Warm Autoimmune Hemolytic Anemia Research Articles

Three different pathways of IgM-antibody-dependent hemolysis are mainly regulated by complement.

Antibodies to red blood cells (RBCs) may hemolyze erythrocytes via Fc-mediated phagocytosis or complement-dependent. Complement activation on RBCs can be detected by C3d-direct antiglobulin test (DAT), which is the only test in immune hematology that directly targets complement. However, a positive DAT with anti-C3d cannot distinguish between C3b-mediated extravascular hemolysis, C5b-C9-mediated intravascular hemolysis and C5b-C8-mediated eryptosis. Furthermore, DAT is not suitable to estimate the strength of hemolysis. Autoimmune hemolytic anemia (AIHA) is a rare disease that is caused by autoantibodies to red blood cells that is divided in warm AIHA and in cold agglutinin disease (CAD). The causative antibodies in CAD and sometimes in warm AIHA are from the IgM class. Depending on strength of complement activation they can induce extravascular hemolysis, intravascular hemolysis and eryptosis. We studied the three types of hemolysis by use of sera from patients with CAD under various conditions. We found that additionally to the routinely applied C3d-DAT, indirect tests for complement activity (free hemoglobin and Annexin V-binding to phosphatidylserine-exposing RBCs) should be used to determine the portion of extravascular, intravascular and eryptotic hemolysis. Eryptotic hemolysis may have a significant share in clinical relevant CAD or IgM warm AIHA, which should be considered for successful treatment.

Pure red cell aplasia and warm autoimmune haemolytic anaemia induced by programmed cell death protein 1 (PD1) inhibitor therapy

A 79-year-old female with a history of resected margin-positive melanoma on 6 months of nivolumab therapy presented to emergency with symptomatic anaemia (Hb 72). There was no bleeding or relevant medical history. Her FBC was otherwise normal aside from reticulocytopenia (6.2x109) with normal haematinics. There was evidence of haemolysis with undetectable haptoglobin, elevated LDH and strong positive direct antiglobulin test (DAT) for IgG/C3d with negative elution. Group and screen showed no alloantibodies with adequate increment and rapid reduction in haemoglobin post-transfusion.

Rise of the planet of rare anemias: An update on emerging treatment strategies.

Therapeutic options for rare congenital (hemoglobinopathies, membrane and enzyme defects, congenital dyserythropoietic anemia) and acquired anemias [warm autoimmune hemolytic anemia (wAIHA), cold agglutinin disease CAD, paroxysmal nocturnal hemoglobinuria (PNH), and aplastic anemia (AA)] are rapidly expanding. The use of luspatercept, mitapivat and etavopivat in beta-thalassemia and pyruvate kinase deficiency (PKD) improves transfusion dependence, alleviating iron overload and long-term complications. Voxelotor, mitapivat, and etavopivat reduce vaso-occlusive crises in sickle cell disease (SCD). Gene therapy represents a fascinating approach, although patient selection, the toxicity of the conditioning regimens, and the possible long-term safety are still open issues. For acquired forms, wAIHA and CAD will soon benefit from targeted therapies beyond rituximab, including B-cell/plasma cell targeting agents (parsaclisib, rilzabrutinib, and isatuximab for wAIHA), complement inhibitors (pegcetacoplan and sutimlimab for CAD, ANX005 for wAIHA with complement activation), and inhibitors of extravascular hemolysis in the reticuloendothelial system (fostamatinib and FcRn inhibitors in wAIHA). PNH treatment is moving from the intravenous anti-C5 eculizumab to its long-term analog ravulizumab, and to subcutaneous and oral proximal inhibitors (anti-C3 pegcetacoplan, factor D and factor B inhibitors danicopan and iptacopan). These drugs have the potential to improve patient convenience and ameliorate residual anemia, although patient compliance becomes pivotal, and long-term safety requires further investigation. Finally, the addition of eltrombopag significantly ameliorated AA outcomes, and data regarding the alternative agent romiplostim are emerging. The accelerated evolution of treatment strategies will need further effort to identify the best candidate for each treatment in the precision medicine era.

The potential of metabolomics as a predictive guide for clinical management in autoimmunity against red blood cells.

Autoimmune-responses leading to increased destruction of red blood cells occur in autoimmune haemolytic anaemia (AIHA). The pathophysiology of AIHA is multifactorial and not fully understood, and clinically it remains challenging to manage relapsed and treatment-refractory cases. Rabelo and colleagues conduct metabolomic profiling in plasma of 26 patients with primary warm AIHA, with consideration of haemolytic activity and relapse occurrence. They identify distinct metabolites to be increased in primary warm AIHA patients, thereby providing an encouraging basis for further validation and exploration of metabolomic profiling as a predictive tool for the management of AIHA. Commentary on: Rabelo et al. Metabolomic profile in patients with primary warm autoimmune haemolytic anaemia. Br J Haematol 2023;200:140-149.

