Long-term response of refractory primary cold agglutinin disease to eculizumab therapy

Abstract

Dear Editor,Cold agglutinin disease (CAD) is an autoimmune hemolyticanemia where cold agglutinins (IgM antibodies) are respon-sible for triggering hemolysis. Primary CAD is character-ized by absence of associated autoimmune disease, under-lying infection, or malignancy [1]. Although treatment forlow-grade hemolysis is not needed, development of severehemolysis with clinical symptoms can occur. To date, treat-ment modalities for CAD have been limited to rituximaband alkylating agents [2–4].Here, we report the first case of refractory CAD withpolyclonal antibodies where a sustained long-term responseto eculizumab was observed. A 61-year-old womanpresented in October 2003 with jaundice, dyspnea, andfatigue. Laboratory results revealed: hemoglobin, 9.4 g/dL;reticulocyte count, 2.7 %; total bilirubin, 6.6 mg/dL; andlactate dehydrogenase, 681 IU/L. A strong cold agglutininwas identified at room temperature which dispersed withwarming to 37 °C. Direct Coombs test was positive forpolyspecific anti-serum for anti-C3d antibody indicatingIgM binding. The cold agglutination titer was 1:5,120.Immunofixation demonstrated clonal IgM immunoglobu-lins. Comprehensive work up for other viral, autoimmune,and neoplastic etiologies wasnegative.Thepatientwasdiagnosed with primary CAD and received one course ofrituximab in 2004 with no response. In December 2008, shedeveloped worsening hemolysis with transfusion depen-dence. She received steroids and emergent plasmapheresisfor two acute hemolytic episodes and was then treated withcyclosporine followed by chlorambucil with minimal effect.In June 2009, she initiated treatment with the terminalcomplement inhibitor, eculizumab, dosed at 600 mg onceweekly for 4 weeks followed by 900 mg every 2 weeks formaintenance. The degree of hemolysis (as measured by totalbilirubin and hemoglobin levels) and fatigue symptomsimproved dramatically with no noticeable side effects(Fig. 1). To date, the patient has remained transfusion inde-pendent on eculizumab for almost 4 years with evidence ofcontinuing chronic low-grade hemolysis despite a recentincrease in maintenance eculizumab dose to 1,200 mg every2 weeks.Primary CAD with polyclonal antibodies is a rare find-ing and may be associated with more refractory disease.Cold agglutinins trigger hemolysis via C3 complementleading to extravascular hemolysis [5]. Eculizumab(Soliris) is a terminal complement inhibitor antibody thatspecifically binds to the C5 complement protein, therebyinhibiting the formation of membrane attack complex andpreventing intravascular hemolysis in paroxysmal nocturnalhemoglobinuria. Although C5 activation is believed tohave only a minor role in CAD, Roth et al. previouslyreported the efficacy of eculizumab in a single patient withtransfusion-dependent refractory CAD associated withmonoclonal antibody and lasting up to 18 months [6, 7].Our report of sustained benefit following eculizumab ther-apy in polyclonal antibody-associated CAD for 43 monthsconfirms this response. Our observation also challenges thecurrent knowledge of pathogenesis in CAD, implicating a