Treatment Of Cold Agglutinin Disease Research Articles

The latest insights into rare blood disorders: Diagnosis and treatment strategies.

Because immune-mediated rare blood disorders are uncommon, healthcare providers often lack the knowledge and experience necessary to identify, diagnose, and treat them in accordance with best practices. As a result, there are significant gaps in care, including delays in diagnosis and suboptimal treatment. To ensure that more patients with these rare disorders are offered quality, evidence-based care, it is essential that healthcare providers possess up-to-date information about best practices and new developments in this area of medicine. In this activity, composed of three podcasts, an expert moderator will interview three expert faculty members about evidence-based guidelines for the diagnosis and treatment of acquired thrombotic thrombocytopenic purpura; developments in the diagnosis and treatment of cold agglutinin disease; and the challenges of achieving enduring remission in patients with immune thrombocytopenia.

Sutimlimab for the Treatment of Cold Agglutinin Disease.

Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia and a bone marrow clonal lymphoproliferative disorder. Hemolysis in CAD is complement-dependent and mediated by the classical activation pathway. Patients also frequently suffer from fatigue and cold-induced circulatory symptoms. Although not all patients need treatment, the symptom burden has previously been underestimated. Effective therapies target the clonal lymphoproliferation or the complement activation. Sutimlimab, a humanized monoclonal IgG4 antibody that binds and inactivates complement protein C1s, is the most extensively investigated complement inhibitor for the treatment of CAD. This review addresses the preclinical studies of sutimlimab and the studies of pharmacokinetics and pharmacodynamics. We then describe and discuss the prospective clinical trials that established sutimlimab as a rapidly acting, highly efficacious, and low-toxic therapeutic agent. This complement inhibitor does not improve the cold-induced circulatory symptoms, which are not complement-mediated. Sutimlimab is approved for the treatment of CAD in the US, Japan, and the European Union. A tentative therapeutic algorithm is presented. The choice of therapy for CAD should be based on an individual assessment, and patients requiring therapy should be considered for inclusion in clinical trials.

Novel therapeutic agents for hemolytic anemia

In recent years, it has become clear that various diseases are caused by complement (related molecule) abnormalities (complementopathies) or are exacerbated by complement (complement-related diseases), and novel therapeutic agents targeting complement (anti-complement agents) are now being developed. Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic stem cell disorder characterized by complement-mediated intravascular hemolysis due to a deficiency of complement regulatory factors, making it a perfect candidate for anti-complement agents. In 2007, the anti-C5 monoclonal antibody eculizumab was approved for PNH, as the first anti-complement agent. The indications for eculizumab are expanding, and aggressive development is underway for new anti-complement agents, not only for PNH but also a variety of other diseases. In addition, the anti-C1s antibody sutimlimab was approved last year for the treatment of cold agglutinin disease, a form of autoimmune hemolytic anemia. This presentation overviews novel anti-complement agents for these hemolytic anemias.

Novel anti-complement therapeutics for hemolytic anemia

The anti-C5 antibody eculizumab was approved in 2007 as the first anti-complement agent for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). While eculizumab's indication has been expanded to include other diseases, the development of new anti-complement agents has been aggressively pursued for various diseases. In PNH, the anti-C5 recycling antibody ravulizumab, which is an improved version of eculizumab, has been developed, with an extended dosing interval of 2 to 8 weeks, vastly improving convenience. The treatment of PNH with terminal complement inhibitors such as eculizumab and ravulizumab presents a new challenge-extravascular hemolysis. To address this issue, the proximal complement inhibitor, a C3 inhibitor called pegcetacoplan, was approved in the United States of America. Furthermore, the amplification loop inhibitors-a factor B inhibitor iptacopan, and a factor D inhibitor danicopan-are being developed. Recently, the anti-C1s antibody sutimlimab was approved for the treatment of cold agglutinin disease, a type of autoimmune hemolytic anemia. This article discusses novel anti-complement therapies for hemolytic anemia.

Sutimlimab for the Treatment of Cold Agglutinin Disease

Cold agglutinin disease is a very rare haemolytic anaemia characterized by antibody-mediated haemolysis, complement activation, thrombosis and poor quality of life. In recent years, our understanding of the complement system and its role in disease has increased dramatically. However, because there is an increased risk of infection with inhibiting complement at the complement 5 and complement 3 levels, blocking the classical complement pathway is being explored instead as a way to strategically inhibit the complement system while minimizing the infection risks. Sutimlimab is a humanized immunoglobulin G4 antibody developed to inhibit the classical complement pathway. Its role and efficacy in treating patients with cold agglutinin disease will be the focus of this paper.