Autoimmune Haemolytic Anaemia, Acute Pericarditis with Cardiac Tamponade as Presenting Manifestations in Systemic Lupus Erythematosus- A Rare Case Report

Systemic Lupus Erythematosus (SLE) is an autoimmune disorder that affects mostly young women in which tissue-binding autoantibodies and immune complexes cause damage to organs and tissues. SLE is characterised by aberrant immunological responses that result in the release of higher levels and immunogenic nucleic acids, proteins, and other self-antigens. Autoimmune Haemolytic Anaemia (AIHA) is a condition in which antibodies against red blood cells are present. It is classified as a warm and cold antibody AIHA. The causes of warm antibody AIHA are autoimmune illnesses, infections, or even malignancy. The presence of Immunoglobulin G (IgG) antibodies can indicate warm autoimmune haemolytic anaemia (warm agglutinin anaemia), which is characterised by fatigue and other constitutional symptoms. Although, autoimmune haemolytic anaemia can be a component of the SLE spectrum, warm autoimmune haemolytic anaemia as the first manifestation of SLE is exceedingly rare. This case report describes a case of a 23-years-old female who presented to the hospital with complaints of breathlessness and chest pain. After evaluation she was found to have pericardial tamponade and AIHA. Pericardiocentesis was done and further investigations confirmed the diagnosis of SLE. She was treated with injectable methylprednisolone, injectable antibiotics, Tab. hydroxychloroquine, Tab. febuxostat ,Tab. colchicine, oral antidiuretic, oral levothyroxine and other supportive management. The lack of unambiguous pathognomonic characteristics or tests, coupled with the variable presentation of SLE, makes diagnosis tricky. Overall, AIHA can be an initial presentation as well as a part of other disease processes, emphasising the significance of a comprehensive work in patients with AIHA.

Autoimmune Haemolytic Anaemia, Acute Pericarditis with Cardiac Tamponade as Presenting Manifestations in Systemic Lupus Erythematosus- A Rare Case Report

Systemic Lupus Erythematosus (SLE) is an autoimmune disorder that affects mostly young women in which tissue-binding autoantibodies and immune complexes cause damage to organs and tissues. SLE is characterised by aberrant immunological responses that result in the release of higher levels and immunogenic nucleic acids, proteins, and other self-antigens. Autoimmune Haemolytic Anaemia (AIHA) is a condition in which antibodies against red blood cells are present. It is classified as a warm and cold antibody AIHA. The causes of warm antibody AIHA are autoimmune illnesses, infections, or even malignancy. The presence of Immunoglobulin G (IgG) antibodies can indicate warm autoimmune haemolytic anaemia (warm agglutinin anaemia), which is characterised by fatigue and other constitutional symptoms. Although, autoimmune haemolytic anaemia can be a component of the SLE spectrum, warm autoimmune haemolytic anaemia as the first manifestation of SLE is exceedingly rare. This case report describes a case of a 23-years-old female who presented to the hospital with complaints of breathlessness and chest pain. After evaluation she was found to have pericardial tamponade and AIHA. Pericardiocentesis was done and further investigations confirmed the diagnosis of SLE. She was treated with injectable methylprednisolone, injectable antibiotics, Tab. hydroxychloroquine, Tab. febuxostat ,Tab. colchicine, oral antidiuretic, oral levothyroxine and other supportive management. The lack of unambiguous pathognomonic characteristics or tests, coupled with the variable presentation of SLE, makes diagnosis tricky. Overall, AIHA can be an initial presentation as well as a part of other disease processes, emphasising the significance of a comprehensive work in patients with AIHA.

Autoimmune hemolytic anemia complicated with acute kidney injury and tubulopathy due to hemoglobin casts

A 62-year-old male patient was admitted for close monitoring of anemia (hemoglobin level, 8.2 g/dl). Hemolytic anemia was observed; however, the direct antiglobulin test (DAT) result (standard tube method) was negative. Nevertheless, autoimmune hemolytic anemia (AIHA) was still suspected; therefore, a DAT (Colum method) and quantifying levels of red-blood-cell bound immunoglobulin G were performed, resulting in a definite diagnosis of warm AIHA. The patient also had an acute kidney injury (AKI) from the time of admission, which was poorly improved by supplemental fluids therapy alone. Therefore, renal biopsy was performed. Renal biopsy revealed acute tubular injury due to hemoglobin columns, and a diagnosed AKI caused by hemolysis due to AIHA. Following the definitive diagnosis of AIHA, the patient was treated with prednisolone, and after approximately 2 weeks, the anemia and nephropathy completely improved, which is maintained to this day. We report this case as a rare case of AKI induced by hemolysis of AIHA and a successful case of renal salvage by early administration of steroid.

A case of Evans syndrome

Evans syndrome is an autoimmune disorder described by Robert Evans in 1951 specifying that a link exists between primary thrombocytopenic purpura and acquired haemolytic anaemia. It is a rare autoimmune disorder characterised by the simultaneous or sequential development of autoimmune haemolytic anaemia (AIHA) and immune thrombocytopenia (ITP) with or without immune neutropenia. Approximately, Evans syndrome represent 5-10% of warm autoimmune haemolytic anaemia cases and 2-5% of ITP cases. It is basically a diagnosis of exclusion. We present a 50-year-old female presented with anaemia, jaundice and petechia. Patient indirect bilirubin was raised, Coombs test was positive, lactate dehydrogenase and reticulocyte count were raised. Based on the Coombs positive haemolytic anaemia and thrombocytopenia patient was diagnosed with Evans syndrome. ANA profile was positive for SS-A suggestive of underlying autoimmune disorder. Evans syndrome is difficult to diagnose and treat. Typically, corticosteroids and other immunosuppressive medications are used to manage the syndrome.

Metabolomic profile in patients with primary warm autoimmune haemolytic anaemia.

