Cold agglutinin disease (CAD) is 4 times as common in colder vs warmer climates, according to research published in Blood. The researchers also noted that treating patients with rituximab plus bendamustine appeared to yield a high, durable response rate.

While anecdotal evidence suggests that CAD is more common and more severe in colder climates, no published data had previously confirmed this. The optimal treatment strategies in CAD were previously unestablished. Therapy is not always indicated in this setting; however, rituximab, has resulted in response rates among patients. The addition of either bendamustine or fludarabine has improved treatment efficacy, although the risk of short-term toxicity and possible adverse effects have been reason for concern.

In a retrospective observational study, researchers aimed to enhance the understandings surrounding the epidemiologic, clinical, and laboratory findings in CAD. In addition, they sought to provide real-world information about long-term outcomes of previously studied treatments, mainly focusing on rituximab-fludarabine and rituximab-bendamustine combinations.

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Data were collected from 24 centers around Europe between 2017 and 2019. Overall, 223 patients were included; 207 (82.5%) patients had confirmed CAD and 25 (10.0%) patients had probable CAD. The mean patient age was 68 years at diagnosis, and 115 (60.2%) patients were diagnosed within 1 year of disease onset.

Among 210 patients with available clinical phenotype data, 146 (69.5%) had hemolytic anemia with grade 1 or absent circulatory symptoms, 44 (21.0%) had hemolytic anemia with grade 2 or 3 circulatory symptoms, and 20 (9.5%) had circulatory symptoms with compensated hemolysis.

Compared with data from Lombardy, Italy, data from Norway suggested a 4-fold increase in CAD with case rates of 5 per 1 million people vs 20.5 per 1 million people, respectively.

Of the 223 included patients, 29 received rituximab with fludarabine, 45 received rituximab with bendamustine, and 56 did not receive treatment.

Thirty-five (78%) patients who were treated with rituximab and bendamustine had a response to treatment; 24 (53%) patients had a complete response. Median response duration was not reached at 88 months.

Among patients who were treated with a rituximab-fludarabine combination, 18 (62%) patients had a response; 11 (38%) patients had a complete response. The estimated median duration of response was 77 months and the estimated 5-year sustained remission was 71%.

Late-occurring malignancies were noted in 9 (31%) patients who received fludarabine vs 4 (9%) patients who received bendamustine.

“Based on the balance between efficacy, short-term toxicity, and risk of long-term adverse effects, our results show that the use of rituximab plus bendamustine is safe and highly efficacious in relatively fit patients who require therapy for CAD,” the authors concluded.

Disclosures: Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.


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