Sargramostim, a glycosylated recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF), is a biosynthetic hematopoietic agent that affects the proliferation and differentiation of a variety of hematopoietic progenitor cells.1, 5, 131, 132
Sargramostim is approved for use in acute myeloid leukemia (AML), acute exposure to radiation, and various bone marrow transplantation (BMT) settings.1 Clinical practice guidelines on the use of myeloid growth factors, such as sargramostim, have been published.238, 239 These guidelines focus on recommendations related to use of these agents in reducing febrile neutropenia risk in patients at increased risk for associated complications.238, 239
Acute Myeloid Leukemia Following Induction Chemotherapy
Sargramostim is used to accelerate neutrophil recovery and reduce the incidence of severe and life-threatening infections following induction chemotherapy in adults ≥55 years of age with AML.1, 220 Safety and efficacy of sargramostim in patients with AML who are <55 years of age have not been determined.1
In a phase 3, randomized, placebo-controlled study in adults 55 to 70 years of age with newly diagnosed AML, use of sargramostim shortened the period of neutrophil recovery and improved the outcome of infectious complications following induction therapy with daunorubicin and cytarabine.220 The incidence of severe infections and deaths associated with the infections was reduced in patients who received sargramostim.220 In addition, disease outcome did not appear to be adversely affected by sargramostim therapy.220 The median duration of absolute neutrophil count (ANC) <500 cells/mm3 or 1000 cells/mm3 was 13 or 14 days, respectively, in patients receiving sargramostim and 16 or 21 days, respectively, in those receiving placebo.220 There was no difference in duration of platelet counts <20,000 cells/mm3 or requirements for red blood cell transfusions.220 Although sargramostim therapy accelerated neutrophil recovery following 1 or 2 cycles of induction chemotherapy in adults with AML, the drug did not shorten the duration of neutropenia following cytarabine consolidation therapy in these patients.220
Autologous Peripheral Blood Progenitor Cell Mobilization and Collection
Sargramostim is used for mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis in adults with cancer undergoing autologous hematopoietic stem cell transplantation (HSCT).1
A retrospective review of data from patients with cancer undergoing peripheral blood progenitor cell (PBPC) collection and autologous transplantation at a single transplant center was conducted, and data obtained from 4 groups of patients who received sargramostim for PBPC mobilization were compared with data from an historical control group of patients who received nonmobilized PBPCs.1 Patients who received sargramostim were enrolled in several sequential trials and cohorts differed in sargramostim dosage (125 or 250 mcg/m2 daily), route of administration (continuous IV infusion or subcutaneous injection), and use of sargramostim following PBPC transplantation.1 Leukapheresis was initiated for all mobilization groups after the leukocyte count reached 10,000 cells/mm3 and continued until both a minimum number of mononucleated cells (MNCs) were collected (6.5 or 8 × 108/kg) and a minimum number of aphereses (5-8) were performed.1 Patients who received the higher dosage of sargramostim (250 mcg/m2 daily) by either IV infusion or subcutaneous injection exhibited the most marked effects in terms of mobilization and posttransplant engraftment.1 PBPCs collected from patients who received sargramostim mobilization at this dosage had higher numbers of granulocyte-macrophage colony-forming units (CFU-GM) than those collected without mobilization.1 After collections were thawed, the mean CFU-GM content was 11.41 × 104/kg in those who received mobilization compared with 0.96 × 104/kg for nonmobilized patients.1 A similar difference was observed in the mean number of erythrocyte burst-forming units (BFU-E) collected in mobilized patients (23.96 × 104/kg) compared with nonmobilized patients (1.63 × 104/kg).1
A retrospective review of data from patients undergoing PBPC transplantation at another transplant center was evaluated to determine the effect of different dosages of sargramostim on mobilization of PBPC.1 Sargramostim was administered by subcutaneous injection at a dosage of 250 mcg/m2 once daily or twice daily until completion of apheresis.1 Apheresis was started on day 5 of sargramostim administration and continued until the targeted MNC count (9 × 108) or CD34+ cell count (1 × 106/kg) was collected.1 There was no difference in CD34+ cell count in patients receiving sargramostim once or twice daily.1
Autologous Peripheral Blood Progenitor Cell and Bone Marrow Transplantation
Sargramostim is used to accelerate myeloid recovery following autologous PBPC or BMT in adults and pediatric patients ≥2 years of age with non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), or Hodgkin lymphoma (HL).1, 5, 7, 8, 12, 55, 75, 77, 78, 91, 96, 173, 174, 196
Results of placebo-controlled studies in adult and pediatric patients with lymphoid malignancy indicate that sargramostim therapy following autologous BMT effectively shortens the time to myeloid engraftment resulting in certain clinical benefits such as decreased duration of post-BMT infectious episodes, decreased requirements for anti-infective therapy, and decreased duration of hospitalization.1, 8, 173, 196 In these studies, the median time to myeloid engraftment (defined as an ANC ≥500 cells/mm3) following BMT was 18 days in those receiving sargramostim and 24 days in those receiving placebo.1 The median duration of infectious episodes (defined as fever and neutropenia; 2 positive blood cultures of the same organism; fever exceeding 38°C and one positive blood culture; or clinical evidence of infection) and hospitalization was 1 and 25 days, respectively, in patients receiving sargramostim and 4 and 31 days, respectively, in those receiving placebo.1 When sargramostim therapy was used following autologous BMT in patients with HL, there also was a trend toward earlier myeloid engraftment compared with patients receiving placebo; however, the median time to engraftment in these patients generally is longer than the median time to engraftment in patients with non-HL or ALL.1
