A phase I/II dose escalation study of intensified cyclophosphamide and autologous blood stem cell rescue in severe, active rheumatoid arthritis

Objective. Based on animal studies and anecdotal case reports, high-dose th erapy and autologous blood stem cell rescue have been proposed as an experi mental treatment for severe, refractory rheumatoid arthritis (RA), This stu dy aimed to establish the toxicity of this treatment and obtain preliminary efficacy data upon which to base future clinical trials. Methods, Two cohorts of 4 patients who fulfilled criteria for severe, activ e, treatment-resistant RA were recruited into a dose-escalation study of cy clophosphamide (CYC) (100 mg/kg or 200 mg/kg) followed by unmanipulated per ipheral blood stem cell rescue. Patient treatment was managed according to a standard supportive care protocol. Disease-modifying drugs were discontin ued before treatment, but corticosteroids were maintained and later tapered where possible. Patients' conditions were assessed using World Health Orga nization toxicity criteria and standard parameters for rheumatic disease. Results. Dose-dependent differences in hematologic toxicity were observed b etween cohorts 1 and 2, although toxicity was similar for other systems and was most significant in the gastrointestinal system. Patients in cohort 1 had only transient responses to therapy, lasting 2-3 months. Substantial im provements were sustained beyond 17-19 months in cohort 2, including steroi d-independent disease remission for 1 patient, although the procedure did n ot completely abolish disease activity. Conclusion, High-dose CYC and unmanipulated autologous blood stem cell resc ue has acceptable dose-dependent toxicity in severe, treatment-resistant RA , and 200 mg/kg of CYC induces substantial clinical responses. Refinement o f this intensive approach might include further intensification of the prep aration regimen, graft manipulation, and posttransplant immunomodulation.