Effect of Eculizumab on Physician-Reported Symptoms in the Russian Cohort of the Paroxysmal Nocturnal Hemoglobinuria (PNH) International Registry
Authors: Lisukov Igor , Kulagin Alexander , Maschan Alexey , Shilova Elena , Abdulkadyrov Kudrat , Zaritskiy Andrey , Ivanova Valentina , Bogdanova Yulia , Volkova Svetlana , Gavrilenko Andrey , Kaporskaya Tatyana , Meresiy Sergey , Schneider Tatyana , Yakupova Svetlana , Anchukova Ludmila , Bakirov Bulat , Kosacheva Natalia , Krinitsina Tatiana , Ustyantseva Viktoria , Shatokhin Yuriy , Vinogradova Elena , Kazankova Tatiana , Rumyantsev Alexander , Afanasyev Boris 
Published: October 2019

Abstract
Background: Paroxysmal nocturnal hemoglobinuria is a rare clonal hematopoietic stem cell disease that can lead to life-threatening complications including thrombotic events (TE), chronic kidney disease (CKD) and pulmonary hypertension. In 2011 the International PNH Registry was implemented in the Russian PNH cohort to assess the natural history of PNH and the effects of treatment with eculizumab.
Aims:We aim to evaluate the change from baseline to last follow-up in physician-reported symptoms, LDH and hemoglobin concentration in treated and untreated PNH patients.
Design and methods: The international PNH Registry is a non-interventional, prospective, multicenter observational study. The study population of this analysis comprised the Russian cohort of the Registry: all patients had a confirmed diagnosis of PNH according to international guidelines. As per local guidelines, blood transfusion dependency and a history of TE were the main indications for treatment with eculizumab. Data are presented as descriptive statistics only. The reporting period includes time from baseline until the earliest of: death; bone marrow transplant; discontinuation from the Registry; discontinuation from eculizumab; last follow-up in the Registry.
Results: As of June 2014, the international PNH Registry has enrolled 479 patients from Russia, 75 patients were ever-treated with eculizumab (15.7%), among whom 60 had available data. The median (range) duration of follow-up of patients after eculizumab treatment was 0.8 (-0.7 – 1.9) years and the median years (range) from disease onset to the start of eculizumab treatment was 8.1 (1 – 30) years. One patient discontinued treatment due to the disappearance of PNH clones and disease manifestations. Fifteen deaths were reported during the reporting period; all in patients never treated with eculizumab.
Table 1. History of medical events at baseline All patients (N = 464) Ever-treated with Eculizumab (N = 60) Never-treated patients (N = 404) History of BMD, n (%) 423* 313 (74) ongoing 39* 12 (31) ongoing 384* 301 (78) ongoing History of TE, n (%) 436* 30 (7) 39* 9 (23) 397* 21 (5) History of any RBC transfusion, n (%) 385* 300 (78) 39* 26 (67) 346* 274 (79) RBC transfusion in past 12 months, n (%) 419* 245 (59) 29* 22 (76) 390* 223 (57) History of CKD, n (%) 435* 24 (6) 39* 1 (3) 396* 23 (6) History of pulmonary hypertension, n (%) 435* 11 (3) 39* 4 (10) 396* 7 (2)
*number of patients with available data
Table 2. Change from baseline to last follow up for physician-reported symptoms All patients Ever-treated with eculizumab Never-treated patients Abdominal pain, n (%): Improved No change Worsened N=196 33 (17) 145 (74) 18 (9) N=29 15 (52) 10 (35) 4 (14) N=167 18 (11) 135 (81) 14 (8) Dysphagia, n (%): Improved No change Worsened N=195 17 (9) 162 (83) 16 (8) N=29 7 (24) 20 (69) 2 (7) N=166 10 (6) 142 (86) 14 (8) Dyspnea, n (%): Improved No change Worsened N=196 55 (28) 127 (65) 14 (7) N=29 15 (52) 12 (41) 2 (7) N=167 40 (24) 115 (69) 12 (7) Fatigue, n (%): Improved No change Worsened N=199 23 (12) 169 (85) 7 (4) N=29 4 (14) 25 (86) – N=170 19 (11) 144 (85) 7 (4) Hemoglobinuria, n (%): Improved No change Worsened N=196 29 (15) 156 (80) 11 (6) N=28 12 (43) 16 (57) – N=168 17 (10) 140 (83) 11 (7)
Median (Q1, Q3) Hb concentrations at baseline in ever-treated and never-treated patients were 7.3 (6.3, 9.2) g/dL and 9.0 (7.2, 11.3) g/dL, respectively, and median (Q1, Q3) changes in Hb concentration from baseline to last follow up were 2.1 (1.2, 3.8) g/dL and 0.75 (-0.4, 2.5) g/dL, respectively. Median (Q1, Q3) LDH level at baseline in ever-treated and never-treated patients were 6.0 (3.6, 8.7) x the upper limit of normal (ULN) and 1.1 (0.8, 1.8) x ULN, respectively, and median (Q1, Q3) changes in LDH level from baseline to last follow up were -4.8 (-6.9, -1.9) and 0.0 (-0.2, 0.3) x ULN, respectively.
Conclusion: This analysis represent the first report on longitudinal outcomes during eculizumab therapy in Russian patients included in the international PNH Registry and are considered essential for planning patients' follow-up, including monitoring of therapeutic effects and prophylaxis against break-through hemolysis. Overall, the data show an improvement in physician-reported symptoms and reduced hemolysis, as measured by plasma LDH level, in patients treated for a relatively short period of time.

Disclosures
Lisukov: Alexion: Honoraria. Kulagin:Alexion: Honoraria. Shilova:Alexion: Honoraria. Afanasyev:Alexion: Honoraria.