124,786 research outputs found
Autoimmune Cytopenias in Chronic Lymphocytic Leukemia: Focus on Molecular Aspects
No full textAutoimmune 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
A Review on Chronic Neutropenia of the Adult: Emerging Clinical Dilemmas
No full textChronic neutropenia of the adult is a cause of often unjustified anxiety for both the patients and the medical community. Various studies show that the condition is generally benign with little risk of infection and clonal evolution. Here we provide a review of the available literature, focusing on patient evaluation and clinical management of the adult with chronic idiopathic/autoimmune neutropenia. Data presented advise to evaluate the clinical severity basing on neutrophil counts (< or > 0.5×109/L) and on the history of infections, to carefully examine personal and family history and to exclude congenital and benign forms of the infancy. Furthermore, nutritional deficit, infections, autoimmune diseases and neoplasms should be looked for and excluded. Hematologic constitutional symptoms, LDH, beta2microglobulin levels and lymphocytosis may hint the diagnosis of an underlying hematologic disease (lymphoproliferative syndrome). Once secondary forms have been excluded, the research for anti-neutrophils autoantibodies and bone marrow evaluation should be performed in case of persistent severe neutropenia, whilst follow up may be enough for mild/moderate cases. The use of G-CSF and prompt broad-spectrum antibiotics, covering for pseudomonas aeruginosa, is suggested in case of febrile neutropenia only. Finally, the introduction of new clinical entities (ICUS, IDUS, CCUS, and CHIP) within the myeloid diseases classification is going to change the diagnostic scenario in the next futur
A Review on Chronic Neutropenia of the Adult: Emerging Clinical Dilemmas
No full textNeutropenia is defined by a decrease of the absolute neutrophil counts (ANCs) below the threshold of 1.8x109/L in the Caucasians and 1.5x109/L in people of African origins. This is valid from 1 year of age until adulthood, as the cut off for normality would be 1x109/L in newborns and children <1 year of age.1 Neutropenia is considered chronic if persists longer than 3 months, and is usually graded into mild (ANCs 1-1.5x109/L), moderate (ANCs 0.5-1 x109/L), and severe forms (ANCs<0.5 x109/L).1 The condition is further classified into congenital and acquired, and the latter in primary and secondary forms.2 Neutropenia cause is often obscure, particularly in adults, where idiopathic neutropenia is one of the most frequent reasons for hematologic referral. Moreover, the general practitioner and the hematologist himself can find it difficult to orientate among emerging clinical dilemmas: how much one should worry about moderate/mild forms? What tests to perform? Which is the priority for visits and workup? Once excluded oncologic and common secondary forms, how will I follow a patient with chronic idiopathic disease? Thereafter, we will focus on the available literature on acquired neutropenia of the adult and provide some practical advice for patient’ evaluation and follow up in the clinical practice
Anemia emolitica autoimmune dall’approccio classico ai nuovi farmaci
No full textL’anemia emolitica autoimmune (AEA) è una malattia ematologica rara la cui incidenza varia tra 0.8 e 3 per 105abitanti/anno nell’adulto e ha una prevalenza di circa 17/105. L’AEA può essere primitiva o secondaria a farmaci, infezioni, malattie autoimmuni e neoplasie. La diagnosi viene posta grazie al test di Coombs. Sebbene l’AEA sia generalmente considerata una patologia benigna e di semplice gestione clinica, i casi più gravi sono spesso refrattari a più linee di terapia e presentano un aumentato rischio di eventi trombotici, con una mortalità complessiva dell’11% (in studi storici) e di circa il 4% in un’ampia coorte di pazienti recentemente pubblicata. In questo articolo verranno discusse le opzioni terapeutiche dell’AEA a partire dall’approccio classico attualmente suggerito dalle linee guida, per poi focalizzarsi sulle nuove terapie “a bersaglio”. Verranno analizzati i pro e i contro dei vari trattamenti e le evidenze dalla letteratura utili nella scelta terapeutica più idonea
Autoimmune hemolytic anemia - progress in emerging treatment options
No full textIntroduction: AIHA is a complex and heterogeneous disease involving antigen-autoantibody reaction, T-cell co-stimulation, complement activation, phagocytosis and bone marrow compensatory response. Several drugs targeting these mechanisms are under development in addition to standard therapies: steroids, immunesuppressors and splenectomy. Areas covered: Rituximab is the first biologic therapy used in AIHA, and its association with bendamustine and fludarabine has been shown more effective in relapse/refractory cold agglutinin disease. In these cases bortezomib was also beneficial with an overall response in about 30% of cases, and several complement inhibitors (eculizumab, BIVV009, and APL-2) are currently under investigation. B-cell receptor inhibitors (ibrutinib, acalabrutinib, and idelalisib) are promising therapeutic options for lymphoproliferative associated secondary forms. Finally, targeting IgG driven extravascular hemolysis (SYNT001 and fostamatinib) is an exciting new treatment approach. Expert opinion: AIHAs have been historically considered benign and easy to treat, however relapsing/refractory cases represent a clinical challenge. In these cases a target therapy would be ideal as traditional treatments are often ineffective/unfeasible. Moreover, the several mechanisms involved may be variably acting in the single patient and unpredictably changing overtime. Since several exciting target-therapies are emerging, only prospective studies would clarify the best choice, association, and sequence of these new drugs
