Safety and Efficacy of Hizentra® Following Pediatric Hematopoietic Cell Transplant for Treatment of Primary Immunodeficiencies.

Primary immunodeficiency disease (PIDD) comprises a group of disorders of immune function. Some of the most severe PIDD can be treated with hematopoietic cell transplant (HCT). Hizentra® is a 20% liquid IgG product approved for subcutaneous administration in adults and children greater than 2 years of age with PIDD-associated antibody deficiency. Limited information is available on the use of Hizentra® in children following HCT for PIDD. A multicenter retrospective chart review demonstrated 37 infants and children (median age 70.1 [range 12.0 to 176.4] months) with PIDD treated by HCT who received Hizentra® infusions over a median duration of 31 (range 4-96) months post-transplant. The most common indication for HCT was IL2RG SCID (n = 16). Thirty-two patients switched from IVIG to SCIG administration, due to one or more of the following reasons: patient/caregiver (n = 17) or physician (n = 12) preference, discontinuation of central venous catheter (n = 16), desire for home infusion (n = 12), improved IgG serum levels following lower levels on IVIG (n = 10), and loss of venous access (n = 8). Serious bacterial infections occurred at a rate of 0.041 per patient-year while on therapy. Weight percentile increased by a mean of 16% during the observation period, with females demonstrating the largest gains. Mild local reactions were observed in 24%; 76% had no local reactions. One serious adverse event (death from sepsis) was reported. Hizentra® was discontinued in 15 (41%) patients, most commonly due to recovery of B cell function (n = 11). These data demonstrate that Hizentra® is a safe and effective option in children who have received HCT for PIDD.

Systemic IgG exposure and safety in patients with primary immunodeficiency: a randomized crossover study comparing a novel investigational wearable infusor versus the Crono pump.

Aim: A novel, Investigational Wearable Infusor (IWI) was evaluated in a randomized, controlled, crossover, open-label study to determine if its delivery of subcutaneous immunoglobulin (IgPro20) achieved a comparable area under the concentration-time curve (AUC) for immunoglobulin G (IgG) versus the Crono S-PID-50 infusion pump (CP). EudraCT: 2016-003798-16. Materials & methods: Patients with primary immunodeficiency (PID) were randomized to receive IgPro20 in Sequence 1 (CP/IWI) or 2 (IWI/CP). The primary end point was AUC for IgG during the final week of each 4-week period. Results: 23 patients were enrolled. Evaluation of area under the concentration-time curve from time 0 (pre-infusion) to 7 days after infusion (AUC0-7 days) (IWI: 1806 h*g/l; CP: 1829 h*g/l) and geometric mean ratio indicated comparable AUCs for IgG for both devices. Conclusion: Similar IgG exposure, indicated by AUC values, can be achieved with IgPro20 using the IWI or CP in PID.

Patients with primary immunodeficiency (PID) are at a higher risk of developing serious infections than healthy individuals. Immunoglobulin G (IgG) replacement therapy reduces this risk, as it raises a patient's antibody levels to help fight off infections. IgG replacement therapy can be performed as an intravenous or subcutaneous (under the skin) infusion. The subcutaneous route is associated with improved quality of life for patients, as therapy can be carried out at home by the patient, allowing for more flexibility, convenience and autonomy. Wearable drug-delivery systems are devices that stick to the body and automatically deliver doses of a drug to the patient. In this study, we investigated whether a novel Investigational Wearable Infusor device could deliver the subcutaneous IgG replacement therapy, IgPro20, in patients with PID. We show that the new infusion device can deliver IgG replacement therapy and allows for similar levels of IgG to be achieved in patients as a comparator device. This wearable drug delivery device simplifies drug administration and could help address some of the challenges associated with self-injection such as complicated infusion preparation, needle phobia and concerns about pain. Trial Registration Number: 2016-003798-16 (EudraCT).

High risk of relapsed disease in patients with NK/T-cell chronic active Epstein-Barr virus disease outside of Asia.

