Abstract

Rituximab and eculizumab, monoclonal antibodies that deplete most B cells and activate the terminal complement, respectively, are used to treat nonmalignant hematologic disorders (NMHDs), sometimes with unfavorable effects on the immune system. Hypogammaglobulinemia and neutropenia have been reported with variable prevalence in patients treated with rituximab. Neutropenia is mild and transient, and serious infectious complications are uncommon, so treatment is not indicated. Hypogammaglobulinemia is of greater concern. There is a lack of agreement on a standardized definition, and pre- and posttreatment immunoglobulin (Ig) levels are not routinely obtained. The association among low Ig levels, infectious risk, and mortality and morbidity in this population is unclear. There are also no formal guidelines on indication, risk factors, and threshold level of IgG to prompt Ig replacement therapy (IgRT). Among patients with NMHD, preexisting or persistent hypogammaglobulinemia (PH) after treatment with rituximab has been linked to underlying primary immunodeficiency disorders; therefore, a high index of suspicion should be maintained, and immunologic and genetic evaluation should be considered. Overall, important strategies in managing patients who are receiving rituximab include routine monitoring of pre- and posttreatment IgG levels, immune reconstitution (eg, B-cell subsets), assessment of vaccination status and optimization before treatment, and individualized consideration for IgRT. Accordingly, we discuss immunizations. Eculizumab, most commonly used in the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome, poses increased risk of meningococcal infections. To decrease the risk of infection, a meningococcal vaccination series is recommended before initiating therapy, and prophylactic antibiotics are preferred during the course of treatment.

Learning Objectives

  • Get familiar with adverse effects and risk factors of anti-CD20 (rituximab)–depleting therapies in NMHDs

  • Get familiar with adverse effects and risk factors of complement-inhibiting therapies (eculizumab, ravulizumab) in NMHDs

Introduction

Rituximab and eculizumab, monoclonal antibodies targeting CD20 and C5 complement, respectively, are off-label treatments for nonmalignant hematologic disorders (NMHDs), sometimes with unfavorable effects on the immune system. The increasing use of rituximab and eculizumab for a variety of conditions has given rise to important clinical questions regarding the best management practices for patients with NMHDs. Our discussion will focus on using these therapies to treat NMHDs. Specifically, we focus on the impact these treatments have on immunologic function and review the current understanding of infection risk, immunization recommendations, and antimicrobial prophylaxis needs of patients receiving these therapies. We highlight these clinical questions by discussing a patient case.

Clinical case

Our patient is a 16-year-old male diagnosed with acute warm autoimmune hemolytic anemia (AIHA) after he returned from a cruise with mild respiratory illness. He was initially treated with high-dose steroids and intravenous immunoglobulins (Ig’s), but he continued to have relapsing episodes of hemolysis. He was thus treated with a 4-dose course of rituximab and completely weaned off steroids; he partially responded with a low normal hemoglobin level and the absence of hemolysis. Complicating his clinical course was the presence of worsening infections, including hospitalization for pneumonia with respiratory distress. Basic immune status was monitored, and it revealed persistent moderate posttreatment hypogammaglobulinemia (lowest IgG level, 300 mg/dL), and pre- and post-rituximab lymphopenia. This prompted referral to the conjoint clinic with hematologists and immunologists where he underwent an extensive work-up that revealed a weak response to pneumococcal vaccination and increased double-negative TCRab+ T cells. The primary immunodeficiency (PID) genetic panel revealed a pathogenic variant in the FAS gene, which has been associated with autoimmune lymphoproliferative syndrome. Checking his history more closely revealed an uncle who died of sepsis after splenectomy for chronic immune thrombocytopenia (ITP). Within 2 years of presenting with AIHA, he also developed ITP, now being classified as Evans syndrome (ES). Because he had persistent hypogammaglobulinemia (PH) with infections, Ig replacement therapy (IgRT) was initiated with good effect. ES responded to mTOR inhibitor therapy. While receiving IgRT, the patient could not receive routine immunizations except the yearly influenza vaccine (Figure 1). This case raises several important clinical questions for risk related to the use of rituximab in NMHD and the need for evaluation for underlying PID in selected cases. These considerations will be the focus of our discussion.

Figure 1.

Diagnostic and treatment saga of a 16-year-old with autoimmune cytopenias. Diagnostic evaluation and steps of managements are color-coded (hematology in red, infection in green, and specific immune defect in yellow). AB, antibody; ALPS, autoimmune lymphoproliferative disease; ct, count; DNT, double negative T cell; HD, high dose; IvIg, intravenous Ig; plt, platelet; RTx, replacement therapy.

Figure 1.

Diagnostic and treatment saga of a 16-year-old with autoimmune cytopenias. Diagnostic evaluation and steps of managements are color-coded (hematology in red, infection in green, and specific immune defect in yellow). AB, antibody; ALPS, autoimmune lymphoproliferative disease; ct, count; DNT, double negative T cell; HD, high dose; IvIg, intravenous Ig; plt, platelet; RTx, replacement therapy.

