Vnitr Lek 2013, 59(9):828-840

Cold agglutinin disease - no response to glucocorticoids and rituximab, what treatment is best for the 3^rd line of therapy? Case report and review of the literature

Z. Adam^1,*, A. Pejchalová², G. Chlupová³, L. Říhová³, L. Pour¹, M. Krejčí¹, L. Červinek¹, Z. Král¹, J. Mayer¹

¹ Interní hematologická a onkologická klinika Lékařské fakulty MU a FN Brno, pracoviště Bohunice, přednosta prof. MUDr. Jiří Mayer, CSc.

² Transfuzní oddělení FN Brno, pracoviště Bohunice, přednostka prim. MUDr. Eva Tesařová, CSc.

³ Oddělení klinické hematologie FN Brno, přednosta prof. MUDr. Miroslav Penka, CSc.

Acquired autoimmune haemolytic anaemia is divided according to the characteristics of immunoglobulin causing haemolysis. The most frequent are haemolytic anaemia with thermal antibodies. They bind to erythrocytes and initiate their destruction in the reticuloendothelial system cells, leading to extravascular haemolysis. Cold agglutinin disease differs significantly from haemolytic anaemia with thermal antibodies. Agglutination is caused by monoclonal antibodies, in most cases class IgM and very rarely class IgG. Under cold conditions they bind to erythrocytes and cause their agglutination and subsequent disorder of blood circulation in body parts with a lower temperature. Agglutinins binding initiate the binding of the complement to the erythrocytes. Under warm conditions the binding becomes loose but the parts of the complement, which are already bound, cause haemolysis, which is mainly of an intravascular nature. The loose haemoglobin causes haemoglobinuria. Description of a patient with the disease. The 1^st symptoms of the disease, i.e. anaemia + circulatory disorders in the acral parts of the body, disappearing under warm conditions followed with haemoglobinuria, led to the diagnosis of cold agglutinin disease. The 1^st line treatment, prednison, did not show any response. The 2^nd line treatment used was rituximab and dexametazon. Rituximab was administered in doses of 500 mg/m² to 4 times in a row in weekly intervals. Dexametazon was administered in doses of 40 mg from 1^st to 4^th day and from 15^th to 18^th day of the cycle. This treatment, however, did not show any response either. Therefore this article brings an overview of all publications regarding the disease treatment with the aim of choosing the most effective treatment options in the case of failure of the monotherapy using rituximab. The 1^st line treatment for cold agglutinin disease is rituximab in monotherapy, usually administered once per week at least for 4 weeks. This treatment shows a response in about one-half of treated patients and the remission duration median after rituximab administration is 11 months. A combination of rituximab with fludarabin was more effective, though more toxic; this combination, in a clinical study, led to 75% of patients responding to treatment, including 20% experiencing complete remission. The treatment response median reached over 66 months. In a small study (10 patients) an increase in the amount of rituximab administrations from 4 to 8 led to a treatment response in 6 patients in whom administration of 4 doses of rituximab had no response. When treating Waldenström macroglobulinemia, effectiveness of the following drugs and their combinations was proven: rituximab, chlorambucil, cyclophosphamide, fludarabin, bortezomib, lenalidomid, bendamustin and alemtuzumab. The same drugs and treatment procedures are used for the treatment of the cold agglutinin disease as for Waldenström macroglobulinemia. Successful treatment with vortezomibem, combinations of rituximab + bendamustin, rituximab + cyclophosphamide or rituximab + fludarabin + cyclophosphamide, were recorded in the form of a description as regards the cold agglutinin disease treatment. An important benefit is also shown through treatment with the monoclonal antibody anti-C5, eculizumab, which is otherwise used for the treatment of paroxysmal nocturnal haemoglobinuria. Eculizumab blocks the C5 element of the component and thus stops haemolysis in a patient with cold agglutinin disease. As cold agglutinin disease is very rare, there are only a few clinical studies and when treating this rare disease we have no other option than to take into account the information contained in the descriptions of the particular cases of cold agglutinin disease and the experience of Waldenström macroglobulinemia disease treatment. The discussion seeks to solve the issue regarding what 3^rd line treatment option to use in the described patient.

Keywords: cold agglutinin disease; autoimmune haemolytic anaemia; Waldenström macroglobulinemia; rituximab; fludarabin; bortezomib; bendamustin; cyclophosphamide; eculizumab

Received: March 4, 2013; Accepted: April 29, 2013; Published: September 1, 2013  Show citation