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Risk Factors for the Development of High-Titer Inhibitors in 260 Children with Severe Hemophilia a Born Between 1990 and 2009: The Remain Study
Journal article

Risk Factors for the Development of High-Titer Inhibitors in 260 Children with Severe Hemophilia a Born Between 1990 and 2009: The Remain Study

  • Mancuso, Maria Elisa Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
  • Fischer, Kathelijn Van Creveldkliniek, University Medical Center Utrecht, Utrecht, Netherlands
  • Santagostino, Elena Maggiore Hospital Policlinico and University of Milan, Milan, Italy
  • Oldenburg, Johannes Institute of Experimental Haematology and Transfusion Medicine, University of Bonn, Bonn, Germany
  • Platokouki, Helen Haemophilia Centre/Haemostasis Unit, Agia Sofia Children's Hospital, Athens, Greece
  • Königs, Christoph Department of Pediatrics, University Hospital Frankfurt, Frankfurt am Main, Germany
  • Escuriola, Carmen Haemophilie Zentrum Rhein Main, Morfelden-Walldorf, Germany
  • Rivard, Georges-Etienne Hematology/Oncology, Centre Hospitalier Universitaire Sainte Justine, Montreal, Canada
  • Cid, Ana Unidad de Hemostasia y Trombosis, Hospital Universitario y Politecnico La Fe, Valencia, Spain
  • Carcao, Manuel Paediatrics; Division of Haematology/Oncology and Child Health Evaluative Sciences, Research Insititute, Hospital for Sick Children, Toronto, Canada
  • Ljung, Rolf Lund University, Malmo, Sweden
  • Petrini, Pia Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden
  • Rafowicz, Anne Centre de Référence pour le Traitement des Maladies Hémorragiques (CRTH), Hôpital Bicêtre, Paris, France
  • Altisent, Carmen Unitat Hemofilia, Hospital Traumatologica, Hospital Vall d'Hebron, Barcelona, Spain
  • Kenet, Gili The Chaim Sheba Medical Center, Thrombosis Unit, National Hemophilia Center, Ramat Gan, Israel
  • Liesner, Raina Great Ormond Street Hospital, London, United Kingdom
  • Kurnik, Karin Pediatric Hemophilia Centre, Munich, Germany
  • Van Geet, Christel Dept. of Hematology, Pediatrics, UZ Gasthuisberg Leuven, Leuven, Belgium
  • Alvarez-Roman, Teresa Hematology Department, Hospital Universitario La Paz, Madrid, Spain
  • Yee, Tin Tin Haemophilia Centre and Haemostasis Unit, The Royal Free Hospital, London, United Kingdom
  • Auerswald, Guenter Hemophilia Treatment Centre, Prof. Hess Children's Hospital, Bremen, Germany
  • Perez-Garrido, Rosario Hospital General Unidad de Hemofilia, Hospitales Universitarios Virgen del Rocio, Sevilla, Spain
  • Nolan, Beatrice Department of Paediatric Haematology, St. James's Hospital, Dublin, Ireland
  • Chambost, Hervé Department of Pediatric Hematology and Oncology, Timone Enfants Hospital, APHM and Aix-Marseille University, Marseille, France
  • Makipernaa, Anne Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland
  • Molinari, Angelo Claudio Dipartimento di Ematologia ed Oncologia, Unità Trombosi ed Emostasi, Ospedale Pediatrico Giannina Gaslini, Genua, Italy
  • Thomas, Angela Royal Hospital for Sick Children, Edinburgh, United Kingdom
  • Chalmers, Elizabeth Department of Haematology, Royal Hospital for Sick Children, Glasgow, United Kingdom
  • Williams, Mike Department of Haematology, The Children's Hospital, Birmingham, United Kingdom
  • Kobelt, Rainer Hämophiliezentrum, Wabern and Children's Hospital of the University of Bern, Bern, Switzerland
  • Van den Berg, Marijke Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, Netherlands
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Published in:
  • Blood. - American Society of Hematology. - 2016, vol. 128, no. 22, p. 3774-3774
Immunology
Cell Biology
Biochemistry
Hematology
English Abstract

