Efficacy of Eculizumab in Pediatric Patients with Paroxysmal Nocturnal Hemoglobinuria in the International PNH Registry
Authors: Urbano-Ispizua Álvaro , Kulasekararaj Austin G. , Bartels Marije , Patriquin Christopher J. , Hoechsmann Britta , Maschan Alexey A. , Wilson Amanda , Gustovic Philippe , Schrezenmeier Hubert 
Published: October 2019

Abstract
Background/Objective: Paroxysmal nocturnal hemoglobinuria (PNH) is an extremely rare disease and is even more rare in children; pediatric cases are estimated to account for <5% of all PNH cases (Ware RE, et al. N Engl J Med. 1991;325:991-996). There is a paucity of published data on outcomes in children with PNH treated with eculizumab. The International PNH Registry (NCT01374360) is a prospective, observational study of patients with PNH regardless of age, and represents the largest cohort of pediatric PNH patients. The objective of this analysis was to evaluate outcomes after initiation of eculizumab in pediatric patients and adult patients enrolled in the Registry.
Methods: The analysis included eculizumab-treated patients enrolled in the Registry as of May 2017. Patients were stratified by age at baseline (defined as the date of eculizumab initiation; age categories, <18 and ≥18 years of age) and assessed at baseline and at last follow-up. Age at the time of disease onset, as defined by earliest reported PNH granulocyte clone, disease diagnosis, or PNH symptom, was also recorded. Patients needed ≥6 months of follow-up post-baseline to be eligible for analyses of change from baseline to last follow-up on eculizumab.
Results: Of 4903 patients enrolled in the Registry as of May 1, 2017, 1725 had been treated with eculizumab and had data available on demographics and enrollment date (<18 years of age at baseline, n=47; ≥18 years of age at baseline, n=1678). In both age groups, the majority of patients were female (66.0%, pediatric cohort; 52.6%, adult cohort), and the majority were white (89.1% and 81.6%, respectively). Median (quartile [Q]1, Q3) age at disease onset was 14.7 (11.0, 15.8) in the pediatric cohort and 33.3 (23.7, 48.2) in the adult cohort; median (Q1, Q3) ages at baseline were 15.8 (14.9, 17.3) and 42.0 (30.8, 57.0), respectively. Fewer pediatric patients had history of thrombotic events (TEs) and other major adverse vascular events (MAVEs) at baseline compared with the adult cohort (Table), which is consistent with findings from a previous Registry analysis (Urbano-Ispizua A, et al. Haematologica. 2017;102:e76-e79). Most patients had ≥6 months of follow-up (n=44/47 [93.6%] and n=1532/1678 [91.3%], respectively) after baseline. Median (minimum, maximum) duration of time between baseline and last follow-up on eculizumab was 3.7 (0.1, 8.7) years in the pediatric cohort and 3.9 (0.0, 12.1) years in the adult cohort. Results for outcomes of interest are summarized in the Table. In both cohorts, mean lactate dehydrogenase ratio decreased from >5 times the upper limit of normal at baseline to normal or near normal range at last follow-up in both age cohorts. There were no TEs reported in the pediatric cohort after baseline, but 2/43 patients (4.7%) with no history of MAVEs at baseline experienced non-TE MAVEs after baseline. Among adult patients, 19/1497 (1.3%) with no history of TEs and 7/1497 (0.5%) with history of TEs experienced TEs after baseline. Non-TE MAVEs after baseline in patients with no history of MAVEs were experienced by 17/1492 patients (1.1%) and non-TE MAVEs after baseline in patients with history of MAVEs were experienced by 15/1492 patients (1.0%). The proportion of patients requiring transfusion was lower at last follow-up in both cohorts compared with baseline (23.0% at last follow-up vs 49.3% at baseline for adults and 32.3% at last follow-up vs 48.4% at baseline for pediatric patients). A similar proportion of patients became transfusion-independent after treatment with eculizumab in both age cohorts (32.3% [10/31] in the pediatric cohort compared with 33.8% [370/1095] in the adult cohort). The proportion of patients with PNH-related symptoms decreased after baseline in both cohorts for most of the symptoms assessed, although fewer than 10 pediatric patients had symptom data available at both baseline and last follow-up.
Conclusions: The effectiveness of eculizumab for reducing intravascular hemolysis and transfusion requirements, and preventing MAVEs (including TEs) was similar in these large cohorts of pediatric patients with PNH and adults with PNH. The higher proportion of patients transfusion-dependent among the pediatric cohort may be associated with the higher likelihood of underlying aplastic anemia in pediatric patients with PNH.
Table. Table.

Disclosures
Urbano-Ispizua: Alexion Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Kulasekararaj:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support . Bartels:Alexion Pharmaceuticals, Inc.: Honoraria, Other: Travel Support and is site investigator for clinical trials with the company, Research Funding. Patriquin:Ra Pharmaceuticals: Consultancy, Research Funding; Octapharma: Honoraria; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support and is site investigator for clinical trials with the company. Hoechsmann:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding. Wilson:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Gustovic:Alexion Pharma GmbH: Employment, Equity Ownership. Schrezenmeier:Alexion Pharmaceuticals, Inc.: Honoraria, Research Funding.