Association of Rituximab Use With Adverse Events in Children, Adolescents, and Young Adults

Abstract

IMPORTANCE Rituximab is among the most frequently used immunotherapies in pediatrics. Few studies have reported long-term adverse events associated with its use for children. OBJECTIVE To describe the use of rituximab and to assess whether its use is associated with shortor long-term adverse events, infections, or time to immune reconstitution in a diverse group of young people. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study included 468 patients aged younger than 21 years who received rituximab for diverse indications between October 1, 2010, and December 31, 2017, at Texas Children's Hospital, a large pediatric referral hospital. Patterns of adverse events, infections, and immune recovery are described. Data analyses were conducted from December 2019 to June 2020. EXPOSURE One or more doses of rituximab. MAIN OUTCOMES AND MEASURES Adverse drug events (eg, anaphylaxis), incidence of mild and severe infections, and time to recovery of B lymphocyte subset counts and immunoglobulin levels. Survival models and logistic regression analyses and were used to identify associated risk factors of infectious and noninfectious adverse drug events. RESULTS We identified 468 patients receiving at least 1 dose of rituximab. The total follow-up time was 11 713 person-months. Of the 468 patients, 293 (62.6%) were female, the median (interquartile range) age at receipt of dose was 14.3 (9.9-16.8) years, and 209 (44.7%) were self-reported White Hispanic. Adverse events associated with rituximab infusion occurred in 72 patients (15.4%), and anaphylaxis occurred in 17 patients (3.6%). Long-term adverse events, such as prolonged neutropenia and leukoencephalopathy, were absent. Infections occurred in 224 patients (47.9%); 84 patients (17.9%) had severe infections, and 3 patients (0.6%) had lethal infections. Concurrent use of intravenous chemotherapy, treatment of systemic lupus erythematosus, neutropenia, and use of intravenous immunoglobulin were associated with increased risk of infection. Among 135 patients (28.8%) followed up to B cell count recovery, CD19 + or CD20 + cell numbers normalized in a median of 9.0 months (interquartile range, 5.9-14.4 months) following rituximab use; 48 of 95 patients (51%) evaluated beyond a year had low-forage B cell counts. Recovery of CD27 + memory B cell number occurred in a median of 15.7 months (interquartile range, 6.0-22.7 months). Among patients with normal baseline values, low immunoglobulin G (IgG) levels developed in 67 of 289 patients (23.2%) and low IgM levels in 118 of 255 patients (40.8%); of these patients evaluated beyond 12 months from rituximab, 16 of 117 (13.7%) had persistently low IgG and 37 (33.9%) of 109 had persistently low IgM.

Hypogammaglobulinaemia following rituximab therapy in childhood nephrotic syndrome

“…The monitoring of IgG levels was not standardized due to the retrospective study design. On the other hand, IgM level, which might be reduced after rituximab, was not measured in this study [14,15]. Its reduction would potentially contribute to infections as well [14,15].…”

“…On the other hand, IgM level, which might be reduced after rituximab, was not measured in this study [14,15]. Its reduction would potentially contribute to infections as well [14,15]. Last but not least, an appropriate control group without rituximab treatment would have been very interesting, since hypogammaglobulinaemia is prevalent among children with NS under intense oral immunosuppression without exposure to rituximab and also before treatment in this study [10,16].…”

“…prophylactic administration due to B-cell repletion rather than actual disease relapse. Of note, 14-50% of these patients had persistently reduced IgG concentrations beyond 1 year after rituximab therapy [11,15]. Reduction in IgM values was also observed in up to 46% of patients [15].…”

“…The incidences of hypogammaglobulinaemia following rituximab therapy in various patient populations ranged from 35 to 65% and are summarized in Table 1 [10,11,15,16,20]. Hypogammaglobulinaemia persisted in a large proportion of patients (50-80%) with low baseline IgG levels.…”

“…lupus, oncological conditions), concurrent immunosuppression (e.g. mycophenolate mofetil, calcineurin inhibitors), and chemotherapy, as well as other complications such as neutropenia [10,15,20,26]. Increased mortalities are also observed in male sex, older patients, and those with serious infections 6 months before and after rituximab [20].…”