Mycophenolate Mofetil after Rituximab for Childhood-Onset Complicated Frequently-Relapsing or Steroid-Dependent Nephrotic Syndrome

Abstract

Background: Rituximab is the standard therapy for childhood-onset complicated frequently relapsing or steroid-dependent nephrotic syndrome (FRNS/SDNS). However, most patients redevelop FRNS/SDNS after peripheral B cell recovery.

Methods: We conducted a multicenter, randomized, double-blind, placebo-controlled trial to examine whether mycophenolate mofetil (MMF) administration after rituximab can prevent treatment failure (FRNS, SDNS, steroid resistance, or use of immunosuppressive agents or rituximab). In total, 39 patients (per group) were treated with rituximab, followed by either MMF or placebo until day 505 (treatment period). The primary outcome was time to treatment failure (TTF) throughout the treatment and follow-up periods (until day 505 for the last enrolled patient).

Results: TTFs were clinically but not statistically significantly longer among patients given MMF after rituximab than among patients receiving rituximab monotherapy (median, 784.0 versus 472.5 days, hazard ratio [HR], 0.59; 95% confidence interval [95% CI], 0.34 to 1.05, log-rank test: P=0.07). Because most patients in the MMF group presented with treatment failure after MMF discontinuation, we performed a post-hoc analysis limited to the treatment period and found that MMF after rituximab prolonged the TTF and decreased the risk of treatment failure by 80% (HR, 0.20; 95% CI, 0.08 to 0.50). Moreover, MMF after rituximab reduced the relapse rate and daily steroid dose during the treatment period by 74% and 57%, respectively. The frequency and severity of adverse events were similar in both groups.

Conclusions: Administration of MMF after rituximab may sufficiently prevent the development of treatment failure and is well tolerated, although the relapse-preventing effect disappears after MMF discontinuation.

Keywords: childhood-onset; clinical trial; complicated frequently-relapsing/steroid-dependent nephrotic syndrome; mycophenolate mofetil; rituximab.

Graphical abstract

Figure 1.

Study design. After rituximab was administered at a dose of 375 mg/m² (maximum dose: 500 mg) once weekly for 4 weeks, on days 1, 8, 15, and 22, MMF was administered at a dose of 1000–1200 mg/m²per day (maximum 2 g/day) twice daily after breakfast and dinner for 17 months (from day 29 until day 505). In the placebo group, rituximab was provided in the same manner, and placebo was administered instead of MMF. The follow-up period was defined as the time from day 506 to the last scheduled treatment date of the last enrolled patient. During the follow-up period, investigators followed-up all participants according to the specified schedule and conducted a follow-up survey using routine clinical data. MZB, mizoribine; Tac, tacrolimus.

Figure 2.

Flow diagram.

Figure 3.

Kaplan–Meier curves for treatment failure (frequent relapses, steroid dependence or resistance, or use of immunosuppressive agents or rituximab)-free survival. The times to treatment failure were not statistically significantly longer throughout the study period (the treatment period and follow-up period) among patients given MMF after rituximab than among patients receiving rituximab monotherapy (HR, 0.59; 95% CI, 0.34 to 1.05; P = 0.07) (see also Table 3a). However, during the treatment period, rituximab followed by MMF decreased the development of treatment failure by 80% compared with rituximab monotherapy (HR, 0.20; 95% CI, 0.08 to 0.50) (see also Table 3b).

Figure 4.

Kaplan–Meier curves or cumulative incidence-free function for secondary outcomes. (A) Kaplan–Meier curves for relapse-free survival. (B) Cumulative incidence-free function for frequent relapses. (C) Cumulative incidence-free function for steroid-dependent relapses. Times to relapse and those to each of component outcomes of treatment failure such as frequent relapses and steroid dependent relapses were approximately 40% longer (although not statistically significantly) among patients given MMF after rituximab than among patients receiving rituximab monotherapy throughout the study (combined treatment and follow-up) period (HR, 95% CI; [A] 0.62, 0.30 to 1.04; [B] 0.56, 0.32 to 1.00; [C] 0.60, 0.34 to 1.08) (see also Tables 5a, 6a, and 7a). However, during the treatment period, MMF after rituximab decreased the occurrence of relapse, frequent relapses, and steroid-dependent relapses by 70%–80% compared with rituximab monotherapy (HR, 95% CI; [A] 0.28, 0.14 to 0.57; [B] 0.20, 0.08 to 0.48; [C] 0.22, 0.09 to 0.53) (see also Tables 5b, 6b, and 7b).

Figure 5.

Peripheral B cell counts. Peripheral CD19-positive cell counts were monitored until day 505. Day 1 was the first day of rituximab administration. Boxes represent the quartile range for each grouping and time period, straight lines (beard) are connected from the top and bottom sides of the boxes to outliers within 1.5 times the quartile range width, and red crosses and blue open circles represent outlying observations in the MMF group and placebo group, respectively.