Immune Phenomena in Myeloid Neoplasms : An “Egg or Chicken” Question
No full textImmune phenomena are increasingly reported in myeloid neoplasms, and include autoimmune cytopenias/diseases and immunodeficiency, either preceding or complicating acute myeloid leukemia, myelodysplastic syndromes (MDS), chronic myeloproliferative neoplasms, and bone marrow failure (BMF) syndromes. Autoimmunity and immunodeficiency are the two faces of a dysregulated immune tolerance and surveillance and may result, along with contributing environmental and genetic factors, in an increased incidence of both tumors and infections. The latter may fuel both autoimmunity and immune activation, triggering a vicious circle among infections, tumors and autoimmune phenomena. Additionally, alterations of the microbiota and of mesenchymal stem cells (MSCs) pinpoint to the importance of a permissive or hostile microenvironment for tumor growth. Finally, several therapies of myeloid neoplasms are aimed at increasing host immunity against the tumor, but at the price of increased autoimmune phenomena. In this review we will examine the epidemiological association of myeloid neoplasms with autoimmune diseases and immunodeficiencies, and the pivotal role of autoimmunity in the pathogenesis of MDS and BMF syndromes, including the paroxysmal nocturnal hemoglobinuria conundrum. Furthermore, we will briefly examine autoimmune complications following therapy of myeloid neoplasms, as well as the role of MSCs and microbiota in these settings
Clinical Applications of Hemolytic Markers in the Differential Diagnosis and Management of Hemolytic Anemia
No full textSeveral hemolytic markers are available to guide the differential diagnosis and to monitor treatment of hemolytic conditions. They include increased reticulocytes, an indicator of marrow compensatory response, elevated lactate dehydrogenase, a marker of intravascular hemolysis, reduced haptoglobin, and unconjugated hyperbilirubinemia. The direct antiglobulin test is the cornerstone of autoimmune forms, and blood smear examination is fundamental in the diagnosis of congenital membrane defects and thrombotic microangiopathies. Marked increase of lactate dehydrogenase and hemosiderinuria are typical of intravascular hemolysis, as observed in paroxysmal nocturnal hemoglobinuria, and hyperferritinemia is associated with chronic hemolysis. Prosthetic valve replacement and stenting are also associated with intravascular and chronic hemolysis. Compensatory reticulocytosis may be inadequate/absent in case of marrow involvement, iron/vitamin deficiency, infections, or autoimmune reaction against bone marrow-precursors. Reticulocytopenia occurs in 20-40% of autoimmune hemolytic anemia cases and is a poor prognostic factor. Increased reticulocytes, lactate dehydrogenase, and bilirubin, as well as reduced haptoglobin, are observed in conditions other than hemolysis that may confound the clinical picture. Hemoglobin defines the clinical severity of hemolysis, and thrombocytopenia suggests a possible thrombotic microangiopathy or Evans' syndrome. A comprehensive clinical and laboratory evaluation is advisable for a correct diagnostic and therapeutic workup of the different hemolytic conditions
The Changing Landscape of Autoimmune Hemolytic Anemia
No full textAutoimmune hemolytic anemia (AIHA) is a greatly heterogeneous disease due to autoantibodies directed against erythrocytes, with or without complement activation. The clinical picture ranges from mild/compensated to life-threatening anemia, depending on the antibody's thermal amplitude, isotype and ability to fix complement, as well as on bone marrow compensation. Since few years ago, steroids, immunesuppressants and splenectomy have been the mainstay of treatment. More recently, several target therapies are increasingly used in the clinical practice or are under development in clinical trials. This has led to the accumulation of refractory/relapsed cases that often represent a clinical challenge. Moreover, the availability of several drugs acting on the different pathophysiologic mechanisms of the disease pinpoints the need to harness therapy. In particular, it is advisable to define the best choice, sequence and/or combination of drugs during the different phases of the disease. In particular relapsed/refractory cases may resemble pre-myelodysplastic or bone marrow failure syndromes, suggesting a careful use of immunosuppressants, and vice versa advising bone marrow immunomodulating/stimulating agents. A peculiar setting is AIHA after autologous and allogeneic hematopoietic stem cell transplantation, which is increasingly reported. These cases are generally severe and refractory to standard therapy, and have high mortality. AIHAs may be primary/idiopathic or secondary to infections, autoimmune diseases, malignancies, particularly lymphoproliferative disorders, and drugs, further complicating their clinical picture and management. Regarding new drugs, the false positivity of the Coombs test (direct antiglobulin test, DAT) following daratumumab adds to the list of difficult diagnosis, together with the passenger lymphocyte syndrome after solid organ transplants. Diagnosis of DAT-negative AIHAs and evaluation of disease-related risk factors for relapse and mortality, notwithstanding improvement in diagnostic approach, are still an unmet need. Finally, AIHA is increasingly described following therapy of solid cancers with inhibitors of immune checkpoint molecules. On the whole, the double-edged sword of new pathogenetic insights and therapies has changed the landscape of AIHA, both providing enthusiastic knowledge and complicating the clinical management of this disease
- …