Autoimmune haemolytic anaemia (AIHA) is a rare clinical condition with immunoglobulin fixation on the surface of erythrocytes, with or without complement activation. The pathophysiology of AIHA is complex and multifactorial, presenting functional abnormalities of T and B lymphocytes that generate an imbalance between lymphocyte activation, immunotolerance and cytokine production that culminates in autoimmune haemolysis. In AIHA, further laboratory data are needed to predict relapse and refractoriness of therapy, and thus, prevent adverse side-effects and treatment-induced toxicity. The metabolomic profile of AIHA has not yet been described. Our group developed a cross-sectional study with follow-up to assess the metabolomic profile in these patients, as well as to compare the metabolites found depending on the activity and intensity of haemolysis. We analysed the plasma of 26 patients with primary warm AIHA compared to 150 healthy individuals by mass spectrometry. Of the 95 metabolites found in the patients with AIHA, four acylcarnitines, two phosphatidylcholines (PC), asymmetric dimethylarginine (ADMA) and three sphingomyelins were significantly increased. There was an increase in PC, spermine and spermidine in the AIHA group with haemolytic activity. The PC ae 34:3/PC ae 40:2 ratio, seen only in the 12-month relapse group, was a predictor of relapse with 81% specificity and 100% sensitivity. Increased sphingomyelin, ADMA, PC and polyamines in patients with warm AIHA can interfere in autoantigen and autoimmune recognition mechanisms in a number of ways (deficient action of regulatory T lymphocytes on erythrocyte recognition as self, negative regulation of macrophage nuclear factor kappa beta activity, perpetuation of effector T lymphocyte and antibody production against erythrocyte antigens). The presence of PC ae 34:3/PC ae 40:2 ratio as a relapse predictor can help in identifying cases that require more frequent follow-up or early second-line therapies.

Energy Trial in Warm Autoimmune Hemolytic Anemia (wAIHA): Design of a Phase 2/3 Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Nipocalimab, an FcRn Blocker

Background: Warm autoimmune hemolytic anemia (wAIHA) is a rare condition characterized by the premature destruction of red blood cells (RBCs) mainly in the presence of pathogenic immunoglobulin G (IgG) autoantibodies that preferentially bind to RBCs at 37°C, resulting in extravascular hemolysis of these RBCs in the spleen (or liver). Patients with wAIHA can experience acute or chronic worsening of anemia, increased risk of thromboembolic events, and premature death. Innovative targeted therapies that address the underlying pathogenesis of wAIHA are needed, as there is currently no approved treatment for this disease. Nipocalimab is a high affinity, fully human, aglycosylated, effectorless IgG1 monoclonal antibody that targets the neonatal Fc receptor (FcRn) to lower circulating IgG levels, including pathogenic autoantibodies. Nipocalimab is being evaluated across multiple IgG-mediated diseases. A completed phase 2 study in patients with generalized myasthenia gravis demonstrated rapid, durable total serum IgG and pathogenic IgG autoantibody reductions and meaningful clinical response [Guptill J, et al. AAN 2021. Presentation 2157]. Aim: Describe the rationale and study design of ENERGY, an ongoing, adaptive, phase 2/3 multicenter, randomized, double-blind, placebo-controlled study that will evaluate the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of nipocalimab compared with placebo in patients with wAIHA (NCT04119050). Methods: Subjects ≥18 years of age who have been diagnosed with primary or secondary wAIHA and are currently receiving treatment for wAIHA or have previously received treatment for wAIHA will be included in the study. Subjects with cold antibody AIHA, cold agglutinin syndrome, mixed type (i.e., warm and cold) AIHA, or paroxysmal cold hemoglobinuria will be excluded. Stable doses of corticosteroids or immunosuppressants will be allowed. Approximately 111 patients will be randomized 1:1:1 to receive nipocalimab at two different dose schedules or placebo. Following completion of 24 weeks of double-blind treatment, patients may enter an open-label extension period to receive nipocalimab for 144 weeks with a follow-up period of 6 weeks after last assessment. Results: ENERGY will include approximately 160 sites across 19 countries, including Brazil, Canada, China, Czech, Egypt, France, Germany, Greece, Hungary, Japan, Israel, Malaysia, Netherlands, Italy, Poland, South Korea, Spain, the United Kingdom, and the United States. The primary endpoint is percentage of participants achieving durable response of improvement in hemoglobin (Hgb). The secondary endpoints include change from baseline in the total score from the Functional Assessment of Chronic Illness Therapy-Fatigue Scale, corticosteroid dose reduction from baseline, and normalization of hemolytic markers. Conclusion/Summary: The results of ENERGY have the potential to identify a novel treatment option to address the significant unmet needs of patients with wAIHA. Enrollment is ongoing in this clinical trial.