The development of anti-FVIII antibodies (i.e., inhibitors) is the major side effect of severe hemophilia A treatment. Inhibitors mainly develop in children during the first 50 exposure days and are classified in low-and high-titer (i.e., peak titer < or > 5 UB/ml). High-titer inhibitors have the major clinical impact. At diagnosis however, the real nature of the antibody is not clear in all patients, since some low-titer inhibitors may progress to high-titer. The determinants of the evolution from low- to high-titer inhibitors are still unclear and the aim of the present study was to investigate potential risk factors associated with the progression from low- to high-titer inhibitors. This study is a follow-up study of the PedNet Registry and includes 260 children with severe hemophilia A and clinically relevant inhibitors, born between 1990 and 2009 and consecutively recruited from 31 hemophilia centers in 16 countries. Clinical and laboratory data were collected from the date of first positive inhibitor test and covered a minimum of 3-years follow-up. Factors potentially associated with progression from low- to high-titer inhibitor development were analyzed using univariate and multivariate logistic regression. F8 mutation type was known in 247 patients (95%), including 202 (82%) null mutations (i.e., large deletions, nonsense mutations and inversions). Positive family history of inhibitors was present in 37 of 99 (37%) with positive family history of hemophilia. At diagnosis 49% (n=127) had low-titer inhibitors, however, upon FVIII re-exposure, 50% of low-titer inhibitors progressed to high-titer and only 25% of patients (n=69) had persistent low-titer inhibitors. Within the first 3 years of follow-up, immune tolerance induction (ITI) was equally implemented in around 80% of low-and high-titer patients but it was started later in children with high-titers (median time to ITI start 4.5 vs 0.3 months; p<0.001) in whom daily regimens and high-dose FVIII were more frequently adopted (89, 67% vs 41, 50% and 98, 74% vs 35, 43%; p=0.01 and <0.001, respectively). Overall high-titer inhibitor development was associated with null F8 mutations (OR 2.8, 95%CI 1.4-5.5) and family history of inhibitors (OR 3.9, 95%CI 1.2-12.6). The progression from low- to high-titer inhibitors during follow up, was associated with the use of high-dose ITI regimens (i.e., >100 IU/kg/day) with an OR of 3.9 (95%CI 1.5-10.0), independent from the effects of F8 mutation type (adjusted OR 3.6, 95%CI 1.4-9.8) and family history of inhibitors (adjusted OR 6.7, 95%CI 1.1-42.6). No difference was found by comparing the use of daily versus non-daily ITI. In conclusion, in a cohort of 260 children with severe hemophilia A and inhibitors, 49% presented with low-titers at diagnosis and 46% of them progressed to high-titers during follow-up. Progression to high-titer inhibitors was associated with the use of high-dose ITI. These results suggest that intensive ITI should be avoided as initial strategy in low-titer inhibitor patients.

Disclosures
Mancuso: Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi/Biogen Idec: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Baxalta: Consultancy, Speakers Bureau; Bayer Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kedrion: Consultancy. Fischer:Wyeth/Pfizer: Research Funding; Biogen: Consultancy; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Biotest Octapharma: Speakers Bureau; CSL Behring: Speakers Bureau; Baxter: Consultancy, Research Funding, Speakers Bureau; Freeline: Consultancy; Bayer: Consultancy, Research Funding, Speakers Bureau. Santagostino:Octapharma: Consultancy; Novo Nordisk: Consultancy; Kedrion: Consultancy; Sobi: Consultancy; Biogen Idec: Consultancy; Roche: Consultancy; Grifols: Consultancy; Pfizer: Consultancy; Baxalta: Consultancy; CSL Behring: Consultancy; Bayer: Consultancy. Escuriola:Baxalta, now part of Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Investigator Clinical Studies, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Biotest: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding; NovoNordisk: Consultancy, Honoraria, Research Funding. Liesner:BPL: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Speakers Bureau; Cangene: Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Baxalta Innovations GmbH, now a part of Shire: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; SOBI: Consultancy, Honoraria, Research Funding, Speakers Bureau; Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Biogen: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria. Nolan:Sobi: Research Funding; Biogen: Research Funding.
Language
  • English
Open access status
bronze
Identifiers
Persistent URL
https://sonar.ch/global/documents/474
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