IVIG Replacement Research Articles

Use of Teclistamab Outside of Clinical Trials in Latin America: Risk of Infections and Immunoglobulin Replacement

Introduction: Teclistamab (TEC) was the first BCMA-targeting bispecific antibody (BsAb) approved. Between November 2022 and February 2023 triple-class relapsed / refractory myeloma (RRMM) patients had access to TEC through Expanded Access Program in Brazil. BCMA-targeting BsAbs trials had shown high rates of infections and, therefore, reports of TEC treatment outside clinical trials and management of its emergent toxicities are of great importance at this moment. Methods: Participants must have been triple-class exposed/refractory, with previous therapies including any proteasome inhibitor, any immunomodulatory drug and any anti-CD38 therapy and have received at least one dose of TEC. We collected prospective data focused on response, safety and adverse events of interest, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity (ICANS), use of immunoglobulin (IVIG), and infections. All participants received acyclovir and trimethoprim-sulfamethoxazole during all TEC therapy. Vaccinations and IVIG replacement were indicated per institutional guidelines. Results: We included 27 RRMM patients (pts), mostly male (60%) with a median age of 59 years (39-77yrs). All pts were triple-class exposed and over 80% triple-class refractory. The overall response rate was 48% (11% complete responses and 34% very good partial responses) and the median overall survival was 14.2 months. CRS occurred in 69% of pts, mostly grade 1 (54%), with 15% of grade 2 CRS. ICANS was rare, reported as grade 2 in 1 patient (4%). In the first three months of TEC, infections were reported in most patients (73%). Severe infections (grade 3 or higher) occurred in 5 patients (20%). Two of them died because of severe bacterial infections. Ten of 27 patients (37%) received IVIG at early phases of therapy. Post baseline IgG levels decreased rapidly, achieving levels < 400mg/dL in 62% of patients. Over time, rate of patients under IVIG replacement therapy increased sharply, covering 92% of them after 6 months of TEC. Concurrently, infection rate decreased significantly, with 3 cases (11%) of grade < 2 infections, mostly upper respiratory viral infections. COVID infections were not described in this cohort. Eleven patients remain alive and under TEC therapy. The most common cause of death were disease progression and refractoriness (13 patients) followed by grade 5 infections (3 patients). Discussion: Our study focused on TEC therapy outside clinical trials and particularly its emergent adverse events. Infections were the most common side effect of this BCMA-targeting BsAb, even after COVID pandemic. Rate of patients receiving IVIG increased over time while infection rate and its severity decreased. Awareness of infection risk of TEC could change this dismal outcome, combined with preventive measures such as broad coverage vaccination, mandatory use of prophylactic antibiotics and IVIG replacement therapy for all treated patients.

Flat Dose Intravenous Immunoglobulin Primary Infection Prophylaxis in Multiple Myeloma Patients on Bispecific Antibody Therapy: Vanderbilt Experience

