Long-Term Follow up of Patients with Cold Agglutinin Disease.

Background: Data regarding long-term follow up of patients (pts) with cold agglutinin disease (CAD) are limited.

Methods: We reviewed our institutional database of pts with CAD from 1981–2003. The diagnosis of CAD was confirmed by the following criteria: hemolysis and/or cold induced agglutination symptoms, cold agglutinin titre of ≥ 1:40, and typical direct anti-globulin test findings. We retrospectively collected pertinent clinical data including: demographics, dates of diagnosis and last follow up, associated hematologic diseases, baseline laboratory test results, treatment, clinical course, and subsequent development of lymphoproliferative diseases.

Results: We identified 18 pts with CAD. Most (15) were females. The median age at diagnosis was 71.5 years (range, 22–92). While all pts presented with hemolysis, only 2 had cold-induced acral signs or symptoms. The median presenting hemoglobin level was 8.4 gm/dl (range, 4.5–13.5). The cause was considered idiopathic in 10 pts, while 8 pts had concomitant lymphoproliferative disorders at diagnosis: chronic lymphocytic leukemia, 1 pt; non-Hodgkin lymphoma (NHL), 3 pts; and monoclonal gammopathy of undetermined significance (MGUS), 5 pts. A serum protein electrophoresis was obtained in 16 pts. Five pts had monoclonal proteins, all IgM (3 κ, 2 λ). Thirteen (72%) pts required treatment for CAD or associated lymphoid malignancies at some point in the course of their disease. The most common treatments administered for CAD were prednisone (9 pts) and cyclophosphamide (3 pts). Prednisone produced an overall response rate of 78%. The responses were durable with a median of 95 months (range, 15–414). No one responded to cyclophosphamide. After a median follow up of 55.5 months (mean, 99.5; range, 12–449), 8 pts were alive, 5 in complete remission (2 maintained on prednisone), and 3 in partial remission (all off therapy). Of those who died (10 pts), only 1 died of CAD due to complications from severe anemia. Two pts subsequently developed lymphoproliferative diseases, MGUS (IgMk) and low grade NHL, 125 and 175 months after diagnosis, respectively. The clinical course of CAD did not seem to be any worse in pts with lymphoid malignancies.

Conclusions: In our series, pts with CAD are frequently associated (44%) with lymphoproliferative disease at diagnosis. They have a relatively benign clinical course with a good likelihood of long-term disease remission. Unlike previous reports, prednisone is quite effective. Among those pts considered to have idiopathic CAD, a lymphoproliferative disease may develop later during the course of their disease.