Cold agglutinin disease (CAD) is a form of autoimmune hemolytic anemia (AIHA). Because it is an exceedingly rare disease, we have only just begun to gain a basic understanding of it, thanks to the work of medical researchers over the past two decades.

In CAD, the autoantibodies are cold agglutinins that agglutinate red blood cells at an optimum temperature of between 3°C to 4°C. If the optimal temperature is present, the classical complement-mediated pathway is activated, resulting in AIHA. 

A team of researchers conducted a Europe-wide study of CAD in an attempt to put pen to paper on what we currently understand about the disease. Their study was published in Blood and will form the basis of our discussion in this article. 

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Just where are the current gaps in our knowledge of CAD? According to the researchers of this study, in quite a few areas. They explain, “Despite previous studies, many questions remain unanswered regarding epidemiology, clinical and hematologic features, and outcomes.” In addition, existing literature does not agree on the effects of CAD on mortality and the risk of thromboembolic events.

Read more about CAD etiology

In CAD, treatment is administered in approximately 70%-80% of patients, even though it may not necessarily be indicated. Among the first-line medications for CAD is rituximab monotherapy, with the possible addition of bendamustine or fludarabine. These medications are known to be slow-acting, and concerns about toxicity and adverse side effects remain. 

One of the targets of current CAD therapies is the complement-mediated pathway. Eculizumab is an anti-C5 antibody that works by blocking the terminal complement cascade in CAD. Therapies targeting the complement-mediated pathway in CAD are still largely under investigation. It should be noted that these therapies do not work on agglutination-mediated circulatory symptoms, since they are not mediated by the complement system. 

Let’s take a look at the European study and examine some of their findings. 

Combination Therapies Show Best Results

This study was rather ambitious in its design. It was a retrospective, multinational, and multicenter study involving European countries such as the UK, Norway, (northern) Italy, Finland, and Denmark. The researchers studied data on patients with confirmed CAD who had been hospitalized or seen as outpatients. 

The definition of “confirmed CAD” was highly specific, including the presence of chronic hemolysis, a positive direct antiglobulin test, as well as the absence of any possible cause of secondary cold agglutinin syndrome, such as lymphoma, cancer, or recent infection. Some of the CAD patients received treatment while others did not.

The study also included the results of the Norwegian 2010 rituximab-fludarabine trial and the Nordic 2017 rituximab-bendamustine trial. There were 3 grades of responses to these medications: no response, partial response, and complete response. The complete response criteria were spelled out clearly: either the complete histologic and flow cytometric regression of any detectable bone marrow lymphoproliferative disorders or a stable (≥2 consecutive measurements) increase in Hb levels of ≥2.0 g/dL or to the normal range with no transfusion required. 

The study recruited 232 patients; 207 had confirmed CAD and 25 had probable CAD. Among them, 175 (75.9%) received treatment. Among the most common treatments prescribed were rituximab monotherapy (n=104), corticosteroids (n=73), and cyclophosphamide (n=20). In addition, there were 29 patients in the Norwegian 2010 rituximab-fludarabine trial and 45 patients in the Nordic 2017 rituximab-bendamustine trial.

In the Norwegian rituximab-fludarabine trial, 18 of the 29 patients (62%) responded, with 11 patients (38%) achieving complete response and 7 patients (24%) achieving partial response. In the Nordic rituximab-bendamustine trial, 35 patients (78%) responded, with 24 patients (53%) achieving complete response and 11 patients (24%) achieving partial response. 

The main findings of this study as they relate to CAD therapies are that rituximab therapy with either fludarabine or bendamustine achieved better clinical results than rituximab monotherapy; the response rates were higher and the response durations were longer. Furthermore, follow-up data suggest that the rituximab-bendamustine combination achieves a better response duration and overall response rates compared to rituximab-fludarabine, with less toxicity. 

Rituximab monotherapy achieved response rates similar to those seen in previous clinical trials. However, in this study, the median response duration was longer than previously reported. In addition, repeated rituximab therapy in relapsed patients does appear to give them a good chance of success. 

Other findings in this study included a slight increase in the risk of thromboembolic events in CAD patients. However, the study team could not confirm an increased risk of myocardial infarction or stroke. They also found that iron overload was observed to be at the level that carried a risk of organ damage in about 20% of patients with CAD, particularly among those with a history of blood transfusions. 

Further Research Needed

The difficulty with rare diseases like CAD is that research is slow-paced, meaning that we can expect to achieve a meaningful and fulsome understanding much later than more common diseases like many of a cardiac or respiratory nature. 

When it comes to rare diseases, we want to raise awareness as much as possible among the public because when that happens, funds flow more easily into research organizations, with the result being that life-saving studies can be conducted with greater urgency. However, this is difficult if not impossible to accomplish if we do not first have a firm grasp of the disease among ourselves as healthcare professionals.

As information about CAD and other rare diseases flourishes, we will be better equipped to know what to tell the public and work together as a society to bring about cures.


Berentsen S, Barcellini W, D’Sa S, et al. Cold agglutinin disease revisited: a multinational, observational study of 232 patients. Blood. Published online July 23, 2020. doi:10.1182/blood.2020005674

Dunkelberger JR, Song WC. Complement and its role in innate and adaptive immune responses. Cell research. Published online December 15, 2009. doi:10.1038/cr.2009.139