Transfusion Medicine Reviews最新文献

Two major steps are identified in the pathogenesis of cold agglutinin disease; clonal B-cell lymphoproliferation and complement-mediated hemolysis. Each of these steps constitutes a target for treatment. In this focused review, we address 2 successful therapeutic approaches; the bendamustine plus rituximab combination as a highly efficacious B-cell directed therapy and the anti-C1s monoclonal antibody sutimlimab as the most extensively studied complement-targeting therapy. We describe and discuss the prospective study of bendamustine plus rituximab and 2 recent, prospective studies of sutimlimab. Bendamustine-rituximab results in a high response rate, frequent complete responses and long median response duration, and the treatment is temporary. However, this therapy is relatively slow-acting and associated with some toxicity. Sutimlimab is also highly efficacious, is far more rapidly acting, and is low-toxic. Disadvantages of sutimlimab are the lack of effect on circulatory symptoms, the probable need for indefinite treatment, and the very high costs. In cold agglutinin disease patients who require treatment, the choice should be based on an individual assessment.

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.

In this review article we provide a critical insight into recent reports evaluating innovative therapies for warm type autoimmune hemolytic anemia (wAIHA). Among published articles, we selected two reports on the use of the proteasome inhibitor bortezomib in association with dexamethasone or rituximab, one study on the spleen tyrosine kinase inhibitor fostamatinib, and a retrospective study on recombinant erythropoietin (rEPO). Among recent scientific communications, we discussed a report on the phosphoinositide 3-kinase delta inhibitor (PI3Kδi) parsaclisib. All studies highlighted a good efficacy although to be confirmed in larger trials and with limitations due to the heterogeneity of wAIHA patients enrolled, the small number of subjects, the concomitant medications allowed, and the short follow-up. Ongoing trials include new B-cell/plasma-cell targeting agents such as the Bruton tyrosine kinase inhibitors ibrutinib and rilzabrutinib, and the anti-CD38 MoAbs daratumumab and its analogue isatuximab. Further drugs in clinical trials target the complement cascade in wAIHA with complement activation, such as the C3 inhibitor pegcetacoplan and the C1q inhibitor ANX005. Finally, an interesting and non-immuno-toxic strategy is to remove the pathogenic autoantibodies via blocking the neonatal Fc receptor, by intravenous nipocalimab and subcutaneous RVT-1401. Such novel agents targeting the several immunopathological mechanisms acting in wAIHA and their possible combination, will increase the therapeutic armamentarium and possibly fill the gap of wAIHA relapsed after/refractory to rituximab. Moreover, these new target therapies may represent a tool for the unmet need of very acute cases.

Antineutrophil cytoplasmic antibody (ANCA) associated vasculitis comprises a rare entity of disorders that affects primarily small and medium-sized blood vessels. Since first documented in 1897, we have come a long way trying to understand the pathogenesis and finding an optimal treatment regimen. The pathogenesis of ANCA vasculitis is not well understood and despite many advances in treatment, the morbidity and mortality remains high. Over the last decade, there have been many advancements toward elucidating the pathogenesis, optimizing current therapies, and discovering new medicines. Presently, one trend is aimed at minimizing the adverse effects of glucocorticoids by reducing their use without sacrificing efficacy and safety. A new medicine targeting the alternative complement system has emerged and intends to replace glucocorticoids. Here, we review three articles that describe these new trends in the management of ANCA vasculitis.

