Outcomes in patients with atypical hemolytic uremic syndrome treated with eculizumab in a long-term observational study

Abstract

Background: There are limited long-term outcome data in eculizumab-treated patients with atypical hemolytic uremic syndrome (aHUS). We report final results from the largest prospective, observational, multicenter study of patients with aHUS treated with eculizumab.

Methods: Patients with aHUS who participated in any of five parent eculizumab trials and received at least one eculizumab infusion were eligible for enrollment in a long-term follow-up study. Rates of thrombotic microangiopathy (TMA) manifestations off versus on eculizumab were evaluated. Additional endpoints included change from baseline estimated glomerular filtration rate (eGFR), long-term renal outcomes, and serious targeted treatment-emergent adverse events.

Results: Among 93 patients (0-80 years of age), 51 (55%) remained on eculizumab and 42 (45%) discontinued; for those who discontinued, 21 (50%) reinitiated therapy. Patients who reinitiated eculizumab had similar baseline clinical characteristics to patients who remained on eculizumab, with higher likelihood of genetic/autoimmune complement abnormalities, more prior TMAs, and longer disease course versus those who did not reinitiate. Mean eGFR improved rapidly and remained stable for up to 6 years on eculizumab. In patients who discontinued, there was a trend toward decreasing renal function over time from discontinuation. Additionally, off-treatment TMA manifestation rates were higher in those aged < 18 years at diagnosis, with identified genetic/autoimmune complement abnormalities, or history of multiple TMAs prior to eculizumab initiation. The safety profile was consistent with previous studies. Three definite and one possible meningococcal infections related to eculizumab were reported and resolved with treatment. Three deaths unrelated to eculizumab were reported.

Conclusions: The current study confirms the efficacy and safety of eculizumab in aHUS, particularly with regard to long-term renal function and TMA events. Pediatric age at disease onset and presence of genetic or autoimmune complement abnormalities are risk factors for TMA events off treatment. Overall, patients who discontinue eculizumab may be at risk for additional TMA manifestations and renal function decreases. Discontinuation of eculizumab, with careful monitoring, is an option in select patients with consideration of patient preference, organ function normalization, and risk factors for relapse, including mutational analysis, age of onset, and history of multiple TMA episodes.

Trial registration: ClinicalTrials.gov NCT01522170 , January 31, 2012.

Keywords: Alternate complement pathway; Atypical hemolytic uremic syndrome; Eculizumab; Thrombotic microangiopathy.

Conflict of interest statement

Ethics approval and consent to participate

All patients and/or parents/guardians provided written informed consent before entry into the current study. Ethics approvals have been obtained by institutional review boards or ethics committees in participating institutions as follows:

