Diagnosis and treatment of autoimmune hemolytic anemia in adults: Recommendations from the First International Consensus Meeting

Autoimmune hemolytic anemia (AIHA) is a highly heterogeneous disease due to increased destruction of autologous erythrocytes by autoantibodies with or without complement involvement. Other pathogenic mechanisms include hyper-activation of cellular immune effectors, cytokine dysregulation, and ineffective marrow compensation. AIHAs may be primary or associated with lymphoproliferative and autoimmune diseases, infections, immunodeficiencies, solid tumors, transplants, and drugs. The direct antiglobulin test is the cornerstone of diagnosis, allowing the distinction into warm forms (wAIHA), cold agglutinin disease (CAD), and other more rare forms. The immunologic mechanisms responsible for erythrocyte destruction in the various AIHAs are different and therefore therapy is quite dissimilar. In wAIHA, steroids represent first line therapy, followed by rituximab and splenectomy. Conventional immunosuppressive drugs (azathioprine, cyclophosphamide, cyclosporine) are now considered the third line. In CAD, steroids are useful only at high/unacceptable doses and splenectomy is uneffective. Rituximab is advised in first line therapy, followed by rituximab plus bendamustine and bortezomib. Several new drugs are under development including B-cell directed therapies (ibrutinib, venetoclax, parsaclisib) and inhibitors of complement (sutimlimab, pegcetacoplan), spleen tyrosine kinases (fostamatinib), or neonatal Fc receptor. Here, a comprehensive review of the main clinical characteristics, diagnosis, and pathogenic mechanisms of AIHA are provided, along with classic and new therapeutic approaches.

https://www.mdpi.com/2077-0383/9/12/3859/pdf

New Insights in Autoimmune Hemolytic Anemia: From Pathogenesis to Therapy Stage 1.

How I treat warm autoimmune hemolytic anemia.

Autoimmune hemolytic anemia (AIHA) is an acquired, heterogeneous group of diseases which includes warm AIHA, cold agglutinin disease (CAD), mixed AIHA, paroxysmal cold hemoglobinuria and atypical AIHA. Currently CAD is defined as a chronic, clonal lymphoproliferative disorder, while the presence of cold agglutinins underlying other diseases is known as cold agglutinin syndrome. AIHA is mediated by autoantibodies directed against red blood cells (RBCs) causing premature erythrocyte destruction. The pathogenesis of AIHA is complex and still not fully understood. Recent studies indicate the involvement of T and B cell dysregulation, reduced CD4+ and CD25+ Tregs, increased clonal expansions of CD8 + T cells, imbalance of Th17/Tregs and Tfh/Tfr, and impaired lymphocyte apoptosis. Changes in some RBC membrane structures, under the influence of mechanical stimuli or oxidative stress, may promote autohemolysis. The clinical presentation and treatment of AIHA are influenced by many factors, including the type of AIHA, degree of hemolysis, underlying diseases, presence of concomitant comorbidities, bone marrow compensatory abilities and the presence of fibrosis and dyserthropoiesis. The main treatment for AIHA is based on the inhibition of autoantibody production by mono- or combination therapy using GKS and/or rituximab and, rarely, immunosuppressive drugs or immunomodulators. Reduction of erythrocyte destruction via splenectomy is currently the third line of treatment for warm AIHA. Supportive treatment including vitamin supplementation, recombinant erythropoietin, thrombosis prophylaxis and the prevention and treatment of infections is essential. New groups of drugs that inhibit immune responses at various levels are being developed intensively, including inhibition of antibody-mediated RBCs phagocytosis, inhibition of B cell and plasma cell frequency and activity, inhibition of IgG recycling, immunomodulation of T lymphocytes function, and complement cascade inhibition. Recent studies have brought about changes in classification and progress in understanding the pathogenesis and treatment of AIHA, although there are still many issues to be resolved, particularly concerning the impact of age-associated changes to immunity.

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Autoimmune hemolytic anemia: current knowledge and perspectives

Autoimmune cytopenias (AICy) and autoimmune diseases (AID) can complicate both lymphoid and myeloid neoplasms, and often represent a diagnostic and therapeutic challenge. While autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) are well known, other rarer AICy (autoimmune neutropenia, aplastic anemia, and pure red cell aplasia) and AID (systemic lupus erythematosus, rheumatoid arthritis, vasculitis, thyroiditis, and others) are poorly recognized. This review analyses the available literature of the last 30 years regarding the occurrence of AICy/AID in different onco-hematologic conditions. The latter include chronic lymphocytic leukemia (CLL), lymphomas, multiple myeloma, myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), myeloproliferative neoplasms, and acute leukemias. On the whole, AICy are observed in up to 10% of CLL and with higher frequencies in certain subtypes of non-Hodgkin lymphoma, whilst they occur in less than 1% of low-risk MDS and CMML. AID are described in up to 30% of myeloid and lymphoid patients, including immune-mediated hemostatic disorders (acquired hemophilia, thrombotic thrombocytopenic purpura, and anti-phospholipid syndrome) that may be severe and fatal. Additionally, AICy/AID are found in about 10% of patients receiving hematopoietic stem cell transplant or treatment with new checkpoint inhibitors. Besides the diagnostic difficulties, these AICy/AID may complicate the clinical management of already immunocompromised patients.

https://www.mdpi.com/2072-6694/13/7/1532/pdf

Autoimmune Complications in Hematologic Neoplasms.

