Description: Sargramostim is a human granulocyte-macrophage colony-stimulating factor (rhuGM-CSF) produced by recombinant DNA technology. Sargramostim is produced by a yeast (S. cerevisiae) expression system. Sargramostim is a glycoprotein of 127 amino acids characterized by 3 primary molecular entities. The amino acid sequence of sargramostim differs from native human GM-CSF by a substitution at the leucine position 23, and the carbohydrate moiety may be different from the native protein. Clinically, sargramostim is used to reduce the duration of neutropenia and incidence of infection in patients receiving myelosuppressive chemotherapy or bone marrow transplantation, for mobilization of peripheral blood progenitor cells for collection, and for bone marrow graft failure or engraftment delay. Cost analyses have shown that colony stimulating factors (CSFs) save money when the risk of febrile neutropenia is > 40%. ASCO clinical guidelines recommend the use of CSFs for primary prophylaxis of neutropenic fever only for chemotherapy regimens where the expected incidence of febrile neutropenia is >= 40% or in special circumstances (e.g., bone marrow compromise or comorbidity). For secondary prophylaxis of febrile neutropenia, ASCO guidelines recommend chemotherapy dose reduction (exclusive of curable tumors such as germ cell tumors) as the primary therapeutic option. Clinical trials have not demonstrated disease-free or overall survival benefit when the dose of chemotherapy was maintained and secondary prophylaxis with CSFs was used.[857] The FDA approved sargramostim in March 1991. In Europe, molgramostim, bacterially derived rhuGM-CSF produced using E. coli, is commonly used. Mechanism of Action: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a multilineage growth factor. Sargramostim has the same biologic activity as native GM-CSF. GM-CSF supports the survival, clonal expansion, and differentiation of progenitors in the granulocyte-macrophage pathways as well as megakaryocytic and erythroid progenitor cells. Other growth factors are required to induce complete maturation of megakaryocytic and erythroid cells. GM-CSF is primarily produced by bone marrow stroma and activated B-cells, T-cells, and monocyte/macrophages. The GM-CSF receptor is expressed on granulocytes, erythrocytes, megakaryocytes, macrophage progenitor cells and mature cells including neutrophils, monocytes, macrophages, dendritic cells, plasma cells, certain T-cells, vascular endothelial cells, uterine celss, and myeloid leukemia cells. Synergy with a variety of other hematopoietic growth factors (e.g., interleukin-3, macrophage colony-stimulating factor, c-kit ligand, and erythropoietin) occurs. GM-CSF has multiple actions on mature neutrophils including protection against apoptosis, induction of degranulation, increased production of reactive oxygen species, and enhanced bacteriocidal activity of neutrophils. The half-life of neutrophils is prolonged following administration of GM-CSF. Following exposure to GM-CSF, neutrophil adhesion to vascular endothelium is enhanced, and migration to other sites may be inhibited. When exposed to GM-CSF, macrophages are activated and release secondary cytokines including granulocyte colony-stimulating factor and interferon-alpha. GM-CSF also stimulates dendritic cell formation from lymphoid or myeloid CD34+ progenitor cells and monocytes. Dendritic cells are antigen-presenting cells that stimulate T-cell and lymphocyte responses. Typically, GM-CSF is not detectable in the serum, even during neutropenia or active infection, leading to the theory that GM-CSF is produced locally in tissues as part of the regulation of inflammation and acts to immobilize and prime local neutrophils. Following administration of exogenous rhuGM-CSF a transient decrease in neutrophil, eosinophil, and monocyte counts is observed, followed by an increase. Chemotactic, antifungal and antiparasitic activities of granulocytes and macrophages are increased with exposure to sargramostim in vitro. Sargramostim increases the cytotoxic activity of monocytes toward certain malignant cell lines and activates polymorphonuclear neutrophils to inhibit the growth of cancer cells. GM-CSF can stimulate the proliferation of leukemias; most require GM-CSF as a growth factor. However, GM-CSF does not cause the initial neoplastic event responsible for the development of leukemia. GM-CSF has been used to recruit leukemic cells into the chemosensitive phases of the cell cycle (i.e., S-phase) and has been shown to increase intracellular phosphorylation of cytarabine. Pharmacokinetics: Sargramostim is administered intravenously or subcutaneously; however, the subcutaneous (SC) route is preferred clinically. Clearance of sargramostim differs depending upon the route of administration suggesting either a saturable metabolism and/or significant differences in bioavailability depending upon route of administration. When administered IV over 2 hours the mean elimination half-life is about 60 minutes. When administered SC, GM-CSF is detected in serum at 15 minutes with a mean elimination half-life of about 162 minutes. Peak plasma levels occur 1�3 hours post SC injection and remain detectable for up to 6 hours. The Cmax of a 250 �g/m2 dose of sargramostim has been reported as 5 ng/ml following IV administration and 1.5 ng/ml after SC injection. The AUC for the IV and SC routes is similar. The magnitude of the increase in neutrophil count with a specific dose of sagramostim is greater after SC administration than after a 2-hour IV infusion. Catabolism of sargramostim to inactive protein fragments in the renal tubules is a major route of elimination. Very little, if any, sargramostim is excreted intact in the urine.

