Rituximab and eculizumab when treating nonmalignant hematologic disorders: infection risk, immunization recommendations, and antimicrobial prophylaxis needs

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.

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.

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 

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 patients^8,10  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.

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.

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 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.

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.

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.

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.

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.

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.

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