In spite of an increasing array of investigations, the relationships between viral infections and allogeneic hematopoietic stem cell transplantation (HSCT) are still controversial, and almost exclusively regard DNA viruses. Viral infections per se account for a considerable risk of morbidity and mortality among HSCT recipients, and available antiviral agents have proven to be of limited effectiveness. Therefore, an optimal management of viral infection represents a key point in HSCT strategies. On the other hand, viruses bear the potential of shaping immunologic recovery after HSCT, possibly interfering with control of the underlying disease and graft-versus-host disease (GvHD), and eventually with HSCT outcome. Moreover, preliminary data are available about the possible role of some virome components as markers of immunologic recovery after HSCT. Lastly, HSCT may exert an immunotherapeutic effect against some viral infections, notably HIV and HTLV-1, and has been considered as an eradicating approach in these indications.

/pdf/viral-infections-in-hsct-detection-monitoring-clinical-5e9wfigwas.pdf

Viral Infections in HSCT: Detection, Monitoring, Clinical Management, and Immunologic Implications.

https://air.unimi.it/bitstream/2434/758717/4/LD%20ritux%20blood%202018.pdf

Low-dose rituximab in autoimmune hemolytic anemia: 10 years after

Growing evidence suggests the impact of microbiome alteration, named dysbiosis, on the development of neoplasms, infections, inflammatory diseases, and immuno-mediated disorders. Regarding hematologic diseases, most data regard hematopoietic stem cell transplant (HSCT). In this review, we systematically evaluate the studies concerning microbiome in malignant and benign hematologic disorders beyond HSCT. A permissive microbiota is associated to the development of hematologic malignancies (including acute leukemia, lymphoma, and multiple myeloma), as well as of iron deficiency anemia, autoimmune cytopenias, and aplastic anemia. This happens through various mechanisms; chronic inflammatory triggering, epithelial barrier alteration, antigen dissequestration, and molecular mimicry. Hematologic therapies (chemo and immunosuppression) may induce/worsen dysbiosis and favour disease progression and infectious complications. Antibiotics may also induce dysbiosis with possible long-term consequences. Finally, novel target therapies are likely to alter microbiome, inducing gut inflammation (i.e. small molecules such as tyrosine-kinase-inhibitors) or enhancing host's immune system (as observed with CAR-T cells and checkpoint inhibitors).

Recent insights into the role of the microbiome in malignant and benign hematologic diseases.

Autoimmune hemolytic anemia (AIHA) may be frequently challenged by infectious complications, mainly as a result of immunosuppressive treatments administered. Furthermore, infectious agents are known triggers of AIHA onset and relapse. Although being risk factors for mortality, infections are an underestimated issue in AIHA. This review will collect the available evidence on the frequency and type of infectious complications in AIHA, detailing the risk related to each treatment (i.e., steroids, rituximab, splenectomy, classic immunosuppressive agents, and new target drugs). Moreover, we will briefly discuss the infectious complications in AIHA secondary to other diseases that harbor an intrinsic infectious risk (e.g., primary immunodeficiencies, systemic autoimmune diseases, lymphoproliferative disorders, solid organ and hematopoietic stem cell transplants). Finally, viral and bacterial reactivations during immune suppressive therapies will be discussed, along with suggested screening and prophylactic strategies.

https://www.mdpi.com/2077-0383/10/1/164/pdf

Infectious Complications in Autoimmune Hemolytic Anemia.

Impact of diagnosis and treatment on response to COVID-19 vaccine in patients with BCR-ABL1-negative myeloproliferative neoplasms. A single-center experience

Francesca Cavallaro

Papers

Viral Infections in HSCT: Detection, Monitoring, Clinical Management, and Immunologic Implications.

Low-dose rituximab in autoimmune hemolytic anemia: 10 years after

Recent insights into the role of the microbiome in malignant and benign hematologic diseases.

Infectious Complications in Autoimmune Hemolytic Anemia.

Impact of diagnosis and treatment on response to COVID-19 vaccine in patients with BCR-ABL1-negative myeloproliferative neoplasms. A single-center experience