Phase IIa Global Study Evaluating Rituximab for the Treatment of Pediatric Patients With Granulomatosis With Polyangiitis or Microscopic Polyangiitis

Abstract

To assess the safety, tolerability, pharmacokinetics, and efficacy of rituximab (RTX) in pediatric patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA).Methods. The Pediatric Polyangiitis Rituximab Study was a phase IIa, international, open-label, single-arm study. During the initial 6-month remission-induction phase, patients received intravenous infusions of RTX (375 mg/m 2 body surface area) and glucocorticoids once per week for 4 weeks. During the follow-up period, patients could receive further treatment, including RTX, for GPA or MPA. The safety, pharmacokinetics, pharmacodynamics, and exploratory efficacy outcomes with RTX were evaluated.Results. Twenty-five pediatric patients with new-onset or relapsing disease were enrolled at 11 centers (19 with GPA [76%] and 6 with MPA [24%]). The median age was 14 years (range 6-17 years). All patients completed the remissioninduction phase. During the overall study period (≤4.5 years), patients received between 4 and 28 infusions of RTX. All patients experienced ≥1 adverse event (AE), mostly grade 1 or grade 2 primarily infusion-related reactions. Seven patients experienced 10 serious AEs, and 17 patients experienced 31 infection-related AEs. No deaths were reported. RTX clearance correlated with body surface area. The body surface area-adjusted RTX dosing regimen resulted in similar exposure in both pediatric and adult patients with GPA or MPA. Remission, according to the Pediatric Vasculitis Activity Score, was achieved in 56%, 92%, and 100% of patients by months 6, 12, and 18, respectively.Conclusion. In pediatric patients with GPA or MPA, RTX is well tolerated and effective, with an overall safety profile comparable to that observed in adult patients with GPA or MPA who receive treatment with RTX. RTX is associated with a positive risk/benefit profile in pediatric patients with active GPA or MPA.

Evaluation of Serious Infection in Pediatric Patients with Low Immunoglobulin Levels Receiving Rituximab for Granulomatosis with Polyangiitis or Microscopic Polyangiitis

“…During the overall study period (up to 4.5 years observation), 23 patients reported 105 infections; 91% were nonserious AEs. Details of infections in PePRS have been reported previously [ 7 ].…”

“…Our analysis also demonstrated that pediatric patients with GPA/MPA treated with rituximab had peripheral B-cell depletion after induction therapy, which was maintained through at least month 18. Previous exploratory analyses of pediatric patients in PePRS and adult patients in the RAVE trial demonstrated that higher rituximab exposure was correlated with longer-lasting B-cell depletion [ 7 ].…”

“…The study design and patient population of the Phase 2a, international, multicenter, open-label, uncontrolled PePRS study (WA25615; NCT01750697; EudraCT 2012-002062-13) has previously been described [ 7 ]. Patients aged ≥ 2 to < 18 years with newly diagnosed or relapsing GPA/MPA were enrolled.…”

“…In 2019 and 2020, rituximab was approved by the US Food and Drug Administration and the European Medicines Agency, respectively, for the treatment of GPA/MPA in pediatric patients aged ≥ 2 years [ 5 , 6 ]. This approval was based on the Phase 2a, international, open-label PePRS trial, which assessed safety, tolerability, pharmacokinetics, and exploratory efficacy outcomes in pediatric patients with GPA/MPA treated with rituximab [ 7 ].…”

“…Assessment of immunologic status and infection risk following rituximab treatment is often complicated by multiple disease- and therapeutic-associated risk factors for recurrent infections and HGG, including preexisting low immunoglobulin levels, prior use of cytotoxic or biologic therapies, and other disease- and age-related factors [ 13 , 14 , 17 ]. The objective of this evaluation was to assess the SI risk in pediatric GPA/MPA patients with prolonged low IgG or IgM serum concentrations following rituximab treatment in the PePRS clinical study [ 7 ]. Peripheral B-cell depletion was also assessed.…”