BACKGROUND Bispecific antibodies (BsAbs) are novel immunotherapeutic agents with prolific anti-multiple myeloma (MM) efficacy in highly relapsed/refractory disease (RRMM). They have been associated with profound and prolonged hypogammaglobinemia which represents a unique challenge regarding increased risk of serious (sometimes fatal) infections. Though IVIG has historically been dosed at 0.4g/kg for secondary prophylaxis, there is still uncertainty in optimal timing, schedule and frequency of supplementation in MM patients. At Vanderbilt University Medical Center, we have adopted a flat dose 10g IVIG prophylaxis schedule, which on average delivers ~36% of historical, weight-based dosing. At present, expert recommendations advise IVIG replacement every 4 weeks in recipients of BsAb starting the second month of therapy and continuing until the end of therapy or until serum IgG levels reach > 400 mg/dL, whichever is longer ( Mohan M et al. Br J Haematol.2023;00:1-11). Considering that MM BsAbs are currently used with continued dosing schedule, adoption and anticipated new BsAb approvals are increasing, IVIG has previously been on national/global shortage (occasionally unavailable), IVIG replacement during hypogammaglobulinemia represents a crucial aspect of adequate infection prophylaxis in MM, we explored the impact of our institutional 10g IVIG prophylaxis on infection rates in RRMM patients receiving BsAbs. Prior studies with comparable BsAbs reported Grade (G) ≥3 infection rate of 32-45% and 18%, in anti-BCMA and anti-GPRC5D BsAbs, respectively. In these trials, overall, 14-53% of patients received IVIG prophylaxis. METHODS We performed a retrospective review using electronic medical record of RRMM patients receiving anti-BCMA or anti-GPRC5D BsAbs from Jan 2019 to Dec 2022, either on clinical trials or as a standard of care at our institution. The inclusion criteria were minimum of two months of BsAb therapy, and the use of at least one month of monthly IVIG prophylaxis for serum IgG < 400 mg/dL. All patients were also on baseline valacyclovir, trimethoprim-sulfamethoxazole and levofloxacin prophylaxis. Routine disease and treatment specifics as well as infection rates and grades were collected. Infections were defined as mild (infections treated outpatient), moderate (required hospital admission) or severe (hospital admission with intensive care unit level of care), next to also being graded by CTCAE v5 with the rest of hematologic and non-hematologic adverse events (AEs). RESULTS A total of 30 patients with RRMM were identified. Table 1 illustrates the demographic and disease specifics: 79% received a median (range) of 4 (2-7) lines of prior therapy, over half were penta-class exposed, 27% were triple and quad refractory, 67% received a prior autologous stem cell transplant and 17% underwent prior treatment with BCMA targeting CAR-T therapy. All except 2 patients received BsAb therapy on clinical trials. Anti-GPRC5D BsAb was used to treat 60% of patients, while the rest (40%) received anti-BCMA BsAb, all of which were given for a median of 27 (12-45) months (Table 1). Overall, 30% of patients had one infectious episode, while 43% had ≥2. Viral infections (57%) were twice as common as bacterial (30%) (Table 2). Infections were mild in 60%, moderate in 23%, and severe in 6.6% of patients. We observed 27% rate of G ≥3 infectious complications. Patients had a median (range) IgG at diagnosis of 1284(196-5431), and 499(210-2246) at the time of onset of first infection (IgG values at the start of BsAb therapy, at first and at ≥2 infections are outlined in Table 2). The rate of G ≥3 neutropenia and lymphopenia was 6.6% and 30% respectively. There were 2 (6.6%) sepsis related deaths, one each with anti-BCMA and anti-GPRC5D BsAbs. Table 2 also describes severity and the rates of cytokine release syndrome and neurotoxicity. CONCLUSIONS We observed relatively lower rate of severe or ≥ G3 infectious events with 10g flat IVIG dosing schedule. While our results represent a small, single-institutional cohort of predominantly anti-GPRC5D treated RRMM patients and require prospective validation in a randomized (IVIG 10g vs 0.4g/kg body weight) fashion, they demonstrate feasibility of reduced level dosing of a critical resource such as IVIG, in the fast expanding, national/global BsAb-based MM armamentarium.

Interstitial cystitis in common variable immunodeficiency: Could it be another autoimmune complication? A descriptive report

IntroductionCommon variable immunodeficiency (CVID) is considered the most common Human Inborn Error of Immunity (HIEI) and involves low IgG and susceptibility to infections. ESID 2014 criteria has expanded diagnostic criteria to include autoimmunity and lymphoproliferation. One less common and not well understood noninfectious complication of CVID is interstitial cystitis (IC), which may be caused by immune dysregulation. We hypothesized that patients with both CVID and IC may have reduced switched memory B cells. We conducted this study using data from United States Immunodeficiency Network (USIDNET) and compared results to patients at our institution to see if there were any variables of interest. Results and DiscussionSeventeen of 1446 patient (1.2%) with CVID in the USIDNET database had a diagnosis of possible interstitial cystitis and all were females. Patients in this group had normal average range for IgG (798 mg/dL) with IVIG replacement, along with normal WBC, platelet, IgM and basic T cell enumeration. B cell phenotyping data was available for only one patient, showing normal memory and switched memory B cells. Data from our institution showed similar normal ranges for all the above labs except one female patient who had low memory and switched memory B cell population and had the mildest IC-related disease course. One male patient had normal memory and switched memory B cell population with mild Tcell lymphopenia, however had the worst IC-related clinical outcome. ConclusionWe failed to observe a strong correlation between low switched memory B cells and IC in patients with CVID. IVIG, despite its immunomodulating effects, also appeared to lack any association. While the severity of IC and male gender for one of our patients may be coincidental, it does raise the suspicion that the phenotype of IC in male CVID patients may be different from their female counterparts. IC may be underreported in USIDNET, leading to limited data and prohibiting any clear causative conclusions we may draw this study. Nevertheless, we believe it is important to raise the awareness of this rare disease, so that we can be cognizant of its heterogeneous manifestations and impacts on morbidity and mortality.

