Long-term efficacy of the complement inhibitor eculizumab in cold agglutinin disease

To the editor:

Cold agglutinin disease (CAD) is characterized by immunoglobulin M (IgM)–mediated hemagglutination and robust complement activation leading to intravascular hemolysis and hemolysis-related symptoms including anemia, fatigue, dyspnea, hemoglobinuria, and acrocyanosis.^1-6  Although CAD can have a mild course, it may be life-threatening, and its chronic nature leads to transfusion dependence in approximately 50% of cases.⁷  Conventional approaches are largely ineffective in controlling hemolysis in patients with CAD.^2,4,7 

Eculizumab (Soliris; Alexion Pharmaceuticals, Cheshire, CT) is a monoclonal antibody that targets complement protein C5 and prevents the cytolytic and proinflammatory effects of complement activation.^8,9  Eculizumab dramatically reduces intravascular hemolysis thereby improving fatigue, anemia, dyspnea, and quality of life and reducing thrombotic events and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria (PNH), a rare form of hemolytic anemia.^6,10,11  Here we report the efficacy of an off-label use of eculizumab in a transfusion-dependent patient with CAD.

A 66-year-old male was diagnosed with CAD in 2001 after experiencing progressive dyspnea and fatigue. Laboratory tests revealed anemia (hemoglobin 10.8 g/dL), increased hemolysis (lactate dehydrogenase [LDH] 438 U/L, bilirubin 4.0 mg/dL) and a monoclonal IgM κ antibody with a cold agglutinin titer of >1:2000. Bone marrow biopsy showed increased erythropoiesis and a minor infiltration by a light chain restricted B-cell population without evidence of lymphoma. The patient was unresponsive to prednisone (1 mg/kg with consecutive reductions over 3 months) and subsequently received 5 courses of rituximab (375 mg/m² weekly for 4 cycles). After an initial response to rituximab, the patient became refractory during additional administrations between 2004 and 2006, and failed treatment with intravenous immunoglobulins in early 2007. Eculizumab therapy was initiated in June 2007 after hemolysis and transfusion requirements increased with frequent episodes of angina pectoris due to concomitant coronary artery disease. As instructed in the prescribing information, the patient was vaccinated against Neisseria meningitidis 14 days before receiving the first dose of eculizumab.

Eculizumab was dosed at 600 mg intravenously every 7 days for 4 weeks, at 900 mg 7 days later, and then chronically at 900 mg every 14 days.¹²  Although detectable cold agglutinins persisted during treatment, hemolysis was significantly reduced as demonstrated by a reduction in levels of serum LDH from a mean of 850 (± 159) U/L in the year before treatment to 456 (± 44) U/L in the year after initiation of eculizumab (normal range, 100-247 U/L; Figure 1). Reduction in chronic hemolysis resulted in an improvement of anemia from a mean hemoglobin level of 9.8 g/dL and transfusion dependence (18 units) before treatment to a hemoglobin of 11.7 g/dL and transfusion independence (0 units) in the year after initiation of eculizumab treatment. Ferritin levels decreased from 666 (± 71) μg/L to 311 (± 26) μg/L (normal range, 20-290 μg/L). The patient reported having “a new active life” with a major improvement in fatigue and quality of life; tolerance to cold weather and temperatures has improved dramatically with no further hemolytic crises or episodes of angina pectoris. Thus far, eculizumab treatment has been continued for 18 months and has been well tolerated.

This is the first report of a clinical response to the complement inhibitor eculizumab in a patient with CAD. Continuous therapy with eculizumab resulted in sustained reduction in hemolysis, elimination of transfusion requirements, and improvement in anemia, fatigue, and overall quality of life. Importantly, since the initiation of eculizumab treatment, hemolysis has been controlled with no exacerbations of the disease. These results provide a rationale for a prospective study of eculizumab in patients with CAD.