ndications...Dosage For the treatment of neutropenia�: �for the treatment of HIV-induced� or drug therapy-induced� neutropenia (e.g., ganciclovir-induced neutropenia� or zidovudine-induced neutropenia�) in immunosuppressed patients or those with HIV disease to decrease the risk of bacterial infections: Parenteral dosage: Adults and children: 150�250 �g/m2/day SC or IV once daily or 2�3 times weekly. Some patients have been treated continuously for up to 6 months. Sargramostim therapy ameliorates the neutropenia due to antiviral agents and other myelosuppressive agents in HIV-infected patients. Although clinical experience with sargramostim in the treatment of opportunistic infections is limited, beneficial effects have been reported in case reports and small studies. The CDC does not routinely recommend this dosage in HIV patients.[1446] �in patients with myelodysplastic syndrome�: Intravenous dosage: Adults: Dosages used range from 150�500 �g/m2/day SC or IV over 1�12 hours. Although data supporting the routine, long-term use of sargramostim is lacking, intermittent administration may be considered in patients with severe neutropenia and recurrent infection.[857] For promotion of myeloid recovery after autologous or allogeneic bone marrow transplantation (BMT): NOTE: Sargramostim has been designated an orphan drug by the FDA for this indication. �in patients with Hodgkin's disease, non-Hodgkin's lymphoma, or acute lymphocytic leukemia, who are undergoing autologous BMT, or for any patient undergoing HLA-matched related allogeneic BMT: Parenteral dosage: Adults: 250 �g/m2/day IV or SC, beginning 2�4 hours following infusion of bone marrow, and not less than 24 hours after the last dose of chemotherapy. Patients should not receive sargramostim until the post marrow infusion ANC is < 500/mm3. Continue until an ANC 1500/mm3 for 3 consecutive days is attained. If a severe reaction occurs, the dose can be reduced by 50% or temporarily discontinued until the reaction abates. Discontinue sargramostim immediately if blast cells appear or disease progression is noted. Children�: A suggested dose is 250 �g/m2/day SC or IV beginning 2�4 hours after marrow infusion and not less than 24 hours after chemotherapy. Continue until an ANC 1500/mm3 for 3 consecutive days is attained. If a first-dose reaction or other adverse reactions occur, therapy can be restarted, after toxicity resolves, at a dose of 125 �g/m2/day. �for decreasing the period of neutropenia following reinfusion of peripheral blood stem cells (PBSCs): Parenteral dosage: Adults and children�: A dosage 250 �g/m2/day SC or as a continuous IV infusion starting 2�4 hours after infusion of PBSC. Continuation of treatment until the absolute neutrophil count is > 1500/mm3 for 3 consecutive days is recommended. �in patients who have received an autologous or allogeneic bone marrow transplantation and in whom engraftment is delayed or has failed: Parenteral dosage: Adults and children�: 250 �g/m2/day IV or SC administered for 14 days. If, after 7 days off therapy, engraftment has not occurred, another 14-day course of therapy may be administered; the dose may be increased to 500 �g/m2/day. If after three courses there is no response, further treatment will probably have no benefit. Discontinue treatment if blast cells appear or disease progression occurs. For peripheral blood stem cell (PBSC) mobilization prior to apheresis (i.e., leukapheresis) in cancer patients undergoing bone marrow ablation: Parenteral dosage: Adults and children�: 250 �g/m2/day SC or as continuous IV infusion, usually beginning on day 5. Dosing should continue through the period of PBPC collection. If WBC > 50,000/mm3, the sargramostim dose should be reduced by 50%. The optimal schedule has not been established. The dose of GM-CSF for mobilization ranged from 125�250 �g/m2/day (either IV or SC) in these studies with a duration of 12 days (range 8�24 days) in some studies.