Стан захищеності імуноскомпроментованих пацієнтів від кору, краснухи, дифтерії та правця

Purpose - to study the state of protection against vaccine-controlled infections in children with primary immunodeficiency (PID) and in children on immunosuppressive therapy. Materials and methods. The object of the study was the level of intensity of humoral immunity against viral (measles, rubella) and bacterial (diphtheria, tetanus) vaccine-controlled infections in immunosuppressed patients. Protective levels of specific IgG antibodies against vaccine antigens were determined in 58 children with primary immunodeficiency and 20 children receiving immunosuppressive therapy. Among the 58 children with primary immunodeficiency, there were 26 children with preserved antibody function and 32 children with antibody deficiencies and combined immunodeficiencies on immunoglobulin replacement therapy. The state of immunity of immunocompromised patients was compared with that of healthy children in the control group. Results. In the group of children with PID with preserved antibody function, vaccinated against measles, rubella and 94.4% of children had a protective level of antibodies against measles, 100% of children against rubella. 78.6% of vaccinated children in this group were protected against tetanus and only 57.1% were protected against diphtheria. All children with PID with impaired antibody production receiving intravenous immunoglobulin replacement therapy (IVIG) were protected against measles, rubella, diphtheria, and tetanus. Among 10 patients on immunosuppressive therapy vaccinated against measles and rubella, antibodies to the measles virus in the protective titer were detected in 80% of children, to rubella - in 90% of patients in this group. Almost all children with rheumatic diseases on immunosuppressive therapy vaccinated against tetanus and diphtheria were protected against these pathogens, except for 2 out of 14 (14,2%) children who did not have antibodies to diphtheria. Children with glomerulonephritis with nephrotic syndrome had insufficient protection against diphtheria and tetanus, only 3 out of 6 (50%) children had antibodies in the protective titer against tetanus, no patient with this pathology had antibodies against diphtheria. Conclusions. The findings of the studies suggest that most patients with PID with preserved antibody function may develop a sufficient immune response to vaccination against viral (measles, rubella) and bacterial (tetanus) infections. IVIG replacement therapy protects children with PID against vaccine-controlled infections that impair antibody production. Most children with rheumatic diseases vaccinated according to the Calendar before starting immunosuppressive therapy retain postvaccination protection of antibodies against vaccine-controlled infections. Immune protection against vaccine-controlled infections is reduced in patients with glomerulonephritis with nephrotic syndrome, they need close monitoring and, if necessary, replacement therapy with immunoglobulins. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors. Key words: primary immunodeficiency, replacement therapy, children, vaccination, immunosuppressive therapy, specific antibodies to measles, rubella, diphtheria and tetanus.

Hematopoietic stem cell transplantation for Inborn Errors of Immunity

Hematopoietic stem cell transplantation for Inborn Errors of Immunity

A case of common variable immune deficiency with lung disease–not just bronchiectasis

Introduction: Common Variable Immune Deficiency (CVID) is the most prevalent form of severe antibody deficiency in children and adults. Most patients suffer recurrent, mainly sinopulmonary, infections. Despite adequate IVIG replacement therapy, chronic lung disease continues to be a main cause of morbidity and mortality. The term granulomatous-lymphocytic interstitial lung disease (GLILD) is frequently used to describe interstitial lung disease associated with immune dysregulation in primary antibody deficiency, such as CVID. Aim: To describe the case of a 10-year-old male with CVID who developed GLILD and his response to treatment with Rituximab. Discussion: Our patient is a young male with CVID and no genetic diagnosis, whose lung functions and general condition continued to deteriorate despite adequate intravenous immunoglobulin replacement therapy and mycophenolate mofetil treatment. After the diagnosis of GLILD, we initiated treatment with a 4-dose weekly course of Rituximab with prompt resolution of his interstitial disease. Although GLILD is a well described condition that accompanies CVID as a manifestation of immune dysregulation, it is still under recognized, especially in the pediatric population. Among experts, there is little uniformity when it comes to diagnostic and treatment approaches. Recent studies showed improved outcomes when using combination therapy with Rituximab, such as in our patient. Statement of Novelty: We shed light on GLILD, an important condition that accompanies CVID, and demonstrate an excellent response to the steroid sparing agent Rituximab. This is a crucial aspect when considering therapeutic choices for the pediatric population.

Minor Clinical Impact of COVID-19 Pandemic on Patients With Primary Immunodeficiency in Israel.

In the last few months the world has witnessed a global pandemic due to severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection causing coronavirus disease 2019 (COVID-19). Obviously, this pandemic affected individuals differently, with a significant impact on populations considered to be at high-risk. One such population, was assumed to be patients with primary genetic defect involving components or pathways of the immune system. While human immunity against COVID-19 is not fully understood, it is, so far, well documented, that both adaptive and innate cells have a critical role in protection against SARS-CoV-2. Here, we aimed to summarize the clinical and laboratory data on primary immunodeficiency (PID) patients in Israel, who were tested positive for SARS-CoV-2, in order to estimate the impact of COVID-19 on such patients. Data was collected from mid-February to end-September. During this time Israel experienced two “waves” of COVID-19 diseases; the first, from mid-February to mid-May and the second from mid-June and still ongoing at the end of data collection. A total of 20 PID patients, aged 4 months to 60 years, were tested positive for SARS-CoV-2, all but one, were detected during the second wave. Fourteen of the patients were on routine monthly IVIG replacement therapy at the time of virus detection. None of the patients displayed severe illness and none required hospitalization; moreover, 7/20 patients were completely asymptomatic. Possible explanations for the minimal clinical impact of COVID-19 pandemic observed in our PID patients include high level of awareness, extra-precautions, and even self-isolation. It is also possible that only specific immune pathways (e.g. type I interferon signaling), may increase the risk for a more severe course of disease and these are not affected in many of the PID patients. In some cases, lack of an immune response actually may be a protective measure against the development of COVID-19 sequelae.

