Treatment with the Terminal Complement Inhibitor Eculizumab Improves Anemia in Patients with Paroxysmal Nocturnal Hemoglobinuria: Phase III Triumph Study Results.
Authors: Schubert Jörg , Hillmen Peter , Dührsen Ulrich , Young Neal S. , Elebute Modupe , Szer Jeffrey , Gianfaldoni Giacomo , Socié Gérard , Browne Paul , Mojcik Christopher F. , Rother Russell P. , Muus Petra 
Published: April 2020

Paroxysmal nocturnal hemoglobinuria (PNH) is a potentially life-threatening acquired hemolytic anemia in which red blood cells (RBCs) lacking complement inhibitory proteins are sensitive to complement-mediated destruction or hemolysis. Intravascular hemolysis in these patients often results in the need for clinical support with packed RBCs (PRBCs) in order to maintain tolerable hemoglobin levels. Eculizumab, a terminal complement inhibitor, has recently been shown in a placebo-controlled randomized phase III clinical trial (TRIUMPH) to reduce intravascular hemolysis and transfusion requirements in patients with PNH. Reported here is a detailed analysis of the effect of eculizumab on various parameters of anemia in these study patients. Eculizumab-treated patients, as compared to placebo, showed an 85.8% decrease in intravascular hemolysis (as measured by LDH area under the curve, p&lt;0.001). This reduction in hemolysis with eculizumab resulted in a 2.5-fold increase in PNH RBC mass from a median of 0.81x1012 cells/L at baseline to 2.05x1012 cells/L at 26 weeks (p&lt;0.001), while the PNH RBC mass in placebo-treated patients remained relatively unchanged (from a median of 1.09x1012 cells/L to 1.16x1012 cells/L). The increase in PNH RBC mass was associated with an increase in hemoglobin levels in eculizumab-treated patients relative to placebo (p&lt;0.001). The number of PRBC units transfused decreased from a median of 10.0/patient with placebo to 0.0/patient with eculizumab (p&lt;0.001), and 51.2% of eculizumab-treated patients became transfusion independent (versus 0.0% of placebo patients, p&lt;0.001). Even patients who required some transfusions while on eculizumab showed a marked reduction in transfusion requirement from a median of 10.0 units per patient with placebo to 6.0 units/patient with eculizumab (p&lt;0.001). The reduction in PRBC units transfused with eculizumab was observed regardless of transfusion requirements prior to treatment, with statistical significance reached in 3 of 3 pre-treatment transfusion strata (4 to 14 units/year; 15–25 units/year; and &gt;25 units/year, p&lt;0.001 for each stratum). Significant reductions were observed in intravascular hemolysis (LDH) in eculizumab-treated patients that achieved transfusion independence (p&lt;0.001) as well as those that did not (p&lt;0.001). Taken together, these data demonstrate that effective control of intravascular hemolysis in PNH with eculizumab results in a substantial improvement in anemia, as evidenced by an increase in endogenous RBC mass, an improvement in hemoglobin levels, and a reduction in transfusion requirements. Substantial and significant reductions in intravascular hemolysis and improvements in anemia with eculizumab are demonstrated regardless of historical transfusion requirements or whether patients achieve transfusion independence during treatment.