The Terminal Complement Inhibitor Eculizumab Reduces Thrombosis in Patients with Paroxysmal Nocturnal Hemoglobinuria.
Authors: Hillmen Peter , Muus Petra , Dührsen Ulrich , Risitano Antonio M. , Schubert Jörg , Young Neal S. , Schrezenmeier Hubert , Szer Jeffrey , Brodsky Robert A. , Hill Anita , Socié Gérard , Rollins Scott A. , Rother Russell P. , Bell Leonard , Luzzatto Lucio 
Published: April 2020

Life-threatening thromboembolism (TE) is the most feared complication in patients with paroxysmal nocturnal hemoglobinuria (PNH). Thrombophilia in PNH likely involves a hypercoagulable state, possibly due to intravascular hemolysis with scavenging of the coagulation regulator nitric oxide, and platelet activation. Approximately 45% of PNH deaths result from TE. Thrombosis is more frequent in patients with larger PNH clones, but can occur in patients with smaller clones. Primary prophylactic anti-coagulation may reduce the thrombotic risk in PNH patients, although controlled studies have not been performed and there is a known serious hemorrhage risk. A randomized, placebo-controlled, 26-week phase 3 study of the terminal complement inhibitor eculizumab in 87 PNH patients (TRIUMPH) recently demonstrated dramatic reductions in intravascular hemolysis and RBC transfusions; 1 TE was reported with placebo and 0 with eculizumab. This single study was not powered to examine the effect of eculizumab on TE, and we prospectively examined the aggregate TE event rate in eculizumab-treated patients from TRIUMPH, the two other PNH trials, and the subsequent phase 3 extension study as compared to each patient’s pre-treatment event rate. Before receiving eculizumab, examination of patient records identified 126 TE events in 195 patients, and 103 were on anticoagulants. While pre-treatment TE event rates were variable in the 3 individual PNH studies, eculizumab reduced TE in each study. The TE event rate with eculizumab treatment was 1.22 per 100 patient years, compared to 7.49 (p&lt;0.001) in the same patients before eculizumab treatment, corresponding to a reduction of 84% (2 events with eculizumab vs. 12.3 events expected). Sensitivity analyses showed the effect to be robust. With restriction of the pre-treatment observation period to the 12-months immediately before initiation of the trials, the TE event rate with eculizumab was reduced 93% from 17.21 to 1.22, respectively (p=0.013). The TE event rate was reduced from 21.95 pre-treatment in patients with TE prior to the trials (n=63) to 3.42 during eculizumab treatment (p&lt;0.001). Most TE events prior to eculizumab treatment occurred in patients receiving anti-coagulants, indicating that this therapy may be insufficient to prevent thrombosis. Of 103 patients on anticoagulants, there were 54 TE events in 30 patients over 385.73 patient years (14.00/100 patient years) pre-eculizumab compared to no TE events with eculizumab in 101 patient years (0.0/100 patient years; p&lt;0.001), demonstrating that eculizumab reduces the risk of thrombosis in anticoagulated, highly thrombophilic PNH patients. These data show that long-term eculizumab treatment results in a clinically and statistically significant reduction in thrombosis in patients with PNH.