• chronic lymphocytic leukaemia
• anaemia
• autoimmune diseases

• Humans
• Rituximab
• Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
• Leukemia, Lymphocytic, Chronic, B-Cell/complications
• Anemia, Hemolytic, Autoimmune/drug therapy
• Anemia, Hemolytic, Autoimmune/complications
• Thrombocytopenia
• Red-Cell Aplasia, Pure
• Steroids
• Recurrence

• AIHA
• CLL
• FISH
• acalabrutinib
• autoimmune hemolytic anemia
• chromoanagenesis
• chronic lymphocytic leukemia
• complex karyotype
• rituximab

• VDAC1
• apoptosis
• cancer
• metabolism
• mitochondria
• plant extract

Mesothelioma, an aggressive cancer with a poor prognosis, is linked to asbestos exposure. However, carbon nanotubes found in materials we are exposed to daily can cause mesothelioma cancer. Cancer cells reprogram their metabolism to support increased biosynthetic and energy demands required for their growth and motility. Here, we examined the effects of silencing the expression of the voltage-dependent anion channel 1 (VDAC1), controlling the metabolic and energetic crosstalk between mitochondria and the rest of the cell. We demonstrate that VDAC1 is overexpressed in mesothelioma patients; its levels increase with disease stage and are associated with low survival rates. Silencing VDAC1 expression using a specific siRNA identifying both mouse and human VDAC1 (si-m/hVDAC1-B) inhibits cell proliferation of mesothelioma cancer cells. Treatment of xenografts of human-derived H226 cells or mouse-derived AB1 cells with si-m/hVDAC1-B inhibited tumor growth and caused metabolism reprogramming, as reflected in the decreased expression of metabolism-related proteins, including glycolytic and tricarboxylic acid (-)cycle enzymes and the ATP-synthesizing enzyme. In addition, tumors depleted of VDAC1 showed altered microenvironments and inflammation, both associated with cancer progression. Finally, tumor VDAC1 silencing also eliminated cancer stem cells and induced cell differentiation to normal-like cells. The results show that silencing VDAC1 expression leads to reprogrammed metabolism and to multiple effects from tumor growth inhibition to modulation of the tumor microenvironment and inflammation, inducing differentiation of malignant cells. Thus, silencing VDAC1 is a potential therapeutic approach to treating mesothelioma.

• Animals
• Apoptosis
• Humans
• Inflammation
• Mesothelioma/genetics
• Mesothelioma/therapy
• Mice
• Nanotubes, Carbon
• RNA, Small Interfering/metabolism
• Tumor Microenvironment
• Voltage-Dependent Anion Channel 1/genetics
• Voltage-Dependent Anion Channel 1/metabolism

• Autoimmune Diseases/complications
• Autoimmune Diseases/therapy
• Humans
• Immunologic Factors/therapeutic use
• Immunosuppression Therapy
• Lymphoma/complications
• Lymphoma/diagnosis
• Lymphoma/therapy
• Thrombocytopenia/complications

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.

• AIHA
• CLL
• rituximab
• steroids
• targeted drugs

Autoimmune cytopenias (AICs) have been reported as a common complication in chronic lymphocytic leukemia (CLL) with autoimmune hemolytic anemia (AIHA), accounting for most cases. According to iwCLL guidelines, AICs poorly responsive to corticosteroids are considered indication for CLL-directed treatment. Chemo-immunotherapy has classically been employed, with variable results, and little data are available on novel agents, the current backbone of CLL therapy. The use of idelalisib in the setting of AICs is controversial and recent recommendations suggest avoiding idelalisib in this setting. Ibrutinib, through ITK-driven Th1 polarization of cell-mediated immune response, is known to produce an immunological rebalancing in CLL, which stands as a fascinating rationale for its use to treat autoimmunity. Although treatment-emergent AIHA has rarely been reported, ibrutinib has shown rapid and durable responses when used to treat AIHA arising in CLL. There is poor evidence regarding the role of BCL-2 inhibitors in CLL-associated AICs and the use of venetoclax in such cases is debated. Furthermore, their frequent use in combination with anti-CD20 agents might represent a confounding factor in evaluating their efficacy. In conclusions, because of their ability to mitigate an immunological dysregulation that is (at least partly) responsible for autoimmunity in CLL, to date BTK-inhibitors stand out as the most suitable choice when treatment of autoimmune cytopenias is required.