Chronic active Epstein-Barr virus (EBV) disease (CAEBV) is characterized by high levels of EBV predominantly in T and/or natural killer cells with lymphoproliferation, organ failure due to infiltration of tissues with virus-infected cells, hemophagocytic lymphohistiocytosis, and/or lymphoma. The disease is more common in Asia than in the United States and Europe. Although allogeneic hematopoietic stem cell transplantation (HSCT) is considered the only curative therapy for CAEBV, its efficacy and the best treatment modality to reduce disease severity prior to HSCT is unknown. Here, we retrospectively assessed an international cohort of 57 patients outside of Asia. Treatment of the disease varied widely, although most patients ultimately proceeded to HSCT. Though patients undergoing HSCT had better survival than those who did not (55% vs 25%, P < .01), there was still a high rate of death in both groups. Mortality was largely not affected by age, ethnicity, cell-type involvement, or disease complications, but development of lymphoma showed a trend with increased mortality (56% vs 35%, P = .1). The overwhelming majority (75%) of patients who died after HSCT succumbed to relapsed disease. CAEBV remains challenging to treat when advanced disease is present. Outcomes would likely improve with better disease control strategies, earlier referral for HSCT, and close follow-up after HSCT including aggressive management of rising EBV DNA levels in the blood.

Subcutaneous Immunoglobulin Therapy with IgPro20 in Patients with Stiff Person Syndrome and Primary Immunodeficiency Disease.

Stiff Person Syndrome (SPS), a rare autoimmune neurologic disorder characterized by fluctuating muscle spasms and rigidity, is mediated by autoantibodies to glutamic acid decarboxylase (GAD) antibodies. Symptoms of SPS have been shown to improve after administration of intravenous immunoglobulin (IVIG) however, there is a paucity of information regarding use of SCIg in SPS. Four patients with Stiff Person Syndrome were treated with SCIgPro20 for a period between 31 to 101 months. Most reactions were local and mild. All patients reported improvement in spasticity, and 2 patients reported improvement in seizure frequency. SCIgPro20 was well tolerated in patients with SPS and was associated with improvement in symptoms.

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.

Safety and Tolerability of Manual Push Administration of Subcutaneous IgPro20 at High Infusion Rates in Patients with Primary Immunodeficiency: Findings from the Manual Push Administration Cohort of the HILO Study.

PURPOSE: To evaluate the safety and tolerability of IgPro20 manual push (also known as rapid push) infusions at flow rates of 0.5-2.0 mL/min. METHODS: Patients with primary immunodeficiency (PID) with previous experience administering IgPro20 (Hizentra®, CSL Behring, King of Prussia, PA, USA) were enrolled in the Hizentra® Label Optimization (HILO) study (NCT03033745) and assigned to Pump-assisted Volume Cohort, Pump-assisted Flow Rate Cohort, or Manual Push Flow Rate Cohort; this report describes the latter. Patients administered IgPro20 via manual push at 0.5, 1.0, and 2.0 mL/min/site for 4 weeks each. Responder rates (percentage of patients who completed a predefined minimum number of infusions), safety outcomes, and serum immunoglobulin G (IgG) trough levels were evaluated. RESULTS: Sixteen patients were treated; 2 patients (12.5%) discontinued at the 1.0-mL/min level (unrelated to treatment). Responder rates were 100%, 100%, and 87.5% at 0.5-, 1.0-, and 2.0-mL/min flow rates, respectively. Mean weekly infusion duration decreased from 103-108 to 23-28 min at the 0.5- and 2.0-mL/min flow rates, respectively. Rates of treatment-related treatment-emergent adverse events (TEAEs) per infusion were 0.023, 0.082, and 0.025 for the 0.5-, 1.0-, and 2.0-mL/min flow rates, respectively. Most TEAEs were mild local reactions and tolerability (infusions without severe local reactions/total infusions) was 100% across flow rate levels. Serum IgG levels (mean [SD]) were similar at study start (9.36 [2.53] g/L) and end (9.58 [2.12] g/L). CONCLUSIONS: Subcutaneous IgPro20 manual push infusions at flow rates up to 2.0 mL/min were well tolerated and reduced infusion time in treatment-experienced patients with PID. TRIAL REGISTRATION: NCT03033745.

Mutations in topoisomerase IIß result in a B cell immunodeficiency.

B cell development is a highly regulated process involving multiple differentiation steps, yet many details regarding this pathway remain unknown. Sequencing of patients with B cell-restricted immunodeficiency reveals autosomal dominant mutations in TOP2B. TOP2B encodes a type II topoisomerase, an essential gene required to alleviate topological stress during DNA replication and gene transcription, with no previously known role in B cell development. We use Saccharomyces cerevisiae, and knockin and knockout murine models, to demonstrate that patient mutations in TOP2B have a dominant negative effect on enzyme function, resulting in defective proliferation, survival of B-2 cells, causing a block in B cell development, and impair humoral function in response to immunization.

