From the Guidelines
Cold agglutinins should be suspected in patients with Waldenström Macroglobulinemia (WM) who present with chronic hemolytic anemia, and testing for cold agglutinins should be performed at diagnosis, as the presence of cold agglutinins can affect determination of IgM levels. In patients with WM, monoclonal IgM may present with cold agglutinin activity, where the monoclonal IgM interacts with specific red cell antigens below physiologic temperatures, producing chronic hemolytic anemia 1. The cold agglutinin titers are typically greater than 1:1,000 in most cases.
Key Points to Consider
- Cold agglutinins can cause chronic hemolytic anemia in patients with WM, and testing for cold agglutinins should be performed at diagnosis 1.
- The presence of cold agglutinins can affect determination of IgM levels, and therefore, testing for cold agglutinins and cryoglobulins should be performed at diagnosis 1.
- When suspected, cryocrit, a test for cryoglobulins, should be obtained, and the presence of cryoglobulins may render falsely low serum IgM levels 1.
- Patients with WM and peripheral neuropathy may harbor antibodies against myelin-associated glycoprotein (MAG) or other glycoproteins or lipids, and serum anti-MAG antibodies can be evaluated in patients with sensory peripheral neuropathies 1.
Management and Treatment
- Management of cold agglutinins in patients with WM primarily focuses on avoiding cold exposure and treating underlying causes.
- However, the specific treatment for cold agglutinins in patients with WM is not well-established, and further research is needed to determine the most effective treatment approach.
- In general, treatment for WM may involve rituximab, bendamustine, ibrutinib, or other therapies, but the role of these therapies in managing cold agglutinins is not well-defined 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 the production of IgM proteins, either monoclonal or polyclonal, which deposit complement on the surface of the red blood cell, leading to spherocytic extravascular hemolysis 3.
Clinical Features and Diagnosis
- Patients with CAD may present with mild anaemia, but approximately one-third of untreated patients have a haemoglobin level of ≤80 g/l, and about 50% have been considered transfusion dependent for shorter or longer periods 2.
- The diagnosis of CAD is supported by the presence of hemolytic variables and cold agglutinin detected in patient's plasma, as well as a positive direct antiglobulin test for complement (C3d) 4.
Treatment Options
- Rituximab monotherapy and fludarabine-rituximab in combination are documented treatment options for CAD 5, 2.
- The rituximab-bendamustine combination is also a recommended first-line treatment, depending on individual patient characteristics 2, 6.
- Other treatment options include rituximab-fludarabine in fit patients or a bortezomib-based regimen as second-line options 2.
- Therapies targeting the classical complement pathway, such as the complement C1s inhibitor, BIVV009, and sutimlimab, have shown promising results in preliminary studies 2, 3.
- Plasma exchange and rituximab treatment may be effective in treating CAD associated with lenalidomide administration 4.
Response to Treatment
- The response to treatment with rituximab and fludarabine combination therapy can be significant, with 76% of patients responding, including 21% achieving complete response and 55% achieving partial response 5.
- The bendamustine-rituximab combination therapy has also been shown to be highly efficient, with 71% of patients responding, including 40% achieving complete response and 31% achieving partial response 6.
- The median response duration for these treatments can be significant, with estimates ranging from 33 months to more than 66 months 5, 6.