Rituximab versus cyclophosphamide as first steroid-sparing agent in childhood frequently relapsing and steroid-dependent nephrotic syndrome.

Background: Approximately 50% of children with steroid-sensitive nephrotic syndrome (SSNS) will suffer from frequent relapses or steroid dependency, prompting the use of so-called steroid-sparing drugs. In this pilot study, we compare the efficacy and safety of rituximab to oral cyclophosphamide as first-line steroid-sparing medications.

Methods: A prospective open-label non-randomized study of children with frequent relapsing or steroid-dependant SSNS. Exclusion criteria were steroid-resistant disease, prescription of immunosuppressive agents other than prednisolone or levamisole, evidence of impaired kidney function, leucopenia, or active infection. The recruited children were allocated either to the oral cyclophosphamide (3 mg/kg/day for 8 weeks) or intravenous rituximab treatment (two doses of 375 mg/m/dose, 2 weeks apart) and were monitored for relapses and side effects for 12 months.

Results: Forty-six subjects were included from two centers; 27 received cyclophosphamide and 19 received rituximab. One-year relapse-free survival was reached in 17 (58.6%) patients treated with cyclophosphamide compared to 16 (84.2%) with rituximab (adjusted HR 0.36; 95% CI 0.09-1.45; p = 0.151). The mean interval to relapse was 6.9 months in the cyclophosphamide group (N = 10) and 6.3 months in the rituximab group (N = 3). Both treatments were associated with a significant (p < 0.001) reduction in prescribed dose of oral alternate-day steroid from 1.02 to 0.36 mg/kg (cyclophosphamide) and 0.86 to 0.08 mg/kg (rituximab). Importantly, a significantly (p = 0.003) higher percentage of patients achieved complete withdrawal of steroid within 3 months of commencing study treatment in the rituximab (73.7%) versus cyclophosphamide (29.6%) group. Transient leucopenia was the most frequent adverse effect observed in the cyclophosphamide group (18.5%) and one patient (3.4%) had acute hepatotoxicity besides severe leucopenia and neutropenia in the 7th week of treatment with complete recovery with the withdrawal of cyclophosphamide and maintenance of remission. A minor infusion-related reaction in the form of a generalized macular skin rash was observed in one patient (5%) in the rituximab group.

Conclusions: Rituximab is non-inferior to cyclophosphamide and safe as a first-line steroid-sparing agent in children with SSNS. A larger multicenter study is required to assess superiority over cyclophosphamide. Graphical abstract.