The Effect of Eculizumab Therapy on Red Cell Response Kinetics in Patients with Paroxysmal Nocturnal Hemoglobinuria.
Authors: Richards Stephen J. , Cullen Matthew J. , Dickinson Anita J. , Hill Anita , Buchanon David , Arnold Louise , Elebute Modupe , Rother Russell P. , Hillmen Peter 
Published: April 2020

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by clonal expansion of PNH red cells that are highly sensitive to lysis by terminal complement. The primary lesion in PNH is bone marrow failure in the form of immune-mediated aplastic anemia and peripheral blood cytopenias of varying severity. We have previously reported the successful control of hemolysis and transfusion in 11 patients with the terminal complement inhibitor eculizumab. Ten of these 11 patients remain on eculizumab therapy after approximately 3 years with maintained reductions in intravascular hemolysis and transfusion. The effectiveness of eculizumab therapy in these patients is through the protection of the PNH red cell from complement-mediated lysis and the expansion of this cell population. Flow cytometry studies have shown that the percentage of PNH red cells increased significantly from a mean of 36.7% before treatment to 58.4% at week 64 of therapy. Importantly, granulocyte, monocyte and platelet PNH clone sizes were &gt;90% before treatment and remained stable for all patients throughout the trial suggesting that the majority of hematopoiesis is derived from PNH stem cells. We hypothesize that the PNH red cell clone should approach the clone size of other myeloid hematopoietic cells in a given patient when hemolysis is prevented by eculizumab therapy as this more accurately depicts PNH stem cell activity. Furthermore, the magnitude and rapidity of response in terms of absolute red cell counts is unknown and could potentially provide important insights into the pathophysiology of PNH. In all patients hemolysis was substantially reduced by 21 days. In 9/11 patients, there was a rapid rise in PNH red cell count with the mean absolute number of PNH red cells increasing from 1.37 x 1012/L before treatment to 1.50 x 1012/L at 2 weeks (P=0.21), 1.74 x 1012/L at 4 weeks (P=0.002), and 2.11 x 1012/L at 12 weeks (P=0.001) of eculizumab treatment. The maximum theoretical red cell response was achieved in a mean of 178 days (range 49 – 419 days). The mean absolute number of PNH red cells increased to 2.37 x 1012/L at maximum response (P=0.001), an increase of 73% (range 36% – 207%). All patients achieved a maximum response prior to 18 months of treatment and clone size was subsequently stable. In 2 patients, despite the effectiveness of eculizumab in resolving hemolysis, there was no change in absolute numbers of PNH red cells pre and post-treatment. This is likely due to a combination of a lower degree of hemolysis and more profound bone marrow insufficiency in these patients. The determination of absolute PNH red cell counts during the first 12 months of eculizumab therapy may identify which patients will become transfusion independent and which patients may benefit from additional growth factor support to boost erythropoiesis. Furthermore, long-term eculizumab therapy appeared to be associated with a stable PNH red cell clone size in this initial clinical study.