Sargramostim

Class: Hematopoietic Agents
VA Class: BL400
Molecular Formula: C₆₃₉H₁₀₀₂O₁₉₆S₈
CAS Number: 123774-72-1
Brands: Leukine

Introduction

Biosynthetic hematopoietic agent that affects the proliferation and differentiation of a variety of hematopoietic progenitor cells; a yeast-derived (Saccharomyces cerevisiae) recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF).^{1 5 131 132}

Uses for Sargramostim

Autologous and Allogeneic Bone Marrow Transplantation

Acceleration of myeloid recovery in adults with non-Hodgkin’s lymphoma, acute lymphocytic (lymphoblastic) leukemia (ALL), or Hodgkin’s disease undergoing cytotoxic chemotherapy and autologous bone marrow transplantation (BMT).^{1 5 7 8 12 55 75 77 78 91 96 173 174 196}

Acceleration of myeloid recovery in patients undergoing allogeneic BMT from HLA-matched related donors.^{1 5 21 112 173} Also has been used to accelerate myeloid recovery in patients receiving allogeneic BMT from unrelated donors†.²¹

Designated an orphan drug by FDA for use in BMT patients for the management of neutropenia associated with BMT and for the promotion of early engraftment.²²²

Peripheral Blood Progenitor Cell Transplantation

Mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis.¹

Acceleration of myeloid engraftment following autologous peripheral blood progenitor cell (PBPC) transplantation.¹

Bone Marrow Transplantation Failure or Engraftment Delay

Prolongation of survival in adults who have undergone allogeneic or autologous BMT and in whom engraftment is delayed or has failed.^{1 18 19} Designated an orphan drug by FDA for use in BMT patients for the treatment of delayed or failed engraftment.²²²

Has been used in a limited number of patients to reduce the period of severe myelosuppression and the risk of infectious complications in patients with delayed engraftment following PBPC transplantation†.¹⁹

Leukemias

Acceleration of neutrophil recovery and reduction of the incidence of severe and life-threatening infections following induction chemotherapy in adults ≥55 years of age with acute myelogenous leukemia (AML);^{1 220} safety and efficacy not established in individuals <55 years of age.¹

Designated an orphan drug by FDA for use in patients with AML to reduce neutropenia and leukopenia and to increase survival.²²²

Use of biosynthetic GM-CSFs in patients with acute leukemia has been controversial, since results of in vitro studies indicate that certain leukemic cell lines have receptors for GM-CSF and that these drugs may have a stimulatory effect on leukemic blast cells in vitro.^{49 52 54 96 203} Some experts state that use of sargramostim in the treatment of myeloid leukemias should be considered investigational and undertaken with caution.^{49 51 88 96 201}

Myelodysplastic Syndromes and Aplastic Anemia

Has been used to increase leukocyte counts in 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);^{5 43 44 45 47 48 77 91 129 150 151 171 172} however, it is unclear whether sargramostim will alter (either increase or decrease) the rate of progression to AML or alter the usually fatal outcome of the disease.^{5 10 43 44 45 47 129 150 151 172 189} Generally should be used under protocol conditions.^{201 206}

Has been used with some success to increase leukocyte counts in a limited number of adults and adolescents ≥15 years of age with moderate to severe aplastic anemia†.^{129 134} Generally should be used under protocol conditions.^{201 206}

Neutropenia Associated with HIV Infection and Antiretroviral Therapy

Treatment to correct or minimize HIV-associated neutropenia† or 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 96 111 136 138 149 158 159 160 161 189 217 218 219 229 231}

Congenital, Cyclic, and Idiopathic Neutropenias

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 Filgrastim may be more effective than sargramostim and other biosynthetic GM-CSFs, since filgrastim results in more consistent increases in neutrophil counts and does not cause eosinophilia.^{5 58 59 77 101}

Chemotherapy-induced Neutropenia

Treatment to increase neutrophil counts and decrease the risk of infectious complications† in patients with malignancies receiving myelosuppressive antineoplastic therapy.^{5 23 24 26 27 28 29 30 31 33 75 81 87 96 109 110 114 115 120 144 162 163 164 165 166 167 169 184 187 198 199} Has been used prophylactically in a limited number of children with refractory solid tumors receiving myelosuppressive therapy†.³⁰

