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Coagulation Disorders Haemophilia
Table 1: Summary of Success Rates of Immune Tolerance
by taking the individual situation of the patient and his or her own
Induction Performed with Plasma-derived Factor VIII or
experience into account.
Recombinant Factor VIII at the Haemophilia Treatment
Centres in Frankfurt, Bonn and Bremen
48,52
Interruption of the Treatment
Frankfurt Bonn and Bremen Frankfurt, Bonn
The immunological interactions during ITI are not very well known.
and Bremen However, it is clear that these reactions are very complex and should
Before 1990–1993 pdFVIII 91% pdFVIII 87% pdFVIII 88%
not be interrupted.
1
Single cases have been reported that show that
(19/21) (44/51) (63/72)
the inhibitor can reappear or that the titre can increase again when ITI
After 1990–1993 pdFVIII 100% pdFVIII 82% pdFVIII 83%
is interrupted or stopped before tolerance is achieved. For the same
(2/2) (23/28) (25/30)
reason, disturbance of the treatment by any immunologically stressful
rFVIII 29% rFVIII 43% rFVIII 36%
(4/14) (6/14) (10/28)
situation should be avoided; these include surgical interventions,
rFVIII → pdFVIII rFVIII → pdFVIII rFVIII → pdFVIII
vaccinations or other therapies influencing the immune system.
80% (8/10) No data 80% (8/10)
pd = plasma-derived; r = recombinant; FVIII = factor VIII.
When to Stop Immune Tolerance Induction
ITI therapy should not be stopped before the inhibitor is permanently
The ITI success rates published by experienced centres are in the range eradicated, because otherwise there is a high risk of inhibitor
of 60–91%, while the success rates from a larger number of centres reappearance. The criteria for permanent eradication and successful ITI
documented in the ITI registries and from a European survey on ITI are undetectable inhibitor level (0BU), normal recovery and normal
practice are lower – in the range of 40–78%.
1
half-life. The critical parameter for normalisation of FVIII half-life is
normalisation of 12-hour recovery. Repeated assessments of 12-hour
Parameters have been identified that may influence the outcome of recovery over six to eight weeks are needed to confirm normalisation
tolerance induction.
3,57
Titre at onset of tolerance induction, time before reducing FVIII dosage. A continuous reduction of about 10% of
between inhibitor detection and start of tolerance induction, the initial ITI dosage should then be started, initiated with the evening
interruption of the treatment, when to stop ITI, dosage of FVIII product doses. If 12-hour recovery remains normal, dosages can be further
and type of FVIII product seem to be the most important parameters. reduced by about 10% every two to four weeks, alternating evening
However, our knowledge about the success of ITI and the parameters and morning doses. When the daily dosage has been reduced to 50%
that influence outcome is mainly empirical and derives from the of the initial ITI dosage, the total dose should be given once daily.
experience of only a few bigger treatment centres
3,53,58,59
and from three Thereafter, dosage and frequency should be slowly tapered down to a
larger registries of patients who have undergone ITI. Many questions are normal prophylactic treatment.
52
still open and need larger studies in order to generate more evidence for
current treatment practice. Dosage of Factor VIII Product
One of the most controversial outcome parameters is the optimal FVIII
Titre at Onset of Tolerance Induction dose regimen for successful ITI. While the international ITI registry
When to start ITI is one of the open questions that need further data. demonstrated a significant advantage of a high-dose regimen
On the one hand, several studies with smaller cohorts and all (200IU/kg/day), which correlates very well with the long-term
retrospective registries indicate that the success rate is highest when experience of many European treatment centres, some other studies –
the inhibitor titre at start of ITI is below 10BU.
1
As a consequence, the and also the North American ITI registry – cannot confirm this result or
majority of treaters prefer to defer the start of ITI until the inhibitor even report an inverse relationship.
4
The International Immune
titre is <10BU, treating the patient with bypassing agents only during Tolerance Study, a multicentre, prospective, randomised trial of ‘good-
this phase. On the other hand, the European survey on ITI practice risk’ patients with severe haemophilia A and inhibitors, was initiated in
revealed that one-third of centres nevertheless start ITI immediately 2002 to definitively determine the influence of FVIII dosing on ITI
after diagnosis and independent of the inhibitor titre.
1
It is not known success.
60
The study hypothesis is that FVIII dosage in this good-risk
whether the overall ITI success rates in these centres are lower, but the population will not influence the overall ITI success rate, but will have
time until tolerance is achieved is shorter; this may be of major an impact only on the time needed for tolerance induction and on
importance, because the time spent living with an inhibitor is also the morbidity. Even if this hypothesis can be confirmed by the study, this
time when critical bleeding situations can occur. result can be seen as an advantage for the high-dose regimen because
longer treatment time and higher morbidity are crucial disadvantages
Time Between Inhibitor Detection and for patients.
Start of Tolerance Induction
This question correlates very closely to the question above. In general, Type of Factor VIII Product
ITI should be initiated as early as possible after inhibitor detection, Currently, the question of which is the superior type of FVIII product
because living with an inhibitor, especially a high-responding inhibitor, for ITI is the most debated question in this field. Common practice has
is critical for the patient. Severe bleedings are often not easy to control been to start ITI with the same product that induced the inhibitory
and in emergency situations adequate treatment may not be response. In the 1970s, 1980s and early 1990s, this was pdFVIII
available.
53
On the other hand, there are data suggesting better ITI products, which contain VWF as a natural complex partner. During
success when the treatment is started after the titre has decreased that time, the first large ITI studies according to the Bonn protocol
below 10BU.
1
Further studies are necessary to provide a clear answer were conducted, with success rates of 85–90%.
3,58
After the
to this question. Until then, the treater has to decide when to start ITI introduction of ultra-high-purified pdFVIII or rFVIII products – which
18 EUROPEAN HAEMATOLOGY
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