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Recent Developments in Immune Tolerance Induction in Haemophilia A
positive result, a further 10 haemophilia A patients were switched to study, The Rescue Immunotolerance Study (RESIST), has been designed to
pdvWF/FVIII concentrate with an 88% success rate in a median of 17 examine this hypothesis. This study will enrol ITI-naïve patients who did
Similarly, eight high-titre inhibitor patients on a high-dose not qualify for the International ITI study because of poor prognostic
pdvWF/FVIII regimen had an 85% tolerance rate within eight to 12 factors and patients who have failed to respond to recombinant FVIII. The
Recent data from Italy and Spain also suggest that the vWF/FVIII ITI-naïve participants will be randomised to receive either the vWF/FVIII
concentrate is successful in patients with poor prognostic factors. Patients concentrate or a vWF-free FVIII concentrate at a standard dose of 200IU
with one or more of the negative factors for treatment with ITI still had a per kg per day. The salvage patients will receive the vWF/FVIII concentrate
positive outcome to the inhibitor treatment.
at a dose of 200IU per kg per day. The primary study end-point will be
partial or complete tolerance to FVIII, with a secondary end-point of time
A study including patients with poor prognostic factors for inhibitor to success and the maintenance of tolerance. The observational research
development concluded less beneficial effects of using the vWF programme on ITI in patients with haemophilia A and F VIII inhibitors
An explanation for the superior effects seen with (ObsITI) evaluates ITI-naïve patients and ITI failures who qualify for neither
vWF-containing concentrate in ITI is that VWF plays an important role RESIST nor the ITI study. ITI courses record and evaluate the impact of
in the stabilisation and function of FVIII.
VWF may also modulate frequency and dosage of F VIII, starting inhibitor titre, product type, peak
the immunogenicity affecting the outcome of ITI.
However, it it unclear titre, interruption of ITI, surgery, severe bleeds, concomitant medications,
whether a switch from recombinant FVIII to vWF-containing concentrates concomitant diseases and previous treatment approaches. In addition,
is responsible for the success of tolerance or if the eradication of the clinical relevance of pre-treatment in vitro testing and the F VIII
inhibitors was due to the extended use of ITI. Meta-analysis of the epitopes on ITI course and outcome will be investigated. In order to gain
International ITI study and the NAITR study showed no correlation more insight into immune mechanisms during ITI, a substudy on
between the outcome of ITI and the type of concentrate used.
To date immunological markers is included.
no prospective randomised trial has directly compared the recombinant
and vWF-containing concentrates. Hence, there is no clear evidence for Future Research Considerations
either product being superior in ITI. A highly debated and controversial area in ITI is the success of tolerance
through the use of recombinant concentrates or vWF/FVIII concentrate. It
Ongoing Immume Tolerance Induction Therapy Trials has still not been established which concentrate has the overall better
Future trials are aiming to clear up some of the concerns over the most success rate. The prospective ITI study, the Rescue Immunotolerance Study
successful ITI regimen. The prospective International ITI study aims to (RESIST) and the ObsITI should provide useful insight into this issue.
compare the efficacy, response time, morbidity and economics of a Research is also limited on why the vWF has been shown to be beneficial
high- and low-dose immune tolerance protocol and identify predictors of in addition to FVIII. The mechanisms involved in ITI need to be evaluated
successful ITI in inhibitor patients with good prognostic factors (aged to further understanding.
below eight years, inhibitor present <12 months, historical peak titre
≥5BU and ≤200BU and starting titre <10 BU). The study began in 2002 Summary
and has randomised 45 severe haemophilia A patients with an inhibitor. Inhibitor development occurs in 30% of all haemophilia patients treated
The study hypothesises that a high-dose ITI regimen will achieve tolerance with factor VIII concentrates. ITI is the main model for the eradication of
more rapidly than a low-dose regimen; however, the overall success of inhibitors in haemophilia A patients. However, ITI procedures fail in a
both will be similar in the long term. It is also proposed that low-dose ITI substantial number of patients. Factors have been identified that may affect
will be more cost-effective than the higher dose and lower starting treatment with ITI, including the level of titre at the start of treatment, the
inhibitor titres will be associated with greater success than higher titres. delay from the detection of inhibitor and the start of ITI therapy and
Preliminary data from the trial have demonstrated that 62% of the the dose of FVIII used. However, the most debated and controversial topic
randomised group of patients undergoing ITI have reached a negative in ITI is the use of either plasma-derived vWF/FVIII or recombinant FVIII
The study has also revealed that severe catheter infections are the concentrates. Early evidence suggests that plasma-derived vWF/FVIII has a
most common serious adverse effect of the ITI therapy, affecting duration higher success rate for tolerance over the recombinant FVIII concentrate;
and outcome of ITI. Some reports have noted the success of using however, later studies have reported conflicting data. The International ITI
vWF/FVIII concentrate as a salvage therapy after failed tolerance with Study, the RESIST study and the ObsITI are ongoing studies examining the
recombinant FVIII, which suggests a role for vWF/FVIII concentrate in dose regimen success and product differences, and should provide further
patients with poor prognosis.
A satellite study of the International ITI insight into the future of ITI. ■
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