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The Efficacy of Single-Dose Administration of Thrombopoietin With Coadministration of Either Granulocyte/Macrophage or Granulocyte Colony-Stimulating Factor in Myelosuppressed Rhesus Monkeys
Karen J. Neelis,
Simone C.C. Hartong,
Torstein Egeland,
G. Roger Thomas,
Dan L. Eaton, and
Gerard Wagemaker
From the Institute of Hematology, Erasmus University Rotterdam, Rotterdam, The Netherlands; Institute of Transplantation Immunology, Oslo, Norway; and Genentech Inc, South San Francisco, CA.
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 × 109/L) and accelerated platelet reconstitution to normal levels 2 weeks earlier than placebo controls. TPO/GM-CSF was more effective than 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 × 109/L by approximately 1 week; TPO/GM-CSF 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, (2) 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 (3) TPO significantly improves the performance of CSFs in alleviating severe neutropenia.
Blood, Vol. 90 No. 7 (October 1), 1997:
pp. 2565-2573
© 1997 by The American Society of Hematology.
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