Original Investigation | Pediatrics

Association of Rituximab Use With Adverse Events in Children, Adolescents,

and Young Adults
Casey Lee McAtee, MD; Joseph Lubega, MD, MPH; Kristen Underbrink, BS; Kristen Curry, PharmD; Pavlos Msaouel, MD, PhD; Martha Barrow, BS; Eyal Muscal, MD, MS;
Timothy Lotze, MD; Poyyapakkam Srivaths, MD; Lisa R. Forbes, MD; Carl Allen, MD, PhD; M. Brooke Bernhardt, PharmD, MS

Abstract Key Points

Question Is the use of rituximab for
IMPORTANCE Rituximab is among the most frequently used immunotherapies in pediatrics. Few
young people associated with short- or
studies have reported long-term adverse events associated with its use for children.
long-term adverse events?

OBJECTIVE To describe the use of rituximab and to assess whether its use is associated with short- Findings This cohort study identified
or long-term adverse events, infections, or time to immune reconstitution in a diverse group of 468 patients younger than 21 years
young people. receiving rituximab for more than 25
indications, among whom infectious and
DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study included 468 patients noninfectious adverse events were
aged younger than 21 years who received rituximab for diverse indications between October 1, 2010, common. The majority of these events
and December 31, 2017, at Texas Children’s Hospital, a large pediatric referral hospital. Patterns of were mild, but a small population
adverse events, infections, and immune recovery are described. Data analyses were conducted from experienced prolonged immune
December 2019 to June 2020. suppression and severe infections
following even single courses of
EXPOSURE One or more doses of rituximab. rituximab.

Meaning Findings suggest that

MAIN OUTCOMES AND MEASURES Adverse drug events (eg, anaphylaxis), incidence of mild and
rituximab appears to be well tolerated
severe infections, and time to recovery of B lymphocyte subset counts and immunoglobulin levels.
among young people, but the observed
Survival models and logistic regression analyses were used to identify associated risk factors of
frequent infections and prolonged
infectious and noninfectious adverse drug events.
recovery of B lymphocyte numbers
highlight the need for better strategies
RESULTS We identified 468 patients receiving at least 1 dose of rituximab. The total follow-up time
to mitigate infection risk in this
was 11 713 person-months. Of the 468 patients, 293 (62.6%) were female, the median (interquartile
population.
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 + Supplemental content
neutropenia and leukoencephalopathy, were absent. Infections occurred in 224 patients (47.9%); 84 Author affiliations and article information are
patients (17.9%) had severe infections, and 3 patients (0.6%) had lethal infections. Concurrent use listed at the end of this article.

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.

(continued)

Open Access. This is an open access article distributed under the terms of the CC-BY License.

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Abstract (continued)

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.

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Corrected on March 1, 2021. doi:10.1001/jamanetworkopen.2020.36321

Introduction
Targeted immunotherapy is a mainstay for treatment of malignant neoplasms, autoimmune disease,
and other disorders of immune dysregulation.1-3 Although 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, particularly 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.10-13 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
Adverse events associated with rituximab use are difficult to predict and, in turn, cause difficult
treatment quandaries. The objective of the present study was to investigate issues relevant to the
pediatrician or subspecialist caring for patients following courses of rituximab. First, we describe
short- and long-term adverse events associated with rituximab use. We further investigate infections
and their associated risk factors. Finally, we describe patterns of B-cell recovery and immunoglobulin
recovery.

Methods
Study Design
We conducted a retrospective cohort study of patients younger than 21 years receiving rituximab at
Texas Children’s Hospital between October 1, 2010, and December 31, 2017. Person-time in the study
spanned between patients’ first rituximab dose and their last follow-up date or the end of the study
period, whichever occurred first. To avoid confounding by other major causes of prolonged
lymphodepletion and infection, we excluded patients receiving rituximab for hematopoietic stem cell
or solid organ transplant, those receiving other lymphodepleting therapy (eg, alemtuzumab), and
those with primary immunodeficiencies. Those receiving rituximab prior to the study period—
identified via electronic search of the medical record—were excluded. This study followed the
Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
Owing to its retrospective nature, the study was approved with a waiver for the requirement of
obtaining informed consent by the institutional review board of Baylor College of Medicine in Houston,
Texas. No one received compensation or was offered any incentive for participating in this study.

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Data Collection
We extracted data from the electronic medical record, including demographic reports, patient
problem lists, microbiology results, laboratory data (including flow cytometry results for peripheral
blood lymphocyte subsets), and allergy lists. Race and ethnicity were self-reported. The record of
each patient was scrutinized for keywords developed by the study team to ensure that relevant
events were captured. Notes documenting rituximab infusions were manually reviewed. Because we
studied patients in routine clinical practice, adverse events were captured only when they reached
medical attention.
Infections and adverse drug events were classified and graded according to the Common
Terminology Criteria for Adverse Events (CTCAE) version 5.0.15 Events that are CTCAE grade 3 or
higher require intravenous medications or hospitalization; they are designated “severe” in this study.
Anaphylaxis was defined per the National Institute of Allergy and Infectious Diseases and Food
Allergy and Anaphylaxis Network.16 All anaphylactic events were confirmed by the investigators.

