Therapies targeting the pathogenic B-cell clone and the classical complement pathway have emerged as a new hope for treating cold agglutinin disease (CAD), allowing clinicians to choose between treatment approaches.

In a new review article published in Transfusion Medicine Reviews, Sigbjørn Berentsen and Geir E. Tjønnfjord highlighted important differences between the B-cell-directed combination of bendamustine plus rituximab and the anti-C1s monoclonal antibody sutimlimab (Enjaymo™).

Though both approaches showed high response rates, frequent complete responses and a long median response duration were reported for the bendamustine-rituximab combination. Moreover, treatment with the bendamustine-rituximab combination is temporary, while sutimlimab may require indefinite treatment. However, sutimlimab is far more rapidly acting and has lower toxicity.

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“The much shorter [time to response] to sutimlimab may be of particular importance for severely anemic patients and those with acute exacerbations that do not resolve spontaneously. On the other hand, the short duration of therapy with bendamustine plus rituximab compares favorably with the probable need for indefinite treatment with sutimlimab,” Berentsen and Tjønnfjord wrote.

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Additionally, sutimlimab monotherapy is not indicated for treating patients with severe circulatory symptoms. The very high cost associated with sutimlimab therapy is another disadvantage.

Given the pros and cons of each approach, Berentsen and Tjønnfjord suggested a potential sequential regimen. “A way to balance these advantages and disadvantages might be to use complement inhibition as a ‘bridge’ to the slower acting but more definitive B-cell directed approach in patients with severe hemolytic anemia,” they wrote.

Ultimately, treatment choice should follow an individual assessment, the researchers wrote.

Berentsen and Tjønnfjord advised that comparisons between B-cell-directed therapy and complement inhibition should be regarded with caution due to the lack of dedicated comparative studies. Moreover, the prospective studies included in their analysis have distinct endpoints and response definitions, which compromise head-to-head comparisons.


Berentsen S, Tjønnfjord GE. Current treatment options in cold agglutinin disease: B-cell directed or complement directed therapy? Transfus Med Rev. Published online August 28, 2022. doi:10.1016/j.tmrv.2022.05.001