GCSFrecombinant human thrombopoietin

Thrombopoietin (TPO) is a naturally occurring glyco-sylated peptide growth factor and the primary regulator of megakaryocytopoiesis. In preclinical models, TPO has been shown to accelerate the reconstitution of BM CD34+ cells and to increase the number of circulating PB progenitor cells after a mid-lethal dose of total body irradiation. TPO has also been shown to enhance proliferation of early progenitor cells committed to the erythroid and myelomonocytic lineage. Results from phase I studies of recombinant human

TPO (rhTPO) in the myelosuppressive and myeloabla-tive settings indicate that rhTPO, alone and combined with chemotherapy and G-CSF, increases the number of progenitor and CD34+ cells in the PB.35 Linker et al.36 conducted a randomized, double-blind, multicenter trial in 134 patients to evaluate the efficacy of rhTPO for mobilization and reconstitution after highdose chemotherapy and PBSCT. For the mobilization phase, patients received study drug at a dose of 0.5 ^g/kg, or 15 ^g/kg, or placebo given intravenously on days 1, 3. and 5 before initiation of G-CSF 10^g/kg per day on day 5 and leukapheresis starting on day 9. After high-dose chemotherapy and PBSCT, patients were randomly assigned to receive rhTPO 1.5 ^g/kg on day 0, +2, +4, and +6 with either G-CSF 5 ^g/kg per day or GM-CSF 250^g/m2 per day, or placebo plus G-CSF 5 ^g/kg per day. Administration of rhTPO followed by G-CSF produced a nearly twofold increase in median CD34+ cell dose per leukapheresis with a higher CD34+ cell yield when rhTPO started before day 5. Comparing rhTPO to placebo, a higher percentage of patients achieved the minimum yield of CD34+ cell more or equal to 2 X 106/kg (92% vs 75%; P = 0.050) as well as the target yield of more or equal to 5 X 106 CD34+ /kg (79% vs 46%; P = 0.011). rhTPO also significantly reduced the median number of aphereses required to achieve both a minimum graft (one rhTPO vs two placebo) and a target graft (two rhTPO vs four placebo). However, rhTPO given after transplantation did not enhance platelet recovery. None of the patients developed neutralizing antibodies that cross-react with endogenous TPO. These results suggest that rhTPO is safe and effective in enhancing mobilization and increasing leukapheresis efficiency.

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