Treatment of cold agglutinin disease and cold agglutinin syndrome

Ensure the diagnosis is correct and a thorough evaluation has been performed. Individuals who lack evidence of a secondary cause of CAS should have a bone marrow evaluation including flow cytometry. Treatment is generally indicated for symptomatic disease; individuals with an incidental finding of CAS or CAD can be observed without treatment.

CAD: cold agglutinin disease; CAS: cold agglutinin syndrome; SLE: systemic lupus erythematosus; CLL: chronic lymphocytic leukemia; RBC: red blood cell; IgM: immunoglobulin M; COVID-19: coronavirus disease 2019.

* Cold agglutinins are IgM antibodies that cause cold-induced RBC agglutination and extravascular hemolysis. The titer and thermal amplitude of the cold agglutinin should be determined. Generally accepted diagnostic criteria for CAD include findings of hemolysis, positive direct antiglobulin (Coombs) test for C3d, and cold agglutinin titer ≥64 at 4°C.

¶ For most individuals with primary CAD, we suggest a rituximab-containing regimen such as rituximab plus bendamustine. For individuals who cannot tolerate multi-agent therapy, single-agent rituximab, bortezomib, or ibrutinib are reasonable alternatives. Sutimlimab may be used in individuals who wish to avoid immunosuppression during the COVID-19 pandemic.

Δ Refer to UpToDate for details of therapy for specific disorders. In some cases, such as early-stage CLL that does not otherwise require treatment, rituximab plus bendamustine (treatment for primary CAD) is appropriate.

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Treatment of cold agglutinin disease and cold agglutinin syndrome