Complement C1s as a diagnostic marker and therapeutic target: Progress and propective.

The molecules of the complement system connect the effectors of innate and adaptive immunity and play critical roles in maintaining homeostasis. Among them, the C1 complex, composed of C1q, C1r, and C1s (C1qr2s2), is the initiator of the classical complement activation pathway. While deficiency of C1s is associated with early-onset systemic lupus erythematosus and increased susceptibility to bacteria infections, the gain-of- function variants of C1r and C1s may lead to periodontal Ehlers Danlos syndrome. As C1s is activated under various pathological conditions and associated with inflammation, autoimmunity, and cancer development, it is becoming an informative biomarker for the diagnosis and treatment of a variety of diseases. Thus, more sensitive and convenient methods for assessing the level as well as activity of C1s in clinic samples are highly desirable. Meanwhile, a number of small molecules, peptides, and monoclonal antibodies targeting C1s have been developed. Some of them are being evaluated in clinical trials and one of the antibodies has been approved by US FDA for the treatment of cold agglutinin disease, an autoimmune hemolytic anemia. In this review, we will summarize the biological properties of C1s, its association with development and diagnosis of diseases, and recent progress in developing drugs targeting C1s. These progress illustrate that the C1s molecule is an effective biomarker and promising drug target.

Sutimlimab for treatment of cold agglutinin disease: why, how and for whom?

Therapies for cold agglutinin disease have been directed at the pathogenic B-cell clone. Sutimlimab, a monoclonal antibody that targets C1s, is the first complement inhibitor to be extensively studied in cold agglutinin disease. Sutimlimab selectively blocks the classical activation pathway and leaves the alternative and lectin pathways intact. Trials have documented high response rates with rapid improvement in hemolysis, hemoglobin levels and fatigue scores and low toxicity. Sutimlimab was recently approved in the USA. This drug appears to be particularly useful in severely anemic patients who require a rapid response, in acute exacerbations that do not resolve spontaneously and in patients in whom chemoimmunotherapy is contraindicated or has failed. The choice of therapy in cold agglutinin disease should be individualized.

Recent progress in the diagnosis and treatment of cold agglutinin disease

Recent progress in the diagnosis and treatment of cold agglutinin disease

Sutimlimab: First Approval

Sutimlimab (sutimlimab-jome; ENJAYMO™) is a humanized monoclonal antibody developed by Sanofi for the treatment of cold agglutinin disease (CAD). Sutimlimab is an immunoglobulin G, subclass 4 (IgG4) monoclonal antibody that inhibits the classical complement pathway by binding to complement protein component 1, s subcomponent (C1s), a serine protease which cleaves C4 and C2 to form the C3 convertase. Inhibition of the classical complement pathway at the level of C1s prevents deposition of complement opsonins on the surface of red blood cell (RBCs), leading to inhibition of haemolysis in patients with CAD. In February 2022, sutimlimab received its first approval in the USA to decrease the need for RBC transfusion due to haemolysis in adults with CAD. Sutimlimab is under regulatory review in Japan and the EU for CAD. This article summarizes the milestones in the development of sutimlimab leading to this first approval for CAD.

Rituximab Use in Warm and Cold Autoimmune Hemolytic Anemia.

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.

Efficacité exemplaire du rituximab dans un cas d’anémie hémolytique à autoanticorps froids

Autoimmune hemolytic anemia with cold autoantibodies or cold agglutinin disease is a rare chronic disorder in which no treatment has, until now, evidence of its effectiveness. We report a patient who successfully responded to rituximab for a cold agglutinin disease refractory to conventional therapy with very good tolerance and a complete remission. There are only few observations that have been reported in the literature regarding the efficacity of rituximab in the treatment of cold agglutinin disease. This promising therapy could, in the future, constitute a real alternative.