Statistical Analysis
Modeling Adverse Drug Events
To evaluate risk of adverse drug events following a single course of rituximab, we used multivariable
Cox proportional hazards models with stepwise selection.17 A rituximab “course” was a group of at
least 1 dose with less than 1 month between doses. Patients were right censored at study end, last
follow-up, or 2 years beyond rituximab use, whichever occurred first. We defined the period at risk as
2 years from a course given in which B cells generally recover within 24 months following rituximab
use.2,6 Adverse events occurring outside of this 2-year window were reported but were not included
in the survival models.
Risks of the following outcomes were assessed independently: incident infections, incident
hypogammaglobulinemia, incident neutropenia (ⱕ1000/μL [to convert neutrophils to ×109/L,
multiply by 0.001]), serum sickness, multifocal leukoencephalopathy, pneumonitis, and secondary
malignant neoplasm. To model risk of recurrent infections, a gamma-distributed shared frailty term
was added to the model to account for clustering by patient.18,19 Documenting neutropenia or
hypogammaglobulinemia relied on data captured in routine practice; otherwise, data were complete.
To model risk of reactions associated with infusion—potentially recurrent events occurring during or
immediately after infusions—we used multivariable logistic regression models with mixed-effects
modeling to account for clustering by patient.20

Model Risk Factors

The risk factors assessed were age, sex, race/ethnicity, number of previous rituximab doses,
oncology diagnosis, lupus diagnosis, concurrent oral immunosuppression (mycophenolate mofetil or
corticosteroid), and concurrent intravenous immunoglobulin (IVIG). For infections, concurrent
Pneumocystis jiroveci prophylaxis and neutropenia (as a dichotomous time-varying covariate) were
added. For reactions associated with infusion, preinfusion prophylaxis (hydrocortisone,
diphenhydramine, or acetaminophen) was added.
Neutropenia was assessed a median of twice monthly (interquartile range [IQR], 1-4 evaluations
per month) during the follow-up period. Sparsity of immunoglobulin level and B-cell count data at
approximate times of infections prohibited their inclusion as risk factors in the infection model;
otherwise, data were complete. All variables included in the adjusted models met the assumption of
proportional hazards using Schoenfeld residuals.21,22
As a post hoc analysis, we used a univariable Cox proportional hazards model as described
above to determine the association between IVIG use and infections in the year prior to patients’ first
dose of IVIG. Time at risk began either 365 days prior to the first dose of rituximab or the patient’s
first clinical encounter, whichever occurred later. Time at risk ended on the day of dose 1 of rituximab.
All tests were 2-sided with α = .05. All analyses were performed from December 2019 to June
2020 in R with use of the Survival and lme4 packages.22-24

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Results
We identified 468 patients receiving rituximab during the study period (Table 1). Of the 468
patients, 293 (62.6%) were female, the median age at dose was 14.3 years (IQR, 9.9-16.8 years), and
209 (44.7%) were self-reported White Hispanic. An additional 276 patients were excluded, most
commonly for lymphodepletion prior to stem cell transplant (115 [41.7%]) or solid organ transplant
(108 [39.1%]) (eTable 1 in the Supplement). The total follow-up time was 11 713 person-months, with
a median follow-up of 21.2 months (IQR, 9.0-37.7 months). The most common indications for
rituximab were systemic lupus erythematosus (124 [26.5%]), nephrotic syndrome (61 [13.0%]),
autoimmune encephalitis (42 [9.0%]), and lymphoma (30 [6.4%]). Patients most often received a
single dose (63 [13.5%]) or a single multidose course of rituximab (253 [54.3%]) with a median of 2
doses per course (range, 2-9 doses). Preinfusion prophylaxis with corticosteroids, acetaminophen, or
diphenhydramine was used prior to 1371 of 1714 total doses (80.0%).

Immediate and Long-term Noninfectious Adverse Drug Events

Noninfectious adverse drug events were common (Table 2). Of 468 patients, 17 (3.6%) experienced
anaphylaxis, most often after the first (n = 9) or second (n = 3) dose, but it occurred as late as the
eighth dose following previously uneventful infusions. Other reactions associated with infusion
occurred in 72 patients (15.4%), typically after the first dose (52 patients [72.2%]). Following these

Table 1. Demographic and Clinical Characteristics of 468 Patients

Receiving Rituximab

Demographic characteristic Patients, No. (%)

Female sex 293 (62.6)
Age at dose, median (interquartile range), y 14.3 (9.9-16.8)
Ethnicity
White Hispanic 209 (44.7)
Non-Hispanic
White 121 (25.9)
Black 99 (21.2)
Asian 23 (4.9)
Other 16 (3.4)
Rituximab courses
Indication for rituximab
Systemic lupus erythematosus 124 (26.5)
Nephrotic syndrome 61 (13.0)
Autoimmune encephalitis 42 (9.0)
Lymphoma 30 (6.4)
Immune thrombocytopenic purpura 26 (5.6)
Multiple sclerosis 23 (4.9)
Other 162 (34.6)
Dosing schedule
Single 63 (13.5)
Single multidose coursea 253 (54.3)
Doses per course, median (range) 2 (2-9)
Multiple courses 152 (32.5)
Concurrent medications
Corticosteroids 356 (76.1)
Mycophenolate mofetil 126 (26.9)
Tacrolimus 22 (4.7)
Pneumocystis jiroveci prophylaxisb 102 (21.8)
a
Two or more doses with less than 1 month between doses, and no
subsequent doses.
b
Trimethoprim-sulfamethoxazole, pentamidine, atovaquone, and/or dapsone.

