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Prevention of thrombocytopenia and neutropenia in a nonhuman primate model
of marrow suppressive chemotherapy by combining pegylated recombinant human
megakaryocyte growth and development factor and recombinant human
granulocyte colony-stimulating factor
LA Harker, UM Marzec, AB Kelly, E Cheung, A Tomer, JL Nichol, SR Hanson and RB Stead
Division of Hematology and Oncology, Yerkes Regional Primate Research
Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
This report examines the effects on hematopoietic regeneration of pegylated
recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF)
(2.5 micrograms/ kg/d) alone and in combination with recombinant human
granulocyte colony stimulating factor (rHu-GCSF) (10 micrograms/ kg/d) for
21 days in rhesus macaques receiving intense marrow suppression produced by
single bolus injections of hepsulfam (1.5 g/m2). In six hepsulfam-only
control animals thrombocytopenia (platelet count < 100 x 10(9)/L) was
observed between days 12 and 25 (nadir 39 +/- 20 x 10(9)/L on day 17), and
neutropenia (absolute neutrophil count < 1 x 10(9)/L) occurred between
days 8 and 30 (nadir 0.167 +/- 0.120 x 10(9)/L on day 15). PEG-rHuMGDF (2.5
micrograms/kg/d) injected subcutaneously into four animals from day 1 to
day 22 following hepsulfam administration produced trough serum
concentrations of 1.9 +/- 0.2 ng/mL and increased the platelet count
twofold over basal prechemotherapy levels (856 +/- 594 x 10(9)/L v baseline
of 416 +/- 88 x 10(9)/L; P = .01). PEG-rHuMGDF alone also shortened the
period of posthepsulfam neutropenia from 22 days to 12 days (P = .01),
although the neutropenic nadir was not significantly altered (neutrophil
count 0.224 +/- 0.112 x 10(9)/L v 0.167 +/- 0.120 x 10(9)/L; P > .3).
rHu-GCSF (10 micrograms/kg/d) injected subcutaneously into four animals
from day 1 to day 22 following hepsulfam administration produced trough
serum concentrations of 1.4 +/- 1.1 ng/mL, and reduced the time for the
postchemotherapy neutrophil count to attain 1 x 10(9)/L from 22 days to 4
days (P = .005). The postchemotherapy neutropenic nadir was 0.554 +/- 0.490
x 10(9)neutrophils/L (P = .3 v hepsulfam-only control of 0.167 +/- 0.120 x
10(9)/L). However, thrombocytopenia of < 100 x 10(9) platelets/L was not
shortened (persisted from day 12 to day 25), or less severe (nadir of 56
+/- 32 x 10(9) platelets/L on day 14; P = .7 compared with untreated
hepsulfam animals). The concurrent administration of rHu-GCSF (10
micrograms/kg/d) and PEG-rHuMGDF (2.5 micrograms/kg/d) in four animals
resulted in postchemotherapy peripheral platelet counts of 127 +/- 85 x
10(9)/L (P = .03 compared with 39 +/- 20 x 10(9)/L for untreated hepsulfam
alone, and P = .02 compared with 856 +/- 594 x 10(9)/L for PEG-rHuMGDF
alone), and shortened the period of neutropenia < 1 x 10(9)/L from 22
days to 4 days (P = .8 compared with rHu-GCSF alone). Increasing
PEG-rHuMGDF to 10 micrograms/kg/d and maintaining the 21-day schedule of
coadministration with rHu-GCSF (10 micrograms/kg/d) in another four animals
produced postchemotherapy platelet counts of 509 +/- 459 x 10(9)/L (P <
10(-4) compared with untreated hepsulfam alone, and P = .04 compared with
2.5 micrograms/kg/d PEG-rHuMGDF alone), and 4 days of neutropenia.
Coadministration of rHu-GCSF and PEG-rHuMGDF did not significantly alter
the pharmacokinetics of either agent. The administration of PEG- rHuMGDF
(2.5 micrograms/kg/d) from day 1 through day 22 and rHu-GCSF (10
micrograms/kg/d) from day 8 through day 22 in six animals produced peak
postchemotherapy platelet counts of 747 +/- 317 x 10(9)/L(P < 10(- 4)
compared with untreated hepsulfam alone, and P = .7 compared with
PEG-rHuMGDF alone), and maintained the neutrophil count > 3.5 x 10(9)/L
(P = .008 v rHu-GCSF therapy alone). Thus, both thrombocytopenia and
neutropenia are eliminated by initiating daily PEG-rHuMGDF therapy on day 1
and subsequently adding daily rHu-GCSF after 1 week in the rhesus model of
hepsulfam marrow suppression. This improvement in platelet and neutrophil
responses by delaying the addition of rHu-GCSF to PEG- rHuMGDF therapy
demonstrates the importance of optimizing the dose and schedule of cytokine
combinations after severe myelosuppressive chemotherap
Volume 89,
Issue 1,
pp. 155-165,
01/01/1997
Copyright © 1997 by The American Society of Hematology
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