FP106PERIODICAL REPEATED RITUXIMAB ADMINISTRATIONS IN CHILDREN WITH REFRACTORY NEPHROTIC SYNDROME; TWO YEARS PROSPECTIVE OBSERVATIONAL STUDY

Abstract

Introduction and Aims: Rituximab(RTX) iseffective inmaintaining remission in nephrotic syndrome (NS), but it's standard administration protocol still has not been established. We designed a protocol consisting of single-dose repeated administration of RTX followed by Mizoribine (MZB). The present study aimed at exploring the optimal method of RTX administration by examining the advantages and disadvantages of our protocol. Methods: This study was a two-years multicenter prospective observational study. We enrolled our pediatric patients with refractory NS, who had steroid dependent during CNI administration or after CNI discontinuation and met the definite conditions, between January to December 2015. RTX infusion (a single dose of 375mg/m2) was repeated 4 times at 6-month intervals. MZB was given orally in a dose of 500 mg and 550 mg a day on 2 days a week. Calcineurin inhibitors (CNI) discontinued at 1 week after their first dose of RTX. The primary endpoints were the relapse-free survival rate and the number of relapses after the RTX administration. The secondary endpoints included the evaluation of changes in adverse reactions such as short stature, obesity, low bone density, and diabetes, associated with the long-term steroid administration, at each RTX administrations. This study was conducted with the approval of the Research Ethics Board of Hokkaido University Hospital. Results: A total of 21 patients were analyzed. The relapse-free survival rate after a year and two years was 52% and 48%, respectively. Only one patient was diagnosed with SDNS/FRNS and one patient with FRNS during the observation period. The frequency of relapses significantly decreased from 2.9 times/patient/year to 0.5 times/patient/year (P < 0.001). Although CNI treatment was discontinued in all patients, no increase in the frequency of recurrence was observed. Significant improvements in all steroid complications were observed in the final examination; the median height-2.0 SD to-1.3 SD, the median obesity index 29% to-3%, bone density-2.4 SD to-2.0 SD and diabetes/borderline diabetes 2/6 to 0/5 patients. Infusion reactions were observed in 44% and considered mild. Two patients had agranulocytosis, and 2 patients had neu-tropenia. There were 25 episodes (0.6 times/patient/year) of infection, although only 1 case with mycoplasma infection required hospitalization. Three patients showed electrocardiogram abnormalities. Anti-rituximab antibody was not detected in any of the patients two years after the start of RTX administration. A significant decreasing of immunoglobulin was observed over the period of 2 years. The titers of specific antiviral antibody against various vaccinations did not show significant decreases. Conclusions: Our protocol was useful and safety for refractory NS, showing excellent outcome. During the observational periods, we were able to switch from the conventional treatment to our protocol completely. All of steroid complications improved consistently, but improvements of bone density and diabetes were limiting and clinically insufficient within the observational period, suggesting the need for longer remission. On the other hand, the RTX dosing of 4 times might have been excessive in some patients. Further investigation is required in terms of the most appropriate method of RTX administration.