The role of plasmapheresis in the multimodal treatment of anti‐Pr cold agglutinin disease

The blood bank received a hemolyzed specimen (see left figure, left tube, preplasmapheresis specimen) from a 56-year-old male with marked anemia (Hb, 5.1 g/dL), fatigue, tachycardia, and a strong cold antibody reactive with all panel cells. He was treated for cold agglutinin disease with steroids, IVIG, rituximab, cyclophosphamide, and transfusion through a blood warmer with mild improvement. Unfortunately, the patient remained transfusion dependent with a decreasing but still elevated LDH. An extensive investigation to rule out malignancy was performed but revealed only lymphadenopathy, mild splenomegaly, and erythroid hyperplasia on marrow biopsy. The cold antibody was nonreactive with enzyme-treated RBCs and was identified as anti-Pr. The DAT was weakly positive (RBC-bound C3). The antibody was reactive at 30°C and very weakly reactive at 37°C. The antibody was predominantly IgM, but microscopic reactivity remained in DTT-treated serum, suggesting a minor component of IgG. The titer was abnormal but not extremely high (128 at 4°C). Pr is present on almost all human RBCs and carried on oligosaccharide side chains attached to RBC membrane-borne glycophorins 1 (majority on glycophorin A). A new explanation for the pathophysiology of hemolysis caused by this antibody in a context of unimpressive serologic results was described by Brain and colleagues 2 and Garratty 3 and involves antibody-induced aggregation of glycophorin A causing destabilization of the RBC membrane phospholipid bilayer, leading to an increase in cation permeability. The patient's room was kept as close to 37°C as possible. To hasten recovery and transition to outpatient treatment, plasmapheresis was initiated to further facilitate removal of the cold antibody. The cold agglutinin disease was treated and hemolysis stabilized by the use of a multimodal approach to therapy, including immunosuppressant medications, IVIG, RBC transfusion, and plasmapheresis: acute hemolysis resolved (see left figure, right tube, postplasmapheresis specimen) and the decrease in LDH accelerated (see figure, right, hospital time course). After two plasmapheresis procedures the patient was discharged with a Hb of 6.9 g/dL but continued to receive weekly outpatient transfusions. This case illustrates the lack of correlation between the relatively benign serology related to anti-Pr and the severity of hemolytic anemia. Plasmapheresis can play an important role in the multimodal treatment of cold agglutinin disease and the transition to outpatient treatment.

Successful treatment of cold agglutinin disease with anti-CD20 antibody (rituximab) in a patient with systemic lupus erythematosus

Cold agglutinin disease (CAD) is a rare cause of anaemia in patients with systemic lupus erythematosus (SLE). CAD is usually refractory to glucocorticosteroid, and other immunosuppressive and/or cytotoxic therapies. We report the case of a 55-years old woman with SLE and CAD that did not respond to high-dose methylprednisolone, cyclosporin A, and double filtration plasma pheresis. Because several recent case reports and studies have indicated promising results of rituximab treatment for CAD and for SLE, rituximab was given weekly at 375 mg/m(2) in two doses. The rituximab was well tolerated, and there were no adverse effects. The hemolysis and SLE improved markedly, and the patient remained disease free eight months later. This is the first report of successful rituximab treatment of CAD in a patient with SLE. We conclude that rituximab is worth trying in such patients if they fail to respond to conventional treatment.

Intérêt du rituximab dans la maladie des agglutinines froides

Purpose. – Cold agglutinin disease is a chronic auto-immune hemolytic anemia related to a lymphoproliferative disorder with a degenerative potential and no codified treatment. This rare affection is related to the production of anti-erythrocytes immunoglobulins M. They are responsible of hemolytic crises sometimes severe and vascular acrosyndrom when submitted to cold temperature. Before rituximab, a monoclonal antibody targeted against the B lymphocyte CD20 antigen, no treatment was really efficient. Methods. – We present 5 patients who have been treated with 4 weekly rituximab perfusions, and then we proceed to a review of the literature concerning the other 23 similar cases. Results. – With a good tolerance, the treatment allowed a remission in all the cases (4 partial, 1 complete). Among the 23 observations published, the rate of answer was 21/23 (of which 14 gave completes). Conclusion. – Rituximab is an alternative treatment of cold agglutinin disease.

CHILDHOOD REFRACTORY AUTOIMMUNE HAEMOLYTIC ANAEMIA: IS THERE A ROLE FOR ANTI‐CD20 THERAPY (RITUXIMAB)?

CHILDHOOD REFRACTORY AUTOIMMUNE HAEMOLYTIC ANAEMIA: IS THERE A ROLE FOR ANTI‐CD20 THERAPY (RITUXIMAB)?