Towards a new era of personalised ITI treatment Back

Claude Négrier, Carmen Escuriola-Ettingshausen, Sébastien Lacroix-Desmazes, Anna Pavlova

Introduction

In patients with severe haemophilia it is known that the incidence of inhibitor is around 30%, the potential impact of the type of factor VIII (FVIII) product administered still being disputed.1 Approximately 85% of FVIII inhibitors are  directed against the A2 or C2 domains of the molecule, and most of the remainder at the amino-terminal region of the A3 domain.2 In about 60% of patients, there are two or three major inhibitor binding sites on the FVIII molecule. Anti-C2 and -A3 antibodies prevent FVIII from interacting normally with von Willebrand factor (VWF) and/or phospholipids, and the anti-A2 and anti-A3 antibodies interfere with the formation and activity of the tenase complex, blocking a pathway to the generation of thrombin. There are various risk factors for the development of inhibitors. These can be divided into genetic/invariable risk factors (F8 gene mutation, family history of inhibitors, severity of haemophilia A, race and ethnicity, and other immune response genes such as IL-10 and TNF-alpha) and environmental/variable risk factors (age and medical conditions at first exposure to FVIII, immunological challenges, invasive clinical procedures, and administration of abnormal FVIII molecules). Chronic joint disease from repeated bleeds into the joints is a serious complication of haemophilia. For those with severe haemophilia and inhibitors, range of motion limitation was found to be significantly greater than for patients with severe haemophilia without inhibitors.3 The frequency  of joint and other bleeds in patients with severe haemophilia is significantly reduced by the administration of prophylaxis with FVIII concentrates and in some patients bleeds are completely abolished.4 For haemophilia patients with inhibitors, immune tolerance induction (ITI) is the only strategy to  eliminate FVIII inhibitors and restore the clinical response to FVIII. At an Octapharma-sponsored satellite symposium held on 27 February at the 2014 meeting of the European Association for Haemophilia and Allied Disorders (EAHAD) in Brussels, Belgium, four leading experts in the field were invited to review the concept of a personalised approach to ITI in patients with haemophilia and inhibitors. This Key Opinions in Medicine captures the main points discussed at the symposium.

Executive summary

  • In patients with severe haemophilia the incidence of inhibitor is around 30%
  • There are various risk factors for the development of inhibitors: these can be divided into genetic/invariable risk factors and environmental/variable risk factors
  • Ethnicity represents another influence factor of inhibitor development: in African–Americans, the susceptibility to inhibitor development is reported to be twice as higher as in white patients
  • Once a patient has developed inhibitors to FVIII they are at risk of developing rapid haemophilic arthropathy
  • For haemophilia patients with inhibitors, immune tolerance induction (ITI) is the only strategy to eliminate FVIII inhibitors and restore the clinical response to FVIII
  • ITI is known to induce neutralising anti-idiotypic antibodies in patients, and induces elimination of FVIII-specific memory B cells in mice
  • Certain factors indicate a good prognosis for success of ITI: these are an inhibitor titre at the start of ITI of < 10 BU, a maximum historical inhibitor titre of < 200 BU, age at start of ITI < 7 years and presence of an inhibitor of < 2 years
  • Therapy-related factors affecting the success of ITI include the dose/frequency of FVIII, the FVIII product type and content of VWF
  • Patients carrying lower-risk F8 defects (small insertions/deletions and missense mutations) had a significantly higher ITI success rate than those carrying high-risk mutations (large deletions, inversions, nonsense mutations and splice site mutations)
  • The ObsITI study is an international, open-label uncontrolled, multicentre observational programme initiated by the Paediatric Haemophilia Centre, Frankfurt, Germany; it is open to all FVIII products and there are several sub-studies
  • In patients with haemophilia, the thrombin generation test (TGT) could be useful for individually tailoring prophylactic regimens
  • Human leucocyte antigen (HLA) alleles and cytokine polymorphisms are among predisposing factors for inhibitor development in patients with severe haemophilia A. In the ObsITI study, the type of HLA allele has been shown to influence the chance of success of ITI
  • Increasing knowledge in genetic and immunological aspects of inhibitor development and mechanisms of FVIII tolerance would enable the identification of other potential predictors of ITI outcome, allowing the implementation of more effective planning and personalisation of ITI therapy.