p sration of significantly more early progenitors than rhGM-CSF (37-42). Additionally, 
when rh!L3 is combined with rhGM-CSF in vitro (38^9,43) or administered prior to rhGM-CSF 
in vivo tremendous synergy occurs when compared to either agent alone (see figure 2) (10, 
14-16). 
RhIL3 has been administered to animals resulting in mild to moderate neutrophilia and 
thrombocytosis (43,44). In patients with refractory cancer at doses ranging from 60 to 500 
pg/mVday x 15 days no significant toxicity was observed and significant increases in neutrophils, 
monocytes, platelets, reticulocyte and eosinophil was produced at the higher doses suggesting 
biological activity although the rise in counts was delayed 7-10 days after administration (45). 
Other patients with marrow graft failure have received doses of rh!L3 up to 500 pg/n^/day by 4 
hour intravenous infusion for 28 days with minimal toxicity (low grade fevers or mild 
headaches) (46). In animal trials rhIL3 has been administered at the same time as rhGM-CSF, 
however, the degree of neutrophilia and megakaryopoiesis was not better than rhIL3 or rhGM- 
CSF alone (10,46). However, in monkeys who underwent autologous BMT and received rhIL3 
prior to administration of rhGM-CSF a marked enhancement of neutrophilia and 
megakaiyopoiesis was observed compared to prospective untreated controls in monkeys 
receiving only rh!L3 or only rhGM-CSF at the same doses (14-16) (see figure 3). 
Toxicity in animals has been observed with rhIL3 at higher doses than used in human 
trials. High doses of rhIL3 (>30 pg/kg/day x 21 days) in non-transplanted monkeys stimulated 
the production of several thousand basophil/mm 3 . Elevated levels of histamine IgE titers and 
ESR were detected in animals with elevated basophil levels (10). This correlated with the 
te^norary development of hives. Histologic analysis of organs from animals who received high 
c j of rh!L3 (> 30 pg/kg/day) revealed trace to severe hepatic, portal, fibrosis and vasculitis 
in 12 of 18 monkeys in addition to increased granulocyte infiltration. Toxicides correlated with 
elevated basophil and eosinophil levels. Lower doses of rh!L3 (< 10 pg/kg/day x 21 days) were 
not associated with eosinophilia and/or basophilia and neither hives nor portal fibrosis was 
observed in any monkeys (n = 18). IgE levels were also not elevated in monkeys receiving < 10 
pg/kg/day of rhIL3. Lower doses (< 10 pk/kg/day) of rhIL3 still stimulated neutrophilia and 
megakaryopoiesis when followed by rhGM-CSF. No life threatening toxicities developed in 
response to rhIL3 administration in any animals at any doses (10,14-16,43,44). 
In vivo rhIL3 has not shown evidence of inducing leukemia. In fact retroviral insertion 
of rhIL3, cDNA into mice resulted in up to a 50 fold increase in peripheral blood cellularity 
with no development of circulating blasts (47). In vitro rh!L3 has stimulated some leukemia 
cells (48,49), had no effect on others (50), inhibited others (51), and has induced differentiation 
(51). Its receptors have been detected on both lymphoid and myeloid precursors. It does not 
appear to affect neutrophil function although it enhances the eosinophil functional activity (52). 
The T 1/2 of rhIL3 detection in plasma is only six minutes with none detected by ELISA two 
hours after IV bolus administration (10). 
This study proposes to evaluate the administration of peripheral blood cells with bone 
marrow with subsequent administration of rhGM-CSF after ABMT and to compare these 
results to patients receiving peripheral blood cells primed with rhIL3 and nonstipulated marrow 
followed by administration of rhGM-CSF after ABMT. This study is designed to take 
advantage of the additional committed progenitor cell load supplied by the peripheral blood 
< and the synergistic effects of rhGM-CSF and rhIL3 stimulated progenitor cells in an 
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Recombinant DNA Research, Volume 16 