Neutropenia still occurs in most patients during the first week following autologous BMT despite use of sargramostim therapy, and patients may be at substantial risk for infection during this time.5 Because sargramostim therapy generally does not completely prevent severe neutropenia following autologous BMT and may not shorten its duration sufficiently to reduce the incidence of infection associated with myeloablative therapy in all patients, benefit of the drug may be reflected principally in reducing the duration of fever, anti-infective therapy, and hospitalization.5, 96 Patients who previously have received extensive radiation therapy or have been exposed to multiple myelotoxic agents may have a limited response to sargramostim therapy following autologous BMT.1
Results of a follow-up analysis of patients with non-HL, ALL, or HL who received sargramostim to accelerate myeloid recovery following cytotoxic chemotherapy and BMT indicate that up to 30-40 months after the procedure, patients who received the drug had no increased risk of graft failure, leukemogenesis, relapse, or death compared with those who received placebo.196 Sargramostim therapy appeared to cause no long-term deleterious effects on bone marrow function and had no appreciable effect on disease-free survival or overall survival.196 The only factors in these patients that appeared to be associated with a high risk of relapse over time or death were a diagnosis of lymphoid leukemia and/or undergoing BMT while in resistant relapse.196
Allogeneic Bone Marrow Transplantation
Sargramostim is used to accelerate myeloid recovery in adult and pediatric patients ≥ 2 years of age undergoing allogeneic BMT from human leukocyte antigen (HLA)-matched related donors.1, 5, 21, 112, 173
Preliminary studies evaluating use of sargramostim in patients undergoing allogeneic BMT were performed in a limited number of adults with chronic myelogenous leukemia (CML), AML, ALL, or severe aplastic anemia undergoing allogeneic BMT from HLA-matched siblings or unrelated donors† .5, 21, 112, 173 In a phase I/II study in patients undergoing allogeneic BMT from HLA-matched siblings, patients who received methotrexate and cyclosporine for graft-versus-host disease prophylaxis were less responsive to sargramostim therapy than those who received prednisone and cyclosporine; patients in the latter group had fewer febrile days and were discharged sooner than patients who received methotrexate.112
Efficacy of sargramostim has been evaluated in a prospective, randomized, placebo-controlled, phase III study in 109 patients with myeloid malignancies (AML, CML), lymphoid malignancies (ALL, NHL), Hodgkin's disease, multiple myeloma, myelodysplastic disease, or aplastic anemia who received allogeneic BMT from HLA-matched related donors.1, 223 Compared with the group that received placebo, patients who received sargramostim had a shorter time to neutrophil engraftment (ANC ≥500 cells/mm3) and a shorter duration of hospitalization.1, 223 The time to myeloid engraftment was 13 days in those who received sargramostim versus 17 days in those who received placebo.1, 223 The number of patients who developed bacteremia and documented infections was lower in the sargramostim group compared with the placebo group.1, 223 In addition, the incidence of grade 3/4 mucositis was lower and the median duration of post-transplant IV anti-infective therapy and median time to last platelet and red blood cell transfusion were shorter in patients who received sargramostim.1, 223
Further study is needed to evaluate efficacy of sargramostim for use in patients receiving allogeneic BMT from unrelated donors† .21 In one phase II study involving sargramostim therapy (250 mcg/m2 daily given by IV infusion over 2 hours beginning within 2 hours after allogeneic BMT and continued for 20-27 days), fewer infections occurred following BMT in patients who received the drug; however, sargramostim did not have a clinically important effect on neutrophil recovery and it is unclear whether the decrease in infections was related directly to the drug.21
Allogeneic or Autologous Bone Marrow Transplantation: Treatment of Delayed Neutrophil Recovery or Graft Failure
Sargramostim is used to increase survival in adult and pediatric patients ≥2 years of age who have undergone allogeneic or autologous BMT and in whom engraftment is delayed or has failed.1, 18, 19 The drug also has been used in a limited number of patients with delayed engraftment following PBPC transplantation†.19 Patients with delayed engraftment following BMT may have a prolonged period of severe myelosuppression and an increased risk of infectious complications, including severe or fatal infections.19
Efficacy of sargramostim has been evaluated in a historically-controlled study involving patients with lymphoid or myeloid leukemia, NHL, HL, aplastic anemia, myelodysplasia, or nonhematologic malignancy who had a delay in engraftment (ANC ≤100 cells/mm3 by day 28 after transplantation), a delay in engraftment (ANC ≤100 cells/mm3 by day 21) with evidence of active infection, or loss of marrow graft after a transient engraftment (manifested as an average ANC ≥500 cells/mm3 for at least 1 week followed by loss of engraftment with an ANC <500 cells/mm3 for at least 1 week beyond day 21 after transplantation).1 A total of 140 eligible adult and pediatric patients from 35 institutions were treated with sargramostim and evaluated in comparison to 103 historical controls from a single institution.1 In patients with graft failure following autologous or allogeneic BMT, those receiving sargramostim had an increased rate of survival at 100 days compared with historical controls who did not receive the drug, and the median survival was twice that of historical controls.1 The median survival in patients with autologous or allogeneic failure was 474 or 97 days, respectively, in those who received sargramostim and 161 or 35 days, respectively, in historical controls who did not receive the drug.1 This increased survival generally occurred as a result of accelerated neutrophil recovery, which was associated with a decreased incidence of infectious complications.5, 18, 19
