Eculizumab in cold agglutinin disease (DECADE): an open-label, prospective, bicentric, nonrandomized phase 2 trial

Abstract

Cold agglutinin disease (CAD) is a complement-dependent disorder, with extravascular and intravascular hemolysis resulting from initial or terminal complement activation, respectively. We tested the efficacy and safety of eculizumab, an inhibitor of the terminal complement pathway. Treatment-requiring patients received 600 mg eculizumab weekly for 4 weeks, followed 1 week later by 900 mg every other week through week 26. The primary end point was the difference in the lactate dehydrogenase level between the first and the last day of therapy. Twelve patients with chronic CAD and 1 patient with an acute cold agglutinin syndrome were included. The median lactate dehydrogenase level decreased from 572 U/L (interquartile range [IQR], 534-685) to 334 U/L (IQR, 243-567; P = .0215), paralleled by an increase in hemoglobin from 9.35 g/dL (IQR, 8.80-10.80) to 10.15 g/dL (IQR, 9.00-11.35; P = .0391; Wilcoxon signed-rank test). Three patients maintained and 8 patients acquired transfusion independence, and 1 patient each showed a reduced or increased transfusion requirement, respectively (P = .0215; exact McNemar’s test). Patients with cold agglutinins with a thermal amplitude of 37°C tended to have less pronounced lactate dehydrogenase responses than patients with cold agglutinins with narrower thermal amplitudes. In the latter, responses were observed at lower serum levels of eculizumab than they were in the former. In contrast to hemolysis, cold-induced circulatory symptoms remained unaffected. In conclusion, eculizumab significantly reduced hemolysis and transfusion requirement in patients with CAD. Suppression of hemolysis caused by cold agglutinins with a wide thermal amplitude may require higher eculizumab doses than used here. The trial is registered with EudraCT (#2009-016966-97) and www.clinicaltrials.gov (#NCT01303952).

<p>Cold agglutinin disease: current challenges and future prospects</p>

“…20,49 The occurrence of hemoglobinuria in about 15% of the patients 4 and the rather frequent finding of hemosiderinuria 29 support this notion, as does the beneficial effect of C5 inhibition with eculizumab. 20,26,49,50 Due to continuous consumption, most patients have low C3 and C4 serum levels, which is probably rate-limiting for the complement-mediated hemolysis. 12,25 During febrile infections and following major surgery or major trauma, acute phase reaction will increase the production of complement proteins.…”

“…3 Less typical clinical features include gangrene, which is uncommon, and cutaneous disorders, sometimes described as livedo reticularis and sometimes as livedo racemosa. 20,27,28 Such atypical vascular manifestations should warrant the exclusion of cryoglobulinemia as a differential diagnosis or a concomitant property of the cold-reactive IgM. 3,27,29…”

“…16,18,48 The absence, or at least modest role, of terminal pathway activation in stable patients can probably be attributed to the protective effect of CD55 and CD59, which, unlike in paroxysmal nocturnal hemoglobinuria (PNH), are intact in CAD. 16,20 At least in some patients and situations, however, C3 is supposed to initiate the terminal complement cascade by binding and splitting C5, resulting in the formation of the C5b-9 complex (membrane attack complex) and intravascular hemolysis. 20,49 The occurrence of hemoglobinuria in about 15% of the patients 4 and the rather frequent finding of hemosiderinuria 29 support this notion, as does the beneficial effect of C5 inhibition with eculizumab.…”

“…16,20 At least in some patients and situations, however, C3 is supposed to initiate the terminal complement cascade by binding and splitting C5, resulting in the formation of the C5b-9 complex (membrane attack complex) and intravascular hemolysis. 20,49 The occurrence of hemoglobinuria in about 15% of the patients 4 and the rather frequent finding of hemosiderinuria 29 support this notion, as does the beneficial effect of C5 inhibition with eculizumab. 20,26,49,50 Due to continuous consumption, most patients have low C3 and C4 serum levels, which is probably rate-limiting for the complement-mediated hemolysis.…”

“…3,[12][13][14][15] Complement activation via the classical pathway is essential for subsequent hemolysis. [16][17][18][19][20][21] Recent advances in CAD include the demonstration of a distinct clonal B-cell LPD, the documentation of effective B-cell-directed therapies, and the development of novel complement-directed therapies. This review will focus on these achievements, which also raise some challenges.…”