Quality and Safety Intervention: Improving Care of Patients Undergoing B-cell Targeted Therapies

Abstract

B-cell targeted therapies (BCTT) are increasingly being used with excellent efficacy across a range of conditions and specialties, including autoimmune diseases and hematologic malignancies. However, with these BCTT, there is the potential for hypogammaglobulinemia and increased risk for infections. It is critical for clinicians to understand and manage secondary immune deficiency to ensure patient safety and optimize therapeutic outcomes. Increased monitoring including evaluating immunoglobulin levels and B-cell flow cytometry prior to the initiation of therapy and periodically afterward can assist in tailored management of these patients, with potential consideration of prophylactic antimicrobials and/or immunoglobulin replacement to improve outcomes through reduction of morbidity and mortality. Conversely, because inborn errors of immunity (IEI) are more frequent in patients receiving BCTT, clinicians should be alert to clinical and immunological red flags suggestive of an underlying IEI. Two illustrative cases are used to present important considerations in the diagnosis, evaluation, and management of patients receiving BCTT.

Introduction

In this Grand Rounds Review article, we describe two clinical cases that illustrate the evaluation and management of patients undergoing B-cell targeted therapies (BCTT). We highlight the importance of a comprehensive evaluation including detailed clinical history and laboratory evaluation (both before and after therapy) as well as the importance of a personalized strategy with careful consideration of risks and benefits, as well as management strategies such as immunoglobulin replacement therapy. In addition, we outline considerations for both adult and pediatric patients.

Case 1 Presentation

A 60-year-old patient is referred from Nephrology for a low IgG level that was detected after receiving rituximab induction followed by maintenance with 1 gram every 6 months for microscopic polyangiitis with proteinuria. The IgG level prompting referral to the Allergy/Immunology Clinic was 521 mg/dL.

Other than a remote history of recurrent sinus infections decades earlier, the patient has remained free of infections and inborn error of immunity (IEI)-associated features such as autoimmune cytopenias, structural lung disease, lymphoproliferation, and enteropathy. Family history is absent for atypical, severe infections as well as unexplained early deaths.

Laboratory evaluation reveals a repeat IgG 381 mg/dL, IgA normal, IgM normal, tetanus titer normal, pneumococcal titers 2/23 protective prior to vaccination and 2/23 protective 6 weeks after vaccination with polysaccharide pneumococcal vaccine. Lymphocyte subsets are notable for complete absence of enumerable B-cell population. There are no IgG levels or other immunology labs available to review from prior to starting rituximab.

One of the first questions when evaluating BCTT-associated hypogammaglobulinemia (HG) is whether the detected HG is primary or secondary. Routinely obtaining pretreatment IgG levels can aid in this determination (QI Point 1, Table 1). While detection of pretreatment HG does not definitely indicate IEI as underlying conditions can also cause HG, it can prompt appropriate immunology work-up as well as provide insight into the degree of subsequent immunosuppression caused by BCTT(1). Indeed, guidelines for ANCA-associated vasculitis, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA) recommend obtaining pretreatment IgG levels as well as continued monitoring on BCTT(2–7).

Table 1.

Quality Improvement Points

#	Quality Improvement Point
1	Routinely obtaining pretreatment IgG levels in both pediatric and adult patients prior to initiating BCTT can aid in the detection of underlying IEI. Guidelines for ANCA-associated vasculitis, systemic lupus erythematosus, and rheumatoid arthritis recommend obtaining pretreatment IgG levels(2–7).
2	Allergy/Immunology involvement is recommended for the nuanced evaluation and management of BCTT-associated HG(1,4,15), either through individual patient assessments or development of clinical programs.
3	Immunoglobulin levels should be interpreted using age-appropriate reference ranges, as adult values are not applicable in children(25).
4	Red flags which should prompt suspicion for an underlying IEI include early age of onset, refractory course, lymphoproliferation, multilineage cytopenia, multiple forms of autoimmunity, infection, family history, and concerning immunophenotyping(37,38). Autoimmune cytopenias are strongly associated with IEI, with AIHA and Evans syndrome conferring the highest risk(29,39,40).
5	Genetic testing should be performed whenever an IEI is suspected to help confirm the diagnosis but can also help guide therapy.(9)