Acute Exposure to Myelosuppressive Doses of Radiation
Sargramostim is used to improve survival in adult and pediatric patients from birth to 17 years of age acutely exposed to myelosuppressive doses of radiation.1
Due to ethical and feasibility issues, efficacy studies evaluating sargramostim in humans with acute radiation syndrome could not be performed.1 The administration of sargramostim for this indication is based on studies conducted in animals and data from studies evaluating the impact of sargramostim on severe neutropenia in patients undergoing autologous or allogeneic BMT following chemotherapy with or without total body irradiation, and in patients with AML following chemotherapy.1 The approved dosage regimen is based on population modeling and simulation analyses.1
Sargramostim has been used in an effort to increase leukocyte counts in some adults with myelodysplastic syndrome† (MDS) classified as refractory anemia (RA), refractory anemia with excess blasts (RAEB), or refractory anemia with excess blasts in transformation (RAEB-T).43, 44, 45, 47, 48, 96, 129, 151, 172 MDS is a heterogeneous group of disorders and several factors may result in considerable variation in response to sargramostim therapy.5, 43, 48, 77, 91, 129 Use of sargramostim in patients with MDS generally results in an increase in the absolute number of granulocytes and monocytes in most patients and an increase in the absolute number of eosinophils and lymphocytes in many patients.5, 44, 45, 47, 91, 129, 172, 189 Although an increase in platelets and/or reticulocytes is evident in a few patients with MDS receiving sargramostim,5, 43, 44, 47, 129, 172 platelet and reticulocyte counts are unaffected in most patients and the need for red blood cell transfusions generally is unchanged during therapy with the drug.44, 45, 91, 129, 172 Prolonged maintenance therapy with sargramostim appears necessary in patients with MDS since leukocyte counts return to pretreatment levels within 2-10 days after sargramostim is discontinued.43, 44, 47, 129, 172
The administration of sargramostim has resulted in some success in increasing leukocyte counts in a limited number of adults and adolescents ≥15 years of age with moderate to severe aplastic anemia†.129, 134 Use of GM-CSF in these patients resulted in an increase in ANCs that was sustained throughout the period of treatment and a transient increase in absolute eosinophil counts; most patients also had an increase in monocyte and lymphocyte counts.56, 57, 96, 129, 134, 139, 189 Erythrocyte and platelet counts and transfusion requirements generally were unaffected, although a few patients had increases in hemoglobin concentrations and/or platelet counts.56, 57, 96, 129, 134, 139, 189
Sargramostim has been used in patients with human immunodeficiency virus (HIV) infection in an effort to correct or minimize HIV-associated neutropenia† and/or for the treatment of drug-induced neutropenia (e.g., neutropenia associated with use of zidovudine, interferon alfa, and/or cytotoxic chemotherapy) in HIV-infected patients†.5, 34, 35, 36, 37, 38, 39, 96, 111, 136, 138, 149, 158, 159, 160, 161, 189, 217 When used in patients with HIV infection, GM-CSF effectively increases the number of neutrophils, monocytes, and eosinophils in most patients; however, the drugs appear to have no consistent effect on the absolute number of lymphocytes nor on the ratio of helper/inducer (CD4+, T4+) to suppressor/cytotoxic (CD8+, T8+) T cells.5, 35, 136, 138, 149, 158, 159, 160, 161 189
Sargramostim has been used with variable success in an effort to increase neutrophil counts in patients with various primary neutropenias, including congenital neutropenia†59, 186 acquired idiopathic neutropenia†, 63 and glycogen storage disease type Ib†.97 While GM-CSF may ameliorate the underlying neutropenia in certain patients with these conditions,5, 60, 62, 63, 91 this effect is unpredictable and not all patients with primary neutropenias respond to the drugs.5, 58, 59, 63, 91, 101 In a study in children 1-19 years of age with severe congenital neutropenia (Kostmann syndrome), sargramostim therapy resulted in an increase in the absolute granulocyte count in all patients.59 However, an increase in the ANC occurred in only one patient; in most patients, the increase in granulocytes during sargramostim therapy resulted from an increase in eosinophils or monocytes rather than neutrophils.59 When sargramostim was used in a few patients with glycogen storage disease type Ib, neutrophil counts increased during therapy with the drug and there was a decrease in inflammatory bowel symptoms. Use of sargramostim in a patient with idiopathic neutropenia also resulted in an increase in the neutrophil count.63
GM-CSF has been used in patients with malignancies receiving myelosuppressive antineoplastic therapy in an attempt to increase neutrophil counts and decrease the risk of infectious complications†.5, 23, 26, 27, 28, 29, 30, 31, 33, 75, 81, 96, 109, 110, 114, 115, 120, 144, 162, 163, 164, 165, 166, 167, 169, 184, 187, 198, 199 Sargramostim has been used prophylactically (i.e., in the absence of fever or other manifestations of infection) in a limited number of children with refractory solid tumors who were receiving myelosuppressive therapy†.30 Use of sargramostim in these children ameliorated the chemotherapy-induced neutropenia and decreased the frequency and/or duration of hospitalization and requirements for anti-infective therapy.30
