title: First prospective report on immune tolerance in poor risk haemophilia A inhibitor patients with a single factor VIII/von Willebrand factor concentrate in an observational immune tolerance induction study.
abstract: BACKGROUND
  Development of neutralizing inhibitors against factor VIII (FVIII) is a major complication of haemophilia A treatment.
  
  
  OBJECTIVE
  The ongoing, international, open-label, uncontrolled, observational immune tolerance induction (ObsITI) study evaluates ITI, the standard of care in patients with inhibitors.
  
  
  METHODS
  Forty-eight prospective patients in this interim analysis received a single plasma-derived, von Willebrand factor-stabilized, FVIII concentrate (pdFVIII/VWF) for ITI. According to recommended Bonn protocol, 'low responders' at ITI start (<5 BU) received 50-100 IU FVIII kg(-1) daily, or every other day; 'high responders' (≥5 BU) received 100 IU FVIII kg(-1) every 12 h.
  
  
  RESULTS
  Forty of 48 patients (83.3%), had at least one risk factor for poor ITI-prognosis at ITI start (i.e. age ≥7 years, >2 years since inhibitor diagnosis, inhibitor titre ≥10 BU at the start of ITI, or prior ITI failure). Nonetheless, 34 patients (70.8%) achieved complete success, 3 (6.3%) partial success, 1 (2.1%) partial response; ITI failed in 10 patients (20.8%), all with poor prognosis factors. All six low responders achieved complete success. ITI outcome was significantly associated with inhibitor titre level at ITI start (P = 0.0068), number of poor prognosis factors for ITI success (P = 0.0187), monthly bleeding rate during ITI (P = 0.0005) and peak inhibitor titre during ITI (P = 0.0007). Twenty-two of 35 high responder patients (62.9%) with ≥1 poor prognosis factor achieved complete success.
  
  
  CONCLUSIONS
  Treatment with a single pdFVIII/VWF concentrate, mainly according to the Bonn protocol, resulted in a high ITI success rate in haemophilia A patients with inhibitors and poor prognosis for ITI success.
authors.affiliation: HZRM, Hämophilie-Zentrum Rhein Main Frankfurt-Mörfelden, Mörfelden-Walldorf, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Kreuz
authors.affiliation: HZRM, Hämophilie-Zentrum Rhein Main Frankfurt-Mörfelden, Mörfelden-Walldorf, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Escuriola Ettingshausen
authors.affiliation: Izmaylovo Children's Hospital Haematological Centre, Moscow, Russia.
authors.forename: V
authors.initials: V
authors.lastname: Vdovin
authors.affiliation: The State Haematological Scientific Centre RAMS, Moscow, Russia.
authors.forename: N
authors.initials: N
authors.lastname: Zozulya
authors.affiliation: The State Haematological Scientific Centre RAMS, Moscow, Russia.
authors.forename: O
authors.initials: O
authors.lastname: Plyushch
authors.affiliation: Izmaylovo Children's Hospital Haematological Centre, Moscow, Russia.
authors.forename: P
authors.initials: P
authors.lastname: Svirin
authors.affiliation: St. Petersburg State Healthcare Institution, St. Petersburg, Russia.
authors.forename: T
authors.initials: T
authors.lastname: Andreeva
authors.affiliation: Children Faculty Hospital with Policlinic, Banská Bystrica, Slovakia.
authors.forename: E
authors.initials: E
authors.lastname: Bubanská
authors.affiliation: Centro Hospitalar Porto, Hospital de Santo António, Porto, Portugal.
authors.forename: M
authors.initials: M
authors.lastname: Campos
authors.affiliation: Children's Hospital Oncology-Hematology Unit, University Medical Center Ljubljana, Ljubljana, Slovenia.
authors.forename: M
authors.initials: M
authors.lastname: Benedik-Dolničar
authors.affiliation: Hospital La Paz, Madrid, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Jiménez-Yuste
authors.affiliation: Children's Hospital Oncology-Hematology Unit, University Medical Center Ljubljana, Ljubljana, Slovenia.
authors.forename: L
authors.initials: L
authors.lastname: Kitanovski
authors.affiliation: Medical Academy, Warsaw, Poland.
authors.forename: A
authors.initials: A
authors.lastname: Klukowska
authors.affiliation: Altai Hematological Center, Altai, Russia.
authors.forename: A
authors.initials: A
authors.lastname: Momot
authors.affiliation: State Healthcare Institution of Omsk Region, Omsk, Russia.
authors.forename: N
authors.initials: N
authors.lastname: Osmulskaya
authors.affiliation: Hospital General Yagüe, Castilla Leon, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Prieto
authors.affiliation: University Hospital REBRO, Zagreb, Croatia.
authors.forename: S Z
authors.initials: SZ
authors.lastname: Šalek
authors.affiliation: Hospital Reina Sofía, Córdoba, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Velasco
authors.affiliation: Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Pavlova
authors.affiliation: Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Oldenburg
authors.affiliation: Octapharma AG, Lachen, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Knaub
authors.affiliation: Octapharma Pharmazeutika Produktionsges.mbH, Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Jansen
authors.affiliation: Octapharma AG, Lachen, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Belyanskaya
authors.affiliation: Octapharma AG, Lachen, Switzerland.
authors.forename: O
authors.initials: O
authors.lastname: Walter
mesh_terms: D000293:Adolescent; D000328:Adult; D057134:Antibodies, Neutralizing / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D004338:Drug Combinations; D005169:Factor VIII / Q000009:adverse effects / Q000276:immunology* / Q000627:therapeutic use*; D005260:Female; D006467:Hemophilia A / Q000150:complications / Q000188:drug therapy* / Q000276:immunology*; D006470:Hemorrhage / Q000150:complications; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D007223:Infant; D008297:Male; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors; D012449:Safety; D055815:Young Adult; D014841:von Willebrand Factor / Q000009:adverse effects / Q000276:immunology* / Q000627:therapeutic use*
chemical_list: D057134:Antibodies, Neutralizing; D004338:Drug Combinations; C509423:factor VIII, von Willebrand factor drug combination; D014841:von Willebrand Factor; D005169:Factor VIII
keywords: Bonn protocol; factor VIII inhibitors; factor VIII/von Willebrand factor concentrate; haemophilia A; immune tolerance induction; poor prognosis for immune tolerance induction