Clinical characteristics of patients with early relapse during B-cell depletion after rituximab treatment for complicated steroid-dependent nephrotic syndrome

Abstract

Several studies have demonstrated that rituximab treatment has a significant beneficial effect on maintaining remission in patients with frequently-relapsing and steroid-dependent nephrotic syndrome (FR/SDNS) as long as B-cell depletion persists [1–3]. In 2010, however, we reported on a 5-year-old boy with complicated SDNS who developed early relapse 2 days after rituximab infusion, even though B-cell depletion was achieved [4]. We concluded that rapid steroid reduction immediately after rituximab treatment should be avoided to prevent early relapse. Although recent studies have shown that early relapse during post-rituximab B-cell depletion occurs in some patients [1, 5], the patient characteristics and therapeutic strategies in this cohort remain unelucidated. Based on our single-center experience, we would like to comment on the clinical characteristics and outcomes of patients who developed early relapse during B-cell depletion after rituximab treatment. Between July 2007 and March 2020, 12 early relapses during B-cell depletion occurred in eight of 92 patients with SDNS who had received a single infusion of rituximab (375 mg/m2; total, 312 infusions) at Saitama Children’s Medical Center, Japan. In the eight patients who developed early relapse, median age at NS onset and at rituximab treatment were 3.7 years (range 1.8–10 years) and 6.1 years (range 4.4–20 years), respectively. After rituximab infusion, early relapse and B-cell recovery (i.e., CD19+ cell count > 1% of total lymphocytes) occurred at a median of 23.5 days (range 2–57 days) and 124 days (range 74–244 days), respectively. These eight patients underwent either rapid reduction/discontinuation of treatment with steroids or immunosuppressive agents, and five of them experienced an episode of infection, such as the common cold or acute gastroenteritis, immediately after rituximab treatment (Table 1). Although complete remission was achieved in all patients treated with high-dose steroids, subsequent relapses occurred in six of the eight patients, and the median time to subsequent relapse after early relapse was 6 months (range 3–18 months). However, none of the patients had regressed to FR/SDNS during the B-cell depletion period. In a retrospective study of 51 patients with FR/SDNS treated with rituximab (weekly for 4 weeks) [5], Kamei et al. similarly reported that eight patients developed early relapse during B-cell depletion (median, 15 days after rituximab treatment). However, seven of the eight patients were able to discontinue steroid treatment at a later stage. In our study, none of the patients experienced FR/SDNS during B-cell depletion after early relapse. Based on these findings, we speculate that early relapse during B-cell depletion may not be due to an essential lack of response to rituximab but rather due to a delayed response to the biological agent, suggesting a time lag of at least 2–3 weeks between rituximab administration and the onset of its beneficial effect. Therefore, we recommend that the rapid reduction of steroids or immunosuppressive agents be avoided during the first 4 weeks after rituximab treatment to prevent early relapse in patients with complicated SDNS. Furthermore, episodes of infections should be considered as triggers of early relapse during the time lag period, even if post-rituximab B-cell depletion is achieved. Prospective studies are warranted to determine the predictive factors and therapeutic strategies for early relapse during B-cell depletion after rituximab treatment.