GM-CSF has also been used to increase neutrophil counts in patients with cytomegalovirus (CMV) infection who develop neutropenia while receiving ganciclovir †60, 99, 156, 205 and with some success in an attempt to increase neutrophil counts in a few patients with other nonmalignant conditions† who developed neutropenia while receiving myelosuppressive drugs.61, 91 Sargramostim180 , has been used effectively in several patients to hasten recovery from sulfasalazine-associated agranulocytosis†; GM-CSF also has been used effectively to treat methimazole-associated agranulocytosis in at least one patient with hyperthyroidism†.179 179, In at least one patient with adult-onset juvenile rheumatoid arthritis, a GM-CSF appeared to effectively treat aplastic anemia associated with the use of gold therapy.188
GM-CSF has been used in a limited number of patients with rheumatoid arthritis for the treatment of neutropenia associated with Felty's syndrome or large granular lymphocytic leukemia†.178, 190 In at least one patient with aplastic anemia who had unremitting psoriasis of more than 40 years' duration, GM-CSF therapy initiated for the treatment of the anemia apparently contributed to remission of the dermatologic condition† .185
In patients with unresectable stage III or IV metastatic melanoma†, the combination of sargramostim plus ipilimumab was associated with an increase in overall survival and reduced toxicity as compared to ipilimumab therapy alone; however, no difference in progression-free survival was observed.235 A Cochrane review evaluated the efficacy and safety of sargramostim for induction of remission in 537 patients with Crohn disease †.236 The review included 3 studies; results revealed no difference between sargramostim and placebo with regard to the proportion of patients who experienced clinical remission, 70- or 100-point clinical response, at least 1 adverse event, or serious adverse events.236 A systematic review and meta-analysis of 7 randomized controlled trials evaluated the efficacy and safety of sargramostin in the treatment of deep second-degree burns†.237 The use of sargramostim was associated with reduced wound healing time and an increased wound healing rate on days 7, 10, 14, and 20 as compared to standard wound care alone.237 The wound healing rate at day 28 was not significantly different between sargramostim and standard care.237
Sargramostim is administered by IV infusion or subcutaneous injection depending on the indication for use.1 The drug is commercially available as a lyophilized powder that must be reconstituted prior to use.1
Sargramostim should be administered under the guidance and supervision of a clinician, but may be self-administered outside of a hospital or medical office setting (e.g., at home) if the clinician determines that the patient and/or caregiver is competent to prepare and safely administer the drug.1 If home use is prescribed, instruct patients and/or caregivers on proper dosage, reconstitution procedures, and administration of the drug.1 Additionally, caution against reuse of syringes and needles and diluent and instruct on proper disposal of such equipment using puncture-resistant containers.1
Store sargramostim single-dose vials under refrigeration (2° to 8°C) in their original carton; do not freeze or shake, and protect from light.1
Sargramostim lyophilized powder should be reconstituted by adding 1 mL of sterile water for injection (without preservative) or bacteriostatic water for injection (with 0.9% benzyl alcohol) to provide a single-dose solution containing 250 mcg/mL.1 Do not mix the contents of vials reconstituted with different diluents together.1 Reconstitute only with sterile water for injection (without preservative) when administering sargramostim to neonates or infants in order to avoid benzyl alcohol exposure.1
Store reconstituted sargramostim solution under refrigeration (2° to 8°C); do not freeze.1 When reconstituted with sterile water for injection (without preservative), use within 24 hours.1 When reconstituted with bacteriostatic water for injection (with 0.9% benzyl alcohol), use within 20 days.1
Prior to administration, visually inspect the solution for discoloration and/or the presence of particulate matter.1 Do not administer the solution if discoloration or particulate matter is present.1
For IV infusion, dilute the reconstituted sargramostim solution in 0.9% sodium chloride.1 If the final concentration of sargramostim is <10 mcg/mL, add albumin (human) to a final concentration of 0.1% in order to prevent adsorption of sargramostim to the drug delivery system.1 Use immediately after dilution.1
Sargramostim is generally infused IV over 2-4 hours.1, 5, 7, 18, 19, 21, 30, 55, 95, 112 The drug also has been administered by IV infusion over 30-60 minutes,59, 129 over 5-12 hours,44, 129 or by continuous IV infusion over 24 hours.1, 5, 47, 48, 54, 59, 73, 119, 134
Do not administer IV sargramostim infusion through an in-line membrane filter.1 Do not add other medications to infusion solutions containing sargramostim.1
No further dilution of the reconstituted vial is required prior to subcutaneous injection of sargramostim.1
Do not administer sargramostim concomitantly with or within 24 hours preceding cytotoxic chemotherapy or radiotherapy or within 24 hours following chemotherapy.1
Acute Myeloid Leukemia Following Induction Chemotherapy
The recommended dosage of sargramostim to shorten time to neutrophil recovery and to decrease the incidence of severe, life-threatening, or fatal infections following induction chemotherapy in adults (≥55 years of age) with acute myeloid leukemia (AML) is 250 mcg/m2/day.1 Administer sargramostim IV over a 4-hour period starting approximately on day 11 or 4 days following the completion of induction chemotherapy, if the day 10 bone marrow is hypoplastic with <5% blasts.1 If a second induction chemotherapy cycle is required, administer sargramostim approximately 4 days after the completion of chemotherapy if the bone marrow is hypoplastic with <5% blasts.1 Continue therapy until an absolute neutrophil count (ANC) >1500 cells/mm3 for 3 consecutive days or a maximum of 42 days.1
