Eculizumab in the management of paroxysmal nocturnal hemoglobinuria: patient selection and special considerations

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant clonal disorder resulting from somatic mutation in the PIG-A gene leading to a deficiency of the membrane-anchoring molecule glycosylphosphatidylinositol. The lack of expression of two glycosylphosphatidylinositol-anchored proteins involved in the regulation of the complement system renders PNH erythrocytes susceptible to complement-mediated lysis. Clinical manifestations include thromboembolic disease, chronic kidney injury, pulmonary hypertension, smooth muscle dysfunction, and chronic hemolysis. Until recently, treatment was mainly supportive with most patients suffering from significant morbidity and shortened survival compared to age-matched controls. The development of eculizumab, a humanized monoclonal antibody directed against the terminal complement protein C5, has resulted in dramatic improvements of survival and reduction in complications. In this paper, we review some special considerations pertaining to the use of eculizumab for PNH.

Paroxysmal nocturnal hemoglobinuria (PNH): An atypical case report

“…[2][3][4][5][6] Effectively the frequency of hemolytic crises is in direct relation to PGI clone size and LDH serum levels. Ecuzulimab (Eculizumab ; Solirix R, Alexion Pharmaceuticals), [6][7][8][9] a humanized monoclonal antibody recently developed is able to block specifically terminal activation of the complement cascade at the C5 level. Prevention of C5 clivage will block C5a induction, a pro-inflammatory molecule, and C5b, initial substrate for erythrocytes cell membrane attacking complexes.…”

“…Despite individual variations, ecuzulimab will improve patients quality of life by reducing almost completely intravascular hemolysis. [7][8][9] Actual diagnosis of PNH, relies on flow cytometry determination of CD55 and CD59 markers at the erythrocyte membrane. Another interesting marker is the FLAER (fluorescentlabeled proaerolysin).…”

“…[3,5,10] These will release Willebrand and VIII factors and express inhibitors of tissular factor and plasminogen activator. [6][7][8][9] A third component of the PNH syndrome tripod is medullary insufficiency, affecting 48% of patients. [3,5,10] Its physiopathology seems to be complex, 2 phenomenons being necessary to obtain bone marrow aplasia.…”

“…Hemolysis was moderate (normal LDH levels), thus ecuzulimab was not retained, as targeted monoclonal antibody. [6][7][8][9][10] In fact clinical presentation was dominated by a progressive medullary failure requiring some transfusional supports before allograft.…”

Therapeutic challenges in pregnant women with paroxysmal nocturnal hemoglobinuria

“…Paroxysmal nocturnal hemoglobinuria (PNH), a rare and acquired hemolytic anemia, is caused by an alteration of hematopoietic stem cells resulting from a somatic mutation in the PIGA gene. [ 1 , 6 ] This gene is involved in the synthesis of glycosylphosphatidylinositol (GPI), an anchor for various membrane proteins, such as the CD55 (complement decay-accelerating factor) and CD59 (membrane inhibitor of reactive lysis), which are regulators of the complement system. [ 1 – 4 , 6 , 7 ] GPI deficiency in PNH results in multiple proteins not being expressed on the cell surface, making the cells exceptionally susceptible to the lytic effects of the complement system.…”