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reactions, most patients (63 [87.5%]) were able to complete the infusion and were given subsequent
doses without a recurrence. Transient hypotension, respiratory distress, or rigors resolving after
pausing the infusion or giving oral antihistamines occurred most commonly.
Moderate neutropenia (<1000/μL) occurred in 95 patients (20.3%), and severe neutropenia
(<500/μL) occurred in 66 patients (14.1%). To isolate the association between rituximab and
neutropenia, we analyzed 72 patients who were not taking other medications known to cause
neutropenia. In this subcohort, moderate neutropenia occurred in 3 patients; it lasted longer than a
month in a single patient and resolved within 2 months.
Owing to the low incidence of other noninfectious adverse events (21 [4.5%]), only risk factors
of neutropenia, hypogammaglobulinemia, and infusion reactions were analyzed in the regression
analysis. Increasing the number of rituximab doses was associated with increased risk of neutropenia
(hazard ratio [HR], 1.64; 95% CI, 1.33-2.04) in the adjusted model (Table 3). Patients receiving IVIG

Table 2. Adverse Drug Events and Infections Among Patients

Receiving Rituximab

Adverse drug event Patients, No. (%)

Anaphylaxis 17 (3.6)
Signs/symptoms
Respiratory compromise 10 (2.1)
Gastrointestinal tract symptoms 8 (1.7)
Skin or mucosal involvement 7 (1.5)
Hypotension 4 (0.8)
Received epinephrine 6 (1.3)
Infusion reactiona 72 (15.4)
Signs/symptoms
Hypotension 16 (3.4)
Cough, wheezing, or dyspnea 14 (3.0)
Rigors 14 (3.0)
Hives, rash, or generalized pruritus 12 (2.6)
Chest or throat tightness 10 (2.1)
Headache 7 (1.5)
Fever 6 (1.3)
Nausea, vomiting, or abdominal pain 6 (1.3)
Hypertension 5 (1.1)
CTCAE grade ≥3 infusion reactionb 7 (1.5)
Infusion terminated 9 (1.9)
Neutropeniac 3 (4.2)
Hypogammaglobulinemiab
IgG 67 (23.2)
IgM 104 (40.8)
Serum sickness 3 (0.6)
Infection
Any severity 224 (47.9)
Severed 84 (17.9)
Requiring ICU 17 (3.6)
Death 3 (0.6)

Abbreviations: CTCAE, Common Terminology Criteria for Adverse Events; ICU,

intensive care unit; IgG, immunoglobulin G; IgM, immunoglobulin M.
a
Infusion reactions excluding anaphylaxis.
b
New-onset hypogammaglobulinemia only (normal baseline).
c
Limited to patients not taking immunosuppressive medications known to
cause neutropenia (n = 72).
d
Infections associated with CTCAE grade 3 events typically requiring
intervention with intravenous medications, hospitalization, or both.

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were more likely to have hypogammaglobulinemia (HR, 2.56; 95% CI, 1.38-4.74). The odds of
infusion reactions decreased with successive doses (odds ratio, 0.30; 95% CI, 0.20-0.45).
Preinfusion prophylaxis did not decrease the odds of infusion reactions.
A single child developed cancer following rituximab use; Hodgkin lymphoma (Epstein-Barr virus
negative) was diagnosed 14 months after treatment with rituximab for immunoglobulin G4 (IgG4)–
related sclerosing disease. There were no cases of progressive multifocal leukoencephalopathy or
pneumonitis.

Infections
Infections were most common in the 6 months following rituximab use, but their incidence
continued to trend downward for 2 years following doses (χ2 trend test, P < .001). Severe infections
were most common in the first month (Figure, A).
Within 2 years of receiving rituximab, infections occurred in 224 patients (47.9%); 84 patients
(17.9%) had severe infections, and 3 patients (0.6%) had lethal infections.
Infections were more common among patients treated for oncologic vs nononcologic
indications (HR, 3.50; 95% CI, 1.37-9.00); therefore, we report incidence separately for each group.
Infections occurred in 198 of 428 nononcology patients (46.3%) and 26 of 40 oncology patients
(65.0%) within 2 years of receiving rituximab. Severe infections (CTCAE grade ⱖ3) occurred in 67
nononcology patients (15.7%) and 17 oncology patients (42.5%). Severe infections were high
immediately after a dose, with 52 of 129 (40.3%) occurring within a month. Multiple infections were
common, occurring in 98 nononcology patients (22.9%; median number of infections, 3 [IQR, 2-4])
and 20 oncology patients (50.0%; median number of infections, 3 [IQR, 2-5]). In total, the incidence
density of infections in the cohort was 64 infections per 100 patient-years; for severe infections, it
was 13 per 100 patient-years.
The most common of 481 infections were upper respiratory tract infections (60 [12.5%]), lower
respiratory tract infections (57 [11.9%]), urinary tract infections (50 [10.4%]), and skin or soft tissue
infections (43 [8.9%]). The most common of 129 severe infections were lower respiratory tract
infections (28 [21.7%]), bacteremia (14 [10.9%]), acute gastroenteritis (11 [8.5%]), and urinary tract

Table 3. Cox Proportional Hazards Model of Risk Factors for Neutropenia or Hypogammaglobulinemia
Following a Single Course of Rituximab

Unadjusted model Adjusted model

Risk factor HR (95% CI) P value HR (95% CI) P value
Neutropenia (<1000/μL)a
Year of age (increasing) 0.94 (0.89-0.99) .03 0.94 (0.89-1.0) .05
Hispanic race/ethnicity 3.40 (0.45-25.50) .23 ND ND
Female sex 0.72 (0.40-1.31) .28 ND ND
Oncology diagnosis 13.86 (6.98-27.54) <.001 6.05 (2.53-14.46) <.001
No. of doses (increasing) 1.93 (1.63-2.29) <.001 1.64 (1.33-2.04) <.001
Concurrent medication
Mycophenolate mofetil 1.13 (0.60-2.10) .70 2.35 (1.12-4.93) .03
Corticosteroid 1.49 (0.69-3.22) .31 ND ND
Hypogammaglobulinemia (IgG)b
Year of age (increasing) 0.97 (0.91-1.03) .27 ND ND Abbreviations: HR, hazard ratio; IgG, immunoglobulin
Hispanic race/ethnicity 0.77 (0.41-1.44) .41 ND ND G; IVIG, intravenous immunoglobulin; ND, not
Female sex 0.88 (0.45-1.71) .70 ND ND determined.
Oncology diagnosis 2.97 (1.16-7.57) .02 1.88 (0.59-5.99) .29 SI conversion factors: To convert neutrophils to
No. of doses (increasing) 1.26 (1.03-1.55) .03 1.23 (0.95-1.60) .12 ×109/L, multiply by 0.001.
a
Concurrent medication For neutropenia, data represent 307 patients
receiving a single course of rituximab with neutrophil
Mycophenolate mofetil 0.94 (0.51-1.73) .84 ND ND
count data available.
Corticosteroid 2.21 (0.68-7.14) .19 ND ND
b
For hypogammaglobulinemia, these data similarly
IVIG 2.39 (1.30-4.38) .005 2.56 (1.38-4.74) .003
represent 252 patients.