• CLL
• anemia
• autoimmune
• hemolytic
• ibrutinib
• idelalisib
• venetoclax

• Adult
• Aged
• Anemia, Hemolytic, Autoimmune/diagnosis
• Anemia, Hemolytic, Autoimmune/pathology
• Anemia, Hemolytic, Autoimmune/therapy
• Antineoplastic Agents/therapeutic use
• Disease Management
• Female
• Humans
• Immunologic Factors/therapeutic use
• Immunosuppressive Agents/therapeutic use
• Male
• Middle Aged
• Rituximab/therapeutic use
• Splenectomy
• Steroids/therapeutic use

Autoimmune hemolytic anemia is a rare condition characterized by destruction of red blood cells with and without involvement of complement. It is associated with significant morbidity and mortality. In warm autoimmune hemolytic anemia, less than 50% of patients remain in long-term remission following initial steroid therapy and subsequent therapies are required. Cold agglutinin disease is a clonal hematologic disorder that requires therapy in the majority of patients and responds poorly to steroids and alkylators. Rituximab has a favorable toxicity profile and has demonstrated efficacy in autoimmune hemolytic anemia in first-line as well as relapsed settings. Rituximab is the preferred therapy for steroid refractory warm autoimmune hemolytic anemia (wAIHA) and as part of the first- and second-line treatment of cold agglutinin disease. This article reviews the mechanism of action of rituximab and the current literature on its role in the management of primary and secondary warm autoimmune hemolytic anemia and cold agglutinin disease.

• autoimmune hemolytic anemia treatment
• cold agglutinin disease
• rituximab
• warm autoimmune hemolytic anemia

• AIHA
• CLL
• ITP
• obinutuzumab

Autoimmune cytopenias, particularly autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP), complicate up to 25% of chronic lymphocytic leukemia (CLL) cases. Their occurrence correlates with a more aggressive disease with unmutated VHIG status and unfavorable cytogenetics (17p and 11q deletions). CLL lymphocytes are thought to be responsible of a number of pathogenic mechanisms, including aberrant antigen presentation and cytokine production. Moreover, pathogenic B-cell lymphocytes may induce T-cell subsets imbalance that favors the emergence of autoreactive B-cells producing anti-red blood cells and anti-platelets autoantibodies. In the last 15 years, molecular insights into the pathogenesis of both primary and secondary AIHA/ITP has shown that autoreactive B-cells often display stereotyped B-cell receptor and that the autoantibodies themselves have restricted phenotypes. Moreover, a skewed T-cell repertoire and clonal T cells (mainly CD8+) may be present. In addition, an imbalance of T regulatory-/T helper 17-cells ratio has been involved in AIHA and ITP development, and correlates with various cytokine genes polymorphisms. Finally, altered miRNA and lnRNA profiles have been found in autoimmune cytopenias and seem to correlate with disease phase. Genomic studies are limited in these forms, except for recurrent mutations of KMT2D and CARD11 in cold agglutinin disease, which is considered a clonal B-cell lymphoproliferative disorder resulting in AIHA. In this manuscript, we review the most recent literature on AIHA and ITP secondary to CLL, focusing on available molecular evidences of pathogenic, clinical, and prognostic relevance.

