Primary chronic cold agglutinin disease: an update on pathogenesis, clinical features and therapy

Abstract

Chronic cold agglutinin disease (CAD) is a subgroup of autoimmune hemolytic anemia. Primary CAD has traditionally been defined by the absence of any underlying or associated disease. The results of therapy with corticosteroids, alkylating agents and interferon-alpha have been poor. Cold reactive immunoglobulins against erythrocyte surface antigens are essential to pathogenesis of CAD. These cold agglutinins are monoclonal, usually IgMkappa autoantibodies with heavy chain variable regions encoded by the V(H)4-34 gene segment. By flowcytometric and immunohistochemical assessments, a monoclonal CD20+kappa+B-lymphocyte population has been demonstrated in the bone marrow of 90% of the patients, and lymphoplasmacytic lymphoma is a frequent finding. Novel attempts at treatment for primary CAD have mostly been directed against the clonal B-lymphocytes. Phase 2 studies have shown that therapy with the chimeric anti-CD20 antibody rituximab produced partial response rates of more than 50% and occasional complete responses. Median response duration, however, was only 11 months. In this review, we discuss the clinical and pathogenetic features of primary CAD, emphasizing the more recent data on its close association with clonal lymphoproliferative bone marrow disorders and implications for therapy. We also review the management and outline some perspectives on new therapy modalities.

Figures

Figure 1

Example of clinical course in primary CAD. Retrospective data from almost ten year follow-up of a female patient, now 74-years old. Abbreviations: Chloramb, chlorambucil; Chol, cholecystitis; Pred, prednisolone; Rit, rituximab.

Figure 2

Blood smear from patient with primary CAD. Most erythrocytes are agglutinated in variably large clumps. Giemsa, oil immersion, objective × 100.

Figure 3

During passage through acral blood vessels, cooling allows IgM cold agglutinin to bind to erythrocytes, causing agglutination and binding of complement C1 complex. C1 esterase activates C4 and C2, generating C3 convertase which binds and splits C3, leading to deposition of C3b on the erythrocyte surface. Upon subsequent warming, IgM removes from the cell surface and the agglutinated cells are detached from each other, while C3b remains bound. C3b may in turn activate C5, leading to the formation of the membrane attack complex and intra vascular cell lysis. Most destruction of C3b-coated erythrocytes, however, is mediated by reticulo-endothelial cells in the liver [15,16,32]. Intrahepatic conversion of C3b is responsible for the deposition of C3d on the surviving erythrocytes which are released into the systemic circulation.

Figure 4

Histopathological appearances in bone marrow trephine biopsy from a patient with primary CAD. Lymphoid infiltrates may be of variable size; large (A), medium-sized (B), or often small and poorly outlined (C) which renders them barely detectable within areas of hyperplastic erythropoiesis unless immunohistological staining is applied (D). A–C, HE-stain; D, Anti-CD20, horseradish peroxidase/diaminobenzidine. All photomicrographs are taken at identical magnification (× 40 objective) to enable comparison of individual infiltrates.