How do you treat refractory cold agglutinin disease?

If the patient has refractory cold agglutinin disease not associated with malignant lymphoproliferative disease, I have used intermediate dose Cytoxan. However, there is recent evidence that inhibition of C1s and thus complement activation by a monoclonal antibody sutimlimab markedly reduces hemolysis. This may become a new approach.

Some options include the following:

1. Bortezomib has about a 32% ORR described in this 2018 study (Blood). The study only gave one cycle of therapy which seems quite short, and in practice, I would consider giving at least 3 before deeming a patient refractory.

2. Different rituximab chemo combinations. There is data for FR in Blood 2010. Also, some data for cyclophosphamide.

The current strategies target the abnormal B-cell clone. Ultimately, the best strategy for a refractory patient you are describing would be targeting the hemolysis mediated by the complement pathway. The C1s inhibitor sutimlimab is likely the closest to FDA approval. Most updated data were presented at ASH 2020.