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infections (10 [7.8%]). Seventeen patients (3.6%) required intensive care, and 3 (0.6%) died. All
deaths were among nononcology patients.
Confirmed viral infections occurred in 40 patients (8.5%), most commonly influenza (n = 26)
and herpes simplex virus (n = 9). Five patients with herpes simplex infections required
hospitalization. Epstein-Barr virus was detected in 3 patients, and cytomegalovirus in 1 patient;
however, surveillance of these viruses was not routine. There were no cases of Pneumocystis jiroveci
pneumonia.
Along with cancer diagnosis, neutropenia (HR, 2.40; 95% CI, 1.17-4.91), treatment of systemic
lupus erythematosus (HR, 1.98; 95% CI, 1.18-3.32), and concurrent use of IVIG (HR, 2.23; 95% CI, 1.41-
3.54) were associated with increased risk of infections in the adjusted model (Table 4). Owing to
their high collinearity, nearly identical findings were observed when lupus diagnosis was replaced
with concurrent use of mycophenolate mofetil (ie, most patients with lupus were taking
mycophenolate, and vice versa). These risk factors were similarly associated with severe infections
(eTable 2 in the Supplement).

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

A Proportion of patients with infections B Absolute CD20+ B lymphocyte counts

0.6 10 000

All infections
Severe infections
1000
Log absolute CD20+

0.4
Proportion

100

0.2
10

1
0
<1 1 to <6 6 to <12 12 to <18 18 to <24 Baseline <1 1 to <6 6 to <12 12 to <18 18 to <24 ≥24
Months Months

C Proportion of patients with low-for-age IgG D Proportion of patients with low-for-age IgM

1.0 1.0

0.8 0.8

0.6 0.6
Proportion

Proportion

0.4 0.4

0.2 0.2

0 0
Baseline <1 1 to <6 6 to <12 ≥12 Baseline <1 1 to <6 6 to <12 ≥12
Months Months

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.

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Of patients with infections who received IVIG following rituximab, 63 (64.3%) were given at
least 1 dose of IVIG prior to their first infection. As well as being at higher risk of infection in the period
after rituximab, those receiving IVIG also had a higher risk of infection in the year prior to their first
dose of rituximab (HR, 3.67; 95% CI, 2.19-6.12).

Immune Reconstitution
Clinicians obtained lymphocyte subsets for a median of 6.3 months (IQR, 2.8-13.3 months) after
courses of rituximab. Peripheral absolute B-cell counts decreased rapidly following rituximab use and
generally recovered within 24 months following the last dose (Figure, B). Of 104 evaluations of CD20
lymphocyte counts within 1 month of rituximab, 100% were low-for-age and only 2 were above 0.
Of 468 patients, 135 (28.8%) had B lymphocyte counts followed up to normalization of either
CD19+ or CD20+ cell counts after a course of rituximab (laboratory evaluations variably reported
CD19+, CD20+, or both populations). Patients achieved normalization of either population in a
median of 9.0 months (IQR, 5.9-14.4 months), up to a maximum of 52.8 months. Of 95 patients
evaluated beyond a year, 48 (51%) had persistently low levels. Recovery of CD19+CD27+ memory B
cell counts occurred in a median of 15.7 months (IQR, 6.0-22.7 months).
Patients with lupus followed up to normalization of CD20+ or CD19+ lymphocyte counts after a
single course of rituximab required a median of 15.3 months (IQR, 12.5-27.9 months) to normalize
compared with 9.4 months (IQR, 6.2-13.8 months) for other patients (Wilcoxon rank sum P = .002).
Although patients with lupus were evaluated at similar intervals and durations as the entire cohort,
the potential for ascertainment bias influencing those receiving follow-up evaluations must be
considered here.
Immunoglobulin levels were available for 358 patients (76.5%). Hypogammaglobulinemia was
common throughout the first year following rituximab use (Figure, C and D). Clinicians followed
immunoglobulin levels for a median of 6.1 months (IQR, 0.9-13.8 months) after rituximab courses. Of
289 patients with normal baseline immunoglobulin levels, 67 (23.2%) were documented to have low
IgG levels after rituximab courses, and 104 of 255 patients (40.8%) were documented to have low
IgM levels after rituximab courses. Among those patients, 51 (76.1%) were followed up to
normalization of IgG, and 64 (61.5%) were followed up to normalization of IgM. Of patients with
normal baseline immunoglobulin levels evaluated later than 12 months from rituximab, 16 of 117
(13.7%) had persistently low IgG and 37 of 109 (33.9%) had persistently low IgM.

