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. 2019 Apr 9:10:93-103.
doi: 10.2147/JBM.S177621. eCollection 2019.

Cold agglutinin disease: current challenges and future prospects

Sigbjørn Berentsen  1 , Alexander Röth  2 , Ulla Randen  3 , Bernd Jilma  4 , Geir E Tjønnfjord  5   6   7
Affiliations

Cold agglutinin disease: current challenges and future prospects

Sigbjørn Berentsen et al. J Blood Med. .

Abstract

Cold agglutinin disease (CAD) is a complement-dependent, classical pathway-mediated immune hemolytic disease, accounting for 15-25% of autoimmune hemolytic anemia, and at the same time, a distinct clonal B-cell lymphoproliferative disorder of the bone marrow. The disease burden is often high, but not all patients require pharmacological treatment. Several therapies directed at the pathogenic B-cells are now available. Rituximab plus bendamustine or rituximab monotherapy should be considered first-line treatment, depending on individual patient characteristics. Novel treatment options that target the classical complement pathway are under development and appear very promising, and the C1s inhibitor sutimlimab is currently being investigated in two clinical Phase II and III trials. These achievements have raised new challenges and further prospects, which are discussed. Patients with CAD requiring therapy should be considered for clinical trials.

Keywords: autoimmune hemolytic anemia; cold agglutinin disease; complement; complement inhibitors; lymphoproliferative; therapy.

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Conflict of interest statement

S Berentsen has received research support from Mundipharma, travel support from Alexion and Apellis, lecture honoraria from Alexion, Bioverativ, and Janssen-Cilag, and has consulted for Apellis, Bioverativ, Momenta Pharmaceuticals, and True North Therapeutics, outside the submitted work. A Röth has received research support from Alexion and Roche, travel support from Alexion and AbbVie, lecture honoraria from Alexion, Roche, and Novartis, and has consulted for Alexion, Bioverativ, Novartis, and True North Therapeutics, outside the submitted work. U Randen reports no conflicts of interest. B Jilma has received reimbursement for travel for presentations and scientific advice from True North Therapeutics (a Bioverativ Company), outside the submitted work. GE Tjønnfjord has received research support from Mundipharma, Janssen-Cilag and Alexion Pharma, and lecture honoraria from Janssen-Cilag, Alexion Pharma, and Roche Pharma, outside the submitted work.

Figures

Figure 1
Figure 1
Cold agglutinin-associated lymphoproliferative bone marrow disorder. Bone marrow trephine biopsy showing intraparenchymatous nodular lymphoid lesions (panels A and B, H&E staining, 40× and 200×, respectively). Immunoperoxidase staining for CD20 highlights intraparenchymatous nodular B-cell infiltration (panel C, 200×). Mast cells are not discerned around the nodular lymphoid lesions (panel D, Giemsa staining, 200×). Notes: Reproduced with permission from Randen U, Trøen G, Tierens A, et al. Primary cold agglutinin-associated lymphoproliferative disease: a B-cell lymphoma of the bone marrow distinct from lymphoplasmacytic lymphoma. Haematologica. 2014;99(3):497–504. Copyright © 2014 Ferrata Storti Foundation.
Figure 2
Figure 2
Role of the classical and terminal complement pathways in cold agglutinin disease and target levels of complement inhibitors. Black arrows, major pathway; gray/dotted arrows, minor pathway. Abbreviations: CA, cold agglutinin; C, complement protein; C1-INH, plasma-derived C1-esterase inhibitor; MAC, membrane attack complex.
See this image and copyright information in PMC

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