Obtain a CBC with differential twice weekly during sargramostim therapy.1 If leukemic regrowth occurs, discontinue sargramostim immediately.1 If grade 3 or 4 adverse reactions occur, reduce the sargramostim dose by 50% or interrupt therapy until the reaction resolves.1 If an ANC >20,000 cells/mm3 occurs, interrupt sargramostim therapy or reduce the dose by 50%.1
Autologous Peripheral Blood Progenitor Cell Mobilization and Collection
The recommended dosage of sargramostim for the mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis in adults with cancer undergoing autologous hematopoietic stem cell transplantation is 250 mcg/m2/day given IV over 24 hours or subcutaneously once daily.1 Continue sargramostim at the same dose throughout the peripheral blood progenitor cell (PBPC) collection period.1
In clinical studies, PBPC collection was usually initiated after 5 days of sargramostim and performed daily until achievement of protocol specified targets; the optimal PBPC collection schedule has not been established.1
Reduce the sargramostim dose by 50% if white blood cell count (WBC) >50,000 cells/mm3.1 If adequate PBPC collection is not achieved, consider other mobilization therapy.1
Autologous Peripheral Blood Progenitor Cell and Bone Marrow Transplantation
The recommended dosage of sargramostim for the acceleration of myeloid reconstitution following autologous PBPC transplantation in adults with non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), or Hodgkin lymphoma (HL) is 250 mcg/m2/day given IV over 24 hours or subcutaneously once daily.1 Initiate immediately after progenitor cell infusion and continue until an ANC >1500 cells/mm3 for 3 consecutive days.1
The recommended dosage of sargramostim for the acceleration of myeloid reconstitution following autologous bone marrow transplantation (BMT) in adults with NHL, ALL, or HL is 250 mcg/m2/day given IV over a 2-hour period beginning 2 to 4 hours after bone marrow infusion, and not <24 hours after the last dose of chemotherapy or radiotherapy.1 Do not administer sargramostim until the post marrow infusion ANC is <500 cells/mm3.1 Continue sargramostim until ANC >1500 cells/mm3 for 3 consecutive days.1
Allogeneic Bone Marrow Transplantation
The recommended dosage of sargramostim for the acceleration of myeloid reconstitution in adults undergoing allogeneic BMT from human leukocyte antigen (HLA)-matched related donors is 250 mcg/m2/day given IV over a 2-hour period beginning 2 to 4 hours after bone marrow infusion, and not <24 hours after the last dose of chemotherapy or radiotherapy.1 Do not administer sargramostim until the post marrow infusion ANC is <500 cells/mm3.1 Continue sargramostim until ANC >1500 cells/mm3 for 3 consecutive days.1
Obtain a CBC with differential twice weekly during sargramostim therapy.1 If disease progression or blast cell appearance occurs, discontinue sargramostim immediately.1 If grade 3 or 4 adverse reactions occur, reduce the sargramostim dose by 50% or interrupt therapy until the reaction resolves.1 If a WBC >50,000 cells/mm3 or ANC >20,000 cells/mm3 occurs, interrupt sargramostim therapy or reduce the dose by 50%.1
Allogeneic or Autologous Bone Marrow Transplantation: Treatment of Delayed Neutrophil Recovery or Graft Failure
The recommended dosage of sargramostim in adults who underwent allogeneic or autologous BMT and in whom neutrophil recovery is delayed or failed is 250 mcg/m2/day for 14 days as a 2-hour IV infusion.1 If neutrophil recovery does not occur after 7 days off therapy, repeat the dose.1 If recovery still does not occur after another 7 days off therapy, may administer a third course of sargramostim 500 mcg/m2/day for 14 days.1 If there is still no improvement, further dose escalation is unlikely to be beneficial.1
Obtain a CBC with differential twice weekly during sargramostim therapy.1 If disease progression or blast cell appearance occurs, discontinue sargramostim immediately.1 If grade 3 or 4 adverse reactions occur, reduce the sargramostim dose by 50% or interrupt therapy until the reaction resolves.1 If a WBC >50,000 cells/mm3 or ANC >20,000 cells/mm3 occurs, interrupt sargramostim therapy or reduce the dose by 50%.1
Acute Exposure to Myelosuppressive Doses of Radiation
The recommended dosage of sargramostim in adults acutely exposed to myelosuppressive radiation doses is 7 mcg/kg subcutaneously once daily.1 Initiate therapy as soon as possible after suspected or confirmed exposure to radiation doses >2 Gray.1
Obtain a baseline CBC with differential and then serial CBCs approximately every third day.1 Continue therapy until the ANC remains >1000 cells/mm3 for 3 consecutive CBCs or exceeds 10,000 cells/mm3 after a radiation-induced nadir.1 Do not delay sargramostim therapy if a CBC is not readily available.1
Estimate the level of radiation exposure via clinical findings (e.g., time to vomiting onset, lymphocyte depletion kinetics), biodosimetry (if available), and information from public health authorities.1
Autologous Peripheral Blood Progenitor Cell and Bone Marrow Transplantation
The recommended dosage of sargramostim for the acceleration of myeloid reconstitution following autologous PBPC transplantation in pediatric patients (≥2 years of age) with NHL, ALL, or HL is 250 mcg/m2/day given IV over 24 hours or subcutaneously once daily.1 Initiate immediately after progenitor cell infusion and continue until ANC >1500 cells/mm3 for 3 consecutive days.1
The recommended dosage of sargramostim for the acceleration of myeloid reconstitution following autologous BMT in pediatric patients (≥2 years of age) with NHL, ALL, or HL is 250 mcg/m2/day given IV over a 2-hour period beginning 2 to 4 hours after bone marrow infusion, and not <24 hours after the last dose of chemotherapy or radiotherapy.1 Do not administer sargramostim until the post marrow infusion ANC is <500 cells/mm3.1 Continue sargramostim until ANC >1500 cells/mm3 for 3 consecutive days.1
Allogeneic Bone Marrow Transplantation
