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Characterization of the clinical effects after the first dose of
bacterially synthesized recombinant human granulocyte-macrophage colony-
stimulating factor
GJ Lieschke, J Cebon and G Morstyn
Ludwig Institute for Cancer Research, Melbourne Tumour Biology Branch,
Victoria, Australia.
Bacterially synthesized recombinant human granulocyte-macrophage colony-
stimulating factor (rhGM-CSF) is an agent with therapeutic potential for
neutropenic states, but even at doses below the maximal tolerated dose
adverse effects occur during short courses of administration. We have
recognized a syndrome of hypoxia and hypotension that follows the first but
not subsequent doses of rhGM-CSF. Thirteen of 42 patients receiving
rhGM-CSF in phase I studies and 4 of 6 patients in a phase II study
developed a reaction that occurred after the first dose of 24 of 78 cycles
of rhGM-CSF therapy. The reaction was characterized by flushing (16 of 24),
tachycardia (16 of 24), hypotension (14 of 24), musculoskeletal pain (13 of
24), dyspnea (12 of 24), nausea and vomiting (11 of 24), rigors (5 of 24),
involuntary leg spasms (3 of 24), and syncope (3 of 24). The reaction did
not occur after any of more than 600 second and subsequent consecutive
rhGM-CSF doses. Oxygen saturation decreased during first-dose reactions by
8% +/- 4% as compared with 3% +/- 1% on first days without reactions (P
less than .001) and 2% +/- 1% on subsequent days (P less than .001).
Pulmonary dysfunction was characterized by hypoxemia (59 +/- 9 mm Hg, mean
+/- SD) that was fully correctable with supplementary oxygen, decreased
single-breath carbon monoxide diffusion capacity, and increased
alveolar-arterial oxygen gradients (25 +/- 6 to 60 +/- 4 mm Hg, mean +/-
SD), but no significant abnormalities on chest roentgenogram or lung
perfusion scan. Factors predisposing to reactions were rhGM-CSF dose
greater than or equal to 3 micrograms/kg (P less than .01), intravenous
(IV) rather than subcutaneous (SC) administration (P less than .05),
occurrence of a reaction after the first dose of a previous cycle of
rhGM-CSF therapy (P less than .01), and for patients receiving 15
micrograms/kg/d by SC bolus, the presence of lung cancer (P less than .05).
Administration of 15 micrograms/kg/d rhGM-CSF by 24-hour SC infusion rather
than SC bolus resulted in a delayed onset of reaction from 30 +/- 8 minutes
to 240 +/- 190 minutes (mean +/- SD, P less than .001), and a slower rate
of initial transient decrease in neutrophil levels and a more prolonged
duration of transient leukopenia. The time of onset of reactions correlated
with the rate of rise of rhGM-CSF levels.(ABSTRACT TRUNCATED AT 400 WORDS)
Volume 74,
Issue 8,
pp. 2634-2643,
12/01/1989
Copyright © 1989 by The American Society of Hematology
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