Predictors for Persistent Hypogammaglobulinemia After Rituximab Therapy in Pediatric Patients

Abstract 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 SD 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.