The CAD5 Study::Therapy for Chronic Cold Agglutinin Disease: A Prospective, Non-randomized International Multicenter Trial on the Safety and Efficacy of Bendamustine and Rituximab Combination Therapy

Background

Chronic cold agglutinin disease (CAD) is mediated by monoclonal cold-reactive autoantibodies that bind to erythrocyte surface antigens, causing hemagglutination and complement-mediated hemolysis. Anemia is severe in one-third of patients (hemoglobin level 8.0 g/dL or lower). Cold-induced circulatory symptoms are present in more than 90% of patients and may be disabling. CAD not associated with overt lymphoma or other disease has traditionally been classified as primary or idiopathic. A monoclonal lymphoproliferative bone marrow disorder can, however, be demonstrated by flow cytometry in 90% and by histology in approximately 75% of these patients, characterized by clonal proliferation of CD20+, kappa+ B-cells.

Approximately two-thirds of the patients experience exacerbation during febrile illnesses. During steady-state CAD, a majority of patients have low levels of complement proteins C3 and C4 because of a continuous consumption. These low levels, in particular low C4 availability, seem to be rate-limiting for hemolysis and prevent full-blown activation of the complement cascade with C5 cleavage and intravascular hemolysis. During acute phase reaction, C3 and C4 levels increase due to an enhanced production, resulting in exacerbation of hemolysis.

Counseling on cold avoidance has been recommended as the treatment of choice for most patients with primary CAD. A systematic review showed, however, that in more than 70% of cases, the physician and/or the patient did not perceive such measures as sufficient). Many standard therapies used in other autoimmune diseases or indolent lymphomas are inefficient, e.g. corticosteroids, alkylating agents, interferon-α and, probably, purine analogue single agent therapy. Treatment with the chimeric monoclonal anti-CD20 antibody rituximab has been shown in prospective studies to induce remission in more than half of patients. Almost all responses were partial, and the median response duration was less than one year. In a subsequent, prospective non-randomized trial of fludarabine and rituximab combination therapy in 29 patients, 22 patients (76%) responded, 6 (21%) achieving CR and 16 (55%) achieving PR. Among 10 patients non-responsive to rituximab monotherapy, CR was observed after the combination therapy in one patient and PR in six. Median increase in Hb level was 3.1 g/dL in the responders and 4.0 g/dL among those who achieved CR. Median time to response was 4.0 months. Lower quartile of response duration was not reached after 33 months, and estimated median response duration was more than 66 months. Targeting the pathogenic B-cell clone efficiently seems important for the achievement of remission.

Though the rituximab-based therapies have been a first major achievement in therapy for CAD, some problems remain to be solved. First, a considerable number of patients do not respond to rituximab monotherapy. Second, although the use of fludarabine and rituximab in combination has resulted in high response rates and prolonged response duration, toxicity is significant and there are still some non-responders. Third, the therapeutic approaches should probably be individualized; e.g., fludarabine therapy may bring about problems in the younger patients because of late-occurring adverse events and in the older ones because of short-term hematologic toxicity.