The initial evaluation of a low IgG level follows IEI guidance, and includes additionally obtaining IgA, IgM, IgE, specific antibody titers to tetanus antitoxoid and Streptococcus pneumonia vaccines, lymphocyte subsets, and B-cell phenotyping if possible(1,8,9). A careful review of the clinical history with a focus on infection history, IEI-associated inflammatory and lymphoproliferative complications, and family history can help identify patients for whom genetic testing should be considered(10). Examples of features particularly concerning for IEI are shown in Table 2. Although both protein and polysaccharide vaccine responses are often attenuated in patients receiving BCTT, documentation of functional antibody status can still aid in the decision-making and can be required by insurance if immunoglobulin replacement therapy (IGRT) is to be initiated in the future(11–14).

Table 2.

Conditions Treated by BCTT that can be Concerning for Underlying IEI

Condition	BCTT Treatment	Features particularly concerning for IEI	Potential IEIs to Consider
Autoimmune Cytopenia	AIHA: Rituximab added to corticosteroids (prednisone 1 mg/kg/day) for severe disease (Hgb <8 g/dL, Evans syndrome) or steroid-refractory cases(54) ITP: Rituximab is 2nd or 3rd-line therapy(55)	Chronic, refractory or relapsing, severe cytopenias(37,56,57)	Diseases of immune dysregulation: ALPS, APECED, IPEX/IPEX-like syndromes, CTLA4 deficiency, LRBA deficiency, DEF6 deficiency, STAT3 GOF Predominantly antibody deficiencies: CVID, IKAROS haploinsufficiency, APDS Combined immunodeficiencies with associated or syndromic features: Kabuki syndrome, WAS Defects in intrinsic and innate immunity: STAT1 GOF (37,56,58)
Lymphoproliferative Disorders	Rituximab is part of first-line regimens for B-cell non-Hodgkin lymphomas (59) Rituximab is a treatment option for post-transplant lymphoproliferative disorders(60)	Diffuse large B-cell lymphoma(61) EBV-driven lymphoproliferation(62–64) Lymphoma at young age: median age at lymphoma diagnosis in IEI patients was 12 years in one study (65), lymphoma occurred between ages 3–12 years in another (66) Lymphoproliferative disease (palpable lymphadenopathy, intestinal lymphadenopathy associated with refractory IBD, hepatosplenomegaly) in non-transplant patients (67) Chronic benign lymphoproliferation (splenomegaly, lymphadenopathy) (68)	Diseases of immune dysregulation: ALPS, IPEX, HLH syndromes EBV Susceptibility / Lymphoproliferative Conditions: XLP1, XLP2, ITK deficiency, XMEN, CD27 deficiency, CD70 deficiency, CTPS1 deficiency, RASGRP1 deficiency Predominantly antibody deficiencies: CVID, AID deficiency, APDS SCID: γc deficiency, Coronin-1A deficiency Combined Immunodeficiencies: CD40 ligand deficiency, ZAP70 deficiency Combined immunodeficiencies with syndromic features: Ataxia telangiectasia, WAS, STAT3 LOF Defects in intrinsic and innate immunity: IFNGR1 deficiency (MSMD), STAT1 GOF, anti-IFN-γ autoantibodies (62,66,67,69)
ILD	Rituximab conditionally recommended as first-line treatment option for systemic autoimmune rheumatic disease (systemic sclerosis, myositis, mixed connective tissue disease, rheumatoid arthritis, Sjogeren’s) ILD (SARD-ILD), management of SARD-ILD that progresses despite first-line treatment Rituximab conditionally recommended as first-line treatment option for rapidly progressive ILD (70)	Autoimmune cytopenias or lymphoproliferation as above Features concerning for GLILD(71,72)	Predominantly antibody deficiencies: CVID (71,72) Diseases of immune dysregulation: APECED, CTLA4 deficiency, LRBA deficiency, STAT3 GOF (73–75) Auto-inflammatory disorders: COPA defect, SAVI (76,77)

