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Summary: Since its first description by Evans in 1951, this syndrome has been linked to chronic immune thrombocytopenia with the concurrent or delayed onset of autoimmune haemolytic anaemia or neutropenia. For decades, the evolution of Evans syndrome (ES) has carried a poor prognosis and often resulted in chronic steroid exposure, multiple immune suppressing medications directed against T or B lymphocytes, and splenectomy. This paper presents a new view of ES based on recent advances in genomics which begin to classify patients based on their underlying molecular variants in previously described primary immune disorders. This has opened up new avenues of targeted therapy or bone marrow transplant at rather than broad long‐term immune suppression or splenectomy. Importantly, recent studies of the full lifespan of ES suggest that at least 80% of those paediatric patients will progress to various clinical or biological immunopathological manifestations with age despite the resolution of their cytopenias. Those patients merit long‐term follow‐up and monitoring in dedicated transition programs to improve outcome at the adult age. [ABSTRACT FROM AUTHOR]

• This article summarises the evidence and indications for BTK inhibitors, including an overview of BTK structure and function, adverse effects, and use in clinical practice. • Emerging roles of BTK in the immune system and in platelets are explored, focussing on those relevant to autoimmune disease. Retrospective data derived from CLL trials is summarised, supporting a potential role for these drugs in autoimmune haematologic conditions. • The landmark rilzabrutinib trial in ITP is discussed, including specific drug characteristics which aim to minimise bleeding risk. • Potential future roles of BTK inhibitors are postulated, including both preclinical data and ongoing clinical trials. Autoreactive B-cells are crucial in the pathogenesis of both haematologic and non-haematologic autoimmune disorders. Therapies targeting B cells and autoantibodies are widely used in clinical practice, however, many patients fail to respond to conventional treatments. An evolving understanding of molecular mechanisms underlying autoimmune haematologic disorders has facilitated the development of novel therapies, including Bruton's Tyrosine Kinase (BTK) inhibitors. BTK is fundamental in B-cell survival, and its inhibition has been used in a wide range of autoimmune and inflammatory conditions, as well as mature B cell malignancies. This paper reviews the role of BTK in immunity, evolution of BTK inhibitors, and the emerging evidence for BTK inhibitors in autoimmune haematologic conditions, primarily immune thrombocytopenia (ITP), and potential future clinical applications. [ABSTRACT FROM AUTHOR]

Simple Summary: This review analyzes the occurrence, clinical characteristics, and prognostic impact and treatment of autoimmune hemolytic anemia (AIHA) in chronic lymphocytic leukemia (CLL). Autoimmune hemolytic anemia is observed in about 10% of CLL. Pathogenesis is multifactorial involving humoral, cellular, and innate immunity, so the different mechanisms are well described in this review which also focuses on drugs associated to CLL-AIHA and on difficulties to diagnose it. There is a comprehensive revision of the main published casistics and then of the treatments; in particular the paper analyzes the main chemo-immunotherapeutic agents used in this setting. Since the therapy depends on the presence and severity of clinical symptoms, disease status, and comorbidities, treatment is nowadays more individualized in CLL and also in CLL-AIHA. Patients not responding to corticosteroids and rituximab are treated with CLL-specific drugs as per current guidelines according to age and comorbidities and new targeted agents against BCR and BCL-2 which can be given orally and have few side effects, are very effective both in progressive CLL and in situations such as AIHA. Chronic lymphocytic leukemia (CLL) patients have a greater predisposition to develop autoimmune complications. The most common of them is autoimmune hemolytic anemia (AIHA) with a frequency of 7–10% of cases. Pathogenesis is multifactorial involving humoral, cellular, and innate immunity. CLL B-cells have damaged apoptosis, produce less immunoglobulins, and could be responsible for antigen presentation and releasing inflammatory cytokines. CLL B-cells can act similar to antigen-presenting cells activating self-reactive T helper cells and may induce T-cell subsets imbalance, favoring autoreactive B-cells which produce anti-red blood cells autoantibodies. Treatment is individualized and it depends on the presence and severity of clinical symptoms, disease status, and comorbidities. Corticosteroids are the standardized first-line treatment; second-line treatment comprises rituximab. Patients not responding to corticosteroids and rituximab should be treated with CLL-specific drugs as per current guidelines according to age and comorbidities. New targeted drugs (BTK inhibitors and anti BCL2) are recently used after or together with steroids to manage AIHA. In the case of cold agglutinin disease, rituximab is preferred, because steroids are ineffective. Management must combine supportive therapies, including vitamins; antibiotics and heparin prophylaxis are indicated in order to minimize infectious and thrombotic risk. [ABSTRACT FROM AUTHOR]