• Evans' syndrome
• autoimmune hemolytic anemia
• chronic lymphocytic leukemia
• immune thrombocytopenia
• molecular

• Autoimmune hemolytic anemia
• Cold agglutinins
• Diagnosis–Treatment
• Warm agglutinins

Complement-mediated hemolytic anemias can either be caused by deficiencies in regulatory complement components or by autoimmune pathogenesis that triggers inappropriate complement activation. In paroxysmal nocturnal hemoglobinuria (PNH) hemolysis is entirely complement-driven. Hemolysis is also thought to be complement-dependent in cold agglutinin disease (CAD) and in paroxysmal cold hemoglobinuria (PCH), whereas warm antibody autoimmune hemolytic anemia (wAIHA) is a partially complement-mediated disorder, depending on the subtype of wAIHA and the extent of complement activation. The pathophysiology, clinical presentation, and current therapies for these diseases are reviewed in this article. Novel, complement-directed therapies are being rapidly developed. Therapeutic terminal complement inhibition using eculizumab has revolutionized the therapy and prognosis in PNH but has proved less efficacious in CAD. Upstream complement modulation is currently being investigated and appears to be a highly promising therapy, and two such agents have entered phase II and III trials. Of these, the anti-C1s monoclonal antibody sutimlimab has shown favorable activity in CAD, while the anti-C3 cyclic peptide pegcetacoplan appears to be promising in PNH as well as CAD, and may also have a therapeutic potential in wAIHA.

• autoimmune hemolytic anemia
• cold agglutinin disease
• complement
• complement inhibitors
• paroxysmal nocturnal hemoglobinuria
• therapy

Internal watershed infarcts (WI) involve white matter between deep and superficial arterial systems of middle cerebral artery. These infarcts are considered to be either from low blood flow or microembolism. Anemia is an extremely rare cause of watershed infarcts. Very few cases of hemolytic anemia causing watershed cerebral infarcts have been reported. Chronic lymphocytic leukemia (CLL) is frequently complicated with secondary autoimmune cytopenia such as autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and pure red cell aplasia. AIHA is present in about 7–10% of patients with CLL. AIHA from CLL presenting as WI is an extremely rare phenomenon with no previously published case reports to the best of our knowledge.

• Autoimmune cytopenias
• Autoimmune hemolytic anemia
• Immune thrombocytopenia
• Pure red cell aplasia
• Small lymphocytic lymphoma

• Agranulocytosis/complications
• Agranulocytosis/drug therapy
• Agranulocytosis/epidemiology
• Anemia, Hemolytic, Autoimmune/complications
• Anemia, Hemolytic, Autoimmune/diagnosis
• Anemia, Hemolytic, Autoimmune/drug therapy
• Anemia, Hemolytic, Autoimmune/epidemiology
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Humans
• Immunosuppressive Agents/therapeutic use
• Leukemia, Lymphocytic, Chronic, B-Cell/complications
• Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
• Leukemia, Lymphocytic, Chronic, B-Cell/pathology
• Protein Kinase Inhibitors/therapeutic use
• Red-Cell Aplasia, Pure/complications
• Red-Cell Aplasia, Pure/drug therapy
• Red-Cell Aplasia, Pure/epidemiology
• Rituximab/administration & dosage
• Thrombocytopenia/complications
• Thrombocytopenia/drug therapy
• Thrombocytopenia/epidemiology

• K12 CA090628 NCI NIH HHS

• Chronic lymphocytic leukemia
• biological treatment
• monoclonal antibodies
• safety profile

• Autoimmune cytopenias
• Autoimmune hemolytic anemia
• Chronic lymphocytic leukemia
• Immune thrombocytopenia

• autoimmune haemolytic anaemia
• cold agglutinin disease
• rituximab

Over the past decade, the administration of anti-CD20 monoclonal antibodies such as rituximab has demonstrated various degrees of effectiveness and has improved patients’ outcomes during the treatment of autoimmune hematological disorders and hematological malignancies. However, the depletion of B-cells, the distribution of T-cell populations, and the reconstruction of host immunity resulting from the use of anti-CD20 monoclonal antibodies potentially lead to severe viral infections, such as hepatitis B virus (HBV), hepatitis C virus (HCV), parvovirus B19, and herpes viruses, in patients who are undergoing immune therapy or immunochemotherapy. Of these infections, HBV- and HCV-related hepatitis are a great concern in endemic areas because of the high morbidity and mortality rates in untreated patients. As a result, prophylaxis against HBV infection is becoming a standard of care in these areas. Parvovirus B19, a widespread pathogen that causes red blood cell aplasia in immunocompromised hosts, also causes hepatitis in healthy individuals. Recently, its association with hepatitis was recognized in a patient treated with rituximab. In addition, adenovirus, varicella-zoster virus, hepatitis E virus, and rituximab itself have been linked to the occurrence of hepatitis during or after rituximab treatments. The epidemiologies and pathogeneses of these etiologies remain unknown. Because of the increasing use of anti-CD20 monoclonal antibodies for the treatment of hematological malignancies or autoimmune hematological disorders, it is imperative that physicians understand and balance the risks of hepatotropic virus-associated hepatitis against the benefits of using anti-CD20 monoclonal antibodies.