Filgrastim has been used more extensively to date than biosynthetic GM-CSFs in patients with chemotherapy-induced neutropenia;^{96 168} intermittent low-grade fevers reported in a large proportion of patients receiving GM-CSF therapy^{5 29 71 95 108 201} but not in those receiving filgrastim therapy.²⁰¹

Sargramostim Dosage and Administration

Administration

Administer by IV infusion^{1 5 30 95 103} or sub-Q injection.^{1 5 34 59 67 95 104} Sub-Q injection is most convenient for self-administration and especially useful for prolonged maintenance therapy.²⁰¹

Do not administer sargramostim within 24 hours before or after radiation therapy or chemotherapy.¹

Intended for use under the guidance and supervision of a clinician; may be self-administered if clinician determines that patient and/or caregiver is competent to safely administer drug after appropriate instruction.¹ (See Advice to Patients.)

IV Administration

For drug compatibility information, see Compatibility under Stability.

IV infusion using an in-line filter is not recommended.^{1 206} Adsorption of the drug could occur.^{1 206}

Reconstitution

Reconstitute vials containing 250 mcg of sargramostim powder with 1 mL of sterile or bacteriostatic water for injection to provide a solution containing 250 mcg/mL.¹ Direct diluent at the side of the vial and gently swirl contents to avoid foaming.¹ Avoid shaking or excessive agitation of vial.¹ Use care to eliminate air bubbles from the needle hub of the syringe containing the diluent to ensure the correct final concentration.¹

Commercially available vials of sargramostim lyophilized powder for injection are for single use only.¹ Do not reenter or reuse vials.¹

Dilution

For IV infusion, dilute sargramostim injection or further dilute reconstituted solutions of sargramostim powder for injection in 0.9% sodium chloride injection.¹

If sargramostim is diluted to a final concentration of <10 mcg/mL, add albumin human to minimize adsorption of the drug to drug delivery system components.¹ Add 1 mg of albumin human per 1 mL of 0.9% sodium chloride injection (e.g., dilute 1 mL of 5% albumin human in 50 mL of 0.9% sodium chloride injection).¹

Rate of Administration

Patients undergoing BMT: Administer by IV infusion over 2 hours.^{1 5 8 21}

For mobilization of hematopoietic progenitor cells or for acceleration of myeloid engraftment following autologous PBPC transplantation: Administer by continuous IV infusion over 24 hours.¹

For BMT failure or engraftment delay: Administer by IV infusion over 2 hours.^{1 5 18 19}

Patients with AML: Administer by IV infusion over 4 hours.¹

Sub-Q Administration

For sub-Q injection, administer sargramostim injection or reconstituted solutions without further dilution.¹

Reconstitution

Reconstitute vials containing 250 mcg of sargramostim powder for injection with 1 mL of sterile or bacteriostatic water for injection to provide a solution containing 250 mcg/mL.¹ Direct diluent at the side of the vial and gently swirl contents to avoid foaming.¹ Avoid shaking or excessive agitation of vial.¹ Use care to eliminate air bubbles from the needle hub of the syringe containing the diluent to ensure the correct final concentration.¹

Commercially available vials of sargramostim lyophilized powder for injection are for single use only.¹ Do not reenter or reuse vials.¹

Dosage

If a severe adverse reaction occurs, reduce dosage by 50% or temporarily discontinue therapy until the reaction abates.¹

Discontinue therapy if blast cells appear on the leukocyte differential or if disease progression occurs.^{1 5}

Temporarily discontinue therapy or reduce dosage by 50% if the ANC is >20,000/mm³ or if the platelet count is >500,000/mm³.¹ Base decision to interrupt therapy or reduce dosage on the clinical condition of the patient.¹

Pediatric Patients

Neutropenia Associated with HIV Infection and Antiretroviral Therapy†

IV or Sub-Q

Adolescents: Dosage of 250 mcg/m² administered by IV infusion or sub-Q injection once daily for 2–4 weeks has been used.²¹⁸

Adults

Autologous or Allogeneic Bone Marrow Transplantation

IV

250 mcg/m² once daily, administered by IV infusion over 2 hours.^{1 5 8 21} Initiate therapy 2–4 hours after infusion of bone marrow (but no sooner than 24 hours after the last course of radiation therapy or the last dose of chemotherapy).^{1 5 8 21} Do not initiate therapy until the posttransplantation ANC is <500/mm³.¹ Continue until the ANC is >1500/mm³ for 3 consecutive days.¹