AIC, autoimmune cytopenia; AIHA, autoimmune hemolytic anemia; ALPS, autoimmune lymphoproliferative syndrome; APECED, autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy; APDS2, activated p110δ syndrome; CVID, common variable immunodeficiency; GLILD, granulomatous lymphocytic interstitial lung disease; GOF, gain of function; HLH, hemophagocytic lymphohistiocytosis; IPEX, immune dysregulation polyendocrinopathy enteropathy X-linked; ITP, immune thrombocytopenia; LOF, loss of function; MSMD, Mendelian Susceptibility to Mycobacterial Disease; SAVI, STING-associated vasculopathy with onset in infancy; SCID, severe combined immunodeficiencies; WAS, Wiskott Aldrich Syndrome; XMEN, XL magnesium EBV and neoplasia

IUIS phenotypic classification(53) used to classify IEIs

Allergy/Immunology involvement, specifically input from providers with clinical immunology expertise, is recommended for the nuanced evaluation and management of BCTT-associated HG(1,4,15), either through individual patient assessments or development of clinical programs (QI Point 2, Table 1). A proposed framework based in expert allergy/immunology opinion has recommended IGRT for isolated severe HG or HG with severe sinopulmonary infections(1,10). In the absence of infections, mild-to-moderate HG with low IgA or IgM and attenuated vaccine responses can support shared decision-making around prophylactic IGRT, with potential benefit increasing as immunosuppression-related abnormalities in these parameters accumulate(1,10).

Via shared decision-making, the decision is made to continue monitoring immunoglobulin levels every 3–4 months. However, over the course of the next year, IgG levels continue to decline until consistently below 200 mg/dL, with IgM also declining to undetectable levels and pneumococcal titers falling to 0/23 protective. Notably, the patient was hospitalized with multifocal pneumonia and acute hypoxemic respiratory failure requiring supplemental oxygen requiring hospitalization and broad-spectrum intravenous antibiotics.

Given the development of infection and worsening immune parameters, the decision is made to initiate intravenous immunoglobulin (IVIG) 500 mg/kg every 4 weeks. However, despite repletion, IgG trough levels remained in the 300–400 mg/dL range, likely due to ongoing urinary protein loss, with the patient experiencing one sinus infection and one ear infection requiring oral antibiotics. He was evaluated for other sources of protein loss including renal and GI losses, and was seen again by nephrology. After further discussion, the patient was switched to weekly subcutaneous immunoglobulin (SCIG) at an equivalent total monthly dose, resulting in improved IgG levels in the 500–600 mg/dL range and infection-free clinical status.

Although the standard target IgG (trough if IVIG) for IGRT replacement dosing is considered 800 mg/dL per IEI guidance, each individual patient’s target level is dependent on what is necessary to achieve a clinically infection-free status(1,16,17). While this often means a higher target level for patients with IEI(17), in our clinical experience treating patients with secondary hypogammaglobulinemia (SHG), particularly those who were infection-free in the moderate HG range, it is possible for this target level to be below 800 mg/dL.

This patient’s case additionally highlights the potential benefits of SCIG. While only IVIG is currently FDA-approved for SHG, and only for chronic lymphocytic leukemia (CLL)-associated SHG (18), reports in SHG suggest that SCIG may be better-tolerated and achieve higher IgG levels, less infections, and less antibiotics(19). In patients with urinary protein loss preventing attainment of target IgG levels as with this patient, SCIG’s pharmacokinetic properties may additionally allow improved IgG levels to be attained. Indeed, given the increasing recognition of SCIG as having specific benefits over IVIG, some CAR T-cell therapy and CLL guidelines have included SCIG as an IGRT option for SHG(20,21).

Rituximab was discontinued 3 years later after sustained clinical remission. During those 3 years, an increase in IgG levels to the 800 mg/dL range was observed on the same dose and frequency of SCIG as proteinuria resolved with disease remission. After rituximab discontinuation, ongoing monitoring showed that the patient’s IgM and IgA levels started increasing, along with further increases in IgG levels. The SCIG dosing was decreased accordingly, and then paused for 6 months with ongoing monitoring. After discontinuation, patient remained infection-free with normal IgG levels.

