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

• Published in: Blood 1997, Vol.89 (1), p.155-165
• Main Authors: HARKER, L. A, MARZEC, U. M, KELLY, A. B, CHEUNG, E, TOMER, A, NICHOL, J. L, HANSON, S. R, STEAD, R. B
• Format: Article
• Language: English
• Subjects: Alkylating Agents - toxicity; Animals; Antineoplastic agents; Biological and medical sciences; Bone Marrow - drug effects; Bone Marrow - pathology; Drug Synergism; Female; Granulocyte Colony-Stimulating Factor - pharmacology; Granulocyte Colony-Stimulating Factor - therapeutic use; Hematopoiesis - drug effects; Immunotherapy; Macaca mulatta; Male; Medical sciences; Megakaryocytes - drug effects; Neoplasm Proteins; Neutropenia - chemically induced; Neutropenia - prevention & control; Neutrophils - drug effects; Pharmacology. Drug treatments; Platelet Count - drug effects; Polyethylene Glycols - pharmacology; Polyethylene Glycols - therapeutic use; Proto-Oncogene Proteins - drug effects; Proto-Oncogene Proteins - physiology; Receptors, Cytokine; Receptors, Thrombopoietin; Recombinant Proteins - pharmacology; Recombinant Proteins - therapeutic use; Sulfonic Acids - toxicity; Thrombocytopenia - chemically induced; Thrombocytopenia - prevention & control; Thrombopoietin - pharmacology; Thrombopoietin - therapeutic use; Time Factors
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.v89.1.155

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