Implications of rituximab (anti-CD20) treatment

Rituximab is a B-cell–depleting therapy used to treat malignant and nonmalignant conditions across several specialties.1  Rituximab works by binding the CD20 antigen expressed on most circulating B cells except plasma cells and results in B-cell destruction through complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and induction of apoptosis.2,3 Figure 2 demonstrates the effect of rituximab and other B-cell–depleting therapies on the B-cell lineage. Rituximab was initially developed for treating non-Hodgkin lymphoma, but it has since gained approval by the US Food and Drug Administration (FDA) for treating chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis in adults. The list of off-label uses is even longer and includes diseases such as nephrotic syndrome, acquired thrombotic thrombocytopenic purpuraP, acquired factor VIII inhibitors, autoimmune cytopenias (AICs) including ITP, AIHA, or its combination (ES).4-7 

Figure 2.

Biologicals targeting B-cell subsets or antibody-mediated immune response. A large selection of antibodies targeting B-cell epitopes, proteosomes, or the complement system are available for therapy in a variety of autoimmune diseases, including NMHDs. Our review focuses on rituximab (anti-CD20) and eculizumab (anti-C5). Shown are mechanisms of targeting B-cell pathology in the treatment of autoimmune and inflammatory diseases associated with PID. Monoclonal antibodies and mechanisms of action are highlighted. Adapted from Walter et al.15 

Figure 2.

Biologicals targeting B-cell subsets or antibody-mediated immune response. A large selection of antibodies targeting B-cell epitopes, proteosomes, or the complement system are available for therapy in a variety of autoimmune diseases, including NMHDs. Our review focuses on rituximab (anti-CD20) and eculizumab (anti-C5). Shown are mechanisms of targeting B-cell pathology in the treatment of autoimmune and inflammatory diseases associated with PID. Monoclonal antibodies and mechanisms of action are highlighted. Adapted from Walter et al.15 

PH secondary to rituximab

The prevalence of hypogammaglobulinemia secondary to rituximab for the treatment of NMHD is highly variable in recent reports (Table 1).1,8-11  As an example, in the context of ITP, Levy et al8  summarized the experience of 32 studies (prospective and retrospective) and showed a very low rate of hypogammaglobulinemia. Conversely, in a cohort of pediatric patients treated with rituximab for AIC, the prevalence of PH was 32%.12  One contributing factor for this variability is the lack of agreement on a definition of hypogammaglobulinemia. Two studies of adult patients8,10  defined hypogammaglobulinemia (IgG <500 mg/dL) differently: one study used <600 mg/dL1  and another used a higher cutoff of <800 mg/dL with the highest incidence of hypogammaglobulinemia (8 [44%] of 18 patients),9  as expected. Only 1 recent study reported outcomes on a solely pediatric cohort with a cutoff based on age-appropriate IgG level.12  Other studies included pediatric patients, but the prevalence of hypogammaglobulinemia was not reported by age.

Table 1.

Studies describing prevalence of hypogammaglobulinemia secondary to rituximab and infections in patients with NMHDs

