Predictors for Persistent Hypogammaglobulinemia After Rituximab Therapy in Pediatric Patients

Hypogammaglobulinemia (HG) is a recognized consequence of rituximab (RTX) therapy, extensively studied in adults but minimally explored in children. We conducted a retrospective cohort study at a tertiary care center to determine prevalence, predictors and clinical outcomes of HG in children after RTX therapy. Patients aged ≤ 18 years treated with RTX for various indications between 2000 and 2020 were included. Patients were classified as having HG when (1) IgG levels were <-2SD below reference for age, or (2) they received immunoglobulin replacement therapy (IGRT). HG after the last RTX dose was observed in 100/141 patients (71%). Persistent HG (>6 months) was observed in 61/95 patients (64%), of whom 10 patients remained in HG for more than 5 years. Low baseline IgG levels and HSCT treatment were significantly associated with persistent HG. Median reconstitution time for CD19+ B cells was 11 months (IQR=[7.3-18.1]). Median reconstitution time for CD19+CD27+IgG+ switched memory B cells was 1.8 years (IQR=[0.87-2.8]) and for every additional 6 months of IgG+ memory B cell depletion, chances of recovering from HG fell by 11% (HR=0.89, 95% CI=[0.81-0.98], p=0.02). Four patients developed a class-switch recombination-deficiency. Recurrent infections, of which 2 fatal, were observed in 18 patients with HG. In conclusion, over 70% of children had low IgG levels and/or required IGRT following RTX therapy. Predictors for persistent HG were low pre-RTX IgG levels and/or patients post-HSCT. Children with HG were often IGRT-dependent, may suffer from (lethal) recurrent infections and can occasionally develop secondary Ig class-switch defects.