Peripheral Blood Progenitor Cell Transplantation

Mobilization of Hematopoietic Progenitor Cells

IV or Sub-Q

250 mcg/m² daily, administered by continuous IV infusion over 24 hours or by sub-Q injection once daily.¹ Continue therapy throughout the period of PBPC collection.¹ Usually, initiate PBPC collection by day 5 of therapy and perform daily until protocol-specified targets are achieved.¹

Reduce dosage by 50% if the leukocyte count increases to >50,000/mm³.¹

Administration Following Reinfusion of PBPC Collection

IV or Sub-Q

To accelerate myeloid engraftment following autologous PBPC transplantation, 250 mcg/m² daily, administered by continuous IV infusion over 24 hours or by sub-Q injection once daily.¹ Initiate immediately following infusion of PBPC and continue until the ANC is >1500/mm³ for 3 consecutive days.¹

Bone Marrow Transplantation Failure or Engraftment Delay

IV

Initially, 250 mcg/m² administered by IV infusion over 2 hours once daily^{1 5 18 19} for 14 consecutive days.^{1 5 19} Discontinue for 7 consecutive days.^{1 5 19}

If engraftment has not occurred after this 7-day interval, administer a second course of therapy.^{1 5} For the second course of therapy, administer 250 mcg/m² by IV infusion over 2 hours once daily for 14 consecutive days.^{1 5} Discontinue for 7 consecutive days.^{1 5}

If engraftment has not occurred after this 7-day interval, administer a third course of therapy.^{1 5} For the third course of therapy, administer 500 mcg/m² by IV infusion over 2 hours once daily for 14 consecutive days.^{1 5}

Leukemias

Acute Myelogenous Leukemia

IV

Initially, 250 mcg/m² administered by IV infusion over 4 hours once daily.¹ Initiate therapy on approximately day 11 or 4 days following completion of induction therapy;¹ use only if the bone marrow is hypoplastic with <5% blast cells on day 10.¹ If a second cycle of induction chemotherapy is necessary, administer sargramostim therapy approximately 4 days after completion of chemotherapy;¹ use only if the bone marrow is hypoplastic with <5% blast cells.¹ Continue sargramostim until the ANC is >1500/mm³ for 3 consecutive days or for a maximum of 42 days.¹

Temporarily discontinue therapy or reduce dosage by 50% if the ANC is >20,000/mm³.¹

Discontinue therapy immediately if leukemia regrowth occurs.¹

Myelodysplastic Syndromes† andAplastic Anemia†

Myelodysplastic Syndromes†

IV

Dosages of 15–500 mcg/m² once daily, administered by IV infusion over 1–12 hours, have been used.^{44 129 172} Alternatively, dosages of 30–500 mcg/m² daily, administered by continuous IV infusion over 24 hours, have been used.^{47 48}

Aplastic Anemia†

IV

Dosages of 15–480 mcg/m² once daily, administered by IV infusion over 1–12 hours, have been used.¹²⁹ Alternatively, dosages of 120–500 mcg/m² daily, administered by continuous IV infusion over 24 hours, have been used.¹³⁴

Neutropenia Associated with HIV Infection and Antiretroviral Therapy†

IV or Sub-Q

Dosage of 250 mcg/m² administered by IV infusion or sub-Q injection once daily for 2–4 weeks has been used.²¹⁸

Prescribing Limits

Adults

Bone Marrow Transplantation Failure or Engraftment Delay

IV

Maximum 3 courses of therapy (500 mcg/m² daily during the third course) recommended.^{1 5}

Leukemias

Acute Myelogenous Leukemia

IV

Maximum 250 mcg/m² once daily for 42 days.¹

Cautions for Sargramostim

Contraindications

• 
  

  Excessive (i.e., ≥10%) leukemic myeloid blasts in the bone marrow or peripheral blood.^{1 5}

  
  


• 
  

  Known hypersensitivity to sargramostim, any ingredient in the formulation, or yeast-derived products.¹

  
  


• 
  

  Concomitant use of chemotherapy or radiation therapy.¹

  
  

