No response to cladribine in five patients with chronic cold agglutinin disease

To the Editor: Chronic cold agglutinin disease (CAD) is a type of autoimmune haemolytic anaemia (AIHA) characterized by the production of cold reactive autoantibodies of IgM kappa type against erythrocyte carbohydrate antigens (1). The ``idiopathic'' or ``primary'' form of CAD has been shown to represent a clonal immunoproliferative bone marrow disease which in most cases can be classi®ed as a symptom producing monoclonal gammopathy of undetermined signi®cance (MGUS) of the IgMkappa type (2, 3). Although most publications on drug therapy are case reports, it can still be concluded that drugs, including corticosteroids, alkylating agents, and alpha-interferon, have failed to demonstrate a convincing effect in this condition (2, 4, 5). The low proliferative activity of the clonal B cells may contribute to their resistance to alkylating agents or steroids. The newer purine analogues, cladribine (2chlorodeoxyadenosine, CdA) and ̄udarabine, have been successfully used for the treatment of several other low-grade B cell lymphoproliferative diseases. Therapy with cladribine has yielded high response rates in patients with hairy cell leukaemia, WaldenstroÈm's macroglobulinaemia, and lowgrade lymphoma (6±8). The mechanism of action of these drugs is probably not phase dependent. Remission after ̄udarabine therapy has been reported in a single case of CAD (9). A probable bene®cial effect of cladribine has also been observed in some polyclonal autoimmune diseases (10). Paradoxically however, both ̄udarabine and cladribine may induce exacerbation of autoimmune haemolysis in patients with chronic lymphocytic leukaemia (11). We performed a small, open, uncontrolled, prospective study to evaluate the possible effect of cladribine therapy in patients with CAD. The study was approved by the Regional Ethical Committee of Health Region 2 in Norway. The inclusion criteria were: 1. CAD diagnosis, as de®ned by the combination of chronic haemolytic anaemia with cold agglutinin titre o64 and a typical pattern for the direct antiglobulin test (DAT). The criteria for DAT in CAD were de®ned as a positive test with polyspeci®c antiserum, negative or only weakly positive with anti-IgG, and strongly positive with anti-C3d (1, 2). 2. The presence of a clonal, immunoproliferative disease, veri®ed by the demonstration of monoclonal IgM band by serum electrophoresis and immuno®xation, clonal lymphoproliferation in bone marrow biopsy, or a kappa/lambda ratio >3.5 using ̄owcytometric immunophenotyping in bone marrow aspirates (2). 3. The presence of clinical symptoms requiring treatment, e.g., anaemia or Raynaud-like symptoms. 4. Absence of contraindications to cladribine treatment. All patients underwent clinical examination, chest X-ray, and abdominal ultrasonography to exclude so-called ``secondary'' cases of CAD. Flowcytometric immunophenotyping was carried out as previously described (2) at one of the participating university hospitals. All bone marrow biopsies were examined by a trained lymphoma pathologist at the Norwegian Radium Hospital and were classi®ed according to the REAL (Revised European± American lymphoma) classi®cation. Cladribine was administered as a 2-h intravenous infusion of 0.14 mg/kg/d for ®ve consecutive days. A second, identical course of cladribine was allowed after 12 wk. The patients were assessed monthly for 6 months, and the haematological and biochemical parameters were measured at each visit. The bone marrow was re-examined after 3 and 6 months. Complete response was de®ned as absence of anaemia or haemolysis, disappearance of clinical symptoms of CAD, undetectable monoclonal serum immunoglobulin, and no signs of clonal lymphoproliferation in bone marrow biopsy and ̄owcytometric immunophenotyping. Partial response was de®ned as a stable increase of Hgb by more than 2 g/100 ml and a 50% reduction of elevated serum IgM level, combined with improvement of the clinical symptoms. Patients were classi®ed as non-responders if they did not achieve a complete or partial response. Five patients were included. The relevant patient and laboratory data are given in Table 1. An IgM Eur J Haematol 2000: 65: 88±90 Printed in UK. All rights reserved Copyright # Munksgaard 2000