Simultaneous administration of TPO and G-CSF after cytoreductive treatment of rhesus monkeys prevents thrombocytopenia, accelerates platelet and red cell reconstitution, alleviates neutropenia, and promotes the recovery of immature bone marrow cells.

ABSTRACT

Simultaneous treatment with human thrombopoietin (TPO) and granulocyte colony-stimulating factor (G-CSF) was evaluated in a placebo-controlled rhesus monkey study using 5 Gy total body irradiation (TBI) to induce 3 weeks of pancytopenia. Daily administration of TPO (10 microg/kg/day injected subcutaneously [sc] days 1-21 after TBI) promoted platelet and reticulocyte recovery, resulting in less profound nadirs and a rapid recovery to normal levels. Platelet transfusions were not required in these animals, in contrast to controls, and hemoglobin levels stabilized rapidly. TPO treatment did not influence neutrophil counts. G-CSF (5 microg/kg/day sc days 1-21) stimulated neutrophil regeneration and had no effect on platelet levels. Simultaneous treatment with TPO and G-CSF was as effective as treatment with TPO alone in preventing thrombocytopenia, although with the former regimen platelet levels did not rise to the supranormal levels seen with the latter. Neutrophil recovery was greatly augmented compared with G-CSF treatment alone, resulting in a less profound nadir and a recovery that started much earlier, as did monocyte, CD11b+, CD16+, and CD56+ cell reconstitution. In addition, TPO strongly promoted the recovery of bone marrow cellularity and granulocyte/macrophage and erythroid progenitor cells The number of bone marrow CD34+ cells was greater by two orders of magnitude in TPO-treated animals than in controls in the second week of treatment, whereas G-CSF by itself had no influence. In the third week after TBI an elevation of LDH1 values was observed in TPO-treated monkeys concurrent with normoblastosis; both of these findings were attributed to rapid erythropoiesis. TPO had no effect on hemostasis parameters. Adverse TPO and/or G-CSF effects were not observed. This study demonstrates that simultaneous TPO and G-CSF treatment after cytoreductive treatment prevents thrombocytopenia, accelerates platelet and red cell reconstitution, alleviates neutropenia, and promotes the recovery of immature bone marrow cells. The effect on CD34+ GM progenitor cells may explain the augmented G-CSF responses in TPO-treated monkeys; it also suggests that TPO may become a key growth factor in the design of treatment regimens to accelerate both immature bone marrow and mature blood cell reconstitution after cytoreductive therapy.