Overall, this patient’s clinical trajectory is more consistent with SHG, which can result in severe infections but improve when iatrogenic causes are removed, or underlying causes lessen in severity or resolve. This immune recovery can vary widely between individuals and cannot be reliably predicted with the current state of medical knowledge(10,22). Increasing IgG levels despite unchanged IGRT dosing, or recovery of IgA, IgM, B-cell counts, and/or switched memory B cells are potential signs of immune recovery that can be followed even in patients on IGRT(1,22). A 4–6-month period (approximately 4–5 half-lives) off IGRT is generally considered adequate to assess patients’ natural, or near-natural, immune function, although pharmacokinetics vary across individuals and IVIG/SCIG formulations(1,10,23).

This case highlights key quality improvement opportunities. IgG levels should be measured prior to BCTT initiation to identify potential IEI and periodically after initiation to detect immunologic changes early. These efforts can be implemented in collaboration with specialties that commonly prescribe BCTT, including Rheumatology, Nephrology, Hematology/Oncology, and Neurology. Identifying and engaging key stakeholders may require focused discussions about workflow with non-physician team members who often drive lab ordering and care coordination. Incorporating IgG screening and monitoring into existing clinical checklists can be particularly effective. As illustrated by this case, evaluation and management is nuanced and many patients would benefit from Allergy/Immunology involvement. However, this clinical need must be balanced with the increasing shortage of allergists/immunologist given the frequency of BCTT-associated HG and the widespread use of BCTT. Establishing referral criteria and clear referral pathways are key components of clinical partnerships between Allergy/Immunology and the aforementioned specialties. Although implementation may be resource-intensive, once in place, standardized monitoring and referral practices has the potential to ultimately reduce physician burden while significantly improving patient care.

Case 2 Presentation

A 12-year-old girl, previously healthy except for intermittent diarrhea over the past year, presented with fatigue, pallor, and easy bruising evolving over two weeks. Family history was notable for autoimmune disease, including a father under investigation for inflammatory bowel disease and an older sibling with vitiligo and autoimmune thyroid disease. Examination revealed scattered petechiae and mild splenomegaly. Laboratory testing showed findings consistent with autoimmune hemolytic anemia (AIHA) associated with immune thrombocytopenia (Evans syndrome). She was treated with high-dose corticosteroids and IVIG, with initial hematologic improvement.

However, the patient developed multiple relapses of Evans syndrome upon tapering of corticosteroid treatment. Because of steroid-dependent disease, she received rituximab, which induced remission. Over the next 12 months, she developed recurrent sinopulmonary infections. Immunologic testing showed significant hypogammaglobulinemia (IgG 390 mg/dL, IgM 22 mg/dL, IgA normal), which was initially attributed to secondary immunodeficiency following rituximab, and immunoglobulin replacement therapy was initiated.

Pediatric patients commonly receive BCTT for autoimmune disorders and malignancies. An increasing number of therapeutic options are now available, including those that target CD20 (rituximab), bispecific T cell engagers that bind CD19 and CD3 simultaneously (blinatumomab) and chimeric antigen receptor (CAR) T cells (tisagenlecleucel), all associated with hypogammaglobulinemia(24). Certain pediatric considerations should be taken into account when diagnosing and evaluating hypogammaglobulinemia. First, immunoglobulin levels should be interpreted using age-appropriate reference ranges, as adult values are not applicable in children(25) (QI Point 3, Table 1). Children may also be more susceptible to hypogammaglobulinemia given the immaturity of the B cell compartment and decreased plasma cell burden(26,27). In pediatric cohorts, secondary hypogammaglobulinemia occurs in up to half of children receiving BCTT, which may increase risk of severe infections(28–32). While more studies are needed in the pediatric populations, such patients may benefit from antibacterial prophylaxis and/or IGRT(1). Risk factors for hypogammaglobulinemia following BCTT include low baseline immunoglobulin levels, prolonged use of rituximab, use of concomitant immunosuppressive therapies, and younger age in children(33).

