Sutimlimab vs B-cell-targeted therapy in cold agglutinin disease: which is the optimal approach?

Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia caused by monoclonal immunoglobulin M autoantibodies that bind to red blood cells and trigger hemolysis through activation of the classical complement pathway. Cold agglutinins are produced by a clonal population of lymphocytes, recognized by the World Health Organization as a low-grade lymphoproliferative disorder. Traditional therapy relied on B-cell-targeted immunosuppression with rituximab, which mainly yielded partial responses in approximately half of the patients. The combination of rituximab with fludarabine or bendamustine significantly increased and prolonged response rates, although with a substantial infectious risk. Sutimlimab, the first C1s complement inhibitor, has shown efficacy in rapidly and sustainably increasing hemoglobin levels, reducing hemolysis, and significantly improving quality of life. However, the drug does not act on the B-cell clone and does not decrease cold agglutinins. Therefore, several unmet needs remain, including identifying patients who can discontinue sutimlimab while maintaining remission, developing combination strategies effective against cold-induced symptoms, and improving infection prevention and control of hemolytic flares. This perspective article briefly recapitulates the pathophysiology of CAD, outlines the evolution of its treatment landscape, and focuses on the role of sutimlimab, including its clinical positioning, therapeutic benefits, and management considerations, offering insights into optimizing care for patients with this challenging condition.