• CD20
• Monoclonal antibody
• Hepatitis
• Hepatitis B virus
• Hepatitis C virus

• Bendamustine
• CLL
• Hemolytic anemia

Ever since the advent of Rituximab and subsequently the emergence of other compounds targeting B cells, a cornucopia of medical applications have been found for this family of compounds. After their establishment as standard of care in many conditions such as rituximab in lymphoma and rheumatoid arthritis, they have been progressively found to aid in the treatment of many other conditions. This area constituted a fertile area of research in the past 12 years. Physicians have investigated the B-cell depleting agents use in cases of autoimmune hematologic cytopenias such as immune thrombocytopenia, Evans syndrome, cold and warm autoimmune hemolytic anemia, and other thrombophilic disorders such as the antiphospholipid syndrome and thrombocytopenic purpura. This chapter presents a historical perspective reviewing the various studies that have been published in this field. In addition, it offers a current assessment of the evidence regarding the use of B-cell depleting agents in the aforementioned conditions.

• Antibodies, Monoclonal, Murine-Derived/therapeutic use
• Autoimmune Diseases/drug therapy
• Autoimmune Diseases/immunology
• Hematologic Diseases/drug therapy
• Hematologic Diseases/immunology
• Humans
• Immunologic Factors/therapeutic use
• Rituximab

• Adult
• Antibodies, Monoclonal/therapeutic use
• Antibodies, Monoclonal, Murine-Derived/adverse effects
• Antibodies, Monoclonal, Murine-Derived/therapeutic use
• Antigens, CD20/immunology
• Antineoplastic Agents
• Autoimmune Diseases/complications
• Autoimmune Diseases/drug therapy
• Hematologic Diseases/complications
• Hematologic Diseases/drug therapy
• Humans
• Rituximab

• Aged
• Antibodies, Monoclonal, Murine-Derived/therapeutic use
• Antineoplastic Agents/therapeutic use
• Autoimmune Diseases/diagnosis
• Autoimmune Diseases/etiology
• Chromosomes, Human, Pair 14/genetics
• Chromosomes, Human, Pair 18/genetics
• Humans
• Leukemia, B-Cell/complications
• Leukemia, B-Cell/drug therapy
• Leukemia, B-Cell/genetics
• Male
• Pancytopenia/diagnosis
• Pancytopenia/etiology
• Rituximab
• Translocation, Genetic/genetics
• Treatment Outcome

• Adult
• Alemtuzumab
• Antibodies, Monoclonal/immunology
• Antibodies, Monoclonal/therapeutic use
• Antibodies, Monoclonal, Humanized
• Antibodies, Monoclonal, Murine-Derived/therapeutic use
• Antibodies, Neoplasm/therapeutic use
• Antineoplastic Agents/therapeutic use
• Autoimmune Diseases/etiology
• Autoimmune Diseases/therapy
• Clinical Trials as Topic
• Combined Modality Therapy
• Humans
• Leukemia, B-Cell/immunology
• Leukemia, B-Cell/therapy
• Leukemia, Lymphocytic, Chronic, B-Cell/complications
• Leukemia, Lymphocytic, Chronic, B-Cell/immunology
• Leukemia, Lymphocytic, Chronic, B-Cell/therapy
• Models, Immunological
• Rituximab

• P50-CA140158 NCI NIH HHS
• P01 CA081534 NCI NIH HHS
• P01 CA81534 NCI NIH HHS
• P01 CA095426 NCI NIH HHS
• P01-CA95426 NCI NIH HHS
• P50 CA140158 NCI NIH HHS