Recommendations for Management of Secondary Antibody Deficiency in Multiple Myeloma.

Secondary antibody deficiency (SAD) is a subtype of secondary immunodeficiency characterized by low serum antibody concentrations (hypogammaglobulinemia) or poor antibody function. SAD is common in patients with multiple myeloma (MM) due to underlying disease pathophysiology and treatment-related immune system effects. Patients with SAD are more susceptible to infections and infection-related morbidity and mortality. With therapeutic advancements improving MM disease control and survival, it is increasingly important to recognize and treat the often-overlooked concurrent immunodeficiency present in patients with MM. The aims of this review are to define SAD and its consequences in MM, increase SAD awareness, and provide recommendations for SAD management. Based on expert panel discussions at a standalone meeting and supportive literature, several recommendations were made. Firstly, all patients with MM should be suspected to have SAD regardless of serum antibody concentrations. Patients should be evaluated for immunodeficiency at MM diagnosis and stratified into management categories based on their individualized risk of SAD and infection. Infection-prevention strategy education, early infection reporting, and anti-infective prophylaxis are key. We recommend prophylactic antibiotics or immunoglobulin replacement therapy (IgRT) should be considered in patients with severe hypogammaglobulinemia associated with a recurrent or persistent infection. To ensure an individualized and efficient treatment approach is utilized, patient's immunoglobin G concentration and infection burden should be closely monitored throughout treatment. Patient choice regarding route and IgRT treatment is also key in reducing treatment burden. Together, these recommendations and proposed management algorithms can be used to aid physician decision-making to improve patient outcomes.

Agents contributing to secondary immunodeficiency development in patients with multiple myeloma, chronic lymphocytic leukemia and non-Hodgkin lymphoma: A systematic literature review.

Introduction: Patients with hematological malignancies (HMs), like chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL), have a high risk of secondary immunodeficiency (SID), SID-related infections, and mortality. Here, we report the results of a systematic literature review on the potential association of various cancer regimens with infection rates, neutropenia, lymphocytopenia, or hypogammaglobulinemia, indicative of SID. Methods: A systematic literature search was performed in 03/2022 using PubMed to search for clinical trials that mentioned in the title and/or abstract selected cancer (CLL, MM, or NHL) treatments covering 12 classes of drugs, including B-lineage monoclonal antibodies, CAR T therapies, proteasome inhibitors, kinase inhibitors, immunomodulators, antimetabolites, anti-tumor antibiotics, alkylating agents, Bcl-2 antagonists, histone deacetylase inhibitors, vinca alkaloids, and selective inhibitors of nuclear export. To be included, a publication had to report at least one of the following: percentages of patients with any grade and/or grade ≥3 infections, any grade and/or grade ≥3 neutropenia, or hypogammaglobulinemia. From the relevant publications, the percentages of patients with lymphocytopenia and specific types of infection (fungal, viral, bacterial, respiratory [upper or lower respiratory tract], bronchitis, pneumonia, urinary tract infection, skin, gastrointestinal, and sepsis) were collected. Results: Of 89 relevant studies, 17, 38, and 34 included patients with CLL, MM, and NHL, respectively. In CLL, MM, and NHL, any grade infections were seen in 51.3%, 35.9% and 31.1% of patients, and any grade neutropenia in 36.3%, 36.4%, and 35.4% of patients, respectively. The highest proportion of patients with grade ≥3 infections across classes of drugs were: 41.0% in patients with MM treated with a B-lineage monoclonal antibody combination; and 29.9% and 38.0% of patients with CLL and NHL treated with a kinase inhibitor combination, respectively. In the limited studies, the mean percentage of patients with lymphocytopenia was 1.9%, 11.9%, and 38.6% in CLL, MM, and NHL, respectively. Two studies reported the proportion of patients with hypogammaglobulinemia: 0-15.3% in CLL and 5.9% in NHL (no studies reported hypogammaglobulinemia in MM). Conclusion: This review highlights cancer treatments contributing to infections and neutropenia, potentially related to SID, and shows underreporting of hypogammaglobulinemia and lymphocytopenia before and during HM therapies.

