Promoting Recognition, Diagnosis and Treatment of Cold Agglutinin Disease Annenberg Center for Health Sciences

Cold Agglutinin Disease (CAD, a type of Autoimmune Hemolytic Anemia, AIHA) is a rare disease, challenging at presentation and can present acutely or with more chronic symptoms
CAD is a subtype of AIHA (accounting for ~20% of all AIHA) caused by IgM autoantibodies, which tend to react at cold temperatures; Cold Agglutinin Syndrome (CAS) is also an AIHA mediated by IgM, associated with systemic disease, most commonly infection or malignancy
Hemolysis in CAD is complement-dependent with mainly extravascular hemolysis, typically in the liver
CAD affects ~one person per million every year; middle-aged and elderly people, 40–80 years of age with average age of onset 60 years of age; more common in women than men

Follow the case of a 62-year-old female who began to feel fatigue and shortness of breath in December 2010 through treatment to April 2017

Unmet medical need due to the high frequency of persistent anemia/hemolysis; immunochemotherapy is unsuccessful in at least 25% of cases because of treatment failure or toxicity; and small B-cell clone shows low proliferation activity and is difficult to target efficiently
Need for rapid acting therapy, especially in specific clinical settings, such as acute and severe exacerbations due to infections, major surgery, trauma, cardiac surgery
As of June 2021, there were six emerging treatments in trials, including Eculizumab, Bortezomib, Sutimlimab (BIVV009) in the CARDINAL and CADENZA trials, Pegcetacoplan (APL-2) and BIVV020 (both multiple and single IV doses)
The CADENCE Registry, a global patient registry launched in 2019, is an important tool in treating CAD and will provide perspective longitudinal data to advance understanding of patient demographics, clinical presentation and characteristics, co-morbidities and disease burden, patterns and use of CA

Treatment goals should be to improve anemia by increasing Hb levels, avoid transfusion, improve circulatory symptoms caused by cold temperatures and reduce inflammatory symptoms
There are a number of non-pharma treatment options, including thermal protection and cold avoidance and transfusions (avoid cold transfusions)
Corticosteroids should not be used to treat CAD
There are several first-line and second-line pharmaceutical treatment strategies, including Rituximab monotherapy, Rituximab-Bendamustine and Rituximab-Fludarabine combination therapies and Bortezomib monotherapy

To identify potential patients, a diagnostic workup of AIHA is essential, including antibody type, patient history and physical exam, hemoglobin levels and blood cell counts, blood smear examination and direct antiglobulin test (DAT)
Diagnostic criteria for CAD include chronic hemolysis, polyspecific DAT positive, monospecific DAT strongly positive for C3d, CA titer ≥64 at 4°C and a bone marrow evaluation (advised in patients with CAD at diagnosis)
Hemoglobin is the most direct indicator of clinical severity