Australia: Alice Springs Hospital, Central Australian HERC, Alice Springs; Royal Adelaide Hospital, SAH HREC / CALHN (CEC), Royal Adelaide HREC (LEC), Adelaide; Austria: Medizinische Universitaet Innsbruck, Ethikkommission der Medizinischen Unitversität Innsbruck, Innsbruck; Medical University Graz Division of Pediatric Nephrology, Ethikkommission der Medizinischen Unitversität Innsbruck, Graz; Belgium: CHU de Liège, Comité d’Ethique Hospitalo-Facuitarire Universitaire de Liège (707) (CEC), Liege; UZ Gent Dienst Nefrologie, Comité d’Ethique Hospitalo-Facuitarire Universitaire de Liège (707) (CEC) UZ Gent Ethisch Comité (LEC), Gent; Canada: Centre Hospitalier Universitaire (CHU) Sainte-Justine, Comité d’éthique de la Recherche CHU Sainte-Justine (LEC), Montreal; The Hospital for Sick Children, The Hospital for Sick Children REB, Toronto; University Health Network, University Health Network REB, Toronto; France: Hôpital Pasteur – CHU de Nice Pole Urologie – Néphrologie, CNOM, CNIL, CCTIRS, Nice; CHU de Bordeaux Pellegrin, CNOM, CNIL, CCTIRS, Bordeaux; Hôpital Robert Debré, Service de Néphrologie Pédiatrique, CNOM, CNIL, CCTIRS, Paris; Le Kremlin Bicetre Hospital, Nephrology Unit, CNOM, CNIL, CCTIRS, Le Kremlin Bicetre; Hôpital Edouard Herriot, CNOM, CNIL, CCTIRS, Lyon; CHU de Nantes-Hôpital, Hotel Dieu - Nephro-Greffe (Nephrology), CNOM, CNIL, CCTIRS, Nantes; CHU de Caen Service de Néphrologie Hôpital Clémenceau, CNOM, CNIL, CCTIRS, Caen; Hôpital Bretonneau, IRC Transplantation Rénale, CNOM, CNIL, CCTIRS, Tours; Hôpital de Bois Guillaume-CHU de Rouen, CNOM, CNIL, CCTIRS, Rouen Cedex; CHU St. Etienne–Hôpital Nord, CNOM, CNIL, CCTIRS, Saint Priest En Jarez; Nouvel Hôpital Civil, CNOM, CNIL, CCTIRS, Strasbourg; CHRU de Lille-Hôpital A. Calmette (Nephrologie), CNOM, CNIL, CCTIRS, Lille; Hôpital Tenon, CNOM, CNIL, CCTIRS, Paris; Centre Hospitalier Inter-Communal de Cornouaille, CNOM, CNIL, CCTIRS, Quimper; Hôpital de la Timone Enfants, Unité de Néphrologie, Service de Pédiatrie Multidisciplinaire, CNOM, CNIL, CCTIRS, Marseille; CHU-CH Charles Nicolle Pavillon de Pédiatrie, CNOM, CNIL, CCTIRS, Rouen; Service de Néphrologie/Hémodialyse, CHR Orléans, CNOM, CNIL, CCTIRS, Orleans; Germany: Medizinische Klinik II - Nephrologie und Klinische Immunologie, Ethik-Kommission an der Medizinischen Fakultät (LEC), Aachen; Hannover University Clinic Adult Nephrology, Medizinische Hochschule Hannover Ethikkomission Vorsitzender (LEC), Hannover; Hannover University Clinic Pediatric Nephrology Medizinische Hochschule Hannover Ethikkomission Vorsitzender (LEC). Hannover; Universitaet Heidelberg, Ethik-Kommission der Medizinischen Fakultät Heidelberg (LEC), Heidelberg; Italy: Fondazione IRCCS Ca Granda, Ospedale Maggiore Policlinico, The IRCCS (Italian Research Hospital) Ca' Granda Foundation, Ospedale Maggiore General Hospital (LEC), Milano; Azienda Ospedaliero-Universitaria Careggi, Comitato Etico dell’Azienda Ospedaliero-Universitaria Careggi (LEC), Firenze; A.O. Papa Giovanni XXIII, Comitato di Bioetica Azienda Ospedali Riuniti di Bergamo (CEC), Bergamo; Istituto Giannina Gaslini, Istituto Giannina Gaslini Ethics Committee for Scientific Biomedical Research (LEC), Genova; Ospedale dei Bambini G. di Cristina, Arnas Civico di Cristina Benfratelli Comitato di Bioetica (LEC), Palermo; Netherlands: Academic Center Amsterdam (AMC), Dept. Nephrology / Dept. Pediatric Nephrology Stichting CGR (CEC), Amsterdam; University Medical Center Nijmegen (UMCN), St. Radboud Dept. Nephrology / Dept. Pediatrics, Stichting CGR (CEC), Nijmegen; Radboud University Medical Center, Stichting CGR (CEC), Nijmegen; Sweden: Karolinska Institutet, Karolinska University Hospital – Huddinge, Regionala Etikprövningsnämnden i Stockholm, Stockholm; Switzerland: INSELSPITAL Universitaetsklinik fuer Kinderheilkunde, Kindernephrologie, Kantonale Ethikkommission Bern (KEK) (LEC), Bern; United Kingdom: Exeter Kidney Unit, Royal Devon and Exeter Hospital (Wonford), NRES Committee South West - Cornwall & Plymouth (CEC), Royal Devon & Exeter NHS Foundation Trust (R&D), Exeter; Great Ormond Street Hospital NRES Committee South West - Cornwall & Plymouth (CEC), UCL Institute of Child Health / Great Ormond Street Hospital for Children NHS Foundation Trust (R&D) London; Newcastle Upon Tyne Hospitals NHS Foundation Trust, NRES Committee South West - Cornwall & Plymouth (CEC), Newcastle upon Tyne Hospital NHS Foundation Trust (R&D), Newcastle upon Tyne; Clinical Apheresis Unit, Level 1, Beatson WoSCC Gartnavel General Hospital, NRES Committee South West - Cornwall & Plymouth (CEC), Greater Glasgow & Clyde Health Board (R&D), Glasgow; City Hospital, Nottingham University Hospitals NHS Trust, NRES Committee South West - Cornwall & Plymouth (CEC), Nottingham University Hospitals NHS Trust (R&D), Nottingham; United States: Driscoll Children’s Kidney Center, Driscoll Children’s Hospital IRB, Corpus Christi, TX; Fort Wayne Medical Oncology and Hematology, WIRB (Western IRB - central IRB), Fort Wayne, IN; Arthur James Cancer Hospital, WIRB (Western IRB - central IRB), Columbus, OH; Weill Cornell Medical College, Weill Cornell Medical College IRB, New York, NY; Fox Valley Hematology, Affinity IRB, Oshkosh, WI; Emory Healthcare-Children’s Center, Emory IRB, Atlanta, GA; Cincinnati Children’s Hospital, CCHMC IRB, Cincinnati, OH; Providence Sacred Heart Medical Center & Children’s Hospital, IRB Spokane, Spokane, WA; Children’s Memorial Hospital, Ann & Robert H. Lurie Children’s Hospital of Chicago IRB, Chicago, IL; Westchester Oncology / Hematology Group (New York Medical College Committee for Protection of Human Subjects), Hawthorne, NY; Methodist Hospital (TMHRI IRB), Houston, TX; Children’s Hospital Boston, Boston Children’s Hospital IRB, Boston, MA; University of Utah School of Medicine Pediatric Pharmacology Program, University of Utah IRB, Salt Lake City, UT; Dunwoody Pediatrics & Children’s Healthcare of Atlanta, WIRB (Western IRB - central IRB), Dunwoody and Atlanta, GA; Seattle Children’s Hospital, Seattle Children’s Hospital IRB, Seattle, WA; Children’s Hospital at Montefiore, Albert Einstein College of Medicine IRB, Bronx, NY; Henry Ford Health System, Henry Ford Health System IRB, Detroit, MI; Vanderbilt University Medical Center, Vanderbilt University IRB, Nashville, TN; Duke University Medical Center, Duke University Health System IRB, Durham, NC. Written informed consent was obtained from all participants.