Table 4. Cox Proportional Hazards Model of Risk Factors for Infections Among 315 Patients Following
a Single Course of Rituximab

Unadjusted model Adjusted model

Risk factor HR (95% CI) P value HR (95% CI) P value
Demographic characteristic
Female sex 0.95 (0.67-1.35) .79 ND ND
Hispanic race/ethnicity 1.24 (0.89-1.73) .20 ND ND
Year of age (increasing) 0.97 (0.94-1.00) .06 ND ND
Abbreviations: HR, hazard ratio; ND, not determined;
Diagnosis and rituximab dosinga
PJP, Pneumocystis jiroveci.
No. of doses (per dose) 1.15 (1.03-1.29) .01 1.00 (0.82-1.24) .96
SI conversion factors: To convert neutrophils to
Oncologic diagnosis 2.36 (1.46-3.80) <.001 3.50 (1.37-9.00) .009 ×109/L, multiply by 0.001.
Lupus erythematosus 1.13 (0.78-1.64) .51 1.98 (1.18-3.32) .009 a
Only diseases with more than 50 participants tested
Moderate neutropeniab 3.71 (1.90-7.26) <.001 2.40 (1.17-4.91) .02 as risk factors.
Severe neutropeniab 5.17 (2.51-10.66) <.001 ND ND b
Moderate (<1000/μL) and severe (<500/μL)
Concurrent medication neutropenia were time-varying covariates. Owing to
Intravenous immunoglobulin 1.65 (1.19-2.30) .003 2.23 (1.41-3.54) <.001 collinearity, only moderate neutropenia was included
in the multivariable model.
PJP prophylaxisc 1.41 (0.96-2.07) .08 ND ND
c
Corticosteroids 1.19 (0.84-0.79) .40 ND ND Pneumocystis jiroveci pneumonia prophylaxis
included trimethoprim-sulfamethoxazole,
Mycophenolate mofetil 1.33 (0.93-1.90) .12 ND ND
pentamidine, atovaquone, and dapsone.

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 JAMA Network Open | Pediatrics Association of Rituximab Use With Adverse Events in Young People

Discussion
We investigated the immediate and long-term adverse events associated with rituximab therapy in a
diverse cohort of 468 children, adolescents, and young adults treated for more than 25 disorders.
The heterogeneity of patient age, race/ethnicity, and diagnoses allowed for an assessment of the
practical challenges in the care of young people receiving rituximab. Trends in these data may inform
clinical care and the investigations surrounding risk factors of adverse drug events, as well as the
appropriate timing of laboratory evaluation and vaccination for children.
The reactions associated with rituximab infusion in the present study were uncommon and
rarely severe; more than three-quarters of patients with infusion reactions were safely given
subsequent doses. Clinical trials involving rituximab report infusion reactions in 50% to 90% of
patients, but these reactions were mild in most cases.3,25-27 Outside of clinical trials, infusion
reactions are documented at much lower rates—reflective of their low acuity.28,29 The incidence of
life-threatening events, such as anaphylaxis, is 1% to 4% across studies.2,26,29,30 As in our cohort,
reactions most often occur following the first dose, but reactions following later doses are
possible.3,26
Severe events, such as leukoencephalopathy and prolonged neutropenia, were absent in the
present study, suggesting that if they do occur in young people, they are extremely rare.2,12,13 Lethal
viral reactivation was also absent in the present study, but rare and severe herpesvirus infections in
the cohort highlight the importance of expectant management of viral infections in these children.
The single incident case of cancer occurred in a patient with IgG4-related disease, a disease
unassociated with cancer.31 Whether rituximab increases risk of cancer remains uncertain.32,33
The reported prevalence of infection following rituximab use is highly variable. The figures
range from 10% to 70%, reflecting the heterogeneity of the populations and the study designs
implemented.2,27,34 When infections are narrowed to the defined criterion of requiring
hospitalization, the incidence becomes more consistent, ranging from 5 to 10 per 100 person-years,
similar to the present cohort.28,29,35
Infections were most common in the first 6 months following rituximab use in the present
study, and incidence trended downward as immune recovery occurred during 2 years (Figure).
Severe infections were particularly high immediately after a dose—40.3% of 129 occurred within a
month—highlighting this period as one in which infection-mitigating strategies should be focused.
Patients receiving IVIG were more likely to have infections, even after controlling for other
causes of infection, such as neutropenia and concurrent immunosuppression (Table 4). This
unexpected finding was previously described in adults treated with rituximab and IVIG.14 We
emphasize that this adverse “effect” associated with IVIG use is most consistent with reverse
causality, the phenomenon whereby patients at higher risk for infection were given IVIG, thus
creating the association. That patients receiving IVIG were more likely to have documented
hypogammaglobulinemia supports this hypothesis. Furthermore, although most patients received
IVIG prior to their first infection, infection incidence was also higher in the IVIG group during the year
preceding rituximab, suggesting that unmeasured confounders produced the association between
IVIG and increased risk of infection.
To date, no randomized clinical trials have reported the efficacy of IVIG following rituximab use
to prevent infections. Data supporting the use of IVIG following cytotoxic chemotherapy are mixed;
IVIG may be associated with decreased risk of infection in patients with leukemia or lymphoma, but
this decreased risk is insignificant following stem cell transplant.36-39
We should consider the possibility that IVIG does not consistently prevent infections in patients
receiving rituximab. First, because IVIG contains only trace amounts of IgM—the deficiency of which
is linked to increased infection risk—it will not correct the pronged deficiency of IgM commonly
induced by rituximab.40,41 Second, because IVIG has a half-life of approximately 30 days, patients
may require IVIG for longer courses to experience a benefit.42 Third, replenishment of IgG may be
insufficient to overcome other major causes of infection, such as neutropenia.38 Ultimately, a