StudyPopulationNDefinition of hypoG (IgG)Prevalence of hypogGFollow-up periodPrevalence of infectionComments
Rao et al, 200911  ITP, AIHA among adult and pediatric patients with ALPS 12  3 (25%) of 12 8 y  All were treated with IVIg; 1 additional patient had total absence of antibody response to polysaccharide vaccines for 4 years; 10 of 12 patients were age 18 years or younger 
Levy et al, 20148  ITP, adult and pediatric patients 189 <500 mg/dL 3 (1.6%) of 189 12 y 3 of 3 patients had recurrent severe infections 2 of 3 patients were later diagnosed with CVID 
  192*  21 of 192* 16 (50%) of 32 of studies had >1 y of follow-up 5 of 192* patients had frequent minor infections IgG levels, when tested, were normal before initiation of rituximab; 1 of 21 patients with hypoG was later diagnosed with CVID 
Reboursiere et al, 20169  ITP, mostly adult patients (2 patients younger than age 18 years) 35 <800 mg/dL; severe, <500 mg/dL 8 (44%) of 18; 1 severe Median, 47 mo No patients were known to have hypoG; 2 of 35 had pneumonia; 3 patients had hypoG before initiation of rituximab and hypoG remained after treatment but did not become severe; 1 patient developed severe hypoG and had normal pre-treatment levels of IgG 
1 of 35 had recurrent herpes 
Barmettler et al, 20181  Hematologic disorder, adult patients 340 <600 mg/dL; mild: 400-599 mg/dL; moderate: 200-399 mg/dL; severe: <199 mg/dL 26 (7.6%) of 340; moderate or severe 18 mo Infection rate in the 6 months before rituximab was 24.1% and after rituximab, it was 23.8% (P = .98) 33 (9.7%) of 340 patients received IgRT after treatment with rituximab 
Deshayes et al, 201910  ITP, adult patients 248 <500 mg/dL 5 (3.5%) of 142 5 y 59 (23.8%) of 248 patients; 21 (8.5%) had severe infection 142 (57%) of 248 patients had IgG levels; 1 patient with known hypoG developed infection 
Ottaviano et al, 202012  ITP, AIHA, ES; pediatric patients only, exclusion criteria was preexisting PID 53 IgG <2 SD for age 17 (32%) of 53 Mean, 30 mo 7 (12%) of 53 patients had infections requiring hospitalization; 9 (17%) of 53 patients were later diagnosed with PID 
8 (15%) of 53 had recurrent respiratory infections 
StudyPopulationNDefinition of hypoG (IgG)Prevalence of hypogGFollow-up periodPrevalence of infectionComments
Rao et al, 200911  ITP, AIHA among adult and pediatric patients with ALPS 12  3 (25%) of 12 8 y  All were treated with IVIg; 1 additional patient had total absence of antibody response to polysaccharide vaccines for 4 years; 10 of 12 patients were age 18 years or younger 
Levy et al, 20148  ITP, adult and pediatric patients 189 <500 mg/dL 3 (1.6%) of 189 12 y 3 of 3 patients had recurrent severe infections 2 of 3 patients were later diagnosed with CVID 
  192*  21 of 192* 16 (50%) of 32 of studies had >1 y of follow-up 5 of 192* patients had frequent minor infections IgG levels, when tested, were normal before initiation of rituximab; 1 of 21 patients with hypoG was later diagnosed with CVID 
Reboursiere et al, 20169  ITP, mostly adult patients (2 patients younger than age 18 years) 35 <800 mg/dL; severe, <500 mg/dL 8 (44%) of 18; 1 severe Median, 47 mo No patients were known to have hypoG; 2 of 35 had pneumonia; 3 patients had hypoG before initiation of rituximab and hypoG remained after treatment but did not become severe; 1 patient developed severe hypoG and had normal pre-treatment levels of IgG 
1 of 35 had recurrent herpes 
Barmettler et al, 20181  Hematologic disorder, adult patients 340 <600 mg/dL; mild: 400-599 mg/dL; moderate: 200-399 mg/dL; severe: <199 mg/dL 26 (7.6%) of 340; moderate or severe 18 mo Infection rate in the 6 months before rituximab was 24.1% and after rituximab, it was 23.8% (P = .98) 33 (9.7%) of 340 patients received IgRT after treatment with rituximab 
Deshayes et al, 201910  ITP, adult patients 248 <500 mg/dL 5 (3.5%) of 142 5 y 59 (23.8%) of 248 patients; 21 (8.5%) had severe infection 142 (57%) of 248 patients had IgG levels; 1 patient with known hypoG developed infection 
Ottaviano et al, 202012  ITP, AIHA, ES; pediatric patients only, exclusion criteria was preexisting PID 53 IgG <2 SD for age 17 (32%) of 53 Mean, 30 mo 7 (12%) of 53 patients had infections requiring hospitalization; 9 (17%) of 53 patients were later diagnosed with PID 
8 (15%) of 53 had recurrent respiratory infections 

ALPS, autoimmune lymphoproliferative syndrome; CVID, common variable immune deficiency; hypoG: hypogammaglobulinemia; IVIg, intravenous Ig; SD, standard deviation.

*

Pooled numbers from systematic review.

The duration of time with hypogammaglobulinemia after treatment with rituximab is of importance. Ottavio et al12  defined PH as 2 standard deviations below the age-appropriate cutoff 12 months after the last dose of rituximab. Children with PH were more likely to have low or slow recovery of IgM and IgA levels and impaired B-cell immune reconstitution. Risk factors for PH included younger age (on average, age 4 years), diagnosis of AIHA/ES vs ITP, and lower IgA and IgM levels before therapy. In fact, a high fraction of patients with PH (53%) were diagnosed with an underlying PID. Curiously, pretreatment lymphocyte counts (T and B cells) and IgG level were not significantly lower among pediatric patients with PH. In this cohort, a history of autoimmune manifestations other than AIC was a risk factor; however, additional immunosuppressants were not associated with PH. Another pediatric study of 63 children with a variety of autoimmune conditions reported that 44% of patients developed hypogammaglobulinemia, and 61% evolved into PH for more than 6 months.13 

Among adults with NMHD who received rituximab, there is a lack of in-depth studies regarding risk factors for developing PH. Conversely, studies in patients with malignancies and rheumatologic disease identify several risk factors for PH, including number of doses of rituximab, older age, use of chemotherapeutic agents, and low IgM at 12 months after rituximab.14,15 

Without routine screening of pre- and posttreatment Ig levels, the detection of hypogammaglobulinemia is likely underreported. In a large cohort of nearly 4500 patients treated with rituximab (with a variety of disorders, including 340 with NMHD), the majority did not have their Ig levels checked before therapy was initiated (85%) or within 18 months after starting therapy (87.5%).1  Of the 15% of patients for whom pretreatment Ig levels were available, nearly half had hypogammaglobulinemia before rituximab was initiated. Among patients with normal Ig levels before treatment, 19% went on to develop mild to severe hypogammaglobulinemia within 18 months of therapy initiation, which qualified them for a diagnosis of PH. Hypogammaglobulinemia also worsened for a portion of patients who had low Ig levels before treatment (23% of patients with mild hypogammaglobulinemia before treatment with rituximab evolved to a moderate or severe category after treatment with rituximab, whereas 21% of patients with moderate hypogammaglobulinemia before treatment with rituximab developed a severe category after treatment with rituximab).1 

To summarize, the prevalence rates and risk factors for transient hypogammaglobulinemia and PH are variable and likely depend on the specific NMHD (eg, ITP vs ES), age of the patient, concomitant immunosuppressive therapy, and underlying PID. Standardizing the definition of hypogammaglobulinemia is essential to better understanding its prevalence and risk factors.