Warnings/Precautions

Warnings

Fluid Retention

Possible edema, capillary leak syndrome, and pleural and/or pericardial effusion.^{1 5 8} Possible precipitation or aggravation of fluid retention, especially in patients with preexisting pleural and pericardial effusions.¹

Monitor body weight and hydration status during therapy.²⁰¹

Use with caution in patients with preexisting fluid retention, pulmonary infiltrates, or CHF.^{1 5}

Respiratory Effects

Possible sequestration of granulocytes in the pulmonary circulation; dyspnea reported occasionally.¹

Use with caution in patients with preexisting lung disease and/or hypoxia.^{1 5}

Give special attention to respiratory symptoms that develop during or immediately following administration.¹ If dyspnea develops during administration, decrease the IV infusion rate by 50%;^{1 5} administer oxygen to provide symptomatic relief if necessary.^{5 106 108} If respiratory symptoms worsen despite reduction in the infusion rate, discontinue the infusion.¹ Subsequent doses may be administered according to the usual dosage schedule with careful monitoring.¹

Cardiovascular Effects

Possible transient, reversible supraventricular arrhythmia.¹

Use with caution in patients with preexisting cardiac disease.¹

Increased incidence of syncope with or without hypotension reported with edetate disodium (EDTA)-containing sargramostim injection (formulation no longer commercially available in the US).^{232 233 234} (See Preparations.) A similar increase in such adverse effects not observed with commercially available sargramostim lyophilized powder for injection (without EDTA).^{232 233 234}

Sensitivity Reactions

Serious allergic or anaphylactic reactions reported rarely.¹

Discontinue sargramostim and initiate appropriate therapy if such reactions occur.¹

General Precautions

First-dose Reaction

Syndrome characterized by respiratory distress, hypoxia, flushing, hypotension, syncope, and/or tachycardia reported following the first dose of sargramostim in each treatment cycle.¹ Manifestations usually resolve with symptomatic treatment and generally do not recur with subsequent doses in the same treatment cycle.¹

If a first-dose reaction occurs, provide symptomatic treatment (e.g., oxygen, IV fluids, acetaminophen or NSAIA).^{106 108}

Chemotherapy and Radiation Therapy

Safety and efficacy of concomitant radiation therapy or myelosuppressive antineoplastic agents not established.¹ Do not administer sargramostim within 24 hours of radiation therapy or a dose of a myelosuppressive antineoplastic agent.¹ (See Interactions.)

Patients who previously received extensive radiation therapy or were exposed to multiple myelotoxic agents (e.g., alkylating agents, anthracycline antibiotics, antimetabolites) may have a limited response to sargramostim therapy following autologous BMT.^{1 93 122}

Patients Receiving Purged Bone Marrow

Is effective in accelerating myeloid recovery following BMT when the marrow is purged by anti-B lymphocyte monoclonal antibodies.¹ Patients receiving chemically purged marrow may not respond to sargramostim if the chemical agents cause a clinically important decrease in the number of responsive hematopoietic progenitors;¹ if the purging process preserves a sufficient number of progenitors (>1.2 × 10⁴ per kg), sargramostim may provide a beneficial effect on myeloid engraftment.¹

Excessive Hematologic Effects

Possible rapid rise in leukocyte count.^{1 134} Marked leukocytosis (leukocyte count ≥100,000/mm³) reported occasionally.⁴⁷ Various effects on platelet counts reported in patients receiving biosynthetic GM-CSFs.^{5 11 24 29 36 94 108 109 122 129}

Monitor CBC and platelet counts twice weekly during therapy to avoid potential complications of excessive leukocytosis and/or thrombocytosis.^{1 5 95} Temporarily discontinue therapy or reduce dosage by 50% if the ANC is >20,000/mm³ or if the platelet count is >500,000/mm³.¹

Effect on Malignant Cells

The possibility that sargramostim could act as a growth factor for any tumor type, particularly myeloid malignancies, has not been excluded.^{1 54 72}

Caution recommended in patients with any malignancy with myeloid characteristics.^{1 43 44 45 47 49 51 88 96 129 215 216} Discontinue therapy if disease progression is detected in patients with non-Hodgkin’s lymphoma, ALL, or Hodgkin’s disease.¹

Has been used in patients with MDS† or AML without evidence of increased relapse rates;^{1 43 44 45 47 48 49 52 54 91 96 129 220} however, regrowth of leukemic cells and an increase in leukemic blasts have occurred in a few patients with AML who were receiving the drug.⁵⁴