Acquired Hemophilia A (AHA) is a rare, life-threatening bleeding disorder from autoantibodies against clotting factor VIII. These autoantibodies occur with increasing incidence with advanced age and are often associated with other medical conditions such as autoimmune diseases and malignancy. Not uncommonly, AHA presents as a new bleeding disorder in a person with prior thrombosis or thrombotic risk. Treatment of AHA focuses on managing and preventing bleeding, as well as immunosuppression with the goal to eradicate the autoantibody. Despite current treatment approaches, morbidity, and mortality are high due to complications from bleeding, immunosuppression, and underlying comorbidities. The most pressing needs to improved outcome for this disease are better bleeding prophylaxis in the outpatient setting and reduction of the need for intense immunosuppression. Because of the rare nature of this disease, there is limited prospective data and most treatment standards have been based on case series. The field has recently focused on improved diagnostics and advanced risk stratification, with a potential of tailoring the need and intensity of immunosuppression. Case reports of off label use of emicizumab, a factor FVIII mimetic approved for congenital hemophilia A, suggest emicizumab may provide effective and safe bleeding prophylaxis in the outpatient setting; this could permit reducing immunosuppression and decreasing the risk of treatment related infections. Two ongoing prospective clinical trials of emicizumab will help clarify the safety and efficacy in AHA.

The antiphospholipid syndrome (APS) is the most common cause of acquired immune-mediated thrombophilia. This syndrome is broadly defined by the presence of arterial or venous thrombosis, or pregnancy morbidity, in the presence of high levels of antiphospholipid antibodies. Despite recognition of this disorder more than 50 years ago, a fundamental unifying pathogenesis has not been determined. Due to this, mechanism-based therapies for APS are not available, and current management following thrombotic events suggests anticoagulation of indeterminate duration, or for obstetric complications, heparin/low molecular weight heparin and aspirin. However, APS is an autoimmune disorder, and several approaches focused on modulating the immune response or its effectors have been employed. Those which have been most extensively studied include hydroxychloroquine, rituximab and eculizumab, an inhibitor of complement C5. In this report, we review in depth, and critique, key clinical studies of these agents. Since all of these studies are small, our conclusions are qualified. However, it appears that hydroxychloroquine may enhance the anticoagulant efficacy of vitamin K antagonists in APS patients, and that rituximab may ameliorate some of the “non-criteria” manifestations of APS. The catastrophic antiphospholipid syndrome (CAPS) is associated with diffuse thrombosis, multi-organ dysfunction, and ∼30% mortality. A high incidence of complement regulatory gene mutations, and compelling data concerning the efficacy of eculizumab in CAPS, suggests an important role for complement in this disorder. However, additional work is needed to clarify the role of complement in non-catastrophic APS, though emerging data suggests that complement inhibition may be effective in preventing thrombosis in these patients as well.

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by isolated thrombocytopenia that may be accompanied clinically by bleeding and reduced health-related quality of life (HRQoL). While corticosteroids, splenectomy, and various immunosuppressants (used off-label) have served as historical mainstays of ITP treatment, their use is associated with adverse effects and morbidity. Over the last 15 years, the advent of the thrombopoietin receptor agonists has revolutionized the management of chronic ITP with high response rates, durable responses, and minimal adverse effects in most patients. With four agents now FDA-approved to manage chronic ITP, there is a renewed emphasis on improving HRQoL and minimizing the toxicities associated with traditional therapies. Promising agents with diverse mechanisms of action, ranging from those targeting Bruton's Tyrosine Kinase to the neonatal Fc receptor, are currently under investigation. This review highlights recent landmark clinical trials which have made significant impacts on ITP management and ongoing drug development. In critically analyzing studies of relevance, we illustrate the changing paradigms of ITP management and how the field is advancing beyond traditional therapies.

The discovery of bacterial enzymes with specificity for IgG antibodies has led to breakthroughs in several autoantibody-mediated diseases. Two such enzymes, IdeS and EndoS, degrade IgG by different mechanisms, and have separately shown promise in numerous animal models of autoimmune diseases. Recently, imlifidase (the international nonproprietary name for IdeS) has advanced to clinical trials, where it has performed remarkably well in desensitizing patients to enable kidney transplantation, and in anti-glomerular basement membrane disease. Conversely, it performed poorly in thrombotic thrombocytopenic purpura. This review summarizes the development of antibody-degrading enzymes, with a discussion of key clinical studies involving imlifidase. The future of the field is also discussed, including the use of these enzymes in other diseases, and the potential for re-dosing.