethylene glycol-epoetin beta is indicated in the treatment of anemia associated with chronic renal disease. The recommended starting dose in patients not currently treated with an ESA is 0.6 μg/kg once every 2 weeks IV or SC.
The warnings and precautions that apply to all ESAs also apply to methoxy polyethylene glycol-epoetin beta (pure red cell aplasia, cardiovascular events, hypertension, effect on tumor growth).
GRANULOCYTE COLONY-STIMULATING FACTOR (FILGRASTIM, NEUPOGEN™)
Filgrastim regulates the production of neutrophils within the bone marrow and also impacts on their function.
Granulocyte Colony-Stimulating Factor Indications
Nonmyeloid malignancies undergoing myelosuppressive chemotherapy with an expected risk of severe neutropenia and fever.
Acute myeloid leukemia, following induction or consolidation therapy.
Nonmyeloid malignancies undergoing myeloablative chemotherapy followed by marrow transplantation.
Mobilization of peripheral blood hematopoietic cells.
Severe chronic neutropenia.
Granulocyte colony-stimulating factor (G-CSF) can be administered SC or IV; the usual recommended dose is 5 μg/kg/day.
Patients treated with G-CSF have experienced allergic-type reactions, severe sickle-cell crises, bone pain, splenomegaly, and splenic rupture. G-CSF has the potential of stimulating the proliferation of myeloid leukemic cells.
PEGYLATED GRANULOCYTE COLONY-STIMULATING FACTOR (PEGFILGRASTIM, NEULASTA™)
Pegfilgrastim is produced by covalently conjugating a 20-kDa polyethylene glycol molecule to the N-terminus of filgrastim. The pegfilgrastim molecule is larger than the threshold for renal clearance, prolonging its half-life in circulation.
Pegfilgrastim is indicated to decrease the incidence of febrile neutropenia in patients with non-myeloid malignancies receiving myelosuppressive chemotherapy associated with a clinically significant incidence of febrile neutropenia. The adult recommended dose is 6 mg SC administered once per chemotherapy cycle.
Splenic rupture, adult respiratory distress syndrome, allergic reactions, severe sickle-cell crises, and proliferation of myeloid leukemic cells have been described in patients treated with filgrastim, which is the parent compound of pegfilgrastim.
GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR (SARGRAMOSTIM, LEUKINE™)
Sargramostim induces a dose-dependent increase in neutrophils and, to a lesser extent, monocytes and eosinophils. When granulocyte-macrophage colony-stimulating factor (GM-CSF) is discontinued, the leukocyte counts decrease to pretreatment levels over 3 to 5 days.
Granulocyte-Macrophage Colony-Stimulating Factor Indications
Following induction chemotherapy in patients with acute myeloid leukemia over the age of 55.
Mobilization of peripheral blood hematopoietic progenitor cells.
Myeloid reconstitution following autologous bone marrow transplantation for non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, and acute lymphoblastic leukemia.
Myeloid reconstitution after allogeneic marrow transplantation.
Allogeneic and autologous bone marrow transplantation engraftment failure or engraftment delay.
GM-CSF can be administered SC or IV. The usual daily recommended dose is 250 μg/m2.
The use of GM-CSF is potentially associated with fluid retention, capillary leak syndrome, pleural and pericardial effusions, sequestration of granulocytes in the pulmonary circulation, supraventricular arrhythmias, as well as renal and hepatic dysfunction. GM-CSF has the potential to stimulate the proliferation of myeloid leukemic cells.
INTERLEUKIN-11 (OPRELVEKIN, NEUMEGA™)
Oprelvekin is a thrombopoietic growth factor that stimulates the proliferation of megakaryocytic progenitors and induces megakaryocyte maturation; it also promotes the integrity of gastrointestinal mucosal epithelial cells.
Oprelvekin stimulates platelet production in a dose-dependent manner with peak platelet counts 14 to 21 days following its administration.
Oprelvekin is indicated for the prevention of severe thrombocytopenia in patients with nonmyeloid malignancies undergoing myelosuppressive chemotherapy. Oprelvekin is not recommended for use following myeloablative chemotherapy.
The usual recommended dosage is 50 μg/kg given once a day SC. The use of Oprelvekin has been associated with allergic or hypersensitivity reactions, including anaphylaxis, papilledema, fluid retention, edema, arrhythmias, pleural effusions, and electrolyte imbalances.
ROMIPLOSTIM (NPLATE™)
Romiplostim is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune idiopathic thrombocytopenia who have had an inadequate response to corticosteroids, immunoglobulins, or splenectomy.
The recommended initial dose is 1 μg/kg once a week SC followed by weekly dose adjustments based on response.
It is recommended to use the lowest dose of Romiplostim to achieve and maintain a platelet count >50,000/μL as necessary to reduce the risk of bleeding.
Romiplostim is associated with an increased risk of marrow fibrosis secondary to reticulin fiber deposition.