Individualized immunoglobulin treatment in pediatric patients with primary humoral immunodeficiency disease.

Primary immunodeficiency diseases (PIDD) are a group of genetic conditions that are generally considered to be under-diagnosed, and gaps may exist in the knowledge of treatment options. This review focuses on the diagnosis of pediatric patients with primary antibody deficiency and considerations for treatment with immunoglobulin (IgG) to optimize multiple dosing variables and minimize adverse events. The possibility of individualizing IgG therapy in clinical practice represents, in this field, the next pivotal step with the goal of improving the quality of life of pediatric patients with PIDD.

Autosomal Dominant Hyper-IgE Syndrome in the USIDNET Registry.

BACKGROUND: Autosomal dominant hyper-IgE syndrome (AD-HIES) is a rare condition. OBJECTIVE: Data from the USIDNET Registry provide a resource to examine the characteristics of patients with rare immune deficiency diseases. METHODS: A query was submitted to the USIDNET requesting deidentified data for patients with physician-diagnosed AD-HIES through July 2016. RESULTS: Data on 85 patients diagnosed with AD-HIES (50 males; 35 females) born between 1950 and 2013, collected by 14 physicians from 25 states and Quebec, were entered into the USIDNET Registry by July 2016. Cumulative follow-up was 2157 years. Of these patients, 45.9% had a family history of HIES. The complications reported included skin abscesses (74.4%), eczema (57.7%), retained primary teeth (41.4%), fractures (39%), scoliosis (34.1%), and cancer (7%). Reported allergic diseases included food (37.8%), environmental (18%), and drugs (42.7%). The mean serum IgE level was 8383.7 kU/mL and was inversely correlated to the patient's age. A total of 49.4% had eosinophilia; 56% were known to be on trimethoprim-sulfamethoxazole, 26.6% on antifungal coverage, and 30.6% on immunoglobulin replacement therapy. Pneumonias were more commonly attributed to Staphylococcus aureus (55.3%) or Aspergillus fumigatus (22.4%); 19.5% had a history of lung abscess; these were most often associated with Pseudomonas aeruginosa (P Fisher's exact test = .029) or A. fumigatus (P Fisher's exact test = .016). Lung abscesses were significantly associated with drug reactions (P χ2 = .01; odds ratio: 4.03 [1.2-12.97]), depression (P Fisher's exact test = .036), and lower Karnofsky index scores (P Mann-Whitney = .007). DISCUSSION: Data from the USIDNET Registry summarize the currently reported clinical characteristics of a large cohort of subjects with AD-HIES.

Characterization of T and B cell repertoire diversity in patients with RAG deficiency.

Recombination-activating genes 1 and 2 (RAG1 and RAG2) play a critical role in T and B cell development by initiating the recombination process that controls the expression of T cell receptor (TCR) and immunoglobulin genes. Mutations in the RAG1 and RAG2 genes in humans cause a broad spectrum of phenotypes, including severe combined immunodeficiency (SCID) with lack of T and B cells, Omenn syndrome, leaky SCID, and combined immunodeficiency with granulomas or autoimmunity (CID-G/AI). Using next-generation sequencing, we analyzed the TCR and B cell receptor (BCR) repertoire in 12 patients with RAG mutations presenting with Omenn syndrome (n = 5), leaky SCID (n = 3), or CID-G/AI (n = 4). Restriction of repertoire diversity skewed usage of variable (V), diversity (D), and joining (J) segment genes, and abnormalities of CDR3 length distribution were progressively more prominent in patients with a more severe phenotype. Skewed usage of V, D, and J segment genes was present also within unique sequences, indicating a primary restriction of repertoire. Patients with Omenn syndrome had a high proportion of class-switched immunoglobulin heavy chain transcripts and increased somatic hypermutation rate, suggesting in vivo activation of these B cells. These data provide a framework to better understand the phenotypic heterogeneity of RAG deficiency.

Subcutaneous Immunoglobulin Replacement Therapy with Hizentra® is Safe and Effective in Children Less Than 5 Years of Age.

