<p>Cold agglutinin disease: current challenges and future prospects</p>

Abstract

Cold agglutinin disease (CAD) is a complement-dependent, classical pathway-mediated immune hemolytic disease, accounting for 15–25% of autoimmune hemolytic anemia, and at the same time, a distinct clonal B-cell lymphoproliferative disorder of the bone marrow. The disease burden is often high, but not all patients require pharmacological treatment. Several therapies directed at the pathogenic B-cells are now available. Rituximab plus bendamustine or rituximab monotherapy should be considered first-line treatment, depending on individual patient characteristics. Novel treatment options that target the classical complement pathway are under development and appear very promising, and the C1s inhibitor sutimlimab is currently being investigated in two clinical Phase II and III trials. These achievements have raised new challenges and further prospects, which are discussed. Patients with CAD requiring therapy should be considered for clinical trials.

New Insights in the Pathogenesis and Therapy of Cold Agglutinin-Mediated Autoimmune Hemolytic Anemia

“…In summary, CAD-associated LPD does not display the features of other indolent B-cell lymphomas types as described by the WHO classification. Therefore, it should be considered a distinct entity (5,14,39,40). Development of diffuse large B-cell lymphoma is uncommon, probably occurring in less than 4% of the patients during 10 years (18).…”

“…In the ward or outpatient department, patients with CAD should keep warm and avoid cold infusions (10,11,119). Any bacterial infection should be treated (10,14,101). Transfusion, when indicated, can be considered safe.…”

“…According to the recent international AIHA consensus document (3), CAD is defined as "an AIHA characterized by a monospecific direct antiglobulin test (DAT) strongly positive for complement fragment C3d and a cold agglutinin (CA) titer of 64 or higher at 4 • C (3,(12)(13)(14). DAT for IgG is usually negative, but can be weakly positive in up to 20% of the patients (15,16).…”

Livedo racemosa in neurological diseases: an update on the differential diagnoses

“…The consensual diagnostic criteria include evidence of chronic hemolysis, a cold agglutinins titer ≥ 1:64 at 4°C and a positive direct antiglobulin test (strongly positive for complement protein C3d and negative or weakly positive for IgG) with no evidence of malignancy [80,81].…”

“…More recently, rituximab as monotherapy or in combination with bendamustine showed favorable results and may be used as first-line therapy. The novel complement-directed therapies are still under investigation [80].…”