KINETIC PARAMETERS OF COMPLEMENT ACTIVATION IN PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA DURING ECULIZUMAB THERAPY

Introduction. Eculizumab inhibits the terminal steps of complement activation and is the standard treatment for paroxysmal nocturnal hemoglobinuria (PNH). Unstable complement inhibition causes "breakthrough" intravascular hemolysis and a suboptimal response to eculizumab therapy in some patients with PNH. Aim: to evaluate the stability of complement inhibition in eculizumab treatment by testing the kinetic parameters of complement activation. Materials and methods. The study included 12 PNH patients receiving long-term eculizumab therapy (median 54 months, range 4-66 months). The median age was 35 years (from 22 to 68 years), 92% of patients were female. The median PNH clone size was 96 % of the granulocytes. The control group consisted of 12 healthy donors (age 25-60 years, women 75%). Complement activation was evaluated immediately prior to the next eculizumab infusion, and then again after 5 and 10 days. Kinetic parameters (induction period, hemolysis rate, T50-the time required to achieve 50 % hemolysis) were recorded separately for the total complement activity and an alternative activation pathway using rabbit red blood cells (rRBC). Results. The parameters of complement activation directly before the next eculizumab administration corresponded to a marked inhibition of the overall activity of the system. The induction period was extended by 7 times compared to the control (median 180 vs 25 seconds, p < 0.0001), and the hemolysis rate was 28 times less (median 1.6 vs 45.1 x 10(6) rRBC/min, p < 0.0001). The T50 value exceeded the control value by 20 times (median 690 vs 35 seconds, p < 0.0001). The parameters of the alternative complement activation pathway were reduced by 2-3 times compared to the control. In one case, repeated tests revealed insufficient complement inhibition, which was associated with pharmacokinetic "breakthrough" hemolysis. The degree of further complement inhibition and the tendency to restore activity varied significantly during dynamic testing on days 5 and 10 after eculizumab infusion. Conclusion. The results of this study demonstrate individual differences in the residual activity of complement in PNH patients receiving long-term eculizumab therapy. Testing of complement activity is necessary with a suboptimal response to eculizumab therapy and when considering therapy correction. Kinetic registration of residual complement-dependent lysis of rabbit red blood cells demonstrates a higher sensitivity than the traditional CH50 study.