Safety and efficacy of the terminal complement inhibitor eculizumab in Japanese patients with paroxysmal nocturnal hemoglobinuria: the AEGIS Clinical Trial

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a progressive and life-threatening disease characterized by complement-mediated chronic hemolysis, resulting in serious life-threatening complications and early mortality. Eculizumab, a humanized anti-C5 monoclonal antibody that inhibits terminal complement activation, has been shown to reduce hemolysis in PNH patients. The pivotal open-label, 12-week phase II registration study (AEGIS) was designed to evaluate the efficacy and safety of eculizumab in Japanese patients with PNH. This trial achieved its primary endpoint of reducing intravascular hemolysis with high statistical significance. Twenty-seven of the 29 patients responded to eculizumab treatment, resulting in an 87% reduction in hemolysis (P < 0.0001) and subsequent improvement in anemia (P = 0.0003) despite reduction in transfusion requirements (P = 0.006). Fatigue and dyspnea significantly improved within 1-2 weeks of eculizumab treatment and the improvement was independent of changes in hemoglobin. Chronic kidney disease (CKD) was common (66%) and eculizumab treatment improved CKD in 41% of patients at 12 weeks (P < 0.001). Elevated thrombotic risk was evident in Japanese PNH patients and eculizumab treatment normalized D: -dimer levels in 45% of patients with elevated D: -dimers at baseline (P < 0.001). The AEGIS results demonstrate that eculizumab is effective, safe and well tolerated in Japanese patients with PNH.

Racial Differences in Paroxysmal Nocturnal Hemoglobinuria Thrombosis and Glycosylphosphatidylinositol-Deficient Granulocytes

“…Of note, the racial differences disappeared when assembling PNH patients with a total leukocyte count ≥3.0x10 8 /l among patients showing evident hemolysis with more than 50% PNH granulocytes ( Figure 1D). Taken together, although hemolysis contributes to the incidence of PNH thrombosis (data not shown), which supports the allegedly identical amelioration of PNH thrombosis after the administration of eculizumab [1,3], it is no longer regarded as a major cause of racial differences ( Figure 1C). Of interest, racial differences were detected among patients with a total leukocyte count <3.0x10 8 /l containing more than 50% PNH clones ( Figure 1D), which implies that underlying factors such as genetic conditions are involved in conventional thrombus formation, even in PNH patients, because these factors make PNH thrombosis likely to be less affected by a possible specific feature of PNH granulocytes and hemolysis.…”

“…Eculizumab, an inhibitor of terminal complement C5, provides patients with PNH with a good quality of life by ameliorating hemolysis and thrombosis, and promotes a better understanding of the complement-mediated molecular pathophysiology of PNH [1][2][3]. However, the underlying reasons for distinct differences in the incidences of thrombosis and bone marrow failure between Caucasian and Asian patients with PNH are still unknown (West vs. Japan, 32% vs. 4%) [4].…”

“…In contrast to thrombosis, cytopenias are more common in Japanese PNH patients than in those in the United States [4]. Based on this background, we attempted to elucidate a plausible link between marrow failure-associated leukocytopenia and the infrequent complication of thrombosis in Japanese PNH patients by analyzing data obtained from our own PNH patients and previous findings [1][2][3][6][7][8][9][10]. We also investigated the reasons for racial differences using GPI-deficient (PNH) granulocyte counts in PNH thrombosis.…”

Polymorphism of the complement receptor 1 gene correlates with the hematologic response to eculizumab in patients with paroxysmal nocturnal hemoglobinuria

“…1,2 Eculizumab effectively controls intravascular hemolysis and its direct consequences in PNH patients, which results in remarkable clinical improvement. 1,3 The natural history of the disease, which had already improved before the introduction of eculizumab (compare the data reported by Hillmen et al, 1995 4 with those reported by de Latour et al, 2008 5 ), may have improved further with the use of this agent. 6 However, the hematologic response to eculizumab is variable.…”

A mini-review on paroxysmal nocturnal hemoglobinuria and a case of Eculizumab treatment of PNH in elderly MDS patient

“…However, HSCT is known to produce high complication rates, mortality, and is performed only for certain indications in cases of hematopoietic aplasia [4,13].…”