Steroid-induced secondary immune deficiency.

Despite their widespread clinical use, oral corticosteroids (OCSs) are well known to be associated with a myriad of adverse effects, including immunosuppression. By inhibiting transcription factors and affecting leukocyte function, prolonged OCS use leads to significant CD4 lymphopenia and often a decrease in serum immunoglobulin (Ig)G. Conversely, OCS use has minimal impact on circulating B cell, serum IgM, or serum IgA levels. Although there is a paucity of literature, individuals treated with prolonged OCS seem to typically maintain humoral response to various vaccinations despite hypogammaglobinemia, but this area warrants additional research, especially in the setting of the coronavirus disease 2019 pandemic. Individuals treated with prolonged OCS use are most at risk for opportunistic infections, especially those with underlying malignancy and history of bone marrow transplant. Risk mitigation strategies to decrease infectious complication with OCS use include limiting the dose and duration of therapy, appropriately completing a full vaccination series, consideration for passive immunization, and prophylaxis against opportunistic infections.

Management of secondary immunodeficiency in hematological malignancies in the era of modern oncology.

Secondary immunodeficiency (SID) in patients with B-cell hematological malignancies is a common condition that presents with recurrent infection. SID is due to both the inherent immune defects due to the malignancy, as well as secondary to cancer therapies, many of which have B-cell depleting properties. The early diagnosis of SID and the optimization of intervention strategies are key to delivering the most effective cancer treatments and reducing infection-related morbidity and mortality. This review discusses current practice, recommendations, and challenges for SID diagnosis, based on the evaluation of clinical history and laboratory assessments, and the effectiveness of specific vaccines and immunoglobulin replacement therapy in reducing the frequency and recurrence of infections in patients with SID, and the healthcare system-associated costs.

Immunosuppression in Patients With Primary Immunodeficiency-Walking the Line.

Individuals with primary immunodeficiency (PIDD) experience not only infectious complications but also immune dysregulation leading to autoimmunity, inflammation, and lymphoproliferative manifestations. Management of these complications often requires treatment with additional immunosuppressive medications, which pose an additional risk of infectious complications. Immunosuppression in individuals with PIDD therefore requires careful assessment and consideration of risks and benefits. Medications should be closely monitored, and strategies for risk mitigation of adverse events considered, such as exposure reduction, appropriate vaccination, use of antibiotics/antivirals, and optimization of immunoglobulin replacement therapy. In a subset of individuals who are not tolerating immune modulation or experiencing disease progression despite appropriate interventions, hematopoietic stem-cell transplantation is a management option.

Effect of Ibrutinib on Hmphocytic Leukemia: a Single-Center Experience.

OBJECTIVE/BACKGROUND: In the era of novel agents, Bruton tyrosine kinase (BTK) inhibitors have changed the dynamics of treating chronic lymphocytic leukemia. However, small studies have shown conflicting results regarding the additive humoral dysfunction with their use. METHODS: We prospectively compared vaccine responses in patients on ibrutinib (n = 10) with matched controls (n = 16) and analyzed whether a protein-based (tetanus-diphtheria toxoid) or a carbohydrate (Pneumovax) moiety will result in an improved immunological response. RESULTS: An appropriate serological response in IgG titers for diphtheria was seen in 40% of patients on ibrutinib and 31% of patients in the control group. About 30% of patients on ibrutinib and 44% of patients in the control group had an adequate response to tetanus toxoid. None of the patients on ibrutinib mounted an adequate response to Pneumovax, while 31% of patients in the control arm responded appropriately. These differences in the results were considered insignificant as all p values were greater than the cut-off of 0.05. CONCLUSION: Our study did not show significant detrimental vaccine responses with ibrutinib and calls for larger multicenter studies to elucidate long-term effects, especially in patients with prior exposure to anti-CD20 monoclonal antibodies.

