Incidence and outcome of severe complications in patients with paroxysmal nocturnal hemoglobinuria: A real life scenario from a single center 30 years experience

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal non-neoplastic hematopoietic stem cell disease whose incidence is 1.5-2.9 cases/million of indivi- duals worldwide. Disease characteristics and natural history have been mostly analyzed by multicenter, retrospective studies, with the limit of heterogeneous approaches. Herein we report the incidence of severe complications and out- come in a real life setting scenario of PNH patients con- secutively diagnosed and managed at our PNH referral Center between January 1985 and June 2018. Methods: Patients received a homogeneous diagnostic and treatment approach according to the period of observation (availability of diagnostic tests and eculizu- mab). All patients treated with eculizumab received vaccination with conjugated anti-meningococcus ACWY- serotypes and, since 2016, conjugated anti-meningococcus B-serotype. In the event of any complication, patients could refer to dedicated Hematology Emergency Rooms (ER) 24 hours daily. The occurrence of renal failure and pulmonary hypertension was specifically evaluated. The renal function was studied according to the Cockcroft-Gault formula and the lung function was prospectively monitored by daytime-on exertion, nocturnal pulsoximetric profiles and complete spirometric tests, with DLCO measurement. Results: Overall,48 PNH patients, median age 36 years (range 17-84), were analyzed. At diagnosis, 26 patients had classic PNH, 19 aplastic PNH and 3 an intermediate form. The cumulative incidences (CI) of thrombosis, and clonal hematologic neoplasm were 29%, and 6%, respectively. CI of pancytopenia in the 26 patients with classic PNH was 23%. One patient showed a spontaneous disappearance of the PNH clone. Since 2005, eculizumab was administered in 28 patients. After eculizumab treatment 50% and 32% of patients reached hemoglobin level > 11g/dL and >8< 11g/ dL without transfusion, respectively, while 18% were non- responsive. During eculizumab treatment no thrombotic event was observed while two severe infectious episodes (respiratory tract and urinary tract infection) were observed in only one of the 28 patients. Extravascular hemolysis was demonstrated in 50% of patients. No patient showed a significant reduction of the renal function.Out of 24 patients prospectively monitored for lung function no pathological alteration in any diurnal or nocturnal pulseoximetric test was observed. No patient showed obstructive or restrictive ventilatory deficiency, nor reduced DLCO values. 30-years overall survival (OS) was 90% (4 patients who died for non- PNH related reasons were censored at the last follow-up).A better OS, even if not statistically significant,was associated to the absence of thrombotic events (90%vs70%), and the period of diagnosis (100% in 2006-2018, 91% in 1996- 2005, 75% in 1985-1995). Conclusions: Our study reports a better OS and lower rate of severe complications in PNH compared to previous experiences. Although renal failure and lung hypertension have been reported by other groups, we did not observe these complications along a prolonged follow-up. We can assume that the availability of a dedicated ER service enabled an early diagnosis and prompt treatment in case of hemoglobinuria crises (reducing the risk or organ damage) or other complications. The use of eculizumab, together with improved supportive approaches, presumably accounts for the trend towards a better survival witnessed over the last decade in the management of PNH patients.