THE RELATIONSHIP BETWEEN THE EFFECT OF IMMUNOGLOBULIN THERAPY AND THE FUNCTIONAL POTENCIES OF THE CELLULAR LINK OF THE IMMUNE SYSTEM IN X-LINKED AGAMMAGLOBULINEMIA

Objective:to evaluate the effectiveness of intravenous immunoglobulins in X-linked agammaglobulinemia, to identify changes in the cellular link of the innate and adaptive immune response associated with an insufficient effect of replacement therapy.Materials and methods:12 patients with X-AGH were under dynamic observation. BTK genetic defect confirmed using next generation sequencing technology. After verification of the diagnosis, patients received IVIG replacement therapy at a saturation dose and then at a maintenance dose. The data of prospective observation for a full year of regular IVIG therapy with an assessment of the severity of the disease, monthly monitoring of the pre-transfusion IgG level and determination of the quantitative and functional parameters of the components of the adaptive and innate immune response every three months are presented.Results:regular replacement therapy contributed to a decrease in the frequency of exacerbations of foci of chronic infection, a decrease in the frequency and duration of antibiotic therapy, however, in 30 % of cases, the frequency of exacerbations remained high, and antibiotic courses were doubled than the standard ones. A comparative analysis of the parameters of the immune system showed that with a smaller effect of IVIG, the functional potentials of T-effectors are less significant than in the comparison group and the properties of neutrophils and natural killers are more inhibited.Summary:the relationship between the severity of the clinical manifestation of XLA on the background of replacement therapy and the preservation of the functional potencies of the cellular components of the immune system provides the basis for a possible combination of IVIG therapy with drugs that affect the properties of cellular elements of the immune system.

Outcome and Risk Factors of Autoimmune Cytopenia after Hematopoietic Cell Transplantation for Children with Primary Immunodeficiency

Introduction Studies focusing on post-HCT AIC in large cohorts of patients transplanted for primary immunodeficiency (PID) are lacking. Objectives We conducted a retrospective analysis of incidence, risk factors, outcome of post-HCT AIC in children with PID and B-cell function following rituximab treatment. Methods Between January 1987-December 2018, 502 PID patients who underwent first HCT for PID at our center were included. Cumulative incidence (CI) of post-HCT AIC was calculated using a competing risk analysis, considering death as a competing event. Fine-and-Gray test was used to identify risk factors of AIC. The selected variables: gender, age at HCT, indication for HCT (SCID versus non-SCID PID), pre-HCT AIC, donor type, donor-recipient ABO matching, stem cell source, ex-vivo T-cell depletion (TCD), stem cell doses, conditioning regimen, serotherapy, GvHD prophylaxis, acute GvHD, chronic GvHD and viraemia. B-lymphocyte immune reconstitution kinetics was compared between surviving patients with post-HCT AIC without rituximab (n=18), post-HCT treated with rituximab (n=12) and controls (n=24). Results 36 (CI, 9%) developed post-HCT AIC, with median onset at 6.5 months (2.5 months - 18.2 years). On univariate analysis, pre-HCT AIC (Fig. A), mismatched donor, alemtuzumab (Fig. B), ATG, acute GvHD (Fig. C) and chronic GvHD were significantly associated with post-HCT AIC. After multivariate analysis, alemtuzumab (p=0.02) was independently associated with post-HCT AIC. Corticosteroid and high-dose IVIg (2gm/kg) achieved remission in 50% (n=18), additional rituximab led to remission in 25% (n=9), and the remaining 25% were treated with various modalities including sirolimus (n=5), bortezomib (n=3), mycophenolate mofetil (n=2), splenectomy (n=2), and second HCT (n=3). The mortality of post-HCT AIC reduced from 25% (4/16) prior to 2011 to 5% (1/20) after 2011. The median follow-up of 5.8 years (0.4-29.1) showed that 26 of 30 survivors (87%) were in complete remission, 4 (13%) were in remission with sirolimus and low dose steroid. Of 12 survivors who were treated with rituximab, immunoglobulin substitution was discontinued in 7 (52%), and 5 (48%) required on-going IVIg replacement. The median interval between HCT and rituximab was 1.95 years (0.96-19.9) in patients who were IVIg dependent and 0.73 (0.30-2.3) in patients who were IVIg-free on last follow-up (p=0.17). B-lymphocyte immune reconstitution kinetics was significant slowly in patients with post-AIC with/without rituximab (Fig. D). Conclusions 5-year CI of post-HCT AIC in children with PID was 9% and there is risk of very late onset post-HCT AIC in patients with Artemis and RAG1 mutations, and activated PI3 delta syndrome. Alemtuzumab pk study might play a role in reducing the incidence of post-HCT AIC. Sirolimus is an effective steroid-sparing immunomodulator in refractory/frequently relapsing post-HCT AIC.