Risk of infection with hypogammaglobulinemia after treatment with rituximab and immunization strategies

When considering our patient, it was important to determine whether the observed hypogammaglobulinemia was associated with an increased risk of infections and whether he might benefit from IgRT. Much of the published literature discussing the risk of infections after treatment with rituximab includes cohorts of adult rheumatology and oncology patients.

Several studies have reported high rates of infections among patients with lymphoma who were treated with rituximab (16.7%-43%).16-19  Infection rates were slightly lower among studies of rheumatologic patients (7%-31%).19-23  Considering NMHD specifically, the infection rates seem to be lower than in rheumatologic or oncologic disorders (Table 1). Among 248 adult patients with ITP treated with rituximab, Deshayes et al10  reported an overall infection rate of 24% and a severe infection rate of 8%. Severe infections included sepsis, pyelonephritis, pneumonia, and sinus and skin or soft tissue infections by Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Enterobacter cloacae, and Pneumocystis jirovecii. There were no reported cases of progressive multifocal leukoencephalopathy. In comparison, Barmettler et al1  reported no significant difference in infection rates before or after initiation of rituximab among adult patients with NMHD; however, there was a trend toward increase in the fraction of patients with severe infections (9% [at less than 12 months after rituximab initiation] vs 15% [at more than 12 months after rituximab initiation]). In the same study, patients had a higher risk of mortality if they had history of serious infections either before and/or after rituximab.1 

In a pediatric cohort of 53 children treated for AIC, 15% developed recurrent respiratory infections and 12% required hospitalization for infections.12  In a US-based national study of more than 2800 pediatric patients treated with rituximab, including 1057 with autoimmunity (359 with AIC [AIHA, ITP, ES] and 284 with PID), a high proportion of patients had at least 1 episode of infection during the 1-year study period (573 [54%] of 1057 in the autoimmunity group and 82 [32%] of 284 in the PID group). Although the PID group had fewer overall infections, they experienced more severe infections (eg, sepsis and herpes).24 

Rituximab is often effective in treating Epstein-Barr virus infections because it resides in B cells. However, there have been reports of reactivation of other viruses, including hepatitis B virus (HBV), herpes simplex virus (HSV), and varicella-zoster virus (VZV), after initiation of rituximab treatment.25  With the exception of HBV, evidence is lacking and there is no general recommendation to support the use of prophylactic acyclovir or valacyclovir to prevent HSV or VZV reactivation.26  In addition, although it is rare, human polyomavirus 2 (commonly referred to as the JC virus or John Cunningham virus) and associated progressive multifocal leukoencephalopathy have been reported and are associated with high mortality rates. Providers should be aware of this potentially fatal infection, which presents with progressive neurologic deficits, which would be a reason for discontinuing rituximab.27 

HVB reactivation.

HVB reactivation has been reported as a serious complication in patients receiving rituximab.26,28  The American Gastroenterological Association published guidelines on the prevention and treatment of HBV reactivation for patients receiving immunosuppressive treatment. According to their guidelines, they classified patients who are hepatitis B surface antigen (HBsAg)–positive/anti-hepatitis B core antibody (HBcAb)–positive or HBsAg-negative/anti-HBcAb–positive and who are receiving treatment with B-cell–depleting agents such as rituximab to be high risk with a greater than 10% risk of HBV reactivation. Thus, patients who are anticipating starting rituximab should be screened for HBV with HBsAg and anti-HBcAb. For patients who are HBsAg-positive or anti-HBcAb-positive with a positive viral load, antiviral prophylaxis is recommended for at least 12 months for patients receiving B-cell–depleting therapies. Sandherr et al26  proposed using lamivudine for HBV prophylaxis in patients with low viral loads and short duration of immunosuppressive therapy. However, in patients with high viral loads (>2000 IU/mL) or anticipated longer duration of therapy (>12 months), an alternative agent such as entecavir or tenofovir are preferred because of the higher resistance rates associated with lamivudine.

Immunizations.

