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

Laurence A. Harker, Ulla M. Marzec, Andrew B. Kelly, Ellen Cheung, Aaron Tomer, Janet L. Nichol, Stephen R. Hanson, Richard B. Stead

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Abstract

This report examines the effects on hematopoietic regeneration of pegylated recombinant human megakaryocyte growth and development factor (PEG- rHuMGDF) (2.5 μg/kg/d) alone and in combination with recombinant human granulocyte colony stimulating factor (rHu-GCSF) (10 μg/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 109/L) was observed between days 12 and 25 (nadir 39 ± 20 x 109/L on day 17), and neutropenia (absolute neutrophil count <1 x 109/L) occurred between days 8 and 30 (nadir 0.167 ± 0.120 x 109/L on day 15). PEG-rHuMGDF (2.5 μg/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 109/L v baseline of 416 ± 88 x 109/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 109/L v 0.167 ± 0.120 x 109/L; P > .3). rHu-GCSF (10 μg/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, end reduced the time for the postchemotherapy neutrophil count to attain 1 x 109/L from 22 days to 4 days (P = .005). The postchemotherapy neutropenic nadir was 0.554 ± 0.490 x 109 neutrophils/L (P = .3 v hepsulfam-only control of 0.167 ± 0.120 x 109/L). However, thrombocytopenia of <100 x 109 platelets/L was not shortened (persisted from day 12 to day 25), or less severe (nadir of 56 ± 32 x 109 platelets/L on day 14; P = .7 compared with untreated hepsulfam animals). The concurrent administration of rHu-GCSF (10 μg/kg/d) and PEG-rHuMGDF (2.5 μg/kg/d) in four animals resulted in postchemotherapy peripheral platelet counts of 127 ± 85 x 109/L (P = .03 compared with 39 ± 20 x 109/L for untreated hepsulfam alone, and P = .02 compared with 856 ± 594 x 109/L for PEG- rHuMGDF alone), and shortened the period of neutropenia <1 x 108/L from 22 days to 4 days (P = .8 compared with rHu-GCSF alone). Increasing PEG-rHuMGDF to 10 μg/kg/d and maintaining the 21-day schedule of coadministration with rHu-GCSF (10 μg/kg/d) in another four animals produced postchemotherapy platelet counts of 509 ± 459 x 109/L (P < 10-4 compared with untreated hepsulfam alone, and P = .04 compared with 2.5 μg/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 μg/kg/d) from day 1 through day 22 and rHu-GCSF (10 μg/kg/d) from day 8 through day 22 in six animals produced peak postchemotherapy platelet counts of 747 ± 317 x 109/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 109/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 myelosuppressire chemotherapy.

Original languageEnglish
Pages (from-to)155-165
Number of pages11
JournalBlood
Volume89
Issue number1
DOIs
StatePublished - 1 Jan 1997

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