When is enough…enough? Developing consensus of definition of failure of immune tolerance induction in patients with haemophilia and inhibitors

Haemophilia. 2014 Jul;20(4):e275-9. doi: 10.1111/hae.12442.


Immune tolerance induction (ITI) is the preferred management of haemophilia A patients who develop high titre inhibitors against factor VIII. However, the optimal ITI regimen, predictors of ITI outcome and definitions of successful and unsuccessful ITI remain unclear. The aim of this project was to develop a consensus on the definition of ITI treatment failure for Australian clinical practice using a modified Delphi approach. Three consecutive surveys were distributed to the directors of 17 haemophilia treatment centres in Australia. Participants were asked to rate their agreement with definitions of ITI treatment failure generated from a literature review. Thirty-five statements regarding ITI achieved consensus (majority agree or strongly agree) during the three survey rounds. After round 3, four statements achieved majority disagreement, and for two statements no consensus was reached. Our study demonstrates that clinicians in Australia necessitate an arbitrary time to assess ITI failure, but that clinical outcomes of ITI are important in assessing response. Assessment over any 3- to 6-month period without a 20% reduction in inhibitor titre is suggestive of failure, but a reduction in bleeding phenotype alone may be sufficient to continue ITI. Overall, a period of 3 or 5 years of ITI may be required to determine response to ITI. Documentation of improvement in clinical measures, supported by the laboratory features of factor VIII inhibitor levels and pharmacokinetics, is essential in assessing the success of failure of ITI in these patients.

Keywords: Delphi approach; haemophilia; immune tolerance induction; inhibitor; treatment failure.

MeSH terms

  • Consensus*
  • Decision Making
  • Delphi Technique*
  • Hemophilia A / drug therapy*
  • Hemophilia A / immunology*
  • Humans
  • Immunosuppression*
  • Thromboplastin / adverse effects
  • Thromboplastin / therapeutic use
  • Treatment Failure


  • Thromboplastin