From the Guidelines
Cold agglutinin disease should be treated with the fludarabine/rituximab combination, which is superior to rituximab alone, although toxicity should be weighed against other combinations such as DRC, BDR, or bendamustine/rituximab, as recommended by the 2014 iwwm-7 consensus 1.
Treatment Overview
Cold agglutinin disease is an autoimmune hemolytic anemia characterized by antibodies that bind to red blood cells at cold temperatures, causing them to clump together and be destroyed. Treatment depends on symptom severity and underlying causes.
- For mild cases, cold avoidance is the primary recommendation—patients should keep warm, especially their extremities, by wearing gloves, socks, and appropriate clothing in cold environments.
- For moderate to severe cases requiring medication, the fludarabine/rituximab combination is the preferred treatment, as it has been shown to be more effective than rituximab alone 1.
- In acute severe cases, plasmapheresis may temporarily remove cold agglutinins.
Disease Management
Patients should avoid cold infusions of IV fluids and blood products, which should be warmed to body temperature. Blood transfusions, if needed, should be given through a blood warmer. The disease works by IgM autoantibodies (cold agglutinins) binding to red blood cell surface antigens at temperatures below normal body temperature, activating the complement system and causing hemolysis.
- Monitoring includes regular complete blood counts, reticulocyte counts, and liver function tests to assess treatment response and disease activity.
- Recent guidelines, such as the 2024 NCCN clinical practice guidelines in oncology, highlight the importance of considering the viscosity level and the presence of cold agglutinins or cryoglobulins in patients with Waldenström macroglobulinemia/lymphoplasmacytic lymphoma 1.
Key Considerations
- The presence of cold agglutinins or cryoglobulins may affect determination of IgM levels, and testing for these should be performed at diagnosis 1.
- Patients with peripheral neuropathy may harbor antibodies against myelin-associated glycoprotein (MAG) or other glycoproteins or lipids, and referral for neurologic consultation should be considered 1.
From the Research
Definition and Pathogenesis
- Cold agglutinin disease (CAD) is an uncommon autoimmune haemolytic anaemia in which a well-defined, clonal low-grade lymphoproliferative disorder of the bone marrow results in erythrocyte destruction mediated by the classical complement pathway 2.
- The disease is characterized by a complement-mediated process which leads to intravascular and extravascular hemolysis 3.
Clinical Features and Diagnosis
- CAD should be considered in the differential diagnosis of elderly patients with unexplained chronic anemia presenting with or without cold-induced symptoms in the extremities, such as the fingers, ears, and nose 3.
- A stepwise approach to laboratory testing can help confirm the diagnosis, with nearly all cold agglutinins being positive for the C3d direct antiglobulin test (DAT) 3.
- Distinction from a warm AIHA is important, as therapy differs for the two entities 3.
Treatment Options
- Corticosteroids are not effective at treating CAD and should not be used as therapy in these patients 2, 3, 4.
- Rituximab monotherapy is recommended as a first-line therapy, with approximately 45-60% of patients responding to treatment 5, 3, 6.
- Combination therapy of rituximab and fludarabine has been shown to be effective in up to 76% of patients, but patients experience more mild side effects with this treatment 5, 3.
- Other treatment options include rituximab-bendamustine and complement-modulating agents, such as eculizumab and sutimlimab, which are currently in phase-3 trials to determine their efficacy and safety in patients with CAD 2, 4.