BACKGROUND: Hizentra® (IGSC 20%) is a 20% liquid IgG product approved for subcutaneous administration in adults and children 2 years of age and older who have primary immunodeficiency disease (PIDD). There is limited information about the use of IGSC 20 % in very young children including those less than 5 years of age. METHODS: A retrospective chart review involved 88 PIDD infants and children less than 5 years of age who received Hizentra®. RESULTS: The mean age at the start of Hizentra® was 34 months (range 2 to 59 months). IGSC 20 % was administered weekly to 86 infants (two additional infants received twice weekly and three times weekly infusions, respectively) and included an average of 63 infusions (range 6-182) for an observation period up to 45.5 months. Infusion by manual delivery occurred in 15 patients. The mean dose was 674 mg/kg/4 weeks. The mean IgG level was 942 mg/dL while on IGSC 20 %, compared to a mean trough IgG level of 794 mg/dL (p < 0.0001) during intravenous or subcutaneous IgG administration prior to IGSC 20 %. Average infusion time was 47 (range 5-120) minutes, and the median number of infusion sites was 2 (range 1-4). Local reactions were mostly mild and observed in 36/88 (41%) children. No serious adverse events were reported. A significant increase in weight percentile (7 % ± 19.2, p = 0.0012) among subjects was observed during IGSC 20% administration. The rate of serious bacterial infections was 0.067 per patient-year while receiving IGSC 20%, similar to previously reported efficacy studies. CONCLUSIONS: Hizentra® is effective in preventing infections, and is well tolerated in children less than age 5 years.

Esophageal infections: an update.

PURPOSE OF REVIEW: Infectious esophagitis generally occurs in patients with impaired immunity. Although methods to suppress the immune system evolve, the potential infectious consequences are poorly understood. The purpose of this article is to review the risk factors, diagnosis, and treatment of infectious esophagitis. RECENT FINDINGS: Minimal pediatric data, including a few case reports and series, involve infectious esophagitis. Esophageal infections are usually caused by the following microbes, in order starting with the most common: Candida albicans, herpes simplex virus, and cytomegalovirus. Uncommon risk factors in these and other reports include epidural triamcinolone and oral budesonide in addition to more common risk factors such as HIV infection, chemotherapeutic agents, and transplant immunosuppressive medications. Rare reports involve immunocompetent patients and treatment of these patients is controversial. SUMMARY: Understanding of infectious esophagitis is growing, and risk factors, diagnosis, and treatments are evolving.

A systematic analysis of recombination activity and genotype-phenotype correlation in human recombination-activating gene 1 deficiency.

BACKGROUND: The recombination-activating gene (RAG) 1/2 proteins play a critical role in the development of T and B cells by initiating the VDJ recombination process that leads to generation of a broad T-cell receptor (TCR) and B-cell receptor repertoire. Pathogenic mutations in the RAG1/2 genes result in various forms of primary immunodeficiency, ranging from T(-)B(-) severe combined immune deficiency to delayed-onset disease with granuloma formation, autoimmunity, or both. It is not clear what contributes to such heterogeneity of phenotypes. OBJECTIVE: We sought to investigate the molecular basis for phenotypic diversity presented in patients with various RAG1 mutations. METHODS: We have developed a flow cytometry-based assay that allows analysis of RAG recombination activity based on green fluorescent protein expression and have assessed the induction of the Ighc locus rearrangements in mouse Rag1(-/-) pro-B cells reconstituted with wild-type or mutant human RAG1 (hRAG1) using deep sequencing technology. RESULTS: Here we demonstrate correlation between defective recombination activity of hRAG1 mutant proteins and severity of the clinical and immunologic phenotype and provide insights on the molecular mechanisms accounting for such phenotypic diversity. CONCLUSIONS: Using a sensitive assay to measure the RAG1 activity level of 79 mutations in a physiologic setting, we demonstrate correlation between recombination activity of RAG1 mutants and the severity of clinical presentation and show that RAG1 mutants can induce specific abnormalities of the VDJ recombination process.

Subcutaneous immunoglobulin replacement therapy with Hizentra® is safe and effective in two infants.

Hizentra® is a 20% liquid IgG product approved for subcutaneous administration in adults and children greater than 2 years of age. We report two infants less than 2 years in which administration of Hizentra® was safe and effective.