Improvement of the thermal amplitude after rituximab treatment for cold agglutinin disease with Waldenström’s macroglobulinemia

Abstract

Dear Editor, Cold agglutinin disease (CAD) is an uncommon autoimmune hemolytic anemia characterized by the production of cold agglutinins (CA) [1]. CA exhibits the strongest affinity for the antigen at 0–4°C but binding may occur at temperatures approaching the normal body temperature of mammals, depending on the thermal amplitude of the antibody. Rituximab has been demonstrated to be useful in treating CAD that is refractory to conventional therapies [2]. However, CA titers did not concur with the observed clinical and hematologic responses, and it has become apparent that the CA titer is not an important index for the clinical features of CAD. The detailed effect(s) of rituximab on CAD have not been reported. We present a case of a 68-year-old man who was diagnosed with Waldenstrom’s macroglobulinemia with CAD in 1999, in whom the thermal amplitude was improved after rituximab treatment. His Hb level was 4.9 g/dL, and an immunoglobulin M (IgM) kappa monoclonal protein was evident at diagnosis (IgM, 58.2 g/L). His bone marrow was diffusely infiltrated with CD20+ lymphoplasmacytoid lymphocytes. The direct antiglobulin test was positive for complement (C3d). CAwas positive with a titer of 8,192 at 4°C. He underwent six courses of cyclophosphamide, adriamycin, vinctistine, and prednisolone and low-dose prednisolone up to July 2007. Due to worsening anemia with acrocyanosis, he was treated with rituximab alone at 375 mg/m four times every 8 weeks. Although the CAD-related symptoms were improved, the high-CA titers at 4°C remained. He relapsed 42 weeks after the initial treatment, and the duration to response was 10 months. After informed consent was obtained, we determined the agglutination titer and tested the thermal amplitude of the patient’s plasma and serum, as described previously [3]. As shown in Table 1, 4 weeks after the initial injection of rituximab, increases of hemoglobin and improvement of the thermal amplitude of the antibody were observed simultaneously. Up to 24 weeks later, the improvement of the thermal amplitude remained. Hemoglobin increased progressively up to 28 weeks. Based on the changes of the thermal range in reactivity of the antibody, the clinical sign(s), such as acrocyanosis, improved along with amelioration of the symptoms related to anemia. Temperatures of 30°C and lower normally occur in the superficial skin vessels of the parts of the body exposed to cold air or water. The thermal range of the antibody is more important than the agglutination titer for clinical symptoms [4]. The present findings suggested that both elevation of hemoglobin and resolution of clinical sign(s) are closely associated with improvement of thermal amplitude of the CA after rituximab treatment. The present case suggested that hemoglobin was elevated as a consequence of the improvement of thermal amplitude after rituximab treatment. Schoellkopf et al. observed a significant and persistent reduction of serum IgM concentration after rituximab Ann Hematol (2010) 89:103–104 DOI 10.1007/s00277-009-0773-z