When used for mobilization of hematopoietic progenitor cells, possible release of tumor cells from the marrow and subsequent collection in the leukapheresis product; effect of reinfusion of tumor cells not well studied and limited data available to date are inconclusive.¹

Laboratory Monitoring

Perform CBC and platelet counts prior to initiation of therapy and routinely (e.g., twice weekly) during therapy.^{1 5 95}

Immunogenicity

Development of anti-GM-CSF antibodies reported occasionally in patients receiving sargramostim.^{1 100 212} Consider the possibility that formation of anti-GM-CSF antibodies during sargramostim therapy theoretically could result in drug-induced neutropenia, neutralization of endogenous GM-CSF activity, or decreased effectiveness of sargramostim.^{1 87 100}

Specific Populations

Pregnancy

Category C.¹

Lactation

Not known whether sargramostim is distributed into milk; use only if clearly needed.^{1 193}

Pediatric Use

Safety and efficacy not established.^{1 5 30 42 59} However, no unusual adverse effects reported during use in children 4 months to 18 years of age (at daily dosages of 60–1000 mcg/m² IV or 4–1500 mcg/m² sub-Q).^{1 5 30 42 59} Some evidence that children may tolerate higher dosages of biosynthetic GM-CSF compared with adults in the treatment of chemotherapy-induced neutropenia†.^{5 30 82}

Avoid administration of solutions containing benzyl alcohol (sargramostim injection, sargramostim powder reconstituted with bacteriostatic water for injection) in neonates.¹ Large amounts of benzyl alcohol (i.e., 100–400 mg/kg daily) have been associated with toxicity in neonates.^{224 225 226 227 228}

Geriatric Use

Experience in patients ≥65 years of age limited to those with AML.¹ Analysis of general trends in safety and efficacy demonstrate a response in geriatric patients similar to that in younger adults.^{76 1} The possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.¹

Hepatic Impairment

Possible increased concentrations of serum bilirubin and hepatic enzymes.^{1 21 44}

Monitor hepatic function every other week during therapy in patients with hepatic impairment.^{1 206}

Renal Impairment

Possible increased S_cr.^{1 21 44}

Monitor renal function every other week during therapy in patients with renal impairment.^{1 206}

Common Adverse Effects

Fever, asthenia, chills, headache, nausea, diarrhea, myalgia, bone pain.^{1 5 47 55 73 87 112 134 172}

Interactions for Sargramostim

Specific Drugs

Drug	Interaction	Comments
Antineoplastic agents	Sensitivity of rapidly dividing cells to cytotoxic chemotherapy may be increased1	Safety and efficacy of concomitant administration not established.1 Administration of sargramostim within 24 hours of administration of chemotherapy is not recommended1
Didanosine	No evidence of synergism against HIV133 200
Myeloproliferative agents (e.g., corticosteroids, lithium)	Possible additive myeloproliferative effects1	Use with caution1
Zalcitabine	No evidence of synergism against HIV133 200
Zidovudine	Possible pharmacologic and/or pharmacokinetic interaction resulting in additive or synergistic antiretroviral effect3 5 35 39 133 135 136 137 149 157 158 161 200

Sargramostim Pharmacokinetics

Absorption

Bioavailability

Peak serum concentrations are attained during or immediately after completion of an IV infusion.¹

Rapidly absorbed following sub-Q injection,^{1 67 104} with peak serum concentrations generally attained within 1–4 hours.^{1 67 104}

Duration

In patients with sargramostim-associated leukocytosis or thrombocytosis, excessive blood cell counts usually return to normal or baseline levels within 2–10 days following interruption of therapy.^{1 11 43 44 47 87 91 94 121 129}

Distribution

Extent

Murine GM-CSF is distributed into various tissues including liver, spleen, and kidney in mice.¹⁰²

Not known whether sargramostim distributes into CSF¹⁹³ or milk or crosses the placenta in humans.^{1 193}

Elimination

Metabolism

Not known whether sargramostim is metabolized.¹⁹³

Elimination Route

Elimination route not known.¹⁹³

Half-life

Terminal elimination half-life is approximately 60 minutes following IV infusion over 2 hours.¹

Following sub-Q administration, terminal elimination half-life is approximately 162 minutes.¹