Real-World Effectiveness of Tixagevimab and Cilgavimab (Evusheld) in Patients With Hematological Malignancies.

Background: Immunocompromised individuals with hematological malignancy have increased risk for poor outcomes and death from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This special population may mount a suboptimal response to vaccination. We assessed the effectiveness of tixagevimab and cilgavimab (Evusheld), a monoclonal antibody combination against SARS-CoV-2, in conjunction with standard preventative measures, at preventing symptomatic incident infection. Methods: Patients aged 18 years and older with hematological malignancy consented to receive Evusheld. Patients were followed longitudinally for development of symptomatic incident SARS-CoV-2 infections. Adverse events were monitored. Results: Two hundred and three patients (94 female) with hematological malignancies and mean age 72 ± 10 years were included. Of the patients, 99.5% had received at least one mRNA vaccination against SARS-CoV-2. Average time of follow-up was 151 ± 50 days. Nineteen patients (9.3%) developed incident symptomatic SARS-CoV-2 infection, with only one (0.5%) requiring hospitalization. During the same follow-up period, local incident rate of infection was 84,123 cases (11.3% of population). Of those, 3,386 cases (4%) of SARS-CoV-2 required hospital admission. The incidence rate ratio was 0.79. No serious adverse events occurred following administration of Evusheld. Conclusion: Patients with hematological malignancy who received Evusheld infrequently developed symptomatic infections or require hospitalization. The high-risk cohort incidence was at least as comparable to the average risk general population. Evusheld appears effective and is well tolerated, and may be administered in conjunction with vaccination and standard prevention measures, at decreasing incident SARS-Co-V2 cases in this high-risk population.

Subcutaneous immunoglobulin replacement for treatment of humoral immune dysfunction in patients with chronic lymphocytic leukemia.

BACKGROUND: Patients with chronic lymphocytic leukemia (CLL) experience hypogammaglobinemia and non-neutropenic infections. In this exploratory proof of concept study, our objective was to determine the prevalence of humoral immunodeficiency in patients with CLL and serum IgG ≥ 400 mg/dL, and to evaluate the efficacy of subcutaneous immunoglobulin (SCIG) in this population. PATIENTS AND METHODS: Patients with CLL with serum IgG ≥ 400 mg/dL were evaluated for serum IgG, IgM, IgA, along with pre/post vaccine IgG titers to diphtheria, tetanus, and Streptococcus pneumoniae. Patients with evidence of humoral dysfunction were treated with SCIG with Hizentra every 7±2 days for 24 weeks. RESULTS: Fifteen patients enrolled with median IgG = 782 mg/dL [IQR: 570 to 827], and 6/15 (40%) responded to vaccination with Td, while 5/15 (33%) responded to vaccination with PPV23. 14/15 (93.3%) demonstrated humoral immunodeficiency as evidenced by suboptimal vaccine responses, and were treated with SCIG. In patients treated with SCIG, serum IgG increased from 670 mg/dL [IQR: 565 to 819] to 1054 mg/dL [IQR: 1040 to 1166] after 24 weeks (95% CI: 271-540). For streptococcus pneumoniae, the median protective serotypes at baseline was 8 [IQR: 4 to 9] and increased to 17 [IQR: 17 to 19] after 24 weeks (95% CI: 6.93-13.72). Non-neutropenic infections (NNI) decreased from 14 to 5 during treatment with SCIG. CONCLUSIONS: Patients with CLL demonstrate humoral immunodeficiency despite IgG > 400 mg/dL. For these patients, SCIG is well tolerated and efficacious in improving serum IgG, specific IgG to streptococcus pneumoniae, and may decrease reliance on antibiotics for the treatment of NNIs. CLINICAL TRIALS REGISTRATION: NCT03730129.