Introduction: Chronic lymphocytic leukemia (CLL), the most common leukemia in Western countries, is a mature B-cell chronic lymphoproliferative disorder characterized by the accumulation of neoplastic CD5+ B lymphocytes, functionally incompetent and usually monoclonal in origin, in bone marrow, lymph nodes and blood. Diagnosis occurs predominantly in elderly patients, with a median age reported between 67 and 72 years. CLL has a heterogeneous clinical course, which can vary from indolent to, less frequently, aggressive forms. Early-stage asymptomatic CLL patients do not require immediate therapeutic intervention, but only observation; treatment is necessary for patients with advanced disease or when "active disease" is observed. The most frequent autoimmune cytopenia (AIC) is autoimmune haemolytic anaemia (AHIA). The main mechanisms underlying the appearance of AIC in CLL are not fully elucidated, the predisposition of patients with CLL to suffering autoimmune complications is variable and autoimmune cytopenia can precede, be concurrent, or follow the diagnosis of CLL. Case presentation: A 74-year-old man was admitted to the emergency room following the finding of severe macrocytic anaemia during blood tests performed that same day, in particular the patient showed a profound asthenia dating back several months. The anamnesis was silent and the patient was not taking any medications. The blood examination showed an extremely high White Blood Cell count and findings of AIHA in CLL-type mature B-cell lymphoproliferative neoplasia. Genetic investigations: Conventional karyotyping was performed and it obtained a trisomy 8 and an unbalanced translocation between the short arm of chromosome 6 and the long arm of chromosome 11, concurrent with interstitial deletions in chromosomes 6q and 11q that could not be defined in detail. Molecular cytogenetics (FISH) analyses revealed Ataxia Telangiectasia Mutated (ATM) monoallelic deletion (with loss of ATM on derivative chromosome 11) and retained signals for TP53, 13q14 and centromere 12 FISH probes. TP53 and IGHV were not mutated. Array-CGH confirmed trisomy of the entire chromosome 8 and allowed us to resolve in detail the nature of the unbalanced translocation, revealing multiple regions of genomic losses on chromosomes 6 and 11. Discussion: The present case report is an unusual CLL case with complex karyotype and refinement of all breakpoints at the gene level by the genomic array. From a genetic point of view, the case under study presented several peculiarities. Conclusions: We report the genetic findings of a CLL patient with abrupt disease onset, so far responding properly to treatments despite the presence of distinct genetic adverse traits including ATM deletion, complex karyotype and chromosome 6q chromoanagenesis event. Our report confirms that interphase FISH alone is not able to provide an overview of the whole genomic landscape in selected CLL cases and that additional techniques are required to reach an appropriate cytogenetic stratification of patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Autoimmune hemolytic anemia (AIHA) can be induced by recent or concomitant infections. Many infectious agents are postulated to be associated with this condition. Treatment of infection induced AIHA still varies. This report describes a previously healthy Thai boy who developed AIHA associated with enterovirus-71 infection. He was successfully treated with oral prednisone. [ABSTRACT FROM AUTHOR]

