One of the most intriguing hematologic disease categories centers on cold agglutinins, which are autoantibodies secreted by B-cells that bind to antigens on the surface of erythrocytes at temperatures ≤37°C. The resultant antigen-antibody complex triggers complement activation and subsequent extravascular hemolysis. When this process is primary or idiopathic it is classified as cold agglutinin disease (CAD), a rare subtype of autoimmune hemolytic anemia (AIHA). [1]
CAD accounts for 15-30% of AIHAs [2] and is recognized by the World Health Organization as a clonal lymphoproliferative process with unique markers on lymphocytes found in the bone marrow. [3] Symptoms include severe, debilitating fatigue and other clinical manifestations of anemia (e.g., weakness, shortness of breath) that can significantly impact patients’ quality of life (QOL). [2[ CAD is typically diagnosed by identifying the presence of hemolysis and further characterizing with a direct antiglobulin testing (DAT) to confirm the presence of the C3d complement protein on the surface of red blood cells (RBCs), as well as via a high a cold agglutinin titer. Cold agglutinins are almost always of the immunoglobulin M (IgM) subtype but in rare instances can be IgG or IgA antibodies. Additionally, bone marrow examination can confirm the presence of the clonal B-cells that are specific to a CAD lymphoproliferative disorder. [4]
Cold agglutinin syndrome (CAS) is also an AIHA subtype that, similar to CAD, is mediated by IgM autoantibodies that interact with RBCs, stimulating complement activation and causing hemolysis. Unlike CAD, CAS typically arises from underlying conditions such as infections (e.g., mycoplasma pneumoniae, Epstein-Barr virus, influenza A), autoimmune disorders (e.g., systemic lupus erythematosus), or other lymphoproliferative malignancies (e.g., diffuse large B-cell lymphoma, Hodgkin’s lymphoma, metastatic melanoma). 5
CAD and CAS are not just RBC-related maladies but are increasingly understood to be systemic inflammatory conditions. As complement is activated by antigen/antibody complexes, a whole-body inflammatory process unfolds, resulting in symptom severity that is often out of proportion to the degree of anemia. Many patients experience severe fatigue, muscle/joint pain, and lethargy despite having normal bloodwork, suggesting that these symptoms are inflammation-mediated. Patients may thus experience anxiety and depression, and may refrain from many activities of daily living in an effort to keep their extremities warm.
Inhibiting the classical complement pathway with sutimlimab
Despite their similarity, CAD and CAS are typically treated differently. For a patient with CAS, treatment is usually directed at the underlying condition, and may be as simple as letting the causative virus run its course. With CAD, management strategies tend to focus either on the classical complement pathway or B-cell-directed therapy.
Sutimlimab (Enjaymo®; Recordati Rare Diseases), the first and only approved therapy for CAD, is a humanized monoclonal antibody that selectively inhibits activation of the classical complement pathway. Specifically, sutimlimab binds to the C1s subcomponent of the C1 complement complex, blocking the complex’s formation and thus preventing classical pathway activation, which is responsible for the hemolysis and systemic inflammation that are characteristic of CAD. [6][7] Results from the CARDINAL and CADENZA clinical trials demonstrated the benefit of complement inhibition in decreasing hemolysis, improving hemoglobin and functional assessment of chronic illness therapy (FACIT) fatigue scores as well as QOL scores. Viewed in totality, these data suggest that inhibiting complement activation also reduces systemic inflammation. [7][8] Together, these dual benefits of complement blockade allow patients to feel better and improve their QOL.
The CADENCE registry: shedding light on the real-world experience of patients treated for CAD/CAS
Historically, there has been a widespread misperception that CAD is a not serious disease, or one that requires treatment. Consequently, there is only limited data in the literature about how CAD affects patients clinically, as well as on the real-world effects of various treatment regimens. CADENCE, the first multinational, longitudinal registry for patients with CAD/CAS, was established to fill that knowledge gap. The registry comprises data from more than 440 patients around the world, including a 63-patient sutimlimab cohort (58 with CAD, 4 with CAS, 1 with an unconfirmed diagnosis; mean age 72.7 years).
As we reported at the 2025 American Society of Hematology (ASH) Annual Meeting [9] , an updated analysis of CADENCE registry data revealed no new safety concerns with sutimlimab after a mean treatment duration of 25.1 months. Only six (9.5%) of the sutimlimab-treated patients experienced adverse events (AEs) possibly related to therapy, as determined by the investigator. Of those six patients, one experienced headache, one had dyspnea, one had ectopic atrial rhythm, one experienced chest pain/stable angina (considered a serious AE, or SAE), and two had acrocyanosis.