Pharmacokinetics and Pharmacodynamics of Nipocalimab Administered at Different Rates of Intravenous Infusion in Healthy Participants: Results of a Phase 1 Placebo-Controlled Single-Dose Study

Background: Warm autoimmune hemolytic anemia (wAIHA) is a rare autoimmune condition driven by autoantibodies that can significantly impact a patient's quality of life. wAIHA is characterized by the premature destruction of red blood cells (RBCs) in the presence of autoantibodies which preferentially bind to RBCs at 37°C. There is currently no approved treatment for wAIHA. Patients with severely symptomatic anemia are typically managed with corticosteroids and rituximab, both of which are associated with potential relapse and adverse events. Nipocalimab, which is in clinical development for the treatment of wAIHA (NCT04119050), is a fully human, aglycosylated, effectorless IgG1 monoclonal antibody that targets the IgG binding site on the neonatal Fc receptor (FcRn) with high affinity to lower circulating IgG levels. This study assessed the pharmacokinetics (PK) and pharmacodynamics (PD) of single doses of nipocalimab administered at different IV infusion rates in healthy adults to support the potential use of shortened infusions in future studies. Nipocalimab was generally safe and well-tolerated at all doses and infusion rates; detailed safety results have been presented separately [Leu JH, et al. EHA 2022. Presentation P1534]. Methods: The trial was a single dose, sequential, randomized, double-blind, placebo-controlled, escalating dose and infusion rate study. Eligible participants were males or females aged 18-55 years with no clinically significant medical or physical conditions. Participants were randomized to 1 of 5 cohorts (n=8 per cohort [6 nipocalimab, 2 placebo]) to receive nipocalimab 30 mg/kg IV infused over 60, 30, 15 or 7.5 min (0.5, 1, 2, or 4 mg/kg/min), nipocalimab 60 mg/kg IV infused over 15 min (4 mg/kg/min) or matching placebo. Escalation to the next dose level was permitted following review by a safety monitoring committee. Pharmacokinetic sampling of nipocalimab was conducted predose, midpoint of infusion (MOI), end of infusion (EOI), EOI + 0.083h, EOI + 0.25h, EOI + 1h, start of infusion + 24h, Day 8, and Day 15 postdose; MOI and EOI varied for each dose. In terms of PD, total serum IgG was assessed. Results: A total of 40 participants (70% female, 93% white) received study drug, of which 30 were included in the PK analysis; 39 completed the study. Mean serum nipocalimab concentration-time profiles were similar following all 30 mg/kg doses regardless of infusion rate; mean serum concentrations were ~2 times higher following a 60 mg/kg infusion. Nipocalimab remained detectable up to ~169 hours postdose for 30 mg/kg groups and ~337 hours postdose for the 60 mg/kg group. Geometric mean peak (Cmax) and overall exposure (AUC) to nipocalimab were unaffected by infusion rate when administered at 30 mg/kg. Following a 60 mg/kg infusion, AUCs were 2.4-2.8 times higher and Cmax was 2.0-2.2 times higher than with 30 mg/kg infusions. Median Tmax was approximately at EOI following the 60 mg/kg infusion. Mean half-life (t½) values were similar in all treatment groups. In terms of total serum IgG, changes from baseline were decreased among all nipocalimab cohorts at all postdose time points. The maximum decrease in mean serum IgG levels was 79% at day 15 with nipocalimab 60 mg/kg. Conclusion: Nipocalimab Cmax and AUC were not affected by infusion rates when given at a dose of 30 mg/kg, but Tmax was delayed at the fastest infusion rates. Following the 60 mg/kg infusion, peak and overall nipocalimab exposures were 2-2.8 times higher than following 30 mg/kg infusions.

Clinical, Immunological Features, Treatments, and Outcomes of Autoimmune Hemolytic Anemia in Patients with RAG Deficiency

Background: The clinical features of patients with recombination activating gene (RAG1 and 2) deficiency are diverse, ranging from severe combined immunodeficiency to combined immunodeficiency with granulomatous disease and/or autoimmunity (CID-G/AI). The latter phenotype has been typically associated with hypomorphic mutations, resulting in residual RAG enzymatic activity and frequent autoimmune manifestations. Autoimmune hemolytic anemia (AIHA) is most common, and its development is thought to be due to the breakdown of T/B-cell tolerance, usually triggered by an environmental factor (e.g., viral infection). Its therapeutic response to standard treatment is often unsatisfactory. However, our understanding of this condition is still limited to case reports and small series. Herein, we systematically present clinical, immunological features, treatments, and outcomes of the largest case series of AIHA in RAG deficiency. Methods: To assemble a highly annotated and curated patient database, we retrospectively collected detailed clinical information of AIHA in patients with RAG deficiency through multi-national collaboration and reviewed all published cases with RAG deficiency and concurrent AIHA from PubMed between 2001 and 2021. Results: We identified 74 patients with RAG deficiency who developed AIHA during their disease course, and characteristics of the cohort are shown in the Table. Of our own case series (n = 20), the median age at clinical and molecular diagnosis was 1.6 and 2.3 years, respectively. There was a slight predominance of female patients (53.7%). RAG1 mutations were found in 75.0% of cases, and CID-G/AI (55.0%) was the predominant clinical phenotype with a median RAG1 activity of 19.3%. AIHA was typically preceded by viral infections (55.0%) and presented with severe symptomatic anemia (median hemoglobin 6.4 g/dL), with recurrent episodes (median 2), and required multiple units of transfusion support (median 5 units). Most cases were warm AIHA with IgG autoantibodies (92.9%) detected by Coombs tests. In parallel, anti-cytokine autoantibodies against IFNα (85.7%), IFNω (57.1%), and IL12 (28.6%) were frequently found in these patients. Despite the use of high-dose corticosteroid (85.0%) and intravenous immunoglobulin (68.8%), more than half of them required additional immunosuppressive treatment (52.6%), and ultimately, 15 (75%) patients underwent allogeneic stem cell transplant. Among them, refractory cytopenias were the indication of transplant in seven patients. Cases reported in the literature (n = 54) had a similar clinical profile to our cohort; therefore, they were combined for further analysis (n = 74). We found a unique immunological profile of patients fulfilled the diagnosis of Evans syndrome (n = 34, 45.9%), including a trend of more female patients (65.5 vs. 42.9%, p = 0.062), a higher frequency of positive Coombs test (96.7 vs. 75.0%, p = 0.023), lower total lymphocyte (median 1009 vs. 2120/µL, p = 0.015), CD8+ (median 102 vs. 226/µL, p = 0.004), CD56+ cell counts (median 209 vs. 382/µL, p = 0.005), and more cases underwent allogeneic stem cell transplant (75.0 vs. 45.9%, p = 0.014). In the combined cohort, the 10-year overall survival was 55.4%, and allogeneic stem cell transplant was associated with reduced mortality (31.7 vs. 57.1%, p = 0.036). Conclusion: Patients with RAG deficiency often experience severe, recurrent, and treatment-refractory cytopenias, including AIHA during their disease course. Those with Evans syndrome demonstrated a unique immunological profile with reduced numbers of cytotoxic cells, which required further mechanistic investigations. Multiple lines of AIHA-directed therapies are typically required, and allogeneic stem cell transplant, if indicated, may improve the long-term outcomes in this population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Rituximab and Bortezomib for Patients with Newly Diagnosed Acquired Haemophilia: Single Arm, Single Center, Prospective Phase 2 Study

