Sustained Control of Hemolysis and Symptoms and Reduced Transfusion Requirements over a Period of 2 Years in Paroxysmal Nocturnal Hemoglobinuria (PNH) with Eculizumab Therapy.
Authors: Hill Anita , Elebute Dupe , Marsh Judith C. , Richards Stephen J. , McNutt Bruce , Petro Beth E. , Rother Russell P. , Hillmen Peter 
Published: April 2020

Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by intravascular hemolysis and venous thrombosis. Deficiency of the terminal complement inhibitor CD59 from PNH red cells results in complement-mediated hemolysis. Eculizumab, a humanized monoclonal antibody that inhibits terminal complement by binding to C5, is effective at controlling intravascular hemolysis in PNH. We now report that 10 of the 11 patients from an initial 3 month study have continued to receive 900mg eculizumab every other week for 2 years. The remaining patient stopped eculizumab after 23 months despite effective control of intravascular hemolysis, as the patient continued to be transfused even after erythropoietin therapy. This patient had the most severe hypoplasia at the start of eculizumab therapy with a platelet count below 30x109/l, suggesting that the ongoing transfusions were due to the bone marrow failure and not continuing hemolysis. Eculizumab was safe and well tolerated with two reported SAEs in the last year, neither of which were attributed to the drug. The dramatic improvement in various parameters of hemolysis persisted during the 2 year treatment period for all patients. Mean LDH levels decreased from 3111 +/− 598 U/L over the 12 months prior to treatment to 634 +/− 34 U/L up to 24 months following treatment (p=0.002). PNH red cells with a complete deficiency of GPI-linked proteins (Type III red cells) progressively increased during the treatment period from a mean of 36.7% to 58.9% (p=0.001) while partially deficient PNH red cells (Type II) increased from 5.3% to 8.7% (p=0.01). There has been no change in the proportion of PNH neutrophils in any of the patients during eculizumab therapy indicating that the increase in the proportion of PNH red cells is due to a reduction in hemolysis and transfusions rather than a change in the PNH clone(s) itself. The mean and median transfusion rates decreased from 2.1 and 1.8 units/patient/month to 0.4 and 0.3 units/patient/month respectively (p&lt;0.001). Three patients remained transfusion independent during the whole 2 year treatment period and the other 7 patients remaining on eculizumab all had at least a three-fold reduction in transfusion requirements. No patients have had a thrombosis during the study period, including 5 patients who were not on warfarin therapy. Prior to eculizumab, some patients suffered with abdominal pain, dysphagia and erectile dysfunction. Following the first dose of eculizumab there has been complete and sustained resolution of these symptoms. In addition, other symptoms related to hemolysis, such as lethargy, have shown a sustained marked improvement. These classical PNH symptoms have been attributed, at lease in part, to the release of free hemoglobin (Hb) during intravascular hemolysis which overwhelms the protective Hb scavenging mechanisms. Free Hb efficiently absorbs and depletes nitric oxide (NO) which is a critical regulator of smooth muscle contraction, vascular tone and platelet activation. The potential role of NO in the symptomologies of PNH are currently under investigation. In summary, we report that eculizumab is well tolerated and has persisting efficacy as demonstrated by decreased hemolysis and transfusions, as well as improvement in the symptoms of PNH, for over 2 years of therapy.