The Risk of Allergic Reaction to SARS-CoV-2 Vaccines and Recommended Evaluation and Management: A Systematic Review, Meta-Analysis, GRADE Assessment, and International Consensus Approach.

Concerns for anaphylaxis may hamper severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunization efforts. We convened a multidisciplinary group of international experts in anaphylaxis composed of allergy, infectious disease, emergency medicine, and front-line clinicians to systematically develop recommendations regarding SARS-CoV-2 vaccine immediate allergic reactions. Medline, EMBASE, Web of Science, the World Health Organizstion (WHO) global coronavirus database, and the gray literature (inception, March 19, 2021) were systematically searched. Paired reviewers independently selected studies addressing anaphylaxis after SARS-CoV-2 vaccination, polyethylene glycol (PEG) and polysorbate allergy, and accuracy of allergy testing for SARS-CoV-2 vaccine allergy. Random effects models synthesized the data to inform recommendations based on the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach, agreed upon using a modified Delphi panel. The incidence of SARS-CoV-2 vaccine anaphylaxis is 7.91 cases per million (n = 41,000,000 vaccinations; 95% confidence interval [95% CI] 4.02-15.59; 26 studies, moderate certainty), the incidence of 0.15 cases per million patient-years (95% CI 0.11-0.2), and the sensitivity for PEG skin testing is poor, although specificity is high (15 studies, very low certainty). We recommend vaccination over either no vaccination or performing SARS-CoV-2 vaccine/excipient screening allergy testing for individuals without history of a severe allergic reaction to the SARS-CoV-2 vaccine/excipient, and a shared decision-making paradigm in consultation with an allergy specialist for individuals with a history of a severe allergic reaction to the SARS-CoV-2 vaccine/excipient. We recommend further research to clarify SARS-CoV-2 vaccine/vaccine excipient testing utility in individuals potentially allergic to SARS-CoV2 vaccines or their excipients.

Safety and Tolerability of Subcutaneous IgPro20 at High Infusion Parameters in Patients with Primary Immunodeficiency: Findings from the Pump-Assisted Administration Cohorts of the HILO Study.

PURPOSE: To evaluate the safety and tolerability of subcutaneous IgPro20 (Hizentra®, CSL Behring, King of Prussia, PA, USA) administered at high infusion parameters (> 25 mL and > 25 mL/h per injection site) in patients with primary immunodeficiency. METHODS: The Hizentra® Label Optimization (HILO) study was an open-label, parallel-arm, non-randomized study (NCT03033745) of IgPro20 using a forced upward titration design for infusion parameters. Patients experienced with pump-assisted IgPro20 infusions received weekly IgPro20 infusions at a stable dose in the Pump-Assisted Volume Cohort (N = 15; 25-50 mL per injection site) and in the Pump-Assisted Flow Rate Cohort (N = 18; 25-100 mL/h per injection site). Responder rates (percentage of patients who successfully completed ≥ 75% of planned infusions), safety outcomes, and serum immunoglobulin G (IgG) trough levels were evaluated. RESULTS: Responder rates were 86.7% (13/15, 25 mL) and 73.3% (11/15, 40 and 50 mL) in the Volume Cohort, and 77.8% (14/18, 25 and 50 mL/h), 66.7% (12/18, 75 mL/h), and 61.1% (11/18, 100 mL/h) in the Flow Rate Cohort. Infusion compliance was ≥ 90% in all patients in the Volume Cohort and in 83.3% of patients in the Flow Rate Cohort. The number of injection sites (Volume Cohort) and the infusion duration (Flow Rate Cohort) decreased with increasing infusion parameters. The rate of treatment-emergent adverse events per infusion was low (0.138 [Volume Cohort] and 0.216 [Flow Rate Cohort]). Serum IgG levels remained stable during the study. CONCLUSION: Pump-assisted IgPro20 infusions are feasible at 50 mL and 100 mL/h per injection site in treatment-experienced patients, which may result in fewer injection sites and shorter infusion times. TRIAL REGISTRATION: NCT03033745 ; registered January 27, 2017.

