Long-Term Efficacy and Safety of Rituximab Versus Tacrolimus in Children With Steroid Dependent Nephrotic Syndrome

Abstract

Introduction: In the Rituximab for Relapse Prevention in Nephrotic Syndrome (RITURNS) trial, we demonstrated superior efficacy of single-course rituximab over maintenance tacrolimus in preventing relapses in children with steroid dependent nephrotic syndrome (SDNS) during a 1-year observation. Here we present the long-term outcomes of all 117 trial completers, who were followed up for another 2 years.

Methods: Relapsing patients in the rituximab arm received a second course of rituximab, either with (n = 44) or without mycophenolate mofetil (MMF) cotreatment (n = 15). In the tacrolimus arm, second line rituximab monotherapy was initiated after relapses (n = 32) or electively (n = 24).

Results: All 12-month relapse-free patients in the rituximab arm relapsed in the second postexposure year, resulting in similar median relapse-free survival times in the 2 trial arms (62 vs. 59 weeks). Second line rituximab in the tacrolimus arm was less effective than first-line therapy in patients switched to rituximab following a relapse (relapse-free survival 55 vs. 63 weeks, P < 0.01). B-cell counts 6 months post-rituximab predicted relapse risk both for first and second line therapy. MMF cotreatment yielded much improved 2-year relapse-free survival as compared to rituximab monotherapy (67% vs. 9%, P < 0.0001). Higher grade 2 adverse event rates were observed post-rituximab versus on tacrolimus (0.87 vs. 0.53 per year).

Conclusion: The superior therapeutic effect of rituximab in SDNS vanishes during the second year post-exposure. Rituximab appears to yield longer remission when applied as first line as compared to second line therapy. Maintenance MMF following rituximab induces long-term disease remission.

Keywords: childhood nephrotic syndrome; rituximab; steroid dependent nephrotic syndrome; tacrolimus.

Graphical abstract

Figure 1

(a) Synopsis of disease activity and therapies applied in rituximab arm (left panel) and tacrolimus arm (right panel) during 3-year observation period. Full square: relapse treated with standard oral prednisone schema; cross: rituximab administration; open circle: censoring event. Blue, red, and green lines indicate times of tacrolimus, MMF, and no maintenance immunosuppressive therapy, respectively. Cases sorted by time to first relapse. (b) Flow chart of relapse activity and follow-up interventions during 3 years follow-up in the 2 trial arms. Blue boxes reflect timing of relapses and secondary interventions in subgroups with early (<12 months), intermediate (12–18 months) and late relapses (>18 months) following primary intervention or elective switching from tacrolimus to rituximab after completion of 12-month randomized trial period.

Figure 2

Long-term relapse-free survival of patients in the rituximab and tacrolimus trial arms. The table below the graph indicates the number of patients still at risk at the respective points in time.

Figure 3

Time to first relapse after first-line versus second-line rituximab therapy. Red: all 60 patients of original rituximab arm; green: 24 patients of original tacrolimus arm electively switched to rituximab from tacrolimus; blue: 32 patients of original tacrolimus arm switched to rituximab after relapsing on tacrolimus. The table below the graph indicates the number of patients still at risk at the respective points in time.

Figure 4

Post-rituximab B-lymphocyte recovery. (a) Left panel: relationship of 6-month B-lymphocyte count and time to first relapse; (b) Right panel: association of 6-month post-rituximab B-lymphocyte counts following first and second course of rituximab. Early, intermediate, and late relapsers are represented by blue, green, and yellow symbols.