Failure of eculizumab to correct paroxysmal cold hemoglobinuria

Abstract

Dear Editor, Paroxysmal cold hemoglobinuria (PCH) is a rare cause of intravascular hemolytic anemia in which an antibody against the P antigen develops and hemolysis ensues via a pathway involving thermally dependent complement binding. Previously an association of syphilis due to crossreactivity of antibody, PCH has since predominantly become a disease of childhood following varicella-zoster virus infection. The childhood form is typically acute, selflimiting, and steroid-responsive. Rare cases of PCH in adults have been described in association with chronic lymphocytic leukemia and lymphoma but never previously with myeloma [1]. We describe a case of steroid-refractory PCH in a patient with myeloma that was only partially corrected with eculizumab, a monoclonal antibody against C5 complement. A 51-year-old Nigerian man with Stage III ISS IgA kappa multiple myeloma in very good partial response following treatment with bortezomib, thalidomide, cyclophosphamide, and dexamethasone was admitted to our hospital with severe hemolytic anemia. At admission, lactate dehydrogenase (LDH) was elevated at 543 U/L (100–200 U/L); bilirubin, 164 μmol/L (<20 μmol/L); and hemoglobin was 60 g/L (125–175 g/L). Initial transfusion requirement were 2 to 4 U of red blood cells per day to achieve a target hemoglobin 60–80 g/L. PCH was diagnosed with the Donath–Landsteiner test following positive urinary hemosiderin on day 21 of admission. No complement C3 was detected on his red cells at diagnosis. Blood film was significant for rosette formation of erythrocytes around neutrophils and erythrophagocytosis by neutrophils (Fig. 1). Syphilis serology and cerebrospinal fluid treponemal PCR were negative. Being refractory to oral prednisolone and cyclophosphamide (1 g/m), he received standard induction with eculizumab 600 mg weekly for 4 weeks [2]. Urinary hemosiderin became negative by day 36; however, hemolysis continued albeit at reduced rate, and was finally controlled following a single dose of intravenous cyclophosphamide 4 g/m. The patient became transfusionindependent 31 days post high-dose cyclophosphamide and hemoglobin returned to normal reference range (136 g/L) at 10 weeks, with normalization of LDH at 9 weeks. This is the first reported case of eculizumab use for treatment of PCH. Failure of eculizumab to control hemolysis in this patient suggests that extravascular clearance of red cells in PCH may be induced by earlier components of complement and opsonization with anti-P antibodies. Moreover, the observation of neutrophil erythG. P. Gregory (*) : S. Opat :H. Quach : J. Shortt :H. Tran Department of Clinical Hematology, Monash Medical Centre, Clayton, VIC, Australia e-mail: g.gregory@alfred.org.au