Therapy for Chronic Cold Agglutinin Disease: A Prospective, Non-randomized International Multicentre Study on the Safety and Efficacy of Rituximab in Combination With Fludarabine.

1. Background

Chronic cold agglutinin disease (CAD) is mediated by monoclonal cold-reactive autoantibodies that bind to erythrocyte surface antigens, causing haemagglutination and complement-mediated haemolysis. Anaemia is severe (Hb 8.0 g/dL or lower) in one-third of patients and complement-induced exacerbation during febrile illness occurs frequently 1-3. Cold-induced circulatory symptoms are present in more than 90% of patients and may be disabling 1. CAD not associated with overt lymphoma or other disease has traditionally been classified as primary or idiopathic. However, a lymphoproliferative bone marrow disorder can be demonstrated by flow cytometry in 90% and by histology in approximately 75% of these patients, characterized by clonal proliferation of CD20+,κ+ B-cells 1,4,5. The histological features are those of lymphoplasmacytic lymphoma in about 50% of the patients 1.

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 1,6-8. Treatment with the chimeric monoclonal anti-CD20 antibody rituximab has been shown in prospective studies to induce remission in more than half of patients 9,10. Almost all responses were partial, however, and the median response duration was less than one year. Further studies are warranted, therefore, in order to explore the possibilities for increasing the response rate and duration.

The purine analogues, cladribine and fludarabine, are not cyclus dependent, and they have yielded partial response rates of 30-75% and complete response rates of 3-10% in lymphoplasmacytic lymphoma 11,12. Although probably clinically inefficient as monotherapy in most CAD patients, clinical effect of fludarabine has been reported in a single case 13, and cladribine has been shown to induce tumour reduction even in this condition 8. In lymphoplasmacytic lymphoma, purine analogue and rituximab combination therapy has resulted in higher response rates and more prolonged remissions as compared to purine analogue single agent therapy 12. The combination has produced favourable results in some patients with the related condition cryoglobulinaemia type I 14. Fludarabine has induced autoimmune haemolytic anaemia in patients with chronic lymphocytic leukaemia, but such events have not been reported in CAD patients 13,15. Moreover, there are reasons to assume that rituximab therapy will further reduce the risk of this adverse effect of fludarabine 16.

2 Clinical study