Stability

Storage

Parenteral

Powder and Solution

2–8°C;^{1 206} do not freeze.¹

Use solutions reconstituted with sterile water for injection within 6 hours.^{1 206} Use solutions reconstituted with bacteriostatic water for injection within 20 days.^{1 206} Administer previously reconstituted solution mixed with freshly reconstituted solution within 6 hours following mixing.¹

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Drug Compatibility

Y-Site CompatibilityHID

Compatible
Amikacin sulfate
Aminophylline
Aztreonam
Bleomycin sulfate
Butorphanol tartrate
Calcium gluconate
Carboplatin
Carmustine
Cefazolin sodium
Cefepime HCl
Cefotaxime sodium
Ceftizoxime sodium
Ceftriaxone sodium
Cefuroxime sodium
Cimetidine HCl
Cisplatin
Clindamycin phosphate
Co-trimoxazole
Cyclophosphamide
Cyclosporine
Cytarabine
Dacarbazine
Dactinomycin
Dexamethasone sodium phosphate
Diphenhydramine HCl
Dopamine HCl
Doxorubicin HCl
Doxycycline hyclate
Droperidol
Etoposide
Famotidine
Fentanyl citrate
Floxuridine
Fluconazole
Fluorouracil
Furosemide
Gentamicin sulfate
Granisetron HCl
Heparin sodium
Idarubicin HCl
Ifosfamide
Immune globulin intravenous
Magnesium sulfate
Mannitol
Meperidine HCl
Mesna
Methotrexate sodium
Metoclopramide HCl
Metronidazole
Mitoxantrone HCl
Pentostatin
Piperacillin sodium–tazobactam sodium
Potassium chloride
Prochlorperazine edisylate
Promethazine HCl
Ranitidine HCl
Teniposide
Ticarcillin disodium–clavulanate potassium
Vinblastine sulfate
Vincristine sulfate
Zidovudine
Incompatible
Acyclovir sodium
Ampicillin sodium
Ampicillin sodium–sulbactam sodium
Chlorpromazine HCl
Ganciclovir sodium
Haloperidol lactate
Hydrocortisone sodium phosphate
Hydrocortisone sodium succinate
Hydromorphone HCl
Hydroxyzine HCl
Imipenem–cilastatin sodium
Lorazepam
Methylprednisolone sodium succinate
Mitomycin
Morphine sulfate
Nalbuphine HCl
Ondansetron HCl
Sodium bicarbonate
Tobramycin sulfate
Variable
Amphotericin B
Amsacrine
Ceftazidime
Vancomycin HCl

ActionsActions

• 
  

  Exerts the pharmacologic effects usually produced by endogenous human GM-CSF.^{1 5 11 85 86 95 132}

  
  


• 
  

  Influences leucopoiesis;^{1 5 85 95} affects the proliferation and differentiation of a variety of hematopoietic progenitor cells,^{1 5 131 132} principally in the granulocyte-macrophage lineage.^{1 11 78 83 84 85 86 87 90 91 132}

  
  


• 
  

  Acts directly on various progenitor target cells^{5 98 150 203} by binding to GM-CSF-specific receptors on their cell surfaces.^{1 5 78 83 84 87 88 91 105 140 141 142}

  
  


• 
  

  Induces partially committed progenitor cells to divide and differentiate in the granulocyte-macrophage pathways.^{1 11 78 83 84 85 86 87 90 91 132 150 151} Also stimulates the proliferation of eosinophils, megakaryocytes, erythroid progenitors, and mast-cell precursors.^{1 11 46 83 84 85 87 90 132 150}

  
  


• 
  

  Alters the kinetics of myeloid progenitor cells within the bone marrow.^{5 82 94 198 203 204} Causes rapid entry of cells into the cell cycle and decreases the cell cycle time.^{5 82 94 198 203 204}

  
  


• 
  

  Produces a dose-dependent^{11 32 78 84 87 91 122} and biphasic increase in the leukocyte count.^{24 93 122}

  
  


• 
  

  Enhances certain functions of normal mature neutrophils, eosinophils, basophils, and macrophages^{78 79 83 85 119 150} (e.g., oxidative metabolism of neutrophils, phagocytosis, eosinophil cytotoxicity, antibody-dependent cellular cytotoxicity, chemotax