Cold agglutinin disease (CAD) is an autoimmune hemolytic anemia (AIHA) mediated by cold agglutinins. It is estimated that CAD accounts for 15% to 30% of AIHAs.
The understanding of CAD pathogenesis has improved in recent decades. As so, there has been great progress of late in diagnosing and treating the disease. These topics have recently been discussed in publications by Sigbjørn Berentsen, MD, PhD, and Wilma Barcellini, MD. Here, we will address some of their considerations.
The First International Consensus Group defined CAD as “an AIHA with a monospecific direct antiglobulin test (DAT) strongly positive for C3d (and negative or weakly positive with IgG [immunoglobulin G]) and a cold agglutinin (CA) titer of 64 or greater at 4°C.”
“We recognize that there may be occasional cases with CA titer <64,” the group wrote. “Patients may have a B-cell clonal lymphoproliferative disorder (LPD) detectable in blood or marrow but no clinical or radiological evidence of malignancy.”
This definition establishes a clear distinction between CAD and the cold agglutinin syndrome (CAS), which is secondary to other diseases (most often infections or cancers).
Learn more about CAD differential diagnosis
LPD in CAD can be misinterpreted as lymphoplasmacytic lymphoma and marginal zone lymphoma due to similar histopathological features. However, a differentiating factor is the presence of the MYD88 L265P mutation, which is found in nearly all cases of lymphoplasmacytic lymphoma but not in CAD.
Also, nearly half of patients with CAD have cold-induced circulatory symptoms, including acrocyanosis or Raynaud-like phenomena.
Findings from the largest registry-based study indicate a 3.1-fold increased risk of thromboembolic events (TEs) in CAD patients when compared with matched controls. The increased risk presents different geographic patterns. While in Europe and North America it is most evident for venous thromboembolic events, in Japan it is most evident for arterial thromboembolic events.
“Successful CAD-directed therapy seems to reduce the frequency of TEs, but there are no data to show any impact of treatment of asymptomatic patients on TE risk,” Dr. Berentsen said.
Differing Treatment Approaches
Though used in many countries, glucocorticoids are not an effective therapy in CAD. Patients require therapeutic regimens with high doses to maintain disease in remission and, nevertheless, response rates are low.
According to Drs. Berentsen and Barcellini, CAD patients with mild or compensated hemolysis who experience no or minimal clinical symptoms and fatigue do not benefit from treatment. However, these patients should be carefully monitored.
Also, nonpharmacologic measures, such as thermal protection to limit hemolysis and relief of any ischemic symptoms, should be adopted.
Read more about CAD treatment
On the other hand, patients with symptomatic anemia or disabling Raynaud-like symptoms are expected to benefit from pharmacological treatment. In these cases, rituximab, an anti-CD20 monoclonal antibody, is commonly used as first-line therapy.
“Prospective and retrospective studies have shown response rates of 45 to 60%, with only rare complete responses,” Drs. Berentsen and Barcellini said. Relapse is usually observed within 12 to 15 months. These episodes can sometimes be controlled with a repeat series of rituximab infusions.
Besides the use of rituximab as a standalone therapy, its use in combination with other drugs has been explored. For instance, the addition of fludarabine allows for higher overall and complete response rates. However, it also leads to more acute and late-onset toxic effects. Additional studies showed promise in the combination of rituximab with bendamustine.
In spite of the recent advances, researchers are continuously seeking improved ways for treating CAD. For instance, “Complement inhibition is a promising new therapeutic approach but cannot be expected to relieve the circulatory symptoms, which are not complement-mediated,” Drs. Berentsen and Barcellini said.
For Dr. Berentsen, appropriate diagnostic workup, which should include DAT, CA titer, and relevant examinations for underlying bone marrow LPD, is of utmost importance for optimal therapy. Also, the decision on whether to treat or not to treat should be carefully pondered. “Because there are no comparative trials, recommendations must be based on nonrandomized studies and will be influenced by personal experience,” he wrote.
A number of therapies have been showing promise in delivering equally efficacious effects in CAD with less toxicity. Dr. Berentsen highlighted novel B-cell–targeting agents (eg, Bruton tyrosine kinase (BTK) inhibitors, phosphatidylinositol 3-kinase d inhibitors, and B-cell lymphoma 2 inhibitors), plasma cell-directed approaches, and complement-directed therapies as strategies that merit further investigation.
Berentsen S, Barcellini W. Autoimmune hemolytic anemias. N Engl J Med. 2021;385(15):1407-1419. doi:10.1056/NEJMra2033982
Berentsen S. How I treat cold agglutinin disease. Blood. 2021;137(10):1295-1303. doi:10.1182/blood.2019003809
Jäger U, Barcellini W, Broome CM, et al. Diagnosis and treatment of autoimmune hemolytic anemia in adults: recommendations from the First International Consensus Meeting. Blood Rev. 2020;41:100648. doi:10.1016/j.blre.2019.100648