The recommended dosage of sargramostim for the acceleration of myeloid reconstitution in pediatric patients (≥2 years of age) undergoing allogeneic BMT from HLA-matched related donors is 250 mcg/m2/day given IV over a 2-hour period beginning 2 to 4 hours after bone marrow infusion, and not <24 hours after the last dose of chemotherapy or radiotherapy.1 Do not administer sargramostim until the post marrow infusion ANC is <500 cells/mm3.1 Continue sargramostim until ANC >1500 cells/mm3 for 3 consecutive days.1
Obtain a CBC with differential twice weekly during sargramostim therapy.1 If disease progression or blast cell appearance occurs, discontinue sargramostim immediately.1 If grade 3 or 4 adverse reactions occur, reduce the sargramostim dose by 50% or interrupt therapy until the reaction resolves.1 If a WBC >50,000 cells/mm3 or ANC >20,000 cells/mm3 occurs, interrupt sargramostim therapy or reduce the dose by 50%.1
Allogeneic or Autologous Bone Marrow Transplantation: Treatment of Delayed Neutrophil Recovery or Graft Failure
The recommended dosage of sargramostim in pediatric patients (≥2 years of age) who underwent allogeneic or autologous BMT and in whom neutrophil recovery is delayed or failed is 250 mcg/m2/day for 14 days as a 2-hour IV infusion.1 If neutrophil recovery does not occur after 7 days off therapy, repeat the dose.1 If recovery still does not occur after another 7 days off therapy, may administer a third course of sargramostim 500 mcg/m2/day for 14 days.1 If there is still no improvement, further dose escalation is unlikely to be beneficial.1
Obtain a CBC with differential twice weekly during sargramostim therapy.1 If disease progression or blast cell appearance occurs, discontinue sargramostim immediately.1 If grade 3 or 4 adverse reactions occur, reduce the sargramostim dose by 50% or interrupt therapy until the reaction resolves.1 If a WBC >50,000 cells/mm3 or ANC >20,000 cells/mm3 occurs, interrupt sargramostim therapy or reduce the dose by 50%.1
Acute Exposure to Myelosuppressive Doses of Radiation
The recommended subcutaneous dosage of sargramostim in pediatric patients (birth to 17 years of age) acutely exposed to myelosuppressive radiation doses is based on weight.1 For patients weighing >40 kg, the dosage is 7 mcg/kg once daily; for those weighing 15 to 40 kg, the dosage is 10 mcg/kg once daily; and for those weighing <15 kg, the dosage is 12 mcg/kg once daily.1 Initiate therapy as soon as possible after suspected or confirmed exposure to radiation doses >2 Gray.1
Obtain a baseline CBC with differential and then serial CBCs approximately every third day.1 Continue therapy until the ANC remains >1000 cells/mm3 for 3 consecutive CBCs or exceeds 10,000 cells/mm3 after a radiation-induced nadir.1 Do not delay sargramostim therapy if a CBC is not readily available.1
Estimate the level of radiation exposure via clinical findings (e.g., time to vomiting onset, lymphocyte depletion kinetics), biodosimetry (if available), and information from public health authorities.1
The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1
The manufacturer makes no specific dosage recommendations for patients with renal impairment.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Serious hypersensitivity reactions, including anaphylaxis, have been reported with therapy.1 Employ appropriate precautions with parenteral sargramostim administration in case a reaction occurs.1 Discontinue sargramostim therapy if a serious allergic or anaphylactic reaction occurs and initiate medical management.1 Sargramostim therapy should be permanently discontinued in patients who experience serious allergic reactions.1
Infusion-related reactions including respiratory distress, hypoxia, flushing, hypotension, syncope, and/or tachycardia may occur following the initial administration of sargramostim in a particular cycle.1 These signs and symptoms resolve with treatment and generally do not recur with subsequent doses in the same cycle.1 Observe patients closely for signs and symptoms of infusion-related reactions, especially patients with pre-existing pulmonary disease.1 Reduce the rate of the sargramostim infusion by 50% if acute symptoms develop.1 Discontinue the infusion if symptoms persist or worsen despite dosage reduction.1 For those who experience infusion-related reactions, subsequent IV infusions may be administered following the standard dose schedule with careful monitoring.1
Risk of Severe Myelosuppression
Do not administer sargramostim with or within 24 hours prior to cytotoxic chemotherapy or radiotherapy or within 24 hours following chemotherapy due to an increased risk of severe myelosuppression.1 In a controlled study, patients randomized to sargramostim and concurrent radiotherapy and chemotherapy experienced a significantly increased incidence of adverse reactions (e.g., grade 3 and 4 infections; grade 3 and 4 thrombocytopenia; increased mortality) as compared to patients administered the identical radiotherapy and chemotherapy without sargramostim.1
Effusions and Capillary Leak Syndrome
Edema, capillary leak syndrome, and pleural and/or pericardial effusion have been reported with therapy.1 In placebo-controlled studies involving 156 patients, the incidences of fluid retention (sargramostim vs. placebo) were: peripheral edema (11% vs. 7%); pleural effusion (1% vs. 0%); and pericardial effusion (4% vs. 1%).1 The incidence of capillary leak syndrome is reported to be <1%.1 Administration of sargramostim may aggravate preexisting fluid retention.1 Dose reduction or interruption of sargramostin, with or without diuretic therapy, may reverse therapy-related fluid retention.1 Use sargramostim with caution in patients with preexisting fluid retention, pulmonary infiltrates, or heart failure.1 Monitor body weight and hydration status during sargramostim administration.1
Supraventricular arrhythmias have been reported with therapy, particularly in patients with a history of cardiac arrhythmia.1 Discontinuation of sargramostim may reverse arrhythmic effects.1 Use sargramostim with caution in patients with preexisting cardiac disease.1