The use of Bruton's tyrosine kinase (BTK) inhibitors has changed the management of patients with B-cell lymphoid malignancies. BTK is an important molecule that interconnects B-cell antigen receptor (BCR) signaling. BTK inhibitors (BTKis) are classified into three categories, namely covalent irreversible inhibitors, covalent reversible inhibitors, and non-covalent reversible inhibitors. Ibrutinib is the first covalent, irreversible BTK inhibitor approved in 2013 as a breakthrough therapy for chronic lymphocytic leukemia patients. Subsequently, two other covalent, irreversible, second-generation BTKis, acalabrutinib and zanubrutinib, have been developed for lymphoid malignancies to reduce the ibrutinib-mediated adverse effects. More recently, irreversible and reversible BTKis have been under development for immune-mediated diseases, including autoimmune hemolytic anemia, immune thrombocytopenia, multiple sclerosis, pemphigus vulgaris, atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's disease, and chronic spontaneous urticaria, among others. This review article summarizes the preclinical and clinical evidence supporting the role of BTKis in various autoimmune, allergic, and inflammatory conditions. [ABSTRACT FROM AUTHOR]

Autoimmune hemolytic anemia (AIHA) can be induced by recent or concomitant infections. Many infectious agents are postulated to be associated with this condition. Treatment of infection induced AIHA still varies. This report describes a previously healthy Thai boy who developed AIHA associated with enterovirus-71 infection. He was successfully treated with oral prednisone. [ABSTRACT FROM AUTHOR]

Background and Objectives: The significance of antibodies to red blood cells (RBCs) is variable and cannot be predicted solely by serological testing. A flow cytometry‐based erythrophagocytosis assay was established using phorbol 12‐myristate 13‐acetate (PMA)‐treated THP‐1 cells and RBCs labelled with PKH26 to assess allo‐ and autoantibodies to RBCs. Materials and Methods: THP‐1 cells were differentiated into macrophage‐like cells by treatment with PMA. RBC samples coated with alloantibodies or autoantibodies were obtained from 16 patients with autoimmune haemolytic anaemia of warm type (wAIHA) as well as from five pregnant women with warm autoantibodies. RBCs from healthy blood donors were used as controls. RBCs were labelled with the red lipophilic fluorescent dye PKH26 and incubated with PMA‐treated THP‐1 cells. After removal of nonadherent RBCs by washing and haemolysis of adherent RBCs, erythrophagocytosis was quantified by flow cytometry. Results: We observed significant phagocytosis of RBCs coated with clinically relevant alloantibodies (i.e. anti‐D and anti‐K) or autoantibodies from patients with active wAIHA, but not of those coated with alloantibodies (anti‐Ch) or autoantibodies from patients and pregnant women without haemolysis. Conclusion: The flow cytometry‐based erythrophagocytosis test described here is quantitative, highly reliable, and may be helpful for the assessment of the clinical significance of antibodies to RBCs. [ABSTRACT FROM AUTHOR]

Immune cytopenias after allogeneic hematopoietic cell transplantation are rare, albeit increasingly recognized, complications. Autoimmune diseases are serious complications of HCT and include immune-mediated cytopenias i.e. autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP) and autoimmune neutropenia. Severe cytopenia is usually defined by decreases of hemoglobin concentration below 7 g/dL, of platelet count below 20 G/L, or of absolute granulocyte count below 0.5 G/L, and it is mediated by the presence of auto-antibodies. ITP occurring in combination with AIHA is known as Evans Syndrome. Immune dysregulation is caused by impaired immune reconstitution and/or loss of self-tolerance. Primary risk factors of autoimmune cytopenias include: peripheral blood or cord blood as a stem cell source, unrelated HCT, non-malignant disease, use of alemtuzumab, acute/chronic graft-versus-host disease (GvHD), cytomegalovirus reactivation, infections, and, in pediatric settings, conditioning omitting total body irradiation. Diagnosis of autoimmune cytopenia is challenging due to a broad differential diagnosis: primary or secondary graft failure, infections, GvHD, disease relapse, drug-induced side effects, transplant-associated thrombotic microangiopathy, ABO-incompatibility, or disseminated intravascular coagulation. Treatment should be tailored to the individual patient, and ranges from watchful waiting to aggressive management in life-threatening situations. Apart from specific treatment adjusted for specific cytopenia, supportive care should include transfusions of leukocyte-reduced and irradiated red blood cell concentrates or pathogen-reduced platelet concentrates; treatment of infections and GvHD; modification of immunosuppression; and supplementation with microelements. Autoimmune cytopenias are usually highly resistant to standard therapy and are associated with increased risks of high morbidity and mortality, particularly when coexisting with other post-transplant complications. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]