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.
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
Harker
L A
LA
Division of Hematology and Oncology, Yerkes Regional Primate Research Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
Marzec
U M
UM
Kelly
A B
AB
Cheung
E
E
Tomer
A
A
Nichol
J L
JL
Hanson
S R
SR
Stead
R B
RB
D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects* / Q000473:pathology; D004357:Drug Synergism; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology* / Q000627:therapeutic use; D006410:Hematopoiesis / Q000187:drug effects*; D008253:Macaca mulatta; D008297:Male; D008533:Megakaryocytes / Q000187:drug effects*; D009363:Neoplasm Proteins; D009503:Neutropenia / Q000139:chemically induced / Q000517:prevention & control*; D009504:Neutrophils / Q000187:drug effects*; D010976:Platelet Count / Q000187:drug effects; D011092:Polyethylene Glycols / Q000494:pharmacology* / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000502:physiology; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013451:Sulfonic Acids / Q000633:toxicity*; D013921:Thrombocytopenia / Q000139:chemically induced / Q000517:prevention & control*; D013926:Thrombopoietin / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors
D000477:Alkylating Agents; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; D011994:Recombinant Proteins; D013451:Sulfonic Acids; C103117:polyethylene glycol-recombinant human megakaryocyte growth and development factor; D016179:Granulocyte Colony-Stimulating Factor; C082218:MPL protein, human; D011092:Polyethylene Glycols; D013926:Thrombopoietin; C052475:hepsulfam