IntroductionThe epidemiology, pathogenetic mechanisms and clinical features of chronic cold agglutinin disease (CAD) have been quite extensively elucidated in the literature, 1-5 but therapy remains suboptimal. [6][7][8][9][10] Although most authors emphasize the importance of avoiding cold exposure, a population based study showed that drug therapy had been attempted in more than 70% of the patients, 9 indicating that counseling is insufficient as sole therapeutic measure in a majority. The requirement for effective pharmacologic treatment is also highlighted by hemoglobin (Hgb) levels less than 8.0 g/dL in one-third and cold-induced circulatory symptoms in more than 90% of unselected patients with CAD, whereas 50% of such patients were found to have received blood transfusions during the course of the disease. 9 Corticosteroids, conventional immunosuppressive drugs and alkylating agents are generally ineffective. 6,9 Treatment with the monoclonal anti-CD20 antibody rituximab is the only well-documented effective therapy, leading to partial responses (PRs) in 45%-60% of the patients, but complete responses (CRs) are rare. 9,11,12 A median response duration of 11 months (range, 2-42 months) has been reported. 11 Although rituximab therapy is effective in polyclonal autoimmune diseases, 13,14 part of the rationale for rituximab in CAD was the demonstration of a monoclonal, B-cell lymphoproliferative bone marrow disorder in more than 90% of patients traditionally classified as having primary CAD. 4,9,11 Histologic signs of nonHodgkin B-cell lymphoma were present in bone marrow biopsy specimens from 75% of unselected patients with CAD in a population based study. 9 The most frequent type was lymphoplasmacytic lymphoma (LPL), which was found in 50% of the patients.We wanted to improve on the results achieved by rituximab single-agent therapy in patients with primary CAD. The purine analogues, eg fludarabine and cladribine, are powerful therapeutic agents in a variety of lymphoproliferative diseases. Although therapy with fludarabine for CAD has not been studied systematically, successful treatment was reported in one patient. 15 Histologic remission of the bone marrow lymphoproliferative disorder was observed after cladribine therapy in a series of 5 patients, but clinical remission was not achieved. 8 Fludarabine therapy, alone or in combination with rituximab, has yielded high response rates in Waldenström macroglobulinemia (WM), which is considered a closely related entity. [16][17][18] Furthermore, treatment with the fludarabine and rituximab combination has been found feasible and efficient in follicular lymphoma. 19 In the present study we have investigated the potential of fludarabine and rituximab in combination in patients with CAD requiring treatment. Methods Study designWe conducted a prospective, uncontrolled multicenter trial of combination therapy with fludarabine and rituximab in patients with CAD requiring An Inside Blood analysis of this article appears at the front of this issue.The publication cos...