As a result of many technological advances in the last two decades, current factor VIII
(FVIII) concentrates (both plasma-derived and recombinant products) are considered very
safe in terms of pathogen safety.
The development of inhibitors against FVIII or factor IX (FIX) is considered as a major
complication during replacement therapy of haemophiliacs.
Prospective studies of previously untreated patients (PUPs) have suggested that
inhibitors develop in up to 33% of patients with moderate to severe haemophilia A.
Several strategies are used to control bleedings in such patients, e.g. high-dose
treatment with FVIII concentrates, treatment with activated prothrombin complex
concentrate (aPCC) or treatment with activated factor VII (FVIIa).
Immune tolerance induction (ITI) in order to eradicate inhibitors in patients suffering
from an inhibitor to FVIII with high dose treatment of FVIII was first reported in 1977
by Brackmann & Gormsen in the so-called "Bonn Protocol" and was investigated from then on
in a series of clinical studies applying the same or a modified version of the "Bonn
Protocol". During these investigations high dose FVIII treatment has been proven
efficacious in inducing immune tolerance and was shown to exert a long lasting effect in
more than 80 % of the patients treated.
The observational immune tolerance induction research program (ObsITI) will allow a
systematic prospective and retrospective data documentation and analysis on the success
rate of ITI by using individualized concentrate selection.
Pre-ITI-phase:
Aim of this evaluation is to assess current pre-ITI treatment strategies in inhibitor
patients from detection of inhibitor until start of ITI (early start vs. delayed start)
and the effect of pre-ITI treatment (prophylaxis and on-demand treatment in case of
bleeds/surgery) with bypassing agents (rFVIIa, NovoSeven®, aPCC, FEIBA®, emicizumab,
Hemlibra®) and / or FVIII on the titre at start of ITI, on the success rate of ITI, the
number of break-through bleeds and life-threatening bleeds.
ObsITI-Rescue ITI Study:
Patients who fail FVIII-stand-alone ITI or who are no candidates for FVIII-stand-alone
ITI and who are treated with ITI regimens including immunosuppressive agents can be
included in this sub-study. Aim of this study is to document ITI regimens including
immunosuppressive therapy (Rituximab, steroids, mycophenolate mofetil/MMF, sirolimus or
other immunosuppressive agents) combined with regular FVIII administration, potential
drug related side effects, outcome and duration of immune tolerance (relapse and
recurrence of inhibitors).
Optional sub-studies:
In order to investigate the role of in vitro tests on individual ITI success rate in
patients undergoing ITI, the inhibitor plasma samples can be assayed against different
FVIII concentrates using the following in vitro tests:
Batch selection: The potential variation in inhibitor reactivity with different
FVIII concentrates/batches of the same concentrate can optionally be studied
according to a modified Oxford method (HZRM Hämophilie-Zentrum Rhein Main, Germany).
Thrombin generation assay (TGA): In this optional in vitro test the plasma samples
from an inhibitor patient can be spiked with different concentrates and the thrombin
generation will be measured using the TGA to evaluate the potential of different
FVIII concentrates to generate thrombin (Haemophilia Centre Malmö, Sweden).
Thrombin Generation Test (TGT): TGT will evaluate the correlation between clinical
bleeding phenotype of patients and their thrombin generation capacity before ITI in
order to predict the patients with the highest risk of bleeding. In vitro efficacy
of two FVIII doses (low and high) in the presence and absence of FEIBA® and
emicizumab will be evaluated (Louis Pradel Cardiology Hospital, Bron, France).
Epitope mapping / IgG Subclasses: The isotypic antibody epitopes on FVIII will be
identified in plasma samples from inhibitor patients. This will help to identify
relevant epitopes recognised by inhibitors in haemophilia A. This research program
will give an opportunity to comprehensively study various aspects of inhibitors and
the induction of immunetolerance in a relevant number of patients. Knowledge about
relevant epitopes from patient plasma rather than from model systems (i.e.
monoclonal antibodies or mouse models) will help to understand the immune response
to FVIII and to develop novel strategies to deplete inhibitors or inhibitor
secreting B cells (Haemophilia Centre, University Hospital Bonn, Germany). Plasma
samples will also be tested for IgG-subclasses specific for FVIII. Most inhibitors
belong to the subclasses IgG1 and IgG4. There are some indications that the ratio of
IgG1 and IgG4 might influence ITI outcome (Haemophilia Centre, University Hospital
Bonn, Germany).
Immunogenotyping / HLA Genotyping: In addition, this study will investigate genetic
risk factors (gene defect responsible for haemophilia, HLA class II alleles, immune
response genes) as a potential variable with impact on course and outcome of ITI.
Recently a significantly higher inhibitor incidence has been found in patients
(brothers) with IL-10.G allele 134, TNFα - 308G>A polymorphism within Hap and
polymorphisms in the CTLA-4-gene compared to those brothers without the above
mentioned polymorphisms (Haemophilia Centre, University Hospital Bonn, Germany).
If patients do not respond to FVIII stand-alone ITI and any immune modulating/
immunosuppressive agents are added to ITI,ITI courses can be followed up in the
ObsITI-Rescue ITI sub-study. Immunosuppressive therapy has to be documented as
concomitant medication. Follow up visits should be done in the same intervals as with
stand-alone FVIII-ITI.