Introduction Acquired haemophilia A (AHA) is a rare autoimmune disorder caused by neutralizing autoantibodies against factor VIII (FVIII). The most common IST treatment used are Steroids-based regimens. However, patients with AHA are often elderly with comorbidities. Steroids-based regimens have significant side effects in patients with AHA. In particular, the risk of dying from infection appears to be higher than the risk of fatal bleeds today. This dilemma highlights the lack of safe and rapid response IST therapy in AHA. Bortezomib targets plasma cells rather than B cells and has reported efficacy in refractory AHA. It is an attractive agent because it depletes plasma cells that can continue to produce autoantibody even after CD20-positive B cells have been depleted by rituximab. The combination of bortezomib and rituximab regimen showed rapid response without severe adverse event in refractory and relapsed warm autoimmune hemolytic anemia. This phase 2, prospective, single-center study was designed to evaluate the efficacy and safety of rituximab and bortezomib (RB) treatment regimen in newly diagnosed AHA patients. Methods All patients 18 years of age or older who met the following criteria were considered as eligible candidates for this study: 1) plasma FVIII activity (FVIII:C) <50 l/dl, detectable inhibitor to FVIII. 2) newly diagnosed without any IST treatment. After obtaining the written informed consent from the patients, the information of demographic and medical history were collected and laboratory tests were performed.The patients were received the following regimens: Rituximab 375mg/m2 intravenous infusion on day 0 and bortezomib 1.3 mg/m2 subcutaneous on day 1,4,8,11. Best supportive care, including administration of hemostatic treatment and blood product transfusions if needed were used. Safety was evaluated according to NCI-CTCAE v4.0. Results From March 2018 to May 2022, 30 patients were eligible for the study. The baseline characteristics of the patients are summarized in Table 1. Overall, 19 patients were male (63.3%). The median age was 53.5 years (range 22 - 90 years). The underlying disorders that could be associated with AHA included rheumatoid arthritis, systemic lupus erythematosus and pemphigus. One patient was diagnosed at her postpartum. One patient was diagnosed soon after surgery. Traditional Chinese medicine was suspected as the inducement in one patient. No patient in our cohort was reported to have coexisting malignancy. 24 patients (80.0%) were regarded as idiopathic AHA. The median time from disease onset to the diagnosis was 36.5 days (range 10-249 days). The median FVIII activity at baseline was 1.5 IU/ml (range 0 to 10.4 IU/ml), and the median inhibitor concentration was 25.6 BU/ ml (range 2.7 to 600 BU/ ml). The bleeding event that precipitated diagnosis was reported as spontaneous in 27 patients (90.0%), by surgery in 3 patients (10.0%). All patients presented with bleeding diathesis as listed in Table 1. Sixteen patients (61.5%) received haemostatic treatment for initial bleeding, all of them received prothrombin complex concentrate (PCC). Nine patients experienced further bleeding after the treatment of BR. All patients completed protocol treatment. Overall, 23 patients (76.7%) achieved CR, 6 patients (20.0%) achieved PR and 1 patients died of cardiac events 3 month after last dose of bortezomib. The ORR was 96.7%. Median time to CR was 74 days (range 12-179 days). After a median follow-up of 39 months (range 3-50 months), one patient had relapse of the disease, 2 months after achieved CR. Major toxicities and adverse events are summarized in Table 2. One patient (3.8%) had grade 3 neutropenia; One patient (3.8%) had grade 4 thrombocytopenia and grade 3 thrombocytopenia each. Eight patients experienced infectious fever, including 2 grade 3 and 2 (7.7%) grade 4. Five patients (19.2%) developed grade 1-2 peripheral neuropathy.No treatment-related deaths occurred. Conclusion Here we report the results of a phase 2 prospective study of newly diagnosed AHA. This study confirmed that rituximab plus bortezomib was an efficient and safe regimen with ORR of 96.7%, and the median time to CR was 74 days.This trial was registered at www.clinicaltrials.gov as #NCT03700229. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Autoimmune Hemolytic Anemia during Pregnancy or Post-Partum: An International Multi-Center Experience

