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Results of a phase I/II trial of recombinant human granulocyte- macrophage
colony-stimulating factor in very low birthweight neonates: significant
induction of circulatory neutrophils, monocytes, platelets, and bone marrow
neutrophils
MS Cairo, R Christensen, LS Sender, R Ellis, J Rosenthal, C van de Ven, C Worcester and JM Agosti
Children's Hospital of Orange County, CA 92668, USA.
Neonates, especially those of very low birthweight (VLBW), have an
increased risk of nosocomial infections secondary to deficiencies in
development. We previously demonstrated that granulocyte-macrophage
colony-stimulating factor (GM-CSF) production and mRNA expression from
stimulated neonatal mononuclear cells are significantly less than that from
adult cells. Recombinant murine GM-CSF administration to neonatal rats has
resulted in neutrophilia, increased neutrophil production, and increased
survival of pups during experimental Staphylococcus aureus sepsis. In the
present study, we sought to determine the safety and biologic response of
recombinant human (rhu) GM-CSF in VLBW neonates. Twenty VLBW neonates (500
to 1,500 g), aged < 72 hours, were randomized to receive either placebo
(n = 5) or rhuGM-CSF at 5.0 micrograms/kg once per day (n = 5), 5.0
micrograms/kg twice per day (n = 5), or 10 micrograms/kg once per day (n =
5) given via 2-hour intravenous infusion for 7 days. Complete blood counts,
differential, and platelet counts were obtained, and tibial bone marrow
aspirate was performed on day 8. Neutrophil C3bi receptor expression was
measured at 0 and 24 hours. GM-CSF levels were measured by a sandwich
enzyme-linked immunosorbent assay at 2, 4, 6, 12, and 24 hours after the
first dose of rhuGM-CSF. At all doses, rhuGM-CSF was well tolerated, and
there was no evidence of grade III or IV toxicity. Within 48 hours of
administration, there was a significant increase in the circulating
absolute neutrophil count (ANC) at 5.0 micrograms/kg twice per day and 10.0
micrograms/kg once per day, which continued for at least 24 hours after
discontinuation of rhuGM-CSF. When the ANC was normalized for each
patient's first ANC, there was a significant increase in the ANC on days 6
and 7 at each dose level. By day 7, all tested doses of rhuGM- CSF resulted
in an increase in the absolute monocyte count (AMC) compared with
placebo-treated neonates. In those receiving rhuGM-CSF 5.0 micrograms/kg
twice per day, there was additionally a significant increase in the day 7
and 8 platelet count. Tibial bone marrow aspirates demonstrated a
significant increase in the bone marrow neutrophil storage pool (BM NSP) at
5.0 micrograms/kg twice per day and 10.0 micrograms/kg once per day.
Neutrophil C3bi receptor expression was significantly increased 24 hours
after the first dose of rhuGM-CSF at 5.0 micrograms/kg once per day. The
elimination half-life (T1/2) of rhuGM-CSF was 1.4 +/- 0.8 to 3.9 +/- 2.8
hours.(ABSTRACT TRUNCATED AT 400 WORDS)
Volume 86,
Issue 7,
pp. 2509-2515,
10/01/1995
Copyright © 1995 by The American Society of Hematology
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