Before rituximab treatment is initiated, immunization status should be assessed. Given that functional B cells are required to develop a robust immune response to vaccination, any pending immunizations should be administered before therapy is initiated. Patients should also be counseled that they might potentially be unresponsive to vaccines after they have been treated with rituximab.25  Nazi et al29  demonstrated that responsiveness to both pneumococcal polysaccharide vaccine and Haemophilus influenzae type b (Hib) conjugate vaccines was impaired for at least 6 months after treatment with rituximab. Additional consideration should be given to patients with NMHD who need to increase their therapy before splenectomy. These patients will be susceptible to encapsulated bacterial infections, and vaccination with polysaccharide and conjugate vaccines against S pneumoniae, H influenzae, and Neisseria meningitidis should be performed before the splenectomy. All patients should continue to receive their annual influenza vaccine. For patients who require IgRT to treat hypogammaglobulinemia, immunizations should be suspended until 6 months after completion of therapy.

Management of PH after treatment with rituximab

There are no formal guidelines and no agreement on the intervention threshold level of IgG or length of treatment for hypogammaglobulinemia before starting IgRT in post-rituximab hypogammaglobulinemia in patients with NMHD. In addition, there is no evidence supporting the use of prophylactic antibiotics for these patients, or any randomized trials that compare antibiotic prophylaxis vs IgRT to prevent infection.30 

One study reported no correlation between IgRT and occurrence of serious infectious complications among hematology patients1 ; in contrast, the association for patients with cancer or rheumatologic diseases was significant.1,15,22,31 

In some cases, the development of hypogammaglobulinemia after treatment with rituximab has led to the diagnosis of an underlying PID.32  Certain autoimmune conditions such as ITP or AIHA may even precede the diagnosis of a PID, as reported among patients with common variable immune deficiency33  and combined immunodeficiencies such as recombination-activating gene defects.34,35  In fact, a recent national study from France has identified monogenic PID in 32 (40%) of 80 patients with ES (age 1.2-41 years).36  In the Italian/United Kingdom pediatric cohort, 9 (17%) of 53 children (age 1-4 years) with AIC who had received treatment with rituximab were diagnosed with PID, even though previously diagnosed PID was an exclusion criteria. The children with PIDs were overrepresented in the PH group (53%).36  Thus, a high level of suspicion for PID should be maintained for patients with ES and those pediatric patients with AIC who develop PH after treatment with rituximab.

Rituximab-associated neutropenia

Late-onset neutropenia has been reported as a benign complication of rituximab therapy, although the mechanism is poorly understood and the literature is limited. A recent study reported that 18% of 197 adult patients with NMHD developed neutropenia after treatment with rituximab (absolute neutrophil count [ANC] ≤1500 cells per mL), of which only 4% were severe (ANC ≤500 cells per mL).37  Despite the presence of neutropenia, there were no episodes of febrile neutropenia and only 2 documented infections.37  Patients who received ≥4 doses of rituximab or combination therapy with rituximab and another immunosuppressant were at greater risk of developing neutropenia and tended to develop a lower median ANC nadir (400 cells per mL).37  These data correlate with a previous systematic review that reported an incidence of neutropenia ranging from 3% to 27% across studies. Onset of neutropenia was often delayed, but duration was limited (38-175 days from the last rituximab dose [duration of 5-77 days]).38  Any associated infections were mild. It is likely that rechallenging with rituximab after an episode of neutropenia will result in additional episodes; however, the clinical significance of this is unclear.37 

There is no evidence to support the routine use of granulocyte colony-stimulating factor or prophylactic antibiotics for patients with NMHD who develop neutropenia while they are receiving rituximab. Kanbayashi et al39  reported an increased risk of infection with the use of granulocyte colony-stimulating factor in lymphoma patients who were receiving rituximab. Close monitoring for resolution is recommended, and additional interventions should be determined on a case-by-case basis.

Complement inhibitors and implications of treatment

Eculizumab and ravulizumab are monoclonal antibodies that target complement protein C5 and prevent the activation of the terminal complement complex C5b-9. Eculizumab is FDA-approved for managing several specific conditions, including paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and refractory generalized myasthenia gravis; however, off-label exploratory use has increased to 39 distinct indications, including AIHA.40  Eculizumab requires frequent dosing (injections every 2 weeks), so ravulizumab was approved by the FDA in 2018 with a similar mechanism of action but a better pharmacologic profile allowing for maintenance dosing every 8 weeks.41  In phase 3 trials, ravulizumab was noninferior to eculizumab in efficacy and safety and thus may be replacing eculizumab as first-line therapy for paroxysmal nocturnal hemoglobinuria because of its more convenient dosing schedule.41-43  Patients receiving eculizumab are at 1000 to 2000 times greater risk of invasive meningococcal infection compared with healthy individuals. Thus the Advisory Committee on Immunization Practices recommends that all patients receive the quadrivalent meningococcal conjugate vaccine and serogroup B meningococcal vaccine at least 2 weeks before initiating eculizumab.44  Vaccination alone, however, may not be sufficient to prevent meningococcal infections, so the use of antibiotic prophylaxis with penicillin is recommended for the duration of eculizumab therapy.45  Patients should be counseled to seek medical attention when signs or symptoms of meningococcal infection develop. Ravulizumab also carries a black box warning for serious meningococcal infection based on results of a phase 2 study in which 2 patients developed meningococcal infection.46  Thus, we recommend that patients receiving ravulizumab also receive the same vaccinations and antibiotic prophylaxis as patients receiving eculizumab.