Consent for publication

Not applicable.

Competing interests

JM has received lecture and/or advisory fees from Alexion Pharmaceuticals, Inc., AstraZeneca, Berlin-Chemie, Daiichi Sankyo, Boehringer Ingelheim, and Novartis. YD has received fees from Alexion Pharmaceuticals, Inc., for participation in a symposium and from Sanofi-Ablynx for participation in advisory boards. FF has received fees for participation in advisory boards, experts’ meetings, and/or teaching courses from Alexion Pharmaceuticals, Inc. CL has received grant/research support and/or consultancy fees from Achillion Pharmaceuticals, Inc., Alexion Pharmaceuticals, Inc., and CSL Behring; has received honoraria from Alexion Pharmaceuticals, Inc. and CSL Behring; has submitted patents for CSL Behring and Finnegan, Henderson, Farabow, Garrett & Dunner; is a member of the Editorial Boards for Kidney International, Nephrology Dialysis Transplantation, and Pediatric Nephrology; is a Steering Committee Member of the Alport Syndrome Treatments and Outcomes Registry (ASTOR) and Member of the Safety Board of the European Treatment Trial for Alport Syndrome (EARLY PRO-TECT); is the aHUS International Registry Scientific Advisory Board Chair and HUS International Chair for Alexion Pharmaceuticals, Inc.; and has participated in the Eculizumab in Adolescent Patients With Plasma Therapy-Resistant aHUS (C08–002; NCT00844844), Eculizumab in Adolescent Patients With Plasma Therapy-Sensitive aHUS (C08–003; NCT00844428), and Eculizumab in Pediatric Patients With Atypical Hemolytic-Uremic Syndrome (C10–003; NCT01193348) clinical studies for Alexion Pharmaceuticals, Inc. ÅL is an employee and stockholder of Alexion Pharma GmbH, Zurich, Switzerland. EEM has participated in the C10–004 adult interventional study (NCT01194973) and in the C11–003 observational, follow-up study (NCT01522170) of atypical hemolytic uremic syndrome patients for Alexion Pharmaceuticals, Inc. FP has received honoraria from Alexion Pharmaceuticals, Inc. ER has received fees for participation in advisory boards, experts’ meetings, and/or teaching courses from Alexion Pharmaceuticals, Inc. NSS has received research funding from GlaxoSmithKline plc. JW is an employee and stockholder of Alexion Pharmaceuticals, Inc. LEW has received fees for participation in advisory boards from Alexion Pharmaceuticals, Inc. LAG has received research funding for Emory University from Alexion Pharmaceuticals, Inc., for his participation in the Eculizumab in Pediatric Patients and aHUS International Registry clinical studies; has received grant/research support and/or consultancy fees from AbbVie Inc., Alexion Pharmaceuticals, Inc., Bristol-Myers Squibb, Advicenne Pharmaceuticals, Mallinckrodt Pharmaceuticals, Otsuka America Pharmaceutical, Inc., and Vifor Pharma; has served as a member of a scientific advisory board for Alexion Pharmaceuticals, Inc., and as a member of data safety monitoring boards for Retrophin, Inc. and Relypsa Pharmaceuticals.

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Figures

Fig. 1

Patient disposition