[1072] [1073] For chemotherapy-induced neutropenia prophylaxis in patients receiving myelosuppressive chemotherapy and to decrease the incidence of febrile neutropenia: �in patients >= 55 years with acute myelogenous leukemia: NOTE: Sargramostim has been designated an orphan drug by the FDA for this indication. Parenteral dosage: Adults >= 55 years: 250 �g/m2/day IV or SC starting on day 11 or 4 days following the completion of induction chemotherapy if, at that time, the day 10 bone marrow was hypoplastic with <= 5% blasts. Sargramostim should be continued until an ANC > 1500/mm3 for 3 consecutive days or a maximum of 42 days. If a second cycle of induction chemotherapy is necessary, sargramostim should be administered as above beginning approximately 4 days after completion of the second induction course. �in patients with malignancies other than acute myelogenous leukemia�: Parenteral dosage: Adults and children: Doses have ranged from 125�500 �g/m2/day SC or IV beginning 24�72 hours after completion of chemotherapy; the most common dosage is 250 �g/m2/day SC. Therapy should be continued for 7�14 days, until the absolute neutrophil count (ANC) reaches a clinically adequate neutrophil count.[857] Usually, sargramostim therapy is stopped when the ANC is > 1500/mm3 for 3 consecutive days. For the treatment of severe aplastic anemia�: Parenteral dosage: Adults and children: Sargramostim is usually used in combination with erythropoietin or immunosuppressive therapy (e.g., antithymocyte globulin and cyclosporine) for the treatment of aplastic anemia. Usual doses are 250�500 �g/day or 5 �g/kg/day SC for durations of 14�90 days, depending upon the treatment regimen. For the adjuvant treatment of malignant melanoma� following surgery for stage III or IV melanoma who are at high-risk for recurrence: Subcutaneous dosage: Adults: The optimal effective dose has not been established. In a phase II trial, sargramostim 125 �g/m2/day SC for 14 days, alternating with 14 days off therapy was given following surgery for 1 year or until disease progression. In comparison to matched historical controls, the overall survival of 48 patients treated with sargramostim was significantly increased in all patients (37.5 months vs. 12.2 months).[1062] For the treatment of human immunodeficiency virus (HIV)� infection: Subcutaneous dosage: Adults: The optimal effective dose has not been established. In a phase III trial, patients currently receiving a stable antiretroviral regimen were randomized to receive sargramostim 250 �g/day SC 3 times weekly or placebo for up to 20 months. Patients receiving sargramostim had significant increases in CD4+ cell and neutrophil counts. Sargramostim significantly reduced the incidence of overall infections and delayed time to first infection. Changes in HIV-RNA levels were not significantly different between the groups.[1063] Maximum Dosage Limits: �Adults: Maximum dosage is not available. �Elderly: Maximum dosage is not available. �Adolescents: Maximum dosage is not available. �Children: Maximum dosage is not available. Patients with hepatic impairment: Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. Patients with renal impairment: No dosage adjustments are needed. �non-FDA-approved indication

