Efficacy of rituximab-bendamustine in cold agglutinin haemolytic anaemia refractory to previous chemo-immunotherapy: a case report.

Introduction Primary cold agglutinin disease (CAD) is a haemolytic anaemia caused by high titres of cold antibodies, usually IgM, directed against red blood cells1,2. Cold agglutinins are present at low titres in all normal individuals, but at high concentrations, the agglutinins can have pathological consequences. In the cool peripheral circulation, cold agglutinin-coated red blood cells activate the complement cascade to the C3b/C3d stage and in the hepatic circulation C3b+ erythrocytes trigger phagocytosis by macrophages. An autoimmune disorder is responsible for the high titres of circulating cold antibodies and CAD accounts for approximately 13-15% of cases of autoimmune haemolytic anaemia3. Moreover, CAD has been found to be associated with a clonal lymphoproliferative disorder in many cases. Indeed, the cold agglutinins are monoclonal IgM in more than 90% of CAD patients and the presence of a lymphoid neoplasm, in particular B-cell non-Hodgkin's lymphoma (NHL), has been observed in approximately 75% of patients with primary CAD4,5. Treatments, including corticosteroids or alkylating agents, which are effective in other forms of autoimmune haemolytic anaemia are usually ineffective in CAD. On the other hand, half of the patients with CAD respond to rituximab alone, a drug that has markedly improved the prognosis of patients with B-cell lymphomas. Moreover, combining rituximab with fludarabine has further improved the outcome of CAD patients, with a 75% overall response rate being achieved in a recent, prospective trial6. Most CAD patients are elderly and their advanced age makes the use of potentially harmful therapies questionable. It is, therefore, reasonable to search for less toxic regimens for CAD patients. Recently, bendamustine, a molecule analogous to fludarabine, has been successfully employed in the treatment of low-grade B-cell NHL7,8. Compared to fludarabine, bendamustine has fewer side effects and an excellent tolerability. Thus, bendamustine with rituximab might be an effective chemo-immunotherapy option for elderly patients with CAD. The case report here presented, gives support to the use of bendamustine in CAD.