Autoimmune hemolytic anemia (AIHA) developing or relapsing during pregnancy or postpartum is a rare finding, and few is known about maternal and fetal outcomes. Furthermore, AIHA management during pregnancy and lactation is not standardized and drug use is often limited by safety concerns. Here, we report the results of a multi-center retrospective cohort study evaluating AIHA impact on pregnancy focusing on disease severity, treatment need and maternal and fetal outcome. Forty-one pregnancies occurring in 31 women were registered from 1997 to 2022 at 11 European centers in Italy, Denmark, France, the Netherlands, USA, and Spain. AIHA was classified according to the direct antiglobulin test as warm, cold, mixed or atypical. Outcomes were compared with a control group of 56 healthy women matched for age at pregnancy and decade of pregnancy. Overall, we observed 21 warm AIHA (13 IgG; 8 IgG+C3d), 2 cold agglutinin diseases, 3 mixed and 5 atypical forms (Table 1). Evans syndrome (i.e., association of AIHA and immune thrombocytopenia or neutropenia) was present in 5 women. Mean age at AIHA diagnosis was 27 (3-39) years and at pregnancy 32 (21-41) years. AIHA diagnosis predated pregnancy in 16 women and had required at least 1 therapy line in all of them, and ≥2 lines in 13 (rituximab, N=8; cytotoxic immunosuppressants, N=6; splenectomy, N=5). Among these 16 patients, 7 had a relapse during pregnancy, 3 during postpartum and 9 were on active treatment at the time of pregnancy (steroids, N=7; cyclosporine, N=1; steroids plus azathioprine, N=1; the latter stopped after positive pregnancy test). A patient with a previous AIHA, relapsed as immune thrombocytopenia during pregnancy. Further 9 patients developed AIHA during gestation and 2 in the postpartum. A patient had AIHA onset during the postpartum of the 1st pregnancy and relapsed during the 2nd one. In total, we observed 22 hemolytic events in 21 women during pregnancy/postpartum. Median Hb and LDH levels were 6.4 g/dL (3.1 - 8.7) and 599 IU/L (269-1631), respectively. Management consisted in blood transfusions (N=11, 50%) and prompt establishment of steroid therapy +/- intravenous immunoglobulins (N=22, 100%), all with response (complete N=15, partial N=7). After delivery, rituximab was necessary in 4 patients and cyclosporine was added in one. Anti-thrombotic prophylaxis was given in 7 patients. Overall, we registered 10 maternal complications (10/41, 24%), including 4 early miscarriages, a premature rupture of membranes, a placental detachment, 2 preeclampsia, a postpartum infection and a biliary colic. Notably, 8/10 complications occurred during active hemolysis and treatment for AIHA. Ten fetal adverse events (10/41, 24%) were reported: a transitory respiratory distress of the newborn in a mother with active AIHA; 4 cases of fetal growth restriction; a preterm birth; an infant reporting neurologic sequelae; a case of AIHA of the new-born requiring intravenous immunoglobulins, blood transfusions and plasma exchange; and 2 perinatal deaths. The latter two occurred in women on active AIHA therapy and were secondary to a massive placental detachment and a symptomatic SARS-CoV-2 infection. Finally, the comparison between AIHA women and the control group showed a similar prevalence of maternal complications (24% in AIHA versus 18% in controls). At variance, AIHA was marked by a significant increase of fetal adverse events versus control group (24% versus 5%, p=0.008), with more severe complications in the former. In conclusion, AIHA developing/reactivating during pregnancy or postpartum is rare but mainly severe, requiring red cell transfusions in half of cases and steroid therapy in all patients. Notably, severe maternal and fetal complications may occur in up to a quarter of cases mostly associated with active hemolysis. Finally, AIHA was significantly associated with severe fetal complications compared with healthy population, further pinpointing the importance of maintaining a high level of awareness. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Primary Epithelioid Pulmonary Angiosarcoma with WAIHA and Thrombocytopenia: A Rare Association

Abstract Introduction/Objective Angiosarcomas accounts for approximately 1%-2% of sarcomas, particularly involving the deep soft tissue. As a subtype, primary epithelioid angiosarcoma is an extremely rare neoplasm. Herein, we present an unusual primary epithelioid angiosarcoma of the right upper lung lobe with multiple nodal and bony metastases and associated severe form of autoimmune hemolytic anemia (WAIHA) and thrombocytopenia. Methods/Case Report Our case is a 79-year-old female with a recent onset of warm type autoimmune hemolytic anemia with positive coombs test and thrombocytopenia. The patient serum was also positive for EBV (IgG and IgM). On chest CT scan, a right upper lobe, metabolically active lung mass with mediastinal lymphadenopathy was found. Metabolically active bilateral osseous lesions identified within thoracic spine, ribs, bilateral humeri and femurs. A transbronchial core biopsy of the lung mass revealed poorly differentiated epithelioid hemorrhagic neoplasm with extensive necrosis and vascular background. The tumor cells are positive for AE1/AE3, CK7, FLI-1, BRG1 (SMARCA4, retained), and vimentin; and faint weak focal membranous staining for CD31, Factor VIII, and ERG. They are negative for CK20, TTF-1, Napsin-A, p63, p40, SMA, Melan-A, HMB45, GATA3, PAX-8, CDX-2, HepPar, synaptophysin, calretinin, CAMTA1, EBER (EBV) and S100 (Figure-1-A-D, H&amp;E, 10X, CK AE2/AE3, FLI-1, CD31). This immunoprofile and histologic features favor epithelioid angiosarcoma. Results (if a Case Study enter NA) NA. Conclusion Comprehensive morphological and immunohistochemical findings supported the diagnosis of epithelioid angiosarcoma. The importance of reporting this case was the unusual pulmonary primary presentation, associated nodal and osseous secondary involvement, together with the unique systemic presentation with warm autoimmune hemolytic anemia and thrombocytopenia in a patient with active EBV infection.

