Paroxysmal nocturnal hemoglobinuria: A long-term single center experience

Introduction: paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disorder of haematopoietic cells characterized by a defect in the glycosylphosphatidylinositol (GPI) anchored molecules. It is characterized by the triad of hemolytic anemia, cytopenias and a high risk of venous thrombosis. In the last 10 years Eculizumab has been employed in the treatment of PNH. Considering the rarity of the disease, so far, related data are the result of multi-center studies. Herein we report the analysis of the largest long-term unicentric series of PNH patients. Patients and Methods: We performed a retrospective analysis in 42 patients (26 female/16 male) followed at our center between February 1985 and September 2016. Median age was 53 years (range 16-79.2). Since 1985 up to 2000 the diagnosis was made by HAM test; starting from 2000, patients were diagnosed by flow cytometry (FC) and the proportion of GPI-AP–deficient granulocytes by FC (clone size) was collected. Moreover, all patients previously diagnosed by Ham test we studied by CF, to confirm the diagnosis and evaluate clone size. During the decade 85-95, 11 patients were diagnosed; 12 during 96-2006; 19 in the last decade. At diagnosis 26 patients had classic PNH, 9 aplastic PNH and 7 intermediate form.1. Results: 30 yrs overall survival (OS) was 84%, censoring, at last follow up, 2 patients dead for non PNH related reasons. In univariate analysis absence of thrombotic events (96% vs 80%) and diagnosis performed during the last decade (100% vs 90% vs 75%) represents factors associated with a better OS, even if statistical significance was not reached. Cumulative incidence of thrombosis, pancytopenia or bicitopenia, and clonal neoplasm were 39%, 18% and 10%, respectively. Up to 2005 treatment options were mainly supportive including blood transfusion or allogenic bone marrow transplantation. Eculizumab was first introduced in 2005 in 4 patients included in Phase III trials (TRIUMPH and SHEPHERD)2, Than the drug has been employed in other 18 patients. Half of patients became transfusion independent, but with Hb level ranging between 8,5 and 11 gr/dl; complete remission was observed in 32%, 18% remained transfusions dependent. A reduction of LDH observed in all patients with improvement of asthenia; no thrombotic event was observed after eculizumab, even if 9 out of 22 patients had recurrent thromboembolisms before the drug. No severe infection were diagnosed, nor renal failure or pulmonary hypertention. One patient developed extravascular hemolysis and receive a succesfully selective splenic artery embolization (SSAE)3 .Ten years OS in Eculizuman group was 92%. No death was due to PNH reason. Discussion: Our unicentric study confirms thrombosis as major complication in PNH patients, and as an important factor influencing OS. We can speculate that the better OS in last decade is due to the use of Eculizumab that reduced thrombotic events. In particular, for patients on eculizumab the curve of OS was 92% at 10 years, even if patients with previous thromboembolism and diagnosis performed before the last decade have been included in this group. Although kidney failure and lung hypertension have been reported in some experiences, we did not observed these complications on a long follow up. We can assume that the availability of a dedicated emergency room allows to perform, promptly, hyper-hydration or transfusion support in case of hemoglobinuric crisis, reducing the risk or organ damage. No infection have been described in our patients. Considering the risk of meningococcus infection we perform a double vaccination with conjugated anti-meningococcus (serotypes ACWY) at least 2 weeks prior to administering the first dose of eculizumab (according by drug schedule) and 2 months after. Moreover, we add Meningococcus B vaccination 3-4 weeks after first dose of drug. However a guideline for vaccination schedule needs to be defined by scientific society.