Administration Parenteral Administration �Sargramostim is administered as an intravenous infusion or subcutaneously. Clinically, the subcutaneous (SC) route is preferred. The SC route serves as a depot injection and allows for increased exposure of sargramostim to hematopoietic cells. Reconstitution: NOTE: Preparations containing benzyl alcohol (e.g., bacteriostatic water for injection) should not be used in neonates. �Reconstitute 250 or 500 �g of sargramostim by adding 1 ml of sterile water for injection (SWI) or bacteriostatic water for injection (BWFI) to give an IV solution containing 250 or 500 �g/ml. Direct the diluent towards the side of the vial and swirl contents gently to prevent excess foaming; do not shake. �Refrigerate reconstituted solution. If prepared with SWI, use as soon as possible and discard any unused portions or any injection left at room temperature for greater than 6 hours. �Reconstituted solutions prepared with BWFI may be stored for up to 20 days at 2�8 degrees C prior to use; discard after 20 days. Previously reconstituted solutions mixed with freshly reconstituted solutions must be administered within 6 hours following mixing. �Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. The solution should be clear and colorless. Intravenous infusion: �Further dilute the reconstituted solution in D5W or NS injection. If the concentration is less than 10 �g/ml, human albumin should be added to the diluting solution before sargramostim is added so that the human albumin concentration is 1 mg/ml (0.1%). The addition of human albumin minimizes adsorption of sargramostim to infusion containers or equipment. �Refrigerate diluted solution if not used immediately. The manufacturer recommends that diluted solutions be used within 6 hours. Based on in-house stability studies performed by the manufacturer, diluted injections are stable for 48 hours at 2�8 degrees C or 25 degrees C. �Infuse IV over 2�4 hours. Do not use in-line filters because adsorption can occur. Subcutaneous injection�: �No further dilution of the reconstituted injection solution required. �Inject subcutaneously taking care not to inject intradermally. �non-FDA-approved indication