Dupilumab as Add-on Therapy for Chronic Rhinosinusitis With Nasal Polyposis in Aspirin Exacerbated Respiratory Disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) affects 7% of asthmatics. Usual therapies are inadequate for asthma and/or nasal polyposis, leading to decreased quality of life. OBJECTIVE: Our objective was to evaluate the efficacy of dupilumab in AERD patients with uncontrolled, chronic rhinosinusitis with nasal polyposis (CRSwNP). METHODS: Patients 18 years and older with a physician diagnosis of AERD and sino-nasal outcome test 22 (SNOT 22) score ≥19 despite standard medical therapy were eligible for the study. Patients received one month of placebo dosing, followed by 6 months of dupilumab. Patients were blinded to the order of therapy. Wilcoxon-paired rank sum test was used to compare study outcomes at baseline and the completion of the study. RESULTS: Ten patients completed the study. The median baseline SNOT 22 score improved from 46 [IQR: 34 to 64.8] to 9.5 [IQR: 2.5 to 19] after 6 months of therapy (p = 0.0050). The median baseline Lund MacKay score improved from 21.5 [IQR: 17 to 23.3] to 4 [IQR: 1.2 to 6] after 6 months of therapy (p = 0.0050). There was also improvement in the following secondary outcomes: asthma control test (ACT), mini asthma quality of life questionnaire (AQLQ), and University of Pennsylvania Smell Identification test (UPSIT). Exhaled nitric oxide (FeNO), total serum IgE, 24-hour urinary leukotriene E4, and serum thymus and activation regulated cytokine (TARC) also decreased. There were no significant study-related adverse events. CONCLUSION: Dupilumab was highly effective as add-on therapy for CRSwNP in AERD, improving patient-reported outcomes, sinus opacification, and markers of T2 inflammation.

The Use of 20% Subcutaneous Immunoglobulin Replacement Therapy in Patients With B Cell Non-Hodgkin Lymphoma With Humoral Immune Dysfunction After Treatment With Rituximab.

BACKGROUND: Rituximab is an anti-CD20 chimeric antibody used to treat autoimmune conditions and B cell neoplasms. We characterized immunoglobulin (Ig) levels and vaccine responses in rituximab-treated B cell non-Hodgkin lymphoma (NHL) patients. Patients with impaired vaccine responses were offered therapy with 20% subcutaneous (subq) Ig. PATIENTS AND METHODS: Patients with a biopsy-proven diagnosis of B cell NHL who had received rituximab within the past 24 months were eligible for the study and underwent the following immune evaluation: serum IgG, IgM, IgA, IgE, T/B cell lymphocyte panel, and pre/post vaccine IgG titers to diphtheria, tetanus, and streptococcus pneumoniae. Patients were vaccinated with tetanus, diphtheria and pneumococcal polysaccharide vaccine. Patients with abnormal vaccine responses were offered prophylactic subq Ig for 52 weeks. RESULTS: Fifteen patients with NHL were enrolled in the study. The median IgG was 628 mg/dL [interquartile range, 489-718 mg/dL]. Three (20%) of 15 patients responded to diphtheria vaccination, 1 (6.7%) of 15 responded to tetanus vaccination, and 3 (20%) of 15 responded to vaccination to streptococcus pneumoniae. Thirteen (86.7%) of 15 met criteria for humoral immunodeficiency. Ten patients received subq Ig, and experienced a significant increase in serum IgG (P = .008). There were no serious adverse events, and there was a decrease in nonneutropenic infections while on subq Ig therapy. CONCLUSIONS: Patients with NHL treated with rituximab may have significant humoral immunodeficiency as defined by abnormal vaccine responses even in the setting of relatively normal IgG levels. For these patients, subq Ig replacement therapy is well-tolerated and efficacious in improving serum IgG, and may decrease reliance on antibiotics for the treatment of nonneutropenic infections.

