The efficacy of single-dose administration of thrombopoietin with coadministration of either granulocyte/macrophage or granulocyte colony- stimulating factor in myelosuppressed rhesus monkeys

Abstract

Thrombopoietin (TPO) was evaluated for efficacy in a placebo-controlled study in rhesus monkeys with concurrent administration of either granulocyte/macrophage colony-stimulating factor (GM-CSF) or granulocyte CSF, (G-CSF). Rhesus monkeys were subjected to 5 Gy total-body irradiation (TBI), resulting in 3 weeks of profound pancytopenia, and received either TPO 5/μg/kg intravenously (IV) at day 1 (n = 4), GM-CSF 25/μg/kg subcutaneously (SC) for 14 days (n = 4), TPO and GM-CSF (n = 4), G-CSF 10 μg/kg/d SC for 14 days (n = 3), TPO and G-CSF (n = 4), or placebo (carrier, n = 4; historical controls, n = 8). Single-dose IV treatment with TPO 1 day after TBI effectively counteracted the need for thrombocyte transfusions (provided whenever thrombocyte levels were <40 x 109/L) and accelerated platelet reconstitution to normal levels 2 weeks earlier than placebo controls. TPO/GM-CSF was more effective then single-dose TPO alone in stimulating thrombocyte regeneration, with a less profound nadir and a further accelerated recovery to normal thrombocyte counts, as well as a slight overshoot to supranormal levels of thrombocytes. Monkeys treated with TPO/GM- CSF uniformly did not require thrombocyte transfusions, whereas those treated with GM-CSF alone needed two to three transfusions, similar to the placebo- treated monkeys, which required, on average, three transfusions. Also, reticulocyte production was stimulated by TPO and further augmented in monkeys treated with TPO/GM-CSF. TPO alone did not stimulate neutrophil regeneration, whereas GM-CSF shortened the period of neutrophil counts less than 0.5 x 109/L by approximately I week; TPO/GMCSF treatment elevated the neutrophil nadir, but did not further accelerate recovery to normal values. TPO also augemented the neturophil response to G-CSF, resulting in similar patterns of reconstitution following TPO/G-CSF and TPO/GM-CSF treatment. TPO/GM-CSF resulted in significantly increased reconstitution of CD34+ bone marrow cells and progenitor cells such as GM-CFU and BFU-E. Adverse effects of combining TPO with the CSFs were not observed. It is concluded that (1) a single IV administration of TPO is sufficient to prevent severe thrombocytopenia following myelosuppression, 12) TPO/G-CSF and TPO/GM-CSF treatment result in distinct response patterns, with TPO/GM-CSF being superior to TPO/G-CSF in stimulating thrombocyte and erythrocyte recovery while being equivalent in stimulating neutrophil recovery; and 13) TPO significantly improves the performance of CSFs in alleviating severe neutropenia.