Effects of bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor in patients with advanced malignancy.
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.
Lieschke
G J
GJ
Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Victoria, Australia.
Maher
D
D
Cebon
J
J
O'Connor
M
M
Green
M
M
Sheridan
W
W
Boyd
A
A
Rallings
M
M
Bonnem
E
E
Metcalf
D
D
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
D003115:Colony-Stimulating Factors; D006133:Growth Substances; D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor