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 short- or 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-for-age 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.

Conclusions and relevance: Rituximab is well tolerated among young people and is associated with few serious adverse events, but infections are common, corresponding to a prolonged period of B cell count recovery often lasting for longer than a year. Further examination of strategies to prevent infections following rituximab should be pursued.

Figure.. B Lymphocyte Recovery, Hypogammaglobulinemia, and Infections at Intervals Following Single Courses of Rituximab

A, Denominator of patients under follow-up at less than 1 month, 316; 1 month to less than 6 months, 294; 6 months to less than 12 months, 240; 12 months to less than 18 months, 186; and 18 months to less than 24 months, 148. B, Box and whisker plot with data log₁₀ transformed for graphical depiction. A constant of 1 was added to all absolute CD20⁺ values prior to log₁₀ transformation to avoid noninfinite values where absolute CD20⁺ = 0. Number of tests obtained at baseline, 92; less than 1 month, 104; 1 month to less than 6 months, 222; 6 months to less than 12 months, 146; 12 months to less than 18 months, 60; 18 months to less than 24 months, 34; and 24 months or longer, 44. The lower and upper ends of the whisker represent minimum and maximum counts for each interval. The lower border of the box represents the 25th percentile; the upper border represents the 75th percentile; the horizontal band, the median; and the solid dots, outliers. C, Denominator of patients under follow-up at baseline, 326; less than 1 month, 236, 1 month to less than 6 months, 294; 6 months to less than 12 months, 210; and 12 months or longer, 142. D, Denominator of patients under follow-up at baseline, 292; less than 1 month, 191; 1 month to less than 6 months, 267; 6 months to less than 12 months, 198; and 12 months or longer, 137.