Leukocytosis (WBC ≥50,000 cells/mm3) has been reported with therapy.1 Monitor CBC with differential twice weekly and consider whether to reduce the dose of sargramostim, or interrupt treatment, based on the clinical condition of the patient.1 A return to normal or baseline blood count levels generally occurs within 3 to 7 days following sargramostim discontinuation.1
Potential Effect on Malignant Cells
Sargramostim may potentially act as a growth factor for any tumor type, especially myeloid malignancies.1 Exercise caution when administering sargramostim to patients with a malignancy with myeloid characteristics.1 If disease progression occurs during sargramostim therapy, discontinue treatment.1
Anti-drug neutralizing antibodies were reported in 82.9% of patients receiving sargramostim for up to 12 months in a clinical study for an unapproved use (i.e., normal neutrophil count and a solid tumor in complete response).1 In this study, the myelostimulatory effect of sargramostim was not sustained by day 155 as evaluated by WBC count.1 Administer sargramostim for the shortest necessary duration.1
Risk of Serious Reactions in Infants Due to Benzyl Alcohol
Administration of solutions containing benzyl alcohol to neonates and low birth weight infants may result in serious and fatal adverse reactions including “gasping syndrome”, which is characterized by CNS depression, metabolic acidosis, and gasping respirations.1 Avoid administration of sargramostim for injection reconstituted with Bacteriostatic Water for Injection (0.9% benzyl alcohol) in these patients.1 Administer these patients lyophilized sargramostim reconstituted with Sterile Water for Injection instead.1 Consider the combined daily metabolic load of benzyl alcohol from all sources if benzyl alcohol-reconstituted sargramostim must be used in neonates and low birth weight infants.1
There are limited data on sargramostim use in pregnant women; however, the drug may cause embryofetal harm based on animal findings.1 In pregnant rabbits, sargramostim administration during organogenesis was associated with adverse developmental outcomes including increased spontaneous abortion at exposures ≥1.3 times the human exposure expected at the recommended human dose.1 Advise women of childbearing potential of the potential fetal risks.1
Benzyl alcohol is a preservative present during reconstitution of sargramostim with Bacteriostatic Water for Injection.1 Benzyl alcohol has been associated with gasping syndrome in neonates and low birth weight infants.1 If sargramostim is necessary during pregnancy, reconstitute the drug only with Sterile Water for Injection without preservatives.1
It is not known whether sargramostim is distributed into milk, affects milk production, or affects the breast-fed infant.1 Use in rabbits during lactation was associated with a reduction in postnatal offspring survival.1 Advise lactating women not to breast-feed during treatment and for at least 2 weeks after the last dose of sargramostim.1
The efficacy and safety of sargramostim have been established in pediatric patients ≥2 years of age for autologous peripheral blood progenitor cells and BMT, allogeneic BMT, and treatment of delayed neutrophil recovery or graft failure based on studies performed in adults and a limited number of pediatric patients.1 The efficacy and safety of sargramostim have also been established in the setting of acute exposure to myelosuppressive doses of radiation among pediatric patients from birth to 17 years of age.1 This approval is based on studies conducted in animals and clinical data supporting the use of sargramostim in patients undergoing autologous or allogeneic BMT following myelosuppressive chemotherapy with or without total body irradiation.1 Modeling and simulations were performed in order to develop pediatric dosage regimens that provide effects comparable to those seen in adults.1
In neonates and low birth weight infants, avoid the use of sargramostim solutions reconstituted with Bacteriostatic Water for Injection due to the presence of the preservative, benzyl alcohol.1 Benzyl alcohol may result in fatal reactions and the “gasping syndrome” in this patient population.1 Additional potential adverse reactions of benzyl alcohol exposure include gradual neurologic deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.1
Experience in patients ≥65 years of age is insufficient to determine whether they respond differently to sargramostim than younger patients1
The most common (>30%) adverse reactions in recipients of autologous BMT include fever, nausea, diarrhea, vomiting, mucus membrane disorder, alopecia, asthenia, malaise, anorexia, rash, GI disorder, and edema.1
The most common (>30%) adverse reactions in recipients of allogeneic BMT include diarrhea, fever, nausea, rash, vomiting, stomatitis, anorexia, increased glucose, alopecia, abdominal pain, low albumin, headache, and hypertension.1
The most common (>30%) adverse reactions in patients with AML include fever, liver toxicity, skin reactions, infections, metabolic laboratory abnormalities, nausea, diarrhea, genitourinary abnormalities, pulmonary toxicity, vomiting, neurotoxicity, stomatitis, alopecia, and weight loss.1
Drugs with Myeloproliferative Effects
Drugs that could potentiate the myeloproliferative effects of sargramostim (e.g., lithium, corticosteroids) should be avoided.1 If concomitant use is unavoidable, patients should be monitored frequently for clinical and laboratory signs of increased myeloproliferative effects.1
Sargramostim, a human granulocyte-macrophage colony-stimulating factor (GM-CSF), is a hematopoietic agent that affects the proliferation and differentiation of a variety of hematopoietic progenitor cells.1, 5, 131, 132 The drug is prepared using recombinant DNA technology and a yeast expression system that utilizes Saccharomyces cerevisiae.1 Sargramostim is a single-chain, glycosylated polypeptide containing 127 amino acids and is characterized by equal proportions of 3 primary molecular species having molecular weights of 19,500, 16,800, and 15,500 daltons.1, 77, 82, 95 The drug has an amino acid sequence identical to that of endogenous human GM-CSF except for a leucine instead of a proline at position 23 and potentially a different carbohydrate moiety.1, 100