Primary immunodeficiencies: general variable immunodeficiency (GVID)

This review provides data on the most common primary immunodeficiency of the humoral immunity – the general variable immunodeficiency, the characteristics of the clinical manifestations of this pathology, as well as the features of diagnostics and treatment. The disease can develop at any age. However, around the world there is a late diagnostics of primary immunodeficiencies. The disease is characterized by a polymorphic nonspecific picture including lesions of almost all body systems. Infectious pathology and oncological diseases are the main cause of death in this group of patients. Early detection of patients with general variable immunodeficiency and the prescription of IVIG replacement therapy will increase the duration and improve their quality of life.

Ataxia Telangiectasia Diagnosed on Newborn Screening–Case Cohort of 5 Years' Experience

Ataxia telangiectasia (AT) is a genetic condition caused by mutations involving ATM (Ataxia Telangiectasia Mutated). This gene is responsible for the expression of a DNA double stranded break repair kinase, the ATM protein kinase. The syndrome encompasses combined immunodeficiency and various degrees of neurological abnormalities and increased risk of malignancy. Typically, patients present early in life with delay in neurological milestones, but very infrequently, with life threatening infections typical of a profound T cell deficiency. It would therefore be unexpected to identify this condition immediately after birth using T cell receptor excision circle (TREC)-based newborn screening (NBS) for SCID. We sought to evaluate the frequency of AT detected by NBS, and to assess immunity as well as the genetic aberrations associated with this early presentation. Here, we describe the clinical, laboratory, and genetic features of patients diagnosed with AT through the Ontario NBS program for SCID, and followed in our center since its inception in 2013. Four patients were diagnosed with AT as a result of low TRECs on NBS. In each case, whole exome sequencing was diagnostic. All of our patients had compound heterozygous mutations involving the FRAP-ATM-TRRAP (FAT) domain of the ATM gene, which appears critical for kinase activity and is highly sensitive to mutagenesis. Our patients presented with profound lymphopenia involving both B and T cells. The ratio of naïve/memory CD45+RA/RO T cells population was variable. T cell repertoire showed decreased T cell diversity. Two out of four patients had decreased specific antibody response to vaccination and hypogammaglobulinemia requiring IVIG replacement. In two patients, profound decreased responses to phytohemagglutinin stimulation was observed. In the other two patients, the initial robust response declined with time. In summary, the rate of detection of AT through NBS had been surprisingly high at our center. One case was identified per year, while the total rate for SCID has been five new cases per year. This early detection may allow for better prospective evaluation of AT shortly after birth, and may assist in formulating early and more effective interventions both for the neurological as well as the immune abnormalities in this syndrome.

Results of a Multicentre, Randomized, Controlled Open-Label Study on the Use of Anti-T-Lymphocyte Globulin (ATLG) and Rituximab for Immunomodulation of Graft-Versus-Host Disease (GvHD) and Graft Failure (GF) in Patients with Non-Malignant Disorders