Contraindications Sargramostim stimulates hematopoiesis, and severe leukocytosis can occur. Complete blood and platelet counts should be performed before and during sargramostim therapy (biweekly). The drug should be discontinued or the dosage reduced by half if the absolute neutrophil count (ANC) rises above 20,000/mm3 before the nadir is achieved, or if the platelet count exceeds 500,000/mm3. Increased blood counts usually return to baseline following cessation of therapy. Since sargramostim is a myeloid growth factor, it is contraindicated in patients with excessive leukemic blasts (>= 10%) in the bone marrow or peripheral blood. Theoretically, sargramostim could act as a growth factor for any tumor type, particularly myeloid leukemia. However, sargramostim-induced proliferation of tumors is difficult to differentiate from the growth of the tumor during the normal disease course. Should disease progression be detected during sargramostim therapy, treatment should be discontinued. Sargramostim has been administered to patients with myelodysplastic syndromes in uncontrolled studies with no evidence of disease progression. Sargramostim is contraindicated for use in patients who have yeast hypersensitivity. Any history of allergy to drugs or products derived from yeast is a contraindication to sargramostim. Patients with preexisting peripheral edema, pulmonary infiltrates, pulmonary edema, or heart failure may be at an increased risk for developing sargramostim-induced fluid retention or pleural and/or pericardial effusion. Body weight and fluid status should be closely monitored during sargramostim administration. Sequestration of granulocytes in the pulmonary circulation may lead to dyspnea is some patients. The yeast-derived product is less likely to cause these cardiopulmonary problems than an earlier, no longer available, E. coli-derived product. Patients receiving the drug should be observed for respiratory problems, particularly patients with preexisting pulmonary disease. If dyspnea occurs during sargramostim infusion, the rate should be decreased by 50%. If symptoms do not improve with the reduction of infusion rate, treatment should be discontinued. Subsequent doses may be administered following the standard dosage schedule with close monitoring. The drug should be administered with caution to hypoxic patients. Occasional transient supraventricular arrhythmia has been reported in uncontrolled trials during administration of sargramostim, particularly in patients with a history of cardiac arrhythmias. These arrhythmias are reversible upon discontinuation of sargramostim. In some patients with pre-existing hepatic disease or renal impairment, administration of sargramostim has resulted in elevated hepatic enzymes including hyperbilirubinemia, and serum creatinine. Dose reduction or interruption of sargramostim therapy has resulted in decreases to baseline levels. Monitor hepatic or renal function in patients with pre-existing dysfunction. The safe and effective use of sargramostim concurrently with cytotoxic chemotherapy has not been established. Rapidly dividing myeloid cells are potentially more sensitive to cytotoxic drugs. Sargramostim should not be used for 24 hours before, or in the 24 hours after administration of cytotoxic chemotherapy. Sargramostim should be avoided in patients receiving concurrent chemotherapy and radiation therapy, especially radiation therapy involving the mediastinum. Patients with small cell lung cancer receiving sargramostim and concurrent thoracic radiotherapy plus chemotherapy had a higher incidence of severe infections and thrombocytopenia compared to those who received the same treatment without sargramostim. In the absence of chemotherapy, patients receiving radiation therapy involving large fields may be treated with sargramostim if prolonged delays in radiation therapy secondary to neutropenia are expected.[857] Sargramostim is classified as FDA pregnancy risk category C. It is not known whether sargramostim may cause harm when administered to a pregnant woman or can affect reproductive capability. Sargramostim should only be given to a pregnant woman only if clearly needed. It is not known if sargramostim is excreted in breast milk. Because many drugs and proteins are excreted in breast milk, sargramostim should only be administered to woman who is breast-feeding her infant only if clearly needed. Liquid sargramostim solutions or lyophilized sargramostim reconstituted with bacteriostatic water for injection should not be given to patients with benzyl alcohol hypersensitivity or neonates. Allergic-type reactions, including bronchial asthmatic events, may occur in certain susceptible individuals. Benzyl alcohol is associated with "gasping syndrome" in neonates.