BALANCING GVHD IMMUNOSUPPRESSION AND COVID19 VIRAL REACTIVATION IN A PATIENT WITH ATYPICAL COMPLETE DIGEORGE SYNDROME

<h3>Introduction</h3> Complete DiGeorge syndrome (DGS) accounts for less than 1% of patients with DGS, with atypical DGS being even rarer. We present a patient with atypical complete DGS who developed autoimmune phenomena attributed to autologous GVHD, and subsequent prolonged respiratory failure due to COVID19 pneumonia while on immunosuppression. <h3>Case Description</h3> A 3-year old male infant of a diabetic mother with complete DGS awaiting thymic transplantation, hypoparathyroidism, hypogammaglobulinemia on IVIG, and recent asymptomatic COVID19 infection was admitted for AKI, electrolyte disarray secondary to malabsorption, and warm autoimmune hemolytic anemia. A month prior he had a persistent eczematous rash, chronic cough, recurrent diarrhea, and thinning hair. Labs revealed uptrending total IgE to 10,000 IU/ml, no eosinophilia, an oligoclonal population of gamma-delta T cells, and increased numbers of CD4+ and CD8+ lymphocytes, which were primarily CD45RO+ central memory T cells. A large portion were activated and expressed HLA-DR. Mitogen proliferation was normal. Given these findings, he was diagnosed with autologous GVHD secondary to autoreactive oligoclonal T cells, and subsequently, atypical complete DGS. Tacrolimus and methylprednisolone were started for immunosuppression. IgE and CD3+ T cells decreased on immunosuppression, but he developed hypoxemic respiratory failure with prolonged intubation due to COVID19 pneumonia. Immunosuppression was gradually weaned. IgE and CD3+ cells increased slightly, but he showed no clinical signs of GVHD and was discharged home after a 3.5 month hospital stay. <h3>Discussion</h3> This case highlights the difficult balance between immunosuppression and viral reactivation. After starting immunosuppression for treatment of GVHD, he developed severe COVID19 pneumonia.

Type O blood, the MCHC, and the reticulocyte count impact the early recurrence of primary warm-antibody autoimmune hemolytic anemia in children: A retrospective cohort analysis.

ObjectivePrimary warm-antibody autoimmune hemolytic anemia (w-AIHA) is prone to recurrence in children. In this study, we aimed to identify risk indicators for the early recurrence of primary w-AIHA and construct an effective recurrence risk assessment model.MethodsThis was a retrospective cohort study. The clinical data of patients hospitalized with primary w-AIHA in the Department of Hematology and Oncology, Children's Hospital of Chongqing Medical University, between 1 January 2018 and 30 September 2021, were collected at the initial diagnosis. Univariate and multivariate logistic regression analyses were used to determine risk indicators for the early recurrence of primary w-AIHA in children, and ROC curve and Kaplan–Meier survival analyses were used for verification. Finally, a risk assessment model for early recurrence in children with primary w-AIHA was constructed using Cox regression and visualized using a nomogram. The model was also verified internally and externally.ResultsThis study included 62 children with primary w-AIHA. Of which, 18 experienced recurrence 1 year after the initial diagnosis. The univariate and multivariate logistic regression analyses showed that type O blood and the reticulocyte count (Ret) were risk indicators for the early recurrence of pediatric primary w-AIHA (P = 0.009, 0.047, respectively). The mean corpuscular hemoglobin concentration (MCHC) is a protective factor (P = 0.040). According to the ROC curve and Kaplan–Meier survival analyses, children with primary w-AIHA whose blood type was O or had an MCHC of <313.5 pg/fL or a Ret of ≥0.161×1012/L had a higher risk of early recurrence (HR = 2.640, 4.430 and 4.450, respectively, and P = 0.040, 0.015 and 0.018, respectively). The blood types (O), MCHCs, and Rets of 56 patients were incorporated into the Cox regression model, and the recurrence risk assessment model for children with primary w-AIHA was successfully constructed and visualized using a nomogram. The calibration curves and decision-curve analysis (DCA) suggested that the risk model has clinical applicability and effectiveness.ConclusionChildren with type O blood and an MCHC value of <313.5 pg/fL or a Ret value of ≥0.161×1012/L have a higher risk of early recurrence. The risk assessment model for the early recurrence of pediatric primary w-AIHA constructed in this study has good clinical applicability and effectiveness.

