title: Effects of bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor in patients with advanced malignancy.
abstract: OBJECTIVE
  To define the clinical and hematologic effects of subcutaneously administered bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF).
  
  
  METHODS
  Single arm nonrandomized dose escalation study.
  
  
  METHODS
  Twenty-one patients with advanced malignancy who were not receiving concurrent myelosuppressive therapy.
  
  
  METHODS
  Subcutaneous administration of rhGM-CSF by once-daily injection to groups of two to four patients at doses of 0.3 to 30 micrograms/kg body weight.d for 10 consecutive days. Some patients received a second 10-day period of daily rhGM-CSF treatment after a 10-day nontreatment interval followed by alternate-day treatment. Clinical status and hematologic values were monitored frequently.
  
  
  RESULTS
  All doses of rhGM-CSF caused an immediate transient fall of 84% to 99% in circulating neutrophils, eosinophils, and monocytes. Continued daily dosing caused a leukocytosis of up to 10-fold with increases in numbers of circulating neutrophils, eosinophils, monocytes, and lymphocytes. There appeared to be a plateau in the increase in neutrophils in the dose range 3 to 15 micrograms/kg.d. Marrow aspirates showed increased proportions of promyelocytes and myelocytes. Alternate-day injection of 15 micrograms/kg maintained a leukocytosis. At doses up to 15 micrograms/kg.d, rhGM-CSF was well tolerated but adverse effects included bone pains, myalgias, rashes, and liver dysfunction. At doses exceeding 15 micrograms/kg.d, pericarditis was a dose-limiting toxicity. Idiopathic thrombocytopenic purpura was reactivated by rhGM-CSF in one patient.
  
  
  CONCLUSIONS
  Bacterially synthesized rhGM-CSF induces a leukocytosis in the dose range of 3 to 15 micrograms/kg.d. These doses are appropriate for phase II studies.
authors.affiliation: Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Victoria, Australia.
authors.forename: G J
authors.initials: GJ
authors.lastname: Lieschke
authors.forename: D
authors.initials: D
authors.lastname: Maher
authors.forename: J
authors.initials: J
authors.lastname: Cebon
authors.forename: M
authors.initials: M
authors.lastname: O'Connor
authors.forename: M
authors.initials: M
authors.lastname: Green
authors.forename: W
authors.initials: W
authors.lastname: Sheridan
authors.forename: A
authors.initials: A
authors.lastname: Boyd
authors.forename: M
authors.initials: M
authors.lastname: Rallings
authors.forename: E
authors.initials: E
authors.lastname: Bonnem
authors.forename: D
authors.initials: D
authors.lastname: Metcalf
mesh_terms: D000328:Adult; D000368:Aged; D003115:Colony-Stimulating Factors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004341:Drug Evaluation; D005260:Female; D005334:Fever / Q000209:etiology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006133:Growth Substances / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D007279:Injections, Subcutaneous; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000628:therapy*; D010146:Pain / Q000209:etiology; D010976:Platelet Count / Q000187:drug effects; D011994:Recombinant Proteins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D003115:Colony-Stimulating Factors; D006133:Growth Substances; D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor