CYCLOSPORINE-A DOES NOT REVERSE CLINICAL RESISTANCE TO PACLITAXEL IN PATIENTS WITH RELAPSED NON-HODGKINS-LYMPHOMA

Purpose: Cyclosporin A has been shown to reverse paclitaxel resistance in vitro by inhibiting P-gp function. Therefore, we determined whethe r addition of cyclosporine to paclitaxel reversed clinical paclitaxel resistance in patients with non-Hodgkin's lymphoma (NHL). Patients and Methods: Patients with relapsed NHL were eligible if they had no inte rvening treatment after failure to respond to paclitaxel (200 mg/m(2) over 3 hours), and if they had adequate marrow, renal, and hepatic fun ction, no serious cardiac disease, no CNS involvement, and no antibodi es to human immunodeficiency virus-1. A cyclosporin A bolus dose (5 mg /kg over 3 hours) was followed by intravenous infusion (15 mg/kg) over 24 hours. Six hours after the beginning of cyclosporin A, the immedia tely preceding paclitaxel dose was administered over 3 hours. All pati ents were premedicated with dexamethasone, diphenhydramine, and cimeti dine. Response wets assessed after two cycles, and those patients who achieved at least a partial response received a maximum of six courses . Results: All 26 patients entered were assessable for toxicity and 25 were assessable for response. One patient whose disease had progresse d during paclitaxel treatment had a partial remission after the additi on of cyclosporin A (response rate, 4%; 95% confidence interval, 1% to 20%). Disease progressed in 17 patients (71%) and did not respond in seven (25%). Serum cyclosporin A A levels measured at the time of init iation of paclitaxel infusion were greeter than 2,000 ng/mL during 81% of cycles. Treatment toxicity included peripheral neuropathy in 57%, myalgia or arthralgia in 30%, neutropenia in 53%, neutropenic fever in 8%, and thrombocytopenia in 42% of patients. One patient with preexis ting asthma had an acute bronchospasm during the first cycle and was r emoved from the study. There were no renal or hepatic toxicity and no infectious or hemorrhagic deaths. Conclusion: Cyclosporin A administer ed on this schedule did not reverse established clinical resistance to paclitaxel, which suggests that P-gp-mediated drug efflux is unlikely to be the only cause of paclitaxel resistance in this patient populat ion. (C) 1996 by American Society of Clinical Oncology.