BACKGROUND: Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is increasingly used to treat a wide range of non-malignant disorders. However, the optimal strategy to be employed for GvHD prevention remains a matter of debate. In particular, the use of ATLG for the prevention of immune-mediated complications in patients transplanted from a matched-related donor (MRD) is still controversial. In the matched unrelated donor (MUD) setting, there is retrospective evidence that Rituximab used as prophylaxis of EBV viremia may protect from acute GvHD (aGvHD) development, but the clinical benefit of pre-transplant Rituximab has never been assessed in prospective randomized studies. METHODS: We conducted a multicentre, randomized, open-label, trial (NCT01810926) in 5 Italian centres enrolling patients with non-malignant haematological and inherited metabolic disorders transplanted from either a MRD or a MUD, selected using high-resolution typing for HLA-class I/II loci and stringent criteria of HLA-compatibility (>9/10). All patients received the same myeloablative regimen consisting of Treosulfan, Thiotepa and Fludarabine. Enrolled patients were randomized (1:1) to receive either standard or intensified GvHD prophylaxis. Cyclosporine-A plus short-term methotrexate was the standard GvHD prophylaxis in MRD HSCT recipients. In the experimental arm, patients were additionally given ATLG (Grafalon®, Neovii, 5 mg/kg/day on day -4,-3, and -2). In patients transplanted from a MUD, standard GvHD prophylaxis consisted of Cyclosporine-A plus short-term methotrexate and ATLG (10 mg/kg on day -4,-3 and-2). In the experimental arm, patients were additionally given Rituximab 200 mg/sq on day -1 (Mabthera®, Roche). In MRD group randomization was stratified by disease (hemoglobinopathies vs. other conditions) and in the MUD group by center. For patients given MRD HSCT, the primary end-point was the probability of survival (SUR) free from: a) primary and secondary GF, b) grade II-IV aGvHD, c) chronic GvHD (cGvHD), d) death, whichever occurred first. For patients transplanted from a MUD, the primary end-point was the SUR probability free from: a) grade II-IV aGvHD, b) EBV viremia (>1,000 copies of viral DNA/ml whole blood), whichever occurred first. Secondary endpoint was overall SUR (OS). Statistical analyses were conducted according to intention-to-treat. FINDINGS: Between August 2011 and February 2018, 126 patients were enrolled. Patient and disease characteristics by randomized treatment are shown in Table 1. Median age at HSCT was 6.1 years in the MRD group (range 0.8-38) and 4.9 years in the MUD group (range 0.9-20.7). Median follow-up was 3.6 years. Among the 51 MRD-HSCT recipients, 25 were randomly assigned to the ATLG group and 26 to the NO-ATLG group. No death and no cases of grade II-IV aGvHD were observed in either of the two randomization arms. Two GF occurred in each of the two arms, while 1 and 2 cases of cGvHD occurred in the ATLG and NO-ATLG groups, respectively. Consequently, no statistically significant difference in the probability of SUR without events was observed (p=0.75) and the 3-years estimates (±SE) were 86.9%±7.1% vs. 83.8%±7.5%, respectively. In the MUD setting, 38 patients were allocated in the Rituximab group and 37 in the NO-Rituximab group. Although no statistically significant difference in OS (p=0.21) was observed between the two arms (3-years estimates: 94.1%±4.1% for Rituximab, 85.7%±5.9% for No-Rituximab), patients receiving Rituximab had a better probability of SUR without events (73.0%±7.3% vs 26.5%±7.3%, respectively; p=0.0002), entirely due to a lower incidence of EBV viremia. One case of fatal post-transplant lymphoproliferative disorder was observed in the No-Rituximab arm. Eight patients developed grade II-IV aGvHD in each of the two arms. No patient has persistent dependence on ivIG replacement therapy. CONCLUSIONS Our data indicate that, in patients with non-malignant disorders given a MRD HSCT, the addition of ATLG does not confer any advantage in the prevention of both acute and chronic GvHD, as well as of GF. In MUD-HSCT recipients, the administration of a fixed dose of pre-transplant Rituximab as part of the conditioning regimen does not affect the risk of aGvHD and transplant-related mortality, while it significantly reduces the incidence of episodes of EBV-viremia, without impairing B-cell recovery. Disclosures Algeri: Bluebird bio: Consultancy, Honoraria; Miltenyi: Honoraria; Atara Biotherapeutics: Consultancy, Honoraria. Merli:Novartis: Honoraria; Sobi: Consultancy; Amgen: Honoraria; Bellicum: Consultancy. Locatelli:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Miltenyi: Honoraria; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

The Natural History of Untreated Primary Hypogammaglobulinemia in Adults: Implications for the Diagnosis and Treatment of Common Variable Immunodeficiency Disorders (CVID).

Background: Adults with primary hypogammaglobulinemia are frequently encountered by clinicians. Where IgG levels are markedly decreased, most patients are treated with subcutaneous or intravenous immunoglobulin (SCIG/IVIG), because of the presumed risk of severe infections. The natural history of untreated severe asymptomatic hypogammaglobulinemia is thus unknown. Similarly, there are no long-term prospective studies examining the natural history of patients with moderate reductions in IgG.Methods: In 2006, we began a prospective cohort study of patients with symptomatic and asymptomatic reductions in IgG who were not immediately commenced on SCIG/IVIG. Over the course of 12 years, 120 patients were enrolled in the NZ hypogammaglobulinemia study (NZHS) including 59 who were asymptomatic.Results: Five patients with profound primary hypogammaglobulinemia (IgG < 3 g/l), who were not on regular SCIG/IVIG have remained well for a mean duration of 139 months. This study has also shown most asymptomatic patients with moderate hypogammaglobulinemia (IgG 3.0–6.9 g/l) have been in good health for a mean observation period of 96 months. We have only identified one asymptomatic patient with moderate hypogammaglobulinemia who experienced progressive decline in IgG levels to <3 g/l and was accepted for IVIG replacement. Prospective monitoring has shown that none have suffered catastrophic infections or any of the severe autoimmune or inflammatory sequelae associated with Common Variable Immunodeficiency Disorders (CVID). Unexpectedly, 18.1% of asymptomatic and 41.6% of symptomatic hypogammaglobulinemic patients spontaneously increased their IgG into the normal range (≥7.0 g/l) on at least one occasion, which we have termed transient hypogammaglobulinemia of adulthood (THA). In this study, vaccine challenge responses have correlated poorly with symptomatic state and long-term prognosis including subsequent SCIG/IVIG treatment.Conclusions: In spite of our favorable experience, we recommend patients with severe asymptomatic hypogammaglobulinemia are treated with SCIG/IVIG because of the potential risk of severe infections. Patients with moderate asymptomatic hypogammaglobulinemia have a good prognosis. Patients with symptomatic hypogammaglobulinemia are a heterogeneous group where some progress to SCIG/IVIG replacement, while many others spontaneously recover. This study has implications for the diagnosis and treatment of CVID.

