THE EFFICACY OF SINGLE-DOSE ADMINISTRATION OF THROMBOPOIETIN WITH COADMINISTRATION OF EITHER GRANULOCYTE MACROPHAGE OR GRANULOCYTE-COLONY-STIMULATING FACTOR IN MYELOSUPPRESSED RHESUS-MONKEYS/

Thrombopoietin (TPO) was evaluated for efficacy in a placebo-controlle d study in rhesus monkeys with concurrent administration of either gra nulocyte/macrophage colony-stimulating factor (GM-CSF) or granulocyte CSF, (G-CSF). Rhesus monkeys were subjected to 5 Gy total-body irradia tion (TBI), resulting in 3 weeks of profound pancytopenia, and receive d either TPO 5 mu g/kg intravenously (IV) at day 1 (n = 4), GM-CSF 25 mu g/kg subcutaneously (SC) for 14 days (n = 4), TPO and GM-CSF (n = 4 ), G-CSF 10 mu g/kg/d SC for 14 days (n = 3), TPO and G-CSF (n = 4), o r 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 wer e <40 x 10(9)/L) and accelerated platelet reconstitution to normal lev els 2 weeks earlier than placebo controls. TPO/GM-CSF was more effecti ve than single-dose TPO alone in stimulating thrombocyte regeneration, with a less profound nadir and a further accelerated recovery to norm al thrombocyte counts, as well as a slight overshoot to supranormal le vels of thrombocytes. Monkeys treated with TPO/GM-CSF uniformly did no t 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, reticu locyte production was stimulated by TPO and further augmented in monke ys treated with TPO/GM-CSF. TPO alone did not stimulate neutrophil reg eneration, whereas GM-CSF shortened the period of neutrophil counts le ss than 0.5 x 10(9)/L by approximately 1 week; TPO/GM-CSF treatment el evated the neutrophil nadir, but did not further accelerate recovery t o normal values. TPO also augemented the neturophil response to G-CSF, resulting in similar patterns of reconstitution following TPO/G-CSF a nd TPO/GM-CSF treatment. TPO/GM-CSF resulted in significantly increase d reconstitution of CD34(+) bone marrow cells and progenitor cells suc h 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 mye losuppression, (2) TPO/G-CSF and TPO/GM-CSF treatment result in distin ct response patterns, with TPO/GM-CSF being superior to TPO/G-CSF in s timulating thrombocyte and erythrocyte recovery while being equivalent in stimulating neutrophil recovery; and (3) TPO significantly improve s the performance of CSFs in alleviating severe neutropenia. (C) 1997 by The American Society of Hematology.