Summary and recommendations

As demonstrated in our case presentation and discussion, there are several important clinical considerations when planning to use rituximab in treating NMHD. Treatment-associated effects include susceptibility for infections and transient or persistent modulation of the immune system. Standardizing the definition of hypogammaglobulinemia, close follow-up of pretreatment immune status, and immune reconstitution (ie, Ig testing, B-cell subset monitoring) are important steps toward recognizing and treating complications and prompting further evaluation for underlying PID. We propose the following recommendations: (1) Assess the vaccination status for all patients and administer vaccinations for S pneumoniae, H influenzae, and N meningitidis if needed before initiating therapy. (2) Screen for HBV infection with HBsAg and anti-HBcAb before initiating therapy. Initiate antiviral prophylaxis for those who are positive. (3) Assess baseline immunologic function before initiating therapy with Ig levels and B-cell subsets. We recommend monitoring Ig levels and B-cell subsets regularly (eg, at 6-month intervals). Patients with preexisting hypogammaglobulinemia or those who develop frequent or severe infections may warrant more frequent monitoring. (4) For patients with prolonged hypogammaglobulinemia after rituximab therapy, we recommend further immunologic evaluation to determine whether there is an underlying PID, particularly in pediatric patients. (5) Consideration for patients with IgRT is unclear, but we recommend this intervention early when infections occur.

Patients who will be treated with complement inhibitors are at increased risk for invasive meningococcal infections. We thus recommend the following for patients being treated with eculizumab or ravulizumab: (1) Assess vaccination status for all patients and administer vaccinations for N meningitidis if needed before initiating treatment. (2) Use antibiotic prophylaxis with penicillin for the duration of therapy. (3) Educate patients on the signs and symptoms of meningococcal infections.

Correspondence

Jolan E. Walter, University of South Florida, 601 4th St South (CRI 4008), St. Petersburg, FL 33701; e-mail: jolanwalter@usf.edu.