Furthermore, additional caution is warranted when evaluating children with hypogammaglobulinemia following BCTT, since common indications for these medications, such as autoimmune diseases and hematological cancers, overlap with presenting features of IEI (Table 2). Indeed, diseases of immune dysregulation represent a subset of IEI, which present with autoimmunity, autoinflammation, and/or lymphoproliferation(34). Importantly, ~18% of IEI present first with immune dysregulation, and ~11% with isolated immune dysregulation(35,36). These types of non-infectious manifestations can evolve over time and include organ-specific disease, autoimmune cytopenias and lymphoproliferation.

Thus, distinguishing between IEI and secondary hypogammaglobulinemia may be challenging in this context. Red flags which should prompt suspicion for an underlying IEI include early age of onset, refractory course, lymphoproliferation, multilineage cytopenia, multiple forms of autoimmunity, infection, family history, and concerning immunophenotyping(37,38). Autoimmune cytopenias are strongly associated with IEI, with AIHA and Evans syndrome conferring the highest risk(29,39,40). Of those with Evans syndrome an estimated 50–60% or more have an identifiable causative gene, which includes: CTLA4, LRBA, FAS, STAT3, and PIK3CD(41–43) (QI Point 4, Table 1).

Because of the combination of refractory autoimmune cytopenias, recurring infections, chronic diarrhea, and a family history of autoimmunity, the patient was referred to clinical immunology. Immune phenotyping revealed reduced switched memory B cells, and a genetic panel for inborn errors of immunity identified a heterozygous pathogenic variant in CTLA4, confirming CTLA4 haploinsufficiency. The patient was started on abatacept, resulting in resolution of gastrointestinal symptoms and sustained remission of autoimmune cytopenias. Family testing later identified the same mutation in her father and sibling, who were also referred to an immunologist for evaluation.

IEI are likely enriched in pediatric patients receiving BCTT. In one study, 4% of children receiving rituximab for autoimmune disease were later diagnosed with an underlying IEI(28), representing an approximately 100-fold greater magnitude compared with the estimated 0.06% prevalence in the general population(44). Therefore, obtaining baseline immunoglobulin levels in all pediatric patients prior to initiating BCTT can be helpful (QI Point 1, Table 1). One caveat is that patients with IEI may initially have normal baseline immunoglobulin levels, and hypogammaglobulinemia may either be later uncovered or accelerated by BCTT, or can simply occur as the natural evolution of the underlying disease(45). Furthermore, baseline IgG may be low in the context of protein loss for example in patients with nephrotic syndrome, a common indication for BCTT, which can further complicate initial interpretation of HG(46).

Expanded T and B immune phenotyping and cytokine testing may also demonstrate abnormalities suggestive of an IEI. This includes an expansion of CD21^lo B cells, and CD45RA- CXCR5+ T follicular helper cells along with abnormally increased serum levels of cytokines like soluble IL-2RA(47,48).

Whenever an IEI is suspected, genetic testing should be undertaken, which can not only help confirm the diagnosis but can also help guide therapy(9) (QI Point 5, Table 1). Indeed, targeted therapy offers the potential of restoring immune function while limiting immune suppression. This is especially important as these individuals are more susceptible to infectious complications from these broad reaching immunosuppressive medications. The use of abatacept for CTLA4 haploinsufficiency is one such example, as highlighted in our case above(49). Other refined treatment strategies based on molecular diagnosis include leniolisib in activated PI3K delta syndrome (APDS) and JAK inhibitors for inborn errors of JAK/STAT signaling, amongst others(50–52). In addition, confirming the genetic cause of an IEI can also be important for disease prognosis, for monitoring and prevention of disease-specific complications, and for family screening and genetic counselling.

Conclusions

As the use of BCTT increases, it is critical that clinicians are aware of the potential for hypogammaglobulinemia and increased risk for infections. Increased monitoring including evaluating immunoglobulin levels and B-cell flow cytometry prior to the initiation of therapy and periodically afterward can assist in tailored management of these patients, with potential consideration of prophylactic antimicrobials and/or immunoglobulin replacement to improve outcomes through reduction of morbidity and mortality. Multidisciplinary quality improvement efforts are essential to ensure timely pretreatment IgG measurement, build effective referral pathways and clinical partnerships for improved evaluation and management, and promote judicious Allergy/Immunology involvement and genetic testing.