Efficiency of complex therapy in patients with a- and hypogammaglobulinemia

Objective:assessment of the effectiveness of the use of Polymuramil in complex with IVG therapy with patients with CVID and ХLA with insufcient replacement therapy.Materials and methods:there were 10 patients with insufcient effectiveness of IVIG replacement therapy, receiving complex IVIG therapy and immunomodulator Polymuramil at a dose of 200 μg / 0.5 ml No. 5 intramuscularly every other day, under study. Surface and intracellular markers of cells of the congenital and acquired immune response, serum immunoglobulins of class A, M, G - in the radial immunodiffusion in the Mancini gel, the oxygen-dependent metabolic activity of neutrophils in NST-test were assessed with the help of flow cytometry, before and afer 3 months and a comparative analysis of the obtained data was conducted.Results:analysis of the data revealed a signifcant increase in markers of lymphocyte activation, which indicates the induction properties of the studied immunomodulator by increasing the activation potentials of the cellular link of adaptive immunity in patients with primary immunodefciency.Summary:in patients with a genetically mediated defect of the humoral immunity against the background of complex therapy with the use of Polymuramil, the activation of congenital and adaptive immunity is registered, which is confrmed, in addition to laboratory indexes, by a decrease in the frequency of exacerbations of chronic inflammatory diseases.

Efficacy-safety of Facilitated Subcutaneous Immunoglobulin in Immunodeficiency Due to Hematological Malignancies. A Single-Center Retrospective Analysis

Hematological malignancies are frequently complicated by secondary immunodeficiency (SID). Immunoglobulin replacement with intravenous gamma globulins (IVIg) reduces infection incidence, antibiotics' need and hospitalization days in these patients. Facilitated subcutaneous immunoglobulin replacement (fSCIg) has been studied in primary immunodeficiency patients and is equally efficacious with several advantages (self-administration, same bioavailability, long infusion intervals, fewer adverse drug reactions). fSCIg has been less extensively studied in SID. We present our retrospective single-center data of fSCIg administration to hematological patients with SID, focusing on efficacy and safety issues. Overall, 33 hematological patients with hypogammaglobulinemia were treated with fSCIg according to ESMO 2015 guidelines, between mid-October 2015 and mid-January 2018 in our Department. The infection rate was very low (18.1%). Shorter infusion intervals further reduced it. ADRs were rare (9%) and mild (grade 1). fSCIg managed to reduce the everyday nursery/hospital burden of our tertiary hospital. fSCIg compares favorably to IVIg replacement in SID patients.

Haematopoietic stem cell transplant for hyper-IgM syndrome due to CD40 defects: a single-centre experience

Hyper-IgM syndrome due to CD40 deficiency (HIGM3) is a rare disease with only a few reported cases of haematopoietic stem cell transplantation (HSCT). In retrospective study, we reviewed all patients with HIGM3 who underwent HSCT at King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia, between 2008 and 2013. Six patients were identified. Three male and three female patients from three families. The median age of diagnosis was 13 months (range, 1-28 months). All lacked CD40 expression on B cells by flow cytometry. The median time from diagnosis to transplantation was 8.5 months (range, 1-17 months). For all patients, the donors were HLA-identical siblings, with the exception of one patient for whom the donor was a sibling with one antigen mismatch. The conditioning regimen was busulfan and cyclophosphamide in five patients and busulfan, cyclophosphamide and antithymocyte globulin in one patient. For GVHD prophylaxis, cyclosporine and methotrexate was used. All patients engrafted. The survival rate was 100%, with a median follow-up of 54 months (range, 30-116 months). One patient developed acute GVHD. All patients showed complete immune recovery with positive CD40 expression on B cells and discontinued IVIG replacement. Our study shows that HSCT is potentially effective at curing the disease.

The Significance of B-cell Subsets in Patients with Unclassified Hypogammaglobulinemia and Association with Intravenous Immunoglobulin Replacement Requirement.

