Cyclosporine in human bone marrow transplantation. Serum concentration, graft-versus-host disease, and nephrotoxicity

Serum concentrations of cyclosporine were studied in 42 patients given cyclosporine for the prevention of graft-versus-host-disease (GVHD) following allogeneic bone marrow transplantation (BMT). Serum trough levels for cyclosporine were determined in each patient at least once weekly during the first 3 months and were compared with the occurrence of GVHD and with nephrotoxicity. Cyclosporine was given as 20 mg/kg i.m. or as a 24-hr infusion for the first 5-7 days. This was followed by a single daily oral dose of 12.5 mg/kg for 6 months. Cyclosporine was then gradually reduced and stopped after one year. After a median observation period of 2 years 25 of the 42 patients (59%) are alive. Twenty six patients (62%) developed GVHD, which was stage II or more in 11 (26%) and fatal in 2 patients (5%). Five patients developed GVHD 6-8 weeks after withdrawal of cyclosporine one year after BMT. All patients improved after restarting cyclosporine. No correlation between cyclosporine serum concentration and GVHD was observed, but patients with GVHD had greater fluctuations of their serum trough levels. Serum creatinine increased in all patients soon after BMT and was correlated with cyclosporine serum concentration during the first month. Serum creatinine, however, rose further despite lower cyclosporine concentrations in the second month. These results show that cyclosporine effectively reduces the severity, but not the incidence, of GVHD suggesting that there is a subset of cells resistant to cyclosporine. The therapeutic range, however, between high doses (which are often associated with nephrotoxicity) and the minimal effective dose of cyclosporine, has yet to be defined.