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 JAMA Network Open | Pediatrics Association of Rituximab Use With Adverse Events in Young People

randomized clinical trial studying the prophylactic use of IVIG—a medication with its own adverse
drug events—should be conducted among children after rituximab use.
The evaluation of B-cell count recovery following rituximab is not standardized. Evaluation
within a month of a dose to confirm lymphodepletion is unnecessary in most cases; of 104 CD20+
evaluations, all had low-for-age values, and only 2 had a value greater than 0 (Figure, B). Similar to
other studies, B cell counts in young people evaluated in the present study usually recovered within a
year, but recovery was often delayed.2,7,27,43 Approximately half of the patients evaluated beyond a
year had low-for-age B cell counts, suggesting that their prolonged suppression is common in
children.
This cohort underscores the substantial population of children with diminished numbers of B
lymphocytes for more than a year after receiving single courses of rituximab. Patients treated for
lupus, in particular, required nearly a year and a half for recovery. Although the possibility of
ascertainment and selection bias must be considered when interpreting these data, the increased
risk of infection in patients with lupus described here highlights the importance of further study of
infections and immune reconstitution in this population.
Finally, CD19+CD27+ memory B cell numbers were especially slow to recover (median, 15.7
months). Memory B cells are required for adequate vaccine response—responses that are attenuated
in adults following rituximab use.44-46 Based on these data and the highly variable, prolonged time
to recovery of memory B cell numbers in children, it may be necessary for clinicians to either
document the return of these cells prior to vaccination or confirm adequate vaccine antibody titers
following routine childhood vaccination.

Strengths and Limitations

To our knowledge, this is the largest study to describe adverse drug events among children receiving
rituximab across the broad spectrum of its use. A retrospective cohort design was necessary to study
its use in the settings of routine clinical practice; thus, the study has the intrinsic weaknesses of
retrospective cohorts, particularly the risk of misclassification bias due to incompleteness or
miscoding in the medical record. Furthermore, subclinical events, particularly asymptomatic viral
reactivations, were unlikely to be captured; however, these events are likely of limited clinical
relevance. To reduce these risks, we used a multifaceted approach of searching the medical record.
Although these data showed long-term trends in immune reconstitution in a large group of
children, adolescents, and young adults after rituximab use, the retrospective design risks
ascertainment bias vis-à-vis unmeasurable influences on likelihood of laboratory evaluation.
Furthermore, the sparseness of immunoglobulin and lymphocyte subpopulation data at times of
infection precluded a more precise investigation of the associations between rituximab,
hypogammaglobulinemia, and infection—thus, this should be studied prospectively alongside
variables identified in this study as associated with infection risk.

Conclusions
Rituximab is well tolerated in children, but infections after its use are common—corresponding to a
prolonged period of depressed B cell numbers and immunoglobulin levels following even single
courses of rituximab. Strategies to reduce infections following rituximab use should be studied
prospectively, particularly the use of IVIG. Finally, the prolonged recovery of memory B cell numbers
following rituximab use should be considered because it is associated with routine childhood
vaccinations.

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 JAMA Network Open | Pediatrics Association of Rituximab Use With Adverse Events in Young People

ARTICLE INFORMATION
Accepted for Publication: December 15, 2020.
Published: February 3, 2021. doi:10.1001/jamanetworkopen.2020.36321
Correction: This article was corrected on March 1, 2021, to fix a typographical error in the abstract.
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 McAtee CL
et al. JAMA Network Open.
Corresponding Author: Casey Lee McAtee, MD, Section of Hematology-Oncology, Department of Pediatrics,
Baylor College of Medicine, One Baylor Plaza, BCM 622, Houston, TX 77030 (casey.mcatee@bcm.edu).
Author Affiliations: Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine,
Houston, Texas (McAtee, Lubega, Underbrink, Barrow, Muscal, Lotze, Srivaths, Forbes, Allen, Bernhardt);
Department of Pharmacy, Texas Children’s Hospital, Houston (Curry); Department of Genitourinary Medical
Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston (Msaouel).
Author Contributions: Drs McAtee and Bernhardt had full access to all the data in the study and take
responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: McAtee, Lubega, Allen, Bernhardt.
Acquisition, analysis, or interpretation of data: McAtee, Lubega, Underbrink, Curry, Msaouel, Barrow, Muscal,
Lotze, Srivaths, Forbes, Bernhardt.
Drafting of the manuscript: McAtee.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: McAtee, Lubega, Msaouel.
Obtained funding: Lubega.
Administrative, technical, or material support: McAtee, Lubega, Underbrink, Barrow, Bernhardt.
Supervision: McAtee, Muscal, Lotze, Srivaths, Forbes, Allen, Bernhardt.
Conflict of Interest Disclosures: Dr Msaouel reported receiving research funds from Gateway for Cancer
Research, Mirati Therapeutics, and Takeda; and receiving personal fees from Axiom Healthcare Strategies, Exelixis,
Mirati Therapeutics, and Pfizer outside the submitted work. Dr Srivaths reported receiving personal fees from
Reata Pharmaceuticals outside the submitted work. Dr Forbes reported receiving personal fees from ADMA
Biologics, Grifols, Horizon Therapeutics, and Takeda outside the submitted work. Dr Bernhardt reported receiving
grants from Celgene during the conduct of the study. No other disclosures were reported.
Funding/Support: This project was funded by the investigator-initiated research grant RFP-US-15-PED-016 (to Dr
Lubega) from Bristol Myers Squibb.
Role of the Funder/Sponsor: The funder was not involved in the design and conduct of the study; collection,
management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and
decision to submit the manuscript for publication.

REFERENCES
1. Kavcic M, Fisher BT, Seif AE, et al. Leveraging administrative data to monitor rituximab use in 2875 patients at 42
freestanding children’s hospitals across the United States. J Pediatr. 2013;162(6):1252-1258. doi:10.1016/j.jpeds.
2012.11.038
2. Dale RC, Brilot F, Duffy LV, et al. Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS
disease. Neurology. 2014;83(2):142-150. doi:10.1212/WNL.0000000000000570
3. Salles G, Barrett M, Foà R, et al. Rituximab in B-cell hematologic malignancies: a review of 20 years of clinical
experience. Adv Ther. 2017;34(10):2232-2273. doi:10.1007/s12325-017-0612-x
4. Weiner GJ. Rituximab: mechanism of action. Semin Hematol. 2010;47(2):115-123. doi:10.1053/j.seminhematol.
2010.01.011
5. Christou EAA, Giardino G, Worth A, Ladomenou F. Risk factors predisposing to the development of
hypogammaglobulinemia and infections post-Rituximab. Int Rev Immunol. 2017;36(6):352-359. doi:10.1080/
08830185.2017.1346092
6. Mitchell CD, Richards SM, Kinsey SE, Lilleyman J, Vora A, Eden TO; Medical Research Council Childhood
Leukaemia Working Party. Benefit of dexamethasone compared with prednisolone for childhood acute
lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 randomized trial. Br J Haematol.
2005;129(6):734-745. doi:10.1111/j.1365-2141.2005.05509.x