Interactions Sargramostim, GM-CSF, induces the proliferation of hematopoietic progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, sargramostim is contraindicated for use in patients during the 24 hours before or after cytotoxic chemotherapy. Sargramostim increases the activation and intracellular retention of cytarabine, ARA-C in leukemia cells, thus potentiating the activity of cytarabine. Other drugs that cause leukocytosis may result in additive effects with sargramostim, GM-CSF. Sargramostim, GM-CSF, can increase the activity of zidovudine, ZDV. Increased intracellular retention of zidovudine in HIV-positive cells leads to enhanced triphosphorylation of the drug to its active form.

Adverse Reactions Since most patients who receive sargramostim have recently undergone cytotoxic chemotherapy and/or bone marrow transplantation, many of the adverse effects reported with sargramostim therapy may actually result from the actions of the previously administered antineoplastic agents. Due to the biological effect of sargramostim, leukocytosis (i.e., leukocyte count > 100,000/mm3) can occur during therapy. Sargramostim should be discontinued if the absolute neutrophil count (ANC) rises above 10,000/mm3 after the nadir is achieved. An ANC > 10,000/mm3 will not increase the effectiveness of the drug, but can increase its toxicity. Peripheral edema (11%), capillary leak syndrome (< 1%), weight gain, pericardial effusion (4%), and pleural effusion (1%) have been reported in patients treated with sargramostim. In patients with pre-existing edema, capillary leak syndrome and/or pericardial effusions, sargramostim therapy may aggravate fluid retention. Body weight and fluid status should be closely monitored in these patients. Fluid retention associated with or worsened by sargramostim has been reversible after interruption of therapy or dose reduction with or without concurrent diuretic therapy. Sequestration of granulocytes in the pulmonary circulation has been associated with dyspnea in some patients. In patients with respiratory symptoms during sargramostim infusions, the rate of infusion should be reduced in half. If respiratory symptoms worsen despite rate reduction, discontinue the infusion. Subsequent IV infusions may be given with careful monitoring. A clinical syndrome can occur with the first sargramostim dose during any particular cycle. Patients can develop dyspnea, flushing, hypoxia hypotension, syncope, and/or tachycardia. Serious allergic reactions including anaphylactoid reactions have been reported with sargramostim. Constitutional symptoms appearing with sargramostim include arthralgia, asthenia, chills, fever, headache, malaise, and myalgia. The fever appears shortly after administration, is usually < 38.5 degrees C, and is of short duration (i.e., less than 4 hours). Symptoms are usually controlled by administration of antipyretics and analgesics such as acetaminophen. Many of the early studies using an E. coli-derived GM-CSF product reported a higher incidence of constitutional symptoms; however, this product is no longer used clinically. A common adverse effect reported during sargramostim therapy is deep, throbbing medullary bone pain, most frequently in the lower back, pelvis, ribs, or sternum (i.e., sites containing bone marrow). Sternal pain can imitate that of an acute myocardial infarction. The severity of the pain usually is increased in patients with more extensive leukocytosis. Bone pain is usually mild to moderate in severity, and can be controlled in most patients with non-opiate analgesics; infrequently, bone pain is severe enough to require opiate analgesics. An injection site reaction, specifically erythema and inflammation, can appear following administration of sargramostim. This reaction can occur in as many as one-third of patients. Rash (unspecified) and pruritus have also been reported. Other adverse reactions reported during sargramostim therapy include abdominal pain, chest pain (unspecified), dizziness, and eosinophilia. Occasional transient supraventricular tachycardia has been reported during sargramostim administration, especially in patients with a history of cardiac arrhythmias. These arrhythmias are reversible upon discontinuation of sargramostim. In some patients with pre-existing renal or hepatic impairment, administration of sargramostim has resulted in elevated hepatic enzymes including hyperbilirubinemia, and serum creatinine. Dose reduction or interruption of sargramostim therapy has resulted in decreases to baseline levels. Monitor hepatic or renal function in patients with pre-existing dysfunction. Neutralizing antibody formation has been observed in 5 of 213 patients (2.3%) after receiving sargramostim by continuous IV infusion or subcutaneous injection for 28�84 days in multiple courses. All 5 patients had impaired hematopoiesis before administration of sargramostim; therefore, the effect of development of anti-GM-CSF antibodies on normal hematopoiesis could not be assessed. Drug-induced neutropenia, neutralization of GM-CSF activity, and diminution of the therapeutic effect of sargramostim secondary to formation of neutralizing antibodies remain a theoretical possibility.

Sargramostim, GM-CSF Leukine�

857. Ozer H, Armitage JO, Bennett CL, et al. 2000 Update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. J Clin Oncol 2000;18:3558�85.

1446. Centers for Disease Control and Prevention. 1999 USPHS/IDSA Guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. Morbid Mortal Weekly Rep 1999;48:1�66.

1062. Spitler LE, Grossbard ML, Ernstoff MS, et al. Adjuvant therapy of stage III and IV malignant melanoma using granulocyte-macrophage colony stimulating factor. J Clin Oncol 2000;18:1614�21.

1063. Angel JB, High K, Rhame F, et al. Phase III study of granulocyte-macrophage colony-stimulating factor in advanced HIV disease: effect on infections, CD4 cell counts, and HIV suppression. Leukine/HIV Study Group. AIDS 2000;14:387�95.

1072. Bishop MR, Anderson JR, Jackson JD et al. High-dose therapy and peripheral blood progenitor cell transplantation: effects of recombinant human granulocyte-macrophage colony-stimulating factor on the autograft. Blood 1994;83:610�6.

1073. Kessinger A, Bishop MR, Anderson JR et al. Comparison of subcutaneous and intravenous administration of recombinant human granulocyte-macrophage colony-stimulating factor for peripheral blood stem cell mobilization. J Hematother 1995;4:81�4.