AAAAI Mast Cell Disorders Committee Work Group Report: Mast cell activation syndrome (MCAS) diagnosis and management.

Our current recommendations for diagnosing and treating primary mast cell (MC) activation syndrome make use of the latest studies and consensus guidelines for clinically recognizing systemic anaphylaxis in real time, regardless of whether allergen-triggered or other pathways are involved; our current understanding of the biomarkers secreted by activated MCs that best discriminate this disorder from other conditions; and the therapeutic drugs that might selectively affect those mediators or MCs themselves. Finding familial or somatic mutations of genes that cause MCs to be hyperactivatable would extend our diagnostic tools and potentially indicate new therapeutic interventions, targeting either the mutated gene product or the associated molecular pathway. In conclusion, we trust that the clinical, laboratory, and therapeutic criteria for primary MC activation syndromes described herein will provide clinicians with practical criteria of sufficient sensitivity and specificity to diagnose most cases without overdiagnosing the disorder in patients who likely have other conditions.

Response to PCV13 vaccination in patients with multiple myeloma versus healthy controls.

Infections are a major cause of morbidity and mortality in individuals with multiple myeloma (MM). These individuals exhibit humoral dysfunction and show a suboptimal response to pneumococcal polysaccharide vaccine (PPV23). Since pneumococcal conjugate vaccine (PCV13) elicits a T cell dependent response, it is recommended in patients with multiple myeloma. This study compares the initial response to PCV13 and durability of the response at 6 months in patients with multiple myeloma versus normal controls. Seven patients with multiple myeloma and 18 control patients were enrolled in the study. Streptococcal pneumonia serotype IgG titers were drawn at baseline, day 30, and day 180 after MM patients and controls received PCV13. Although vaccination with PCV13 produced a similar initial response in patients with multiple myeloma compared to control subjects, the duration of response may have waned in patients with multiple myeloma as compared to control subjects.

Screening for Humoral Immunodeficiency in Patients with Community-Acquired Pneumonia.

BACKGROUND: Immunodeficiency is an underrecognized risk factor for infections, such as community-acquired pneumonia (CAP). OBJECTIVE: We evaluated patients admitted with CAP for humoral immunodeficiency. DESIGN: Prospective Cohort Study. SETTING: Inpatients. PATIENTS, INTERVENTION, AND MEASUREMENTS: We enrolled 100 consecutive patients admitted with a diagnosis of CAP from February 2017 to April 2017. Serum IgG, IgM, IgA, and IgE levels were obtained within the first 24 hours of admission. CURB-65 score and length of hospital stay were calculated. The Wilcoxon rank-sum test, Kruskal-Wallis test, and simple linear regression analysis were used in data analysis. RESULTS: The prevalence of hypogammaglobinemia in patients with CAP was 38% (95% confidence interval: 28.47% to 48.25%). Twenty-seven of 100 patients had IgG hypogammaglobinemia (median: 598 mg/dL, IQ range: 459-654), 23 of 100 had IgM hypogammaglobinemia (median: 38 mg/dL, IQ range: 25-43), and 6 of 100 had IgA hypogammaglobinemia (median: 36 mg/dL, IQ range: 18-50). The median hospital length of stay for patients with IgG hypogammaglobinemia was significantly higher when compared to patients with normal IgG levels (five days, IQ range [3-10] vs three days, IQ range [2-5], P = .0085). Fourteen patients underwent further immune evaluation, resulting in one diagnosis of multiple myeloma, three patients diagnosed with specific antibody deficiency, and one patient diagnosed with selective IgA deficiency. CONCLUSION: There is a high prevalence of hypogammaglobinemia in patients hospitalized with CAP, with IgG and IgM being the most commonly affected classes. IgG hypogammaglobinemia was associated with an increased length of hospitalization. Screening immunoglobulin levels in CAP patients may also uncover underlying humoral immunodeficiency or immunoproliferative disorders.