Sargramostim appears to elicit the pharmacologic effects usually produced by endogenous human GM-CSF.5, 11, 85, 86, 95, 132 Endogenous GM-CSF, a growth factor, is a multilineage colony-stimulating factor (CSF)4, 5, 11, 46, 78, 83, 84, 85, 86, 90, 91, 132, 150, 151 that principally affects the proliferation, differentiation, and activation of granulocytes and macrophages by inducing partially committed progenitor cells (i.e., neutrophils, monocytes/macrophages, dendritic cells derived from myeloid cell lines) to divide and differentiate in the granulocyte-macrophage pathways.1, 11, 78, 83, 84, 85, 86, 90, 91, 132, 150, 151 In addition, in conjunction with other growth factors, endogenous GM-CSF stimulates the proliferation of several other cell types including eosinophils, megakaryocytes, erythroid progenitors, and mast-cell precursors.1, 11, 46, 83, 84, 85, 90, 132, 150 Endogenous GM-CSF also enhances certain functions of mature neutrophils and monocytes, including chemotaxis, phagocytosis, and antibody-dependent cellular cytotoxicity (ADCC).3, 4, 5, 11, 46, 78, 79, 83, 84, 85, 86, 88, 90, 91, 92, 119, 150, 151, 154, 175, 182
Endogenous human GM-CSF is produced by both hematologic and tissue cells including fibroblasts, T cells, macrophages, and endothelial cells.5, 76, 78, 83, 84, 85, 86, 91, 132 The mechanisms that control production and secretion of GM-CSF from these cells have not been fully elucidated.50, 78, 83, 85, 132 Presence of several factors, including interleukin-1 (lymphocyte-activating factor), tumor necrosis factor, and endotoxin, appears to stimulate production and release of endogenous GM-CSF from various cells.78, 85, 91 Nonimmune activation of fibroblasts and endothelial cells and immune activation of T cells appear to lead to synthesis and release of GM-CSF.83, 91 Although it has been suggested that a feedback mechanism based on the level of circulating neutrophils regulates production of another growth factor, endogenous granulocyte CSF (G-CSF), there is no evidence that endogenous levels of GM-CSF increase in response to severe neutropenia.50
Like endogenous GM-CSF, sargramostim appears to act directly on target cells by binding to GM-CSF-specific receptors on their cell surfaces.1, 5, 78, 83, 84, 88, 91, 105, 140, 141, 142 How this binding to receptors results in the various intracellular events necessary to affect proliferation, differentiation, and cell function has not been fully elucidated to date.5, 78, 140, 142 Although glycosylation is not necessary for binding of CSFs to receptors on target cells, the degree of glycosylation may affect the biologic activity of GM-CSF by reducing receptor binding affinity.11, 85, 131, 132
The GM-CSF receptor binding site on target cells appears to be complex and is composed of at least 2 subunits.5, 84, 141, 142 The α subunit is a low-affinity receptor site.141, 142 The β subunit cannot bind GM-CSF when expressed alone but acts as a high-affinity receptor site when expressed in conjunction with the α subunit;141, 142 the β subunit is cross-reactive and also binds interleukin-3 (multicolony-stimulating factor, multi-CSF).5, 141, 142 GM-CSF receptors are present on all cells of the neutrophil, monocyte, and eosinophil lineages; mature cells generally have fewer receptors than more premature and progenitor cells.83, 84, 85, 140, 141, 202 Neutrophils contain only the α/β complex and therefore have only high-affinity receptors.141 Although the clinical importance is unclear, GM-CSF receptors also have been found on certain leukemic cell lines (including some derived from human myeloid leukemia cells), cell lines derived from human small cell lung carcinoma, osteogenic sarcoma, breast carcinoma, and malignant melanoma cells as well as human placenta and human vascular endothelial cells.4, 46, 84, 85, 91, 140, 141, 150, 154, 215, 216
In most patients, there is an initial plateau in leukocyte counts that is achieved after 3-7 days of GM-CSF therapy.122 This initial plateau is followed by a slight decrease (despite continued GM-CSF therapy) and a second increase and plateau occurring 4-5 days after the first plateau.122 It has been suggested that the initial increase in leukocyte count represents redistribution of cells from the bone marrow after maturation, shortened maturation time, enhanced demargination of intravascular neutrophils, and inhibited extravascular migration of neutrophils; the second increase probably occurs because of an increase in the proliferative fraction of hematopoietic cells within the bone marrow.5 Alternatively, it has been suggested that the second peak in neutrophil response occurs because GM-CSF induces production of other factors (e.g., interleukin-3, interleukin-5) that function in conjunction with GM-CSF to augment the leukocyte response. Following discontinuance of biosynthetic GM-CSF therapy, leukocyte counts return to pretreatment levels within 2-10 days.11, 43, 44, 47, 91, 94, 121, 129
Following IV infusion of sargramostim, peak serum concentrations were attained during or immediately after completion of the infusion.1 After subcutaneous administration, sargramostim was detected within 15 minutes and reached peak serum concentrations between 2.5 and 4 hours.1 When compared to the IV route, the absolute bioavailability with the subcutaneous route was 75%.1
Following subcutaneous administration, the terminal elimination half-life of sargramostim is 1.4 hours.1 The observed total body clearance/subcutaneous bioavailability is 23 L/hour.1 The metabolic fate of sargramostim has not been fully elucidated to date, and it is not known whether the drug is metabolized or how it is eliminated from the body.1 Because sargramostim is a protein, it is expected to degrade to small peptides and individual amino acids.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection, for subcutaneous or IV use | 250 mcg | Partner Therapeutics |
1. Partner Therapeutics. Leukine® (sargramostim) prescribing information. Lexington, MA; 2022 May.
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