JAMA Network Open. 2021;4(2):e2036321. doi:10.1001/jamanetworkopen.2020.36321 (Reprinted) February 3, 2021 11/13

Downloaded From: https://jamanetwork.com/ on 11/06/2022

 JAMA Network Open | Pediatrics Association of Rituximab Use With Adverse Events in Young People

7. Worch J, Makarova O, Burkhardt B. Immunreconstitution and infectious complications after rituximab

treatment in children and adolescents: what do we know and what can we learn from adults? Cancers (Basel).
2015;7(1):305-328. doi:10.3390/cancers7010305
8. Mahmoud I, Jellouli M, Boukhris I, et al. Efficacy and safety of rituximab in the management of pediatric
systemic lupus erythematosus: a systematic review. J Pediatr. 2017;187:213-219.e2. doi:10.1016/j.jpeds.2017.
05.002
9. Bonanni A, Calatroni M, D’Alessandro M, et al. Adverse events linked with the use of chimeric and humanized
anti-CD20 antibodies in children with idiopathic nephrotic syndrome. Br J Clin Pharmacol. 2018;84(6):1238-1249.
doi:10.1111/bcp.13548
10. Chang WY, Chiu YC, Chiu FW, et al. High risk of clinical relapse in patients with chronic hepatitis B virus
infection after cessation of prophylactic antiviral therapy for rituximab-containing chemotherapy. J Infect Dis.
2020;222(8):1345-1352. doi:10.1093/infdis/jiaa256
11. Mert D, Merdin A, Ceken S, Sinan Dal M, Ertek M, Altuntas F. Development of pneumonitis after rituximab
treatment in a patient with lymphoma. J Oncol Pharm Pract. 2020;26(4):1009-1010. doi:10.1177/
1078155219879496
12. Berger JR, Malik V, Lacey S, Brunetta P, Lehane PB. Progressive multifocal leukoencephalopathy in rituximab-
treated rheumatic diseases: a rare event. J Neurovirol. 2018;24(3):323-331. doi:10.1007/s13365-018-0615-7
13. Weissmann-Brenner A, Brenner B, Belyaeva I, Lahav M, Rabizadeh E. Rituximab associated neutropenia:
description of three cases and an insight into the underlying pathogenesis. Med Sci Monit. 2011;17(11):CS133-CS137.
doi:10.12659/MSM.882034
14. Barmettler S, Ong M-S, Farmer JR, Choi H, Walter J. Association of immunoglobulin levels, infectious risk, and
mortality with rituximab and hypogammaglobulinemia. JAMA Netw Open. 2018;1(7):e184169. doi:10.1001/
jamanetworkopen.2018.4169
15. U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE)
v5.0. Published November 27, 2017. Accessed January 17, 2020. https://ctep.cancer.gov/protocoldevelopment/
electronic_applications/docs/ctcae_v5_quick_reference_5x7.pdf
16. Anagnostou K. Anaphylaxis in children: epidemiology, risk factors and management. Curr Pediatr Rev. 2018;14
(3):180-186. doi:10.2174/1573396314666180507115115
17. Andersen PK, Gill RD. Cox's regression model for counting processes: a large sample study. Ann Statistics.
1982;10(4):1100-1120. doi:10.1214/aos/1176345976
18. Sagara I, Giorgi R, Doumbo OK, Piarroux R, Gaudart J. Modelling recurrent events: comparison of statistical
models with continuous and discontinuous risk intervals on recurrent malaria episodes data. Malar J. 2014;13:293.
doi:10.1186/1475-2875-13-293
19. Stürmer T, Glynn RJ, Kliebsch U, Brenner H. Analytic strategies for recurrent events in epidemiologic studies:
background and application to hospitalization risk in the elderly. J Clin Epidemiol. 2000;53(1):57-64. doi:10.
1016/S0895-4356(99)00137-7
20. Agresti A. Categorical Data Analysis. 3rd ed. John Wiley & Sons; 2013.
21. Grambsch P, Therneau T. Proportional hazards tests and diagnostics based on weighted residuals. Biometrika.
1994;81:512-526. doi:10.1093/biomet/81.3.515
22. Therneau TM. survival: Survival Analysis. Accessed January 14, 2021. https://CRAN.R-project.org/package=survival
23. Bates D, Machler M, Bolker B, Walker S. Fitting linear mixed-effects models using lme4. J Stat Software. 2017;
67(1):1-48. doi:10.18637/jss.v067.i01
24. R Core Team. The R project for statistical computing. Updated November 2, 2020. Accessed December 20,
2020. https://www.R-project.org/
25. Iijima K, Sako M, Nozu K, et al; Rituximab for Childhood-onset Refractory Nephrotic Syndrome (RCRNS) Study
Group. Rituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-
dependent nephrotic syndrome: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet. 2014;
384(9950):1273-1281. doi:10.1016/S0140-6736(14)60541-9
26. Onrust SV, Lamb HM, Balfour JA. Rituximab. Drugs. 1999;58(1):79-88. doi:10.2165/00003495-
199958010-00009
27. Ahn YH, Kim SH, Han KH, et al. Efficacy and safety of rituximab in childhood-onset, difficult-to-treat nephrotic
syndrome: a multicenter open-label trial in Korea. Medicine (Baltimore). 2018;97(46):e13157-e13159. doi:10.1097/
MD.0000000000013157