References

References
1.
Barmettler
S
,
Ong
MS
,
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
.
2.
Johnson
P
,
Glennie
M
.
The mechanisms of action of rituximab in the elimination of tumor cells
.
Semin Oncol
.
2003
;
30
(
1 suppl 2
):
3
-
8
.
3.
Kimby
E
.
Tolerability and safety of rituximab (MabThera)
.
Cancer Treat Rev
.
2005
;
31
(
6
):
456
-
473
.
4.
Michel
M
,
Terriou
L
,
Roudot-Thoraval
F
, et al
.
A randomized and double-blind controlled trial evaluating the safety and efficacy of rituximab for warm auto-immune hemolytic anemia in adults (the RAIHA study)
.
Am J Hematol
.
2017
;
92
(
1
):
23
-
27
.
5.
Berentsen
S
,
Ulvestad
E
,
Gjertsen
BT
, et al
.
Rituximab for primary chronic cold agglutinin disease: a prospective study of 37 courses of therapy in 27 patients
.
Blood
.
2004
;
103
(
8
):
2925
-
2928
.
6.
Stiakaki
E
,
Perdikogianni
C
,
Thomou
C
, et al
.
Idiopathic thrombocytopenic purpura in childhood: twenty years of experience in a single center
.
Pediatr Int
.
2012
;
54
(
4
):
524
-
527
.
7.
Bader-Meunier
B
,
Aladjidi
N
,
Bellmann
F
, et al
.
Rituximab therapy for childhood Evans syndrome
.
Haematologica
.
2007
;
92
(
12
):
1691
-
1694
.
8.
Levy
R
,
Mahévas
M
,
Galicier
L
, et al
.
Profound symptomatic hypogammaglobulinemia: a rare late complication after rituximab treatment for immune thrombocytopenia. Report of 3 cases and systematic review of the literature
.
Autoimmun Rev
.
2014
;
13
(
10
):
1055
-
1063
.
9.
Reboursiere
E
,
Fouques
H
,
Maigne
G
, et al
.
Rituximab salvage therapy in adults with immune thrombocytopenia: retrospective study on efficacy and safety profiles
.
Int J Hematol
.
2016
;
104
(
1
):
85
-
91
.
10.
Deshayes
S
,
Khellaf
M
,
Zarour
A
, et al
.
Long-term safety and efficacy of rituximab in 248 adults with immune thrombocytopenia: Results at 5 years from the French prospective registry ITP-ritux
.
Am J Hematol
.
2019
;
94
(
12
):
1314
-
1324
.
11.
Rao
VK
,
Price
S
,
Perkins
K
, et al
.
Use of rituximab for refractory cytopenias associated with autoimmune lymphoproliferative syndrome (ALPS)
.
Pediatr Blood Cancer
.
2009
;
52
(
7
):
847
-
852
.
12.
Ottaviano
G
,
Marinoni
M
,
Graziani
S
, et al
.
Rituximab unveils hypogammaglobulinemia and immunodeficiency in children with autoimmune cytopenia
.
J Allergy Clin Immunol Pract
.
2020
;
8
(
1
):
273
-
282
.
13.
Khojah
AM
,
Miller
ML
,
Klein-Gitelman
MS
, et al
.
Rituximab-associated Hypogammaglobulinemia in pediatric patients with autoimmune diseases
.
Pediatr Rheumatol Online J
.
2019
;
17
(
1
):
61
.
14.
Reddy
V
,
Martinez
L
,
Isenberg
DA
,
Leandro
MJ
,
Cambridge
G
.
Pragmatic treatment of patients with systemic lupus erythematosus with rituximab: Long-term effects on serum immunoglobulins
.
Arthritis Care Res (Hoboken)
.
2017
;
69
(
6
):
857
-
866
.
15.
Casulo
C
,
Maragulia
J
,
Zelenetz
AD
.
Incidence of hypogammaglobulinemia in patients receiving rituximab and the use of intravenous immunoglobulin for recurrent infections
.
Clin Lymphoma Myeloma Leuk
.
2013
;
13
(
2
):
106
-
111
.
16.
Cabanillas
F
,
Liboy
I
,
Pavia
O
,
Rivera
E
.
High incidence of non-neutropenic infections induced by rituximab plus fludarabine and associated with hypogammaglobulinemia: a frequently unrecognized and easily treatable complication
.
Ann Oncol
.
2006
;
17
(
9
):
1424
-
1427
.
17.
De Angelis
F
,
Tosti
ME
,
Capria
S
, et al
.
Risk of secondary hypogammaglobulinaemia after rituximab and fludarabine in indolent non-Hodgkin lymphomas: A retrospective cohort study
.
Leuk Res
.
2015
;
39
(
12
):
1382
-
1388
.
18.
Nishio
M
,
Endo
T
,
Fujimoto
K
, et al
.
FCGR3A-158V/F polymorphism may correlate with the levels of immunoglobulin in patients with non-Hodgkin’s lymphoma after rituximab treatment as an adjuvant to autologous stem cell transplantation
.
Eur J Haematol
.
2009
;
82
(
2
):
143
-
147
.
19.
Makatsori
M
,
Kiani-Alikhan
S
,
Manson
AL
, et al
.
Hypogammaglobulinaemia after rituximab treatment-incidence and outcomes
.
QJM
.
2014
;
107
(
10
):
821
-
828
.
20.
Aguiar
R
,
Araújo
C
,
Martins-Coelho
G
,
Isenberg
D
.
Use of rituximab in systemic lupus erythematosus: A single center experience over 14 years
.
Arthritis Care Res (Hoboken)
.
2017
;
69
(
2
):
257
-
262
.
21.
Besada
E
.
Low immunoglobulin levels increase the risk of severe hypogammaglobulinemia in granulomatosis with polyangiitis patients receiving rituximab
.
BMC Musculoskelet Disord
.
2016
;
17
(
1
):
6
.
22.
Roberts
DM
,
Jones
RB
,
Smith
RM
, et al
.
Immunoglobulin G replacement for the treatment of infective complications of rituximab-associated hypogammaglobulinemia in autoimmune disease: a case series
.
J Autoimmun
.
2015
;
57
:
24
-
29
.
23.
Venhoff
N
,
Effelsberg
NM
,
Salzer
U
, et al
.
Impact of rituximab on immunoglobulin concentrations and B cell numbers after cyclophosphamide treatment in patients with ANCA-associated vasculitides
.
PLoS One
.
2012
;
7
(
5
):
e37626
.
24.
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.e1
.
25.
Malpica
L
,
van Duin
D
,
Moll
S
.