Given the importance of the complement system in helping to fight certain kinds of infection, there is a concern that inhibiting this system may leave patients vulnerable to infection. Of the sutimlimab-treated patients with CAD who experienced SAEs, one developed sepsis due to a recent untreated Capnocytophaga canimorsus bacteremia infection; another patient – a 90-year-old male with CAD – succumbed to a low-right-lung pneumonia; neither of these infections was of the type we typically worry about with complement inhibition. Notably, none of the SAEs reported in patients with CAD were considered related to sutimlimab.
Overall, sutimlimab was generally well tolerated. The safety findings were consistent with an elderly population with CAD/CAS, as well as with earlier clinical trial data. 7,8 The CADENCE results thus add to the growing body of evidence supporting the role of sutimlimab as a classical complement pathway inhibitor in treating patients with CAD.
Future directions: What’s in store from the CADENCE registry
Follow-up of the CADENCE registry patients will continue through 2028, with a final report
expected in 2031. Presumably, by that time we will be able to assess whether sutimlimab extends survival compared to other therapies or no therapy. We also hope additional follow-up data shed light on whether sutimlimab impacts development of blood clots (e.g., deep vein thrombosis, pulmonary emboli) — one of the “hidden” complications of CAD. Data from other complement-mediated disease states suggest that complement inhibition lowers the risk of thrombosis; [10] we are therefore optimistic about seeing similar benefits in patients with CAD.
Regardless of what future data show, we hope the CADENCE registry heightens physicians’
awareness that CAD is not a benign disease. It significantly impacts patients’ health and quality of life, and it increases the risk of mortality compared to age-matched controls without CAD. [11] We hope additional data will provide further validation of classical complement pathway inhibition as a viable therapeutic strategy in CAD/CAS, and of the clinical utility of sutimlimab in these patient populations.
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Clinical Trials
Cold Agglutinin Disease Real World Evidence Registry (CADENCE) – ClinicalTrials.gov ID NCT05791708
Sutimlimab (BIVV009) for the Adult Participants With Cold Agglutinin Disease (CAD) Who Have Completed Phase 3 Studies (CARDINAL or CADENZA) in Japan – ClinicalTrials.gov ID NCT05132127
A Study to Assess the Efficacy and Safety of BIVV009 (Sutimlimab) in Participants With Primary Cold Agglutinin Disease Who Have a Recent History of Blood Transfusion (Cardinal Study) – ClinicalTrials.gov ID NCT03347396
A Study to Assess the Efficacy and Safety of BIVV009 (Sutimlimab) in Participants With Primary Cold Agglutinin Disease Without A Recent History of Blood Transfusion (Cadenza) – ClinicalTrials.gov ID NCT03347422
A Phase 2a Study Evaluating BIVV020 in Adults With Persistent/Chronic Immune Thrombocytopenia (ITP) – ClinicalTrials.gov ID NCT04669600
Highlights of Prescribing Information
Sutimlimab (Enjaymo®; Recordati Rare Diseases)[Prescribing Information]
Reference
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[2] Berentsen S, D’Sa S, Randen U, Malecka A, Vos JMI. Cold agglutinin disease: improved understanding of pathogenesis helps define targets for therapy. Hemato. 2022;3(4):574-594.
[3] Zanelli M, Nizzoli ME, Sanguedolce F, et al. Primary cold agglutinin disease: a recently recognised diagnostic entity in WHO and ICC. Histpoathology. 2023;83(2):330-332.
[4] Collie JC. Cold agglutinin disease workup. Medscape. 2024 Mar 30. [Link]
[5] Döngelli H, Özsan GH. Cold agglutinin syndrome as a precursor for the diagnosis of low-grade lymphoma: a case report. Medicine International. 2025;5(12).
[6] Berentsen S. New insights in the pathogenesis and therapy of cold agglutinin-mediated autoimmune hemolytic anemia. Front Immunol. 2020;11:590.
[7] Röth A, Barcellini W, D’sa S, et al. Sutimlimab in cold agglutinin disease. N Engl J Med. 2021;384(16):1323–1334.
[8] Röth A, Berentsen S, Barcellini W, et al. Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial. Blood. 2022;140(9):980-991.
[9] Röth A, Michel M, Barcellini W, et al. Real-world safety of sutimlimab in patients with CAD/CAS: a multinational, multicenter, observational, prospective cohort study. Presented at 67 th American Society of Hematology (ASH) Annual Meeting and Exposition, Orlando, Fla., December 8, 2025. Poster #6242.
[10] Hillmen P, Muus P, Dϋhrsen U. et al. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood. 2007;110(12):4123-4128.
[11] Bylsma LC, Ording AG, Rosenthal A, et al. Occurrence, thromboembolic risk, and mortality in Danish patients with cold agglutinin disease. Blood Adv. 2019;3(20):2980-2985.
Featured image: American Society of Hematology 61th Annual Meeting at the Orange County Convention Center. Photo Courtesy: American Society of Hematology © 2019 ASH/Nick Agro.
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