JAMA Network Open. 2021;4(2):e2036321. doi:10.1001/jamanetworkopen.2020.36321 (Reprinted) February 3, 2021 12/13

Downloaded From: https://jamanetwork.com/ on 11/06/2022

 JAMA Network Open | Pediatrics Association of Rituximab Use With Adverse Events in Young People

28. Tony H-P, Burmester G, Schulze-Koops H, et al; GRAID investigators. Safety and clinical outcomes of rituximab
therapy in patients with different autoimmune diseases: experience from a national registry (GRAID). Arthritis Res
Ther. 2011;13(3):R75. doi:10.1186/ar3337
29. Kearsley-Fleet L, Sampath S, McCann LJ, et al. Use and effectiveness of rituximab in children and young people
with juvenile idiopathic arthritis in a cohort study in the United Kingdom. Rheumatology (Oxford). 2019;58(2):
331-335. doi:10.1093/rheumatology/key306
30. Prytuła A, Iijima K, Kamei K, et al. Rituximab in refractory nephrotic syndrome. Pediatr Nephrol. 2010;25(3):
461-468. doi:10.1007/s00467-009-1376-6
31. Hirano K, Tada M, Sasahira N, et al. Incidence of malignancies in patients with IgG4-related disease. Intern
Med. 2014;53(3):171-176. doi:10.2169/internalmedicine.53.1342
32. Fleury I, Chevret S, Pfreundschuh M, et al. Rituximab and risk of second primary malignancies in patients with
non-Hodgkin lymphoma: a systematic review and meta-analysis. Ann Oncol. 2016;27(3):390-397. doi:10.1093/
annonc/mdv616
33. Aksoy S, Arslan C, Harputluoglu H, Dizdar O, Altundag K. Malignancies after rituximab treatment: just
coincidence or more? J BUON. 2011;16(1):112-115.
34. Hauser SL, Waubant E, Arnold DL, et al; HERMES Trial Group. B-cell depletion with rituximab in relapsing-
remitting multiple sclerosis. N Engl J Med. 2008;358(7):676-688. doi:10.1056/NEJMoa0706383
35. Tambralli A, Beukelman T, Cron RQ, Stoll ML. Safety and efficacy of rituximab in childhood-onset systemic
lupus erythematosus and other rheumatic diseases. J Rheumatol. 2015;42(3):541-546. doi:10.3899/jrheum.
140863
36. Kivity S, Katz U, Daniel N, Nussinovitch U, Papageorgiou N, Shoenfeld Y. Evidence for the use of intravenous
immunoglobulins—a review of the literature. Clin Rev Allergy Immunol. 2010;38(2-3):201-269. doi:10.1007/
s12016-009-8155-9
37. Boughton BJ, Jackson N, Lim S, Smith N. Randomized trial of intravenous immunoglobulin prophylaxis for
patients with chronic lymphocytic leukaemia and secondary hypogammaglobulinaemia. Clin Lab Haematol. 1995;
17(1):75-80. doi:10.1111/j.1365-2257.1995.tb00322.x
38. Raanani P, Gafter-Gvili A, Paul M, Ben-Bassat I, Leibovici L, Shpilberg O. Immunoglobulin prophylaxis in
hematopoietic stem cell transplantation: systematic review and meta-analysis. J Clin Oncol. 2009;27(5):770-781.
doi:10.1200/JCO.2008.16.8450
39. Bass EB, Powe NR, Goodman SN, et al. Efficacy of immune globulin in preventing complications of bone
marrow transplantation: a meta-analysis. Bone Marrow Transplant. 1993;12(3):273-282.
40. Langereis JD, van der Flier M, de Jonge MI. Limited innovations after more than 65 years of immunoglobulin
replacement therapy: potential of IgA- and IgM-enriched formulations to prevent bacterial respiratory tract
infections. Front Immunol. 2018;9:1925. doi:10.3389/fimmu.2018.01925
41. Gupta S, Gupta A. Selective IgM deficiency—an underestimated primary immunodeficiency. Front Immunol.
2017;8:1056. doi:10.3389/fimmu.2017.01056
42. Ochs HD, Melamed I, Borte M, et al. Intravenous immunoglobulin 10% in children with primary
immunodeficiency diseases. Immunotherapy. 2018;10(14):1193-1202. doi:10.2217/imt-2018-0074
43. Mitchell C, Crayne CB, Cron RQ. Patterns of B cell repletion following rituximab therapy in a pediatric
rheumatology cohort. ACR Open Rheumatol. 2019;1(8):527-532. doi:10.1002/acr2.11074
44. Bedognetti D, Zoppoli G, Massucco C, et al. Impaired response to influenza vaccine associated with persistent
memory B cell depletion in non-Hodgkin’s lymphoma patients treated with rituximab-containing regimens.
J Immunol. 2011;186(10):6044-6055. doi:10.4049/jimmunol.1004095
45. Roll P, Palanichamy A, Kneitz C, Dorner T, Tony H-P. Regeneration of B cell subsets after transient B cell
depletion using anti-CD20 antibodies in rheumatoid arthritis. Arthritis Rheum. 2006;54(8):2377-2386. doi:10.
1002/art.22019
46. van Assen S, Holvast A, Benne CA, et al. Humoral responses after influenza vaccination are severely reduced
in patients with rheumatoid arthritis treated with rituximab. Arthritis Rheum. 2010;62(1):75-81. doi:10.1002/
art.25033

SUPPLEMENT.
eTable 1. Indications for Study Exclusion Among 276 Patients
eTable 2. Cox Proportional Hazards Model of Predictors of Severe Infections Following a Single Course of
Rituximab

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