Patients with unclassified hypogammaglobulinemia (UCH) constitute a diagnostic and therapeutic dilemma, because information concerning the clinical and immunological characteristics of these patients is insufficient. To evaluate B-cell subsets in cases with UCH and common variable immunodeficiency (CVID) and their association with treatment requirement in UCH patients. The study included 41 UCH, 25 CVID, and 36 healthy individuals between the ages of 4-18 years. The absolute count of total memory and switched memory B-cells were lower in the CVID cases in comparison to the control group. Additionally, the absolute count of marginal zone-like B cells in the 4-10 year age group, and the absolute count of switched plasmablasts in the 10-18 year age group were lower in CVID cases when compared to both the control and UCH groups. The UCH group was categorized based on IVIG replacement therapy. Therefore, the percentage of switched memory B cells was significantly lower in the IVIG-receiving group (10.6% ± 3.10%) compared to the control group (14.0% ± 5.60%). However, there was no significant difference between the IVIG-receiving group and the CVID group. Regarding the comparison of the non-IVIG replacement group and the CVID group, the absolute count of total memory B cells, marginal zone-like B cells, and switched memory B cells were significantly higher in the UCH group. B-lymphocyte subsets in UCH cases that did not require IVIG replacement were similar to the control group. On the other hand, the percentage of switched memory B-cells in the UCH cases that required IVIG replacement was not different from that of the CVID cases.

Angioedema como única manifestación inicial de hipogammaglobulinemia

Common variable immunodeficiency is characterized by hypogammaglobulinemia and the inability to respond to vaccines. Patients mostly manifest infections, however only less than 5 % have pathological conditions as autoimmunity, granulomatous inflammation, and splenomegaly or lymphoproliferative disease among others, without showing infections. We report the case of a woman who debuted with localized cutaneous affection, facial angioedema, without other early symptoms. After diagnosis splenomegaly and bronchiectasis were documented. Angioedema and bronchiectasis responded with IVIG replacement. We also review the dermatological manifestations associated with CVID.

Disease burden for patients with primary immunodeficiency diseases identified at reference hospitals in Guanajuato, Mexico.

BackgroundIn addition to the deleterious effect on health, there is considerable economic and psychosocial morbidity associated with primary immunodeficiency diseases (PID). Also, the cost of a late diagnosis frequently results in a heavy disease burden on the patient. The objective of this study was to collect and analyze data on patients with PID in the state of Guanajuato in Mexico, to indirectly estimate the burden of the disease.MethodsAn observational, longitudinal, and comparative study was conducted. A total of 44 patients were included and grouped according to the updated classification of PID.ResultsThe median time elapsed from the onset of symptoms to the reference and diagnosis by a tertiary hospital was of 2.17 (IQR = 6.44) years. Before diagnosis, the number of hospitalizations/year per patient was 0.86 (IQR = 2.28), the number of visit to emergency room/year per patient was 0.92 (IQR = 1.77), the number of doctor’s visits/year per patient was 15 (IQR = 11.25), whereas the school/work absence days per patient were reported in 52.72 (IQR = 56.35) days per year. After diagnosis, 20 patients (45.45%) received IVIG replacement therapy, and all of them presented a significant improvement (p <0.05) in all the mentioned variables. Characteristically, even when patients with PID received IVIG, there was still an important disease burden when comparing them against healthy controls. Complications secondary to PID were detected in 19 patients (43.18%). The reported overall mortality rate was 6.82% (n = 3).ConclusionsWe were able to indirectly estimate an important disease burden in patients with PID; which is considered to be preventable, at least in part, with effective interventions like health planning, research, collaboration with primary care providers, and generation of policies and practices, in order to improve the quality of life and care of families with PID.

Incidence and risk factors of bacterial infections in children following autologous hematopoietic stem cell transplantation: Single-center experience from Jordan.

Bacterial infection is a serious sequela following AHSCT; however, limited data are available regarding pediatric recipients, especially in developing countries. We retrospectively analyzed the incidence and risk factors of bacterial infections during the first 100days after AHSCT in children at KHCC in Amman, Jordan between January, 2005 and September, 2013. A total of 65 patients were identified, with median age of fouryr (1-17). Forty-seven patients (72.3%) had solid tumors and 18 (27.7%) had lymphoma. Bacterial infections were documented in 33 patients (50%), with a total of 63 episodes. Gram-negative infection (57.1%) was more prevalent than Gram-positive infection (38%). The risk of bacterial infections was higher among patients less than fiveyr of age (p=0.028) and those who developed hypogammaglobulinemia requiring IVIG replacement (p=0.001). Patients with solid tumors developed more bacterial infections compared to patients with lymphoma (p=0.0057). No deaths were attributed to bacterial infection. Bacterial infection rate is high among recipients of AHSCT in Jordan with Gram-negative bacteria being the most common.