Cold Agglutinin Disease (CAD)

In a population-based retrospective study conducted in Norway, the mean survival of patients with cold agglutinin disease (CAD) was 12.5 years after onset. The median age at onset was 67 years.1 A multinational observational study reported that the median estimated survival was 16 years after diagnosis, and the 5-year survival rate was estimated to be 83%. The median age at diagnosis was 68 years.2 

Therapy Outcomes

Criteria for complete remission included complete histologic and flow cytometric regression of any detectable bone marrow lymphoproliferative disease. Response was defined as a stable (>2 consecutive measurements) increase in hemoblogin levels of more than 2.0 g/dL or an increase to normal range and no transfusion requirement.2

Responder rates for patients who receive rituximab at least once2:

  • Nonresponders: 6% 
  • Respond once then unresponsive: 55% 
  • Respond more than once: 39% 
  • Median duration of response: 15 months

Responder rates for patients who receive rituximab/fludarabine2:

  • Responders: 62%
  • Complete remission: 38%
  • Partial response: 24%
  • Median duration of response duration: 77 months
  • Five-year sustained remission rate: 71%

Responder rates for patients receiving rituximab/bendamustine2

  • Responders: 78%
  • Complete remission: 53%
  • Partial response: 24% 
  • Five-year sustained remission rate: 77%

Risk for Complications

Patients with CAD are at greater risk than the general population for the development of venous thromboembolism, and they are also at increased risk for the development of hematologic and solid organ malignancies. Common late-onset hematologic malignancies include diffuse large B-cell lymphoma, acute myelogenous leukemia, acute lymphocytic leukemia, and myelodysplastic syndrome. Late-onset solid tumors also develop in some patients.2 


1. Berentsen S, Ulvestad E, Langholm R, et al. Primary chronic cold agglutinin disease: a population based clinical study of 86 patients. Haematologica. 2006;91(4):460-466.

2. Berentsen S, Barcellini W, D’Sa S, et al. Cold agglutinin disease revisited: a multinational, observational study of 232 patients. Blood. 2020;136(4):480-488. doi:10.1182/blood.2020005674

Reviewed by Harshi Dhingra, MD, on 9/7/2021.