AN UNCOMMON INFECTIOUS IMPOSTER OF LUNG CANCER: A CASE OF ASPERGILLUS NODULES

AN UNCOMMON INFECTIOUS IMPOSTER OF LUNG CANCER: A CASE OF ASPERGILLUS NODULES

A PHASE 1 PLACEBO-CONTROLLED SINGLE-DOSE STUDY OF NIPOCALIMAB ADMINISTERED AT DIFFERENT RATES OF INTRAVENOUS INFUSION IN HEALTHY ADULTS

Warm autoimmune hemolytic anemia (wAIHA) is a rare, life-threatening disorder characterized by the destruction of red blood cells by pathogenic IgG autoantibodies. There is currently no approved treatment for wAIHA. Nipocalimab is a fully human, aglycosylated, effectorless IgG1 monoclonal antibody that blocks the IgG binding site on the neonatal Fc receptor (FcRn) with high affinity, which is in clinical development for the treatment of wAIHA. In a prior phase 1 study in healthy adults receiving single and multiple ascending doses infused intravenously (IV) over 2 hours, nipocalimab was well-tolerated with an adverse event profile comparable to placebo. However, shorter durations of nipocalimab infusion may be more convenient for patients. Here we assess the safety and tolerability of single doses of nipocalimab administered at different IV infusion rates in healthy adults to support the potential use of shortened infusions in future studies. The trial was a single dose, sequential, randomized, double-blind, placebo-controlled, escalating dose and infusion rate study. Eligible participants were males or females aged 18-55 years with no clinically significant medical or physical conditions. Participants were randomized to 1 of 5 cohorts (n = 8 per cohort [6 nipocalimab, 2 placebo]) to receive nipocalimab 30 mg/kg IV infused over 60, 30, 15 or 7.5 min (0.5, 1, 2, or 4 mg/kg/min), nipocalimab 60 mg/kg IV infused over 15 min (4 mg/kg/min) or matching placebo. Escalation to the next dose level was permitted following review by a safety monitoring committee. Safety was assessed by the frequency and nature of treatment-emergent adverse events (TEAEs). A total of 40 participants (70% female, 93% white) received study drug and were included in the safety analysis; 39 completed the study. A total of 12 participants (40%) experienced TEAEs across all nipocalimab dosing cohorts and 1 (10%) participant experienced TEAEs following administration of placebo. The most frequently reported TEAE was headache, reported by 6 participants with nipocalimab and 1 participant with placebo. Nausea was reported by 3 participants receiving nipocalimab. Grade 2 injection site reactions were reported by 2 participants but were considered unrelated to the investigational agent. None of the TEAEs were severe, and no participants discontinued treatment due to TEAEs; there were no serious adverse events or deaths. Only 4 participants experienced AEs that occurred within 24 hours after the infusion that were considered related to the study drug. Lower rates of nipocalimab infusion were associated with fewer TEAEs, while participants receiving 4 mg/kg/min (as either 30 mg/kg infused over 7.5 min or 60 mg/kg infused over 15 min) reported more TEAEs. Single doses of nipocalimab, when administered at doses up to 60 mg/kg and infusion rates up to 4 mg/kg/min were safe and well-tolerated in healthy adults. The frequency of reported TEAEs was lower in participants receiving IV nipocalimab at rates of 1 or 2 mg/kg/min, providing a target infusion rate for current and future studies. JHL, AV, LEL are employees of Janssen Research & Development, LLC, and AMBP is an employee of Janssen Latin America, which are a wholly owned subsidiaries of Johnson & Johnson, and may own stock or stock options in Johnson & Johnson.

S2704 A New Protein Losing Enteropathy: Autoimmune Cryptolytic Enterocolitis

Introduction: Protein losing enteropathy (PLE) can be classified into erosive, non-erosive, and increased interstitial pressure PLE. Presenting signs are often chronic non-bloody diarrhea, anasarca, abdominal pain, and weight loss. We present a complex case of a PLE presentation with a novel diagnosis. Case Description/Methods: A 30-year-old woman with a history of migraines presented with severe abdominal pain and chronic diarrhea. She was on long-term combined estrogen-progestin oral contraceptive pills (OCP) and chronic high dose non-steroidal anti-inflammatory (NSAID) medications. She was exposed to mycoplasma pneumoniae one month prior to presentation, without other infectious exposures. Laboratory tests were notable for hemoglobin 6 g/dL, albumin 0.5 g/dL, stool pathogen PCR negative, and fecal calprotectin >3000µg/g. Extensive infectious work up only revealed Mycoplasma IgM+. Inflammatory markers and alpha-1 anti-trypsin clearance were elevated, and she was found to have warm autoimmune hemolytic anemia. CT angiography excluded ischemia and vasculitis (autoimmune serologies were negative), revealing diffuse enterocolitis, confirmed on magnetic resonance enterography with ileal ulcers. Endoscopic evaluation revealed diffuse superficial ulcerations terminal ileum and colon with diffuse mucosal sloughing. Histopathology revealed diffusely injured crypts with crypt drop-out and minimal inflammation, without any findings to suggest infection, inflammatory bowel disease (IBD) or autoimmune enteritis (Figure). Normal B-cell switching studies excluded common variable immunodeficiency (CVID). Due to profound anasarca and inability to tolerate oral intake, albumin infusions and total parenteral nutrition were started. There was minimal response to systemic or topical steroids. Diarrhea was mildly improved with albumin repletion, and she was empirically started on vedolizumab. Discussion: Given the absence of classic IBD findings, negative infectious and immunological testing, we present the first case of autoimmune cryptolytic enterocolitis, a histopathologic diagnosis of unclear etiology and pathogenesis. The patient has responded to vedolizumab infusions as an empiric treatment for an IBD-like entity. Nevertheless, supporting the autoimmune component of this entity, is a possible concomitant potential pathway of molecular mimicry in the setting of post-mycoplasma infection along with chronic high dose NSAID and OCP exposure.Figure 1.: Terminal Ileum and Sigmoid Colon with Diffuse Crypt Dropout.