LACK OF EFFICACY OF THROMBOPOIETIN AND GRANULOCYTE-COLONY-STIMULATINGFACTOR AFTER HIGH-DOSE TOTAL-BODY IRRADIATION AND AUTOLOGOUS STEM-CELL OR BONE-MARROW TRANSPLANTATION IN RHESUS-MONKEYS

The efficacy of recombinant human thrombopoietin (TPO) and recombinant human granulocyte colony stimulating factor (G-CSF) in stimulating pl atelet and neutrophil recovery was evaluated in a placebo-controlled s tudy involving transplantation of limited numbers (1-3x10(4)/kg) of hi ghly purified autologous stem cells (CD34(++)/RhLA-DRdull) into rhesus monkeys after the animals were subjected to 8 Gy of total body irradi ation (TBI) (x-rays). The grafts shortened profound TBI-induced pancyt openia from 5 to 6 weeks to 3 weeks, Daily subcutaneous (sc) injection of TPO (10 mu g/kg/day, days 1-21 after TBI) did not stimulate platel et regeneration after transplantation either alone or in combination w ith G-CSF (5 mu g/kg/day sc, days 1-21 after TBI), G-CSF treatment fai led to prevent neutropenia in the monkeys and did not stimulate recove ry to normal neutrophil levels. Simultaneous administration of TPO and G-CSF did not influence the observed recovery patterns. To test the h ypothesis that the limited number of cells transplanted or the subset chosen was responsible for the lack of effectiveness of TPO, three add itional monkeys were transplanted with 10(7)/kg unfractionated autolog ous I;one marrow cells. Two Of these animals received TPO and the othe r served as a control. In this setting, as well, TPO treatment did not prevent thrombocytopenia. This study demonstrates that treatment with TPO does not accelerate platelet reconstitution from transplanted ste m cells after high dose TBI, These findings contrast with the rapid TP O-stimulated platelet recovery in myelosuppression induced by 5 Cy of TBI in rhesus monkeys; we conclude from this that the clinical effecti veness of the TPO response depends on the availability of TPO target c ells in the first week after TBI, that is, before endogenous TPO level s reach the saturation paint. In addition, protracted isolated thrombo cytopenia was observed in two G-CSF-treated monkeys, one of which also received TPO. Furthermore, TPO treatment for 7 days in the 6th week a fter TBI during severe thrombocytopenia in one monkey produced prompt clinical improvement and an increase in platelet counts.