Preventing infectious complications when treating non-malignant immune-mediated hematologic disorders
.
Am J Hematol
.
2019
;
94
(
12
):
1396
-
1412
.
26.
Sandherr
M
,
Hentrich
M
,
von Lilienfeld-Toal
M
, et al
.
Antiviral prophylaxis in patients with solid tumours and haematological malignancies–update of the Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO)
.
Ann Hematol
.
2015
;
94
(
9
):
1441
-
1450
.
27.
Carson
KR
,
Focosi
D
,
Major
EO
, et al
.
Monoclonal antibody-associated progressive multifocal leucoencephalopathy in patients treated with rituximab, natalizumab, and efalizumab: a Review from the Research on Adverse Drug Events and Reports (RADAR) Project
.
Lancet Oncol
.
2009
;
10
(
8
):
816
-
824
.
28.
Reddy
KR
,
Beavers
KL
,
Hammond
SP
,
Lim
JK
,
Falck-Ytter
YT
;
American Gastroenterological Association Institute
.
American Gastroenterological Association Institute guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy
.
Gastroenterology
.
2015
;
148
(
1
):
215
-
219
.
29.
Nazi
I
,
Kelton
JG
,
Larché
M
, et al
.
The effect of rituximab on vaccine responses in patients with immune thrombocytopenia
.
Blood
.
2013
;
122
(
11
):
1946
-
1953
.
30.
Wijetilleka
S
,
Mukhtyar
C
,
Jayne
D
, et al
.
Immunoglobulin replacement for secondary immunodeficiency after B-cell targeted therapies in autoimmune rheumatic disease: Systematic literature review
.
Autoimmun Rev
.
2019
;
18
(
5
):
535
-
541
.
31.
Marco
H
,
Smith
RM
,
Jones
RB
, et al
.
The effect of rituximab therapy on immunoglobulin levels in patients with multisystem autoimmune disease
.
BMC Musculoskelet Disord
.
2014
;
15
(
1
):
178
.
32.
Barmettler
S
,
Price
C
.
Continuing IgG replacement therapy for hypogammaglobulinemia after rituximab–for how long?
J Allergy Clin Immunol
.
2015
;
136
(
5
):
1407
-
1409
.
33.
Cunningham-Rundles
C
.
Autoimmune manifestations in common variable immunodeficiency
.
J Clin Immunol
.
2008
;
28
(
suppl 1
):
S42
-
S45
.
34.
Farmer
JR
,
Foldvari
Z
,
Ujhazi
B
, et al
.
Outcomes and treatment strategies for autoimmunity and hyperinflammation in patients with RAG deficiency
.
J Allergy Clin Immunol Pract
.
2019
;
7
(
6
):
1970
-
1985.e4
.
35.
Walter
JE
,
Farmer
JR
,
Foldvari
Z
,
Torgerson
TR
,
Cooper
MA
.
Mechanism-based strategies for the management of autoimmunity and immune dysregulation in primary immunodeficiencies
.
J Allergy Clin Immunol Pract
.
2016
;
4
(
6
):
1089
-
1100
.
36.
Hadjadj
J
,
Aladjidi
N
,
Fernandes
H
, et al
;
members of the French Reference Center for Pediatric Autoimmune Cytopenia (CEREVANCE)
.
Pediatric Evans syndrome is associated with a high frequency of potentially damaging variants in immune genes
.
Blood
.
2019
;
134
(
1
):
9
-
21
.
37.
Malpica Castillo
LE
,
Palmer
S
,
Zhu
A
,
Deal
AM
,
Chen
SL
,
Moll
S
.
Incidence and time course of neutropenia in patients treated with rituximab-based therapy for non-malignant immune-mediated hematologic diseases
.
Am J Hematol
.
2020
;
95
(
5
):
E117
-
E120
.
38.
Wolach
O
,
Bairey
O
,
Lahav
M
.
Late-onset neutropenia after rituximab treatment: case series and comprehensive review of the literature
.
Medicine (Baltimore)
.
2010
;
89
(
5
):
308
-
318
.
39.
Kanbayashi
Y
,
Nomura
K
,
Fujimoto
Y
, et al
;
Japan Haematology/Oncology Study (J-HOST) Group
.
Risk factors for infection in haematology patients treated with rituximab
.
Eur J Haematol
.
2009
;
82
(
1
):
26
-
30
.
40.
Kim
MS
,
Prasad
V
.
The clinical trials portfolio for on-label and off-label studies of eculizumab
.
JAMA Intern Med
.
2019
;
180
(
2
):
315
-
317
.
41.
Stern
RM
,
Connell
NT
.
Ravulizumab: a novel C5 inhibitor for the treatment of paroxysmal nocturnal hemoglobinuria
.
Ther Adv Hematol
.
2019
;
10
:
2040620719874728
.
42.
Lee
JW
,
Sicre de Fontbrune
F
,
Wong Lee Lee
L
, et al
.
Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study
.
Blood
.
2019
;
133
(
6
):
530
-
539
.
43.
Kulasekararaj
AG
,
Hill
A
,
Rottinghaus
ST
, et al
.
Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study
.
Blood
.
2019
;
133
(
6
):
540
-
549
.
44.
O’Leary
ST
,
Kimberlin
DW
.
Update From the Advisory Committee on Immunization Practices
.
J Pediatric Infect Dis Soc
.
2017
;
6
(
4
):
311
-
316
.
45.
McNamara
LA
,
Topaz
N
,
Wang
X
,
Hariri
S
,
Fox
L
,
MacNeil
JR
.
High risk for invasive meningococcal disease among patients receiving eculizumab (Soliris) despite receipt of meningococcal vaccine
.
MMWR Morb Mortal Wkly Rep
.
2017
;
66
(
27
):
734
-
737
.
46.
Röth
A
,
Rottinghaus
ST
,
Hill
A
, et al
.
Ravulizumab (ALXN1210) in patients with paroxysmal nocturnal hemoglobinuria: results of 2 phase 1b/2 studies
.
Blood Adv
.
2018
;
2
(
17
):
2176
-
2185
.

Competing Interests

Conflict-of-interest disclosure: J.E.W. is a consultant to Takeda, CSL-Behring, and X4 Pharmaceuticals; received investigator-initiated grants from X4 Pharmaceuticals, and serves as principal investigator on clinical trials sponsored by Takeda, Octapharma, Lediant, and Momenta. E.E. declares no competing financial interests.

Author notes

Off-label drug use: None disclosed.