Heterogeneity and Peculiarities Of a Small Series Of Patients Affected By Paroxysmal Nocturnal Hemoglobinuria Treated With Eculizumab

Paroxysmal nocturnal hemoglobinuria (PNH) derives from a non malignant clonal expansion of hematopoietic stem cells (HSCs) harbouring somatic mutations of the X-linked PIG-A gene, leading to the complete or partial loss of glycosylphosphatidylinositol membrane-anchored proteins (GPI-APs) from the cell surface of the HSCs and of their mature progeny. The resulting intravascular hemolysis is caused by uncontrolled activation of the complement cascade and determines hemoglobinuria, anemia, fatigue, renal impairment, pulmonary hypertension, smooth muscle dystonias and thromboembolism, with a bad quality of life. Moreover PNH is usually embedded with a various degree of bone marrow (BM) failure syndromes, from mild cytopenias up to aplastic anemia.We describe 5 PNH patients: 3 males and 2 females; median age was 36 year (18-54). All developed PNH after other haematologic disorders. The first one was a rare case occurring after autologous stem cell transplantation(ASCT) for relapsing non-Hodgkin’s lymphoma; the second had experienced an aplastic anemia, successfully treated with immunosuppressive therapy; two were affected by anemia and thrombocytopenia of unspecified nature; in the fifth young patient (18 ys), hereditary spherocytosis had been diagnosed 2 years before, based on erythrocyte membrane protein analysis and splenectomy had been performed. All patients had strong intravascular hemolysis (reticulocytosis, elevated LDH, gross hemosiderinuria); the flow cytometry immunophenotyping study of GPI-APs expression on peripheral blood cells showed large cellular populations of erythrocytes, granulocytes and monocytes which had undetectable expression of GPI-APs, suggesting PNH. According to the previous hematological disorders or therapy (ASCT) in the mentioned series of patients, PNH occurred after 2, 5, 9, 1 and 2 years respectively. Three patients were transfusion dependent. After unsuccessful therapy with prednisone, folate and even cycles of steroid therapy, the terminal complement inhibitor eculizumab (EC) was started. All the patients received vaccination against Neisseria meningitides. EC was infused according to the standard schedule, 600 mg weekly for 4 weeks, followed by 900 mg every other week. EC was started respectively after 7 months, 24 months and 8 years from PNH diagnosis in the first three patients and after 4 months from PNH diagnosis in in the last 2 patients. The intravascular hemolysis was completely controlled in all patients. Only one patient continued but reduced erythrocyte transfusions; she shows significant extravascular hemolysis, building up GPI- C3d coated erythrocytes (DAT ++), and is candidate for splenectomy. Despite the different haematological response all 5 patients experienced a dramatic clinical improvement in the quality of life. In the transplant patient the cytometry showed a progressive reduction and ultimately extinction of the pathological clone; this provided the unique possibility to discontinue treatment after 12 months, then maintaining remission for some years. Probably in this case, EC did not play any direct role in the kinetics of the PNH clone, while the conditions which led to expansion of the clone were somehow unique and possibly related to the ASCT and resulted transient. Our small series, including even 2 rare cases (one pediatric PNH patient and one occurred after ASCT) shows how variable are the clinical and biological spectrum of manifestations in this strange and fascinating disease; moreover its clinical evolution in each single patient remains frequently unpredictable.