Abstract
Rituximab is among the most frequently used immunotherapies in pediatrics. Few studies have reported long-term adverse events associated with its use for children. 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. 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. One or more doses of rituximab. 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. 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. 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.
Highlights
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
Increasing the number of rituximab doses was associated with increased risk of neutropenia in the adjusted model (Table 3)
Infections were more common among patients treated for oncologic vs nononcologic indications (HR, 3.50; 95% CI, 1.37-9.00); we report incidence separately for each group
Summary
Targeted immunotherapy is a mainstay for treatment of malignant neoplasms, autoimmune disease, and other disorders of immune dysregulation.[1,2,3] harnessing the immune system has changed the treatment landscape for many diseases, these therapies may bring with them risks and adverse secondary events.Rituximab is a chimeric human/murine monoclonal antibody against CD20 that depletes B cells through immune-mediated cytotoxicity and induction of apoptosis.[4,5] It induces prolonged B-cell count suppression and diminishes circulating antibodies.[2,6,7] B lymphocyte numbers typically recover within 6 to 12 months, but few studies have described long-term immune reconstitution in children following treatment with rituximab, across its broad range of indications.[2,6]The adverse events associated with rituximab include infusion reactions, anaphylaxis, and infections.[3,8,9] Rare but serious events—described primarily in adults—include progressive multifocal encephalopathy, prolonged neutropenia, and fatal viral reactivation.[10,11,12,13] Data regarding risk factors associated with adverse drug reactions, infections, and prolonged immune recovery are limited, being derived primarily from studies of adults or small, single-disease cohorts in children.[3,5,9,14]. Targeted immunotherapy is a mainstay for treatment of malignant neoplasms, autoimmune disease, and other disorders of immune dysregulation.[1,2,3] harnessing the immune system has changed the treatment landscape for many diseases, these therapies may bring with them risks and adverse secondary events. The adverse events associated with rituximab include infusion reactions, anaphylaxis, and infections.[3,8,9] Rare but serious events—described primarily in adults—include progressive multifocal encephalopathy, prolonged neutropenia, and fatal viral reactivation.[10,11,12,13] Data regarding risk factors associated with adverse drug reactions, infections, and prolonged immune recovery are limited, being derived primarily from studies of adults or small, single-disease cohorts in children.[3,5,9,14]
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