PROFIT: PRospective studie OF Immune Tolerance induction (ITI)

Nowadays the development of neutralizing antibodies against factor VIII (FVIII)
or factor IX (FIX), so called inhibitors, is one of the most serious
complications during the treatment of haemophilia A and haemophilia B
respectively. This complication occurs in approximately 33% of all patients
with severe haemophilia A and in 5-10% of all patients with haemophilia B,
mostly during the first treatment period. As a consequence of these inhibitors
traditional replacement therapy with FVIII or FIX becomes ineffective, making
it necessary to switch to other, often less effective and more expensive,
treatment options. This all leads to a significant increase in morbidity and
treatment costs and a decrease in patients' quality of life.
The treatment used to eliminate these inhibitors is called Immune Tolerance
Induction (ITI). During this therapy repeated administration of high doses of
FVIII or FIX ultimately leads to eradication of the inhibitor in approximately
2/3 of all patients.
However, the pathophysiology of inhibitor development and the working mechanism
of ITI is not fully elucidated. This lack of knowledge is mainly the result
from the lack of clinical information about the phenotypic and functional
changes of the different FVIII- or FIX-specific immune cell populations that
are involved in the immune responses during factor replacement therapy in
general and during ITI more specifically. Many information is derived from
animal models. However, the utility of these models is limited as
recapitulating the frequent infusion schedule used in ITI protocols in mice is
technically difficult and unethical and moreover translation of data from
animal models to clinical practice in humans is very challenging.
Therefore the best way to answer some of the questions regarding the mechanism
of tolerance induction, both natural and artificial in case of ITI, is to
follow patients during (the first phases of) factor replacement therapy,
including ITI, and to set up a biobank.
By prospectively collecting blood samples during factor replacement therapy and
evaluating the immunological responses during this therapy, important insight
in the mechanism of inhibitor development and tolerance induction can be
obtained. This insight might eventually result in better prevention of
inhibitor development and/or an improvement of the high demanding treatment of
inhibitors by ITI. Moreover information about tolerance induction is not only
beneficial for haemophilia, but also applies to many different other diseases,
especially auto-immune and auto-inflammatory disorders.

Primary Objective:
Improve the knowledge about the immune response during FVIII/FIX replacement
therapy in patients with haemophilia A and B respectively. This involves both
the mechanism of:
1) primary tolerance induction to FVIII/FIX in previously untreated patients
(PUPs),
as well as
2) secondary tolerance induction during ITI in (treated) patients who developed
inhibitors.

Specifically, this immune response means the changes over time in the different
FVIII- or FIX-specific immune cell populations, the number and function of
regulatory immune cells and cytokine production.

Secondary Objective(s):
To set up a biobank to collect blood samples which provide valuable data for
future research on the development of inhibitors and/or immune tolerance
induction in patients with haemophilia.

Single centre, prospective observational cohort study.

In order to participate in this study patients will be prospectively followed,
whereby the first blood withdrawal will take place during the first phase of
the treatment (< 5 EDs).
If patients don't develop an inhibitor, a blood withdrawal for study purposes
will be taken tree times more (at 5-10 EDs, 15-20 EDs and 50 EDs).
If patients develop an inhibitor and start with ITI, they will be followed from
the start of ITI until 2 years after the finish of ITI. During this period
clinical data about the treatment regimen and the course of the inhibitor titer
will be collected and regularly bloodsamples will be taken for immunological
research.
The blood withdrawals for study purposes will always be combined with an
already scheduled outpatient clinic visit and venipuncture, both as part of
standard of care.
Therefore no extra visit to the hospital and no extra venipunctures are
necessary in order to participate in this study. The only difference is that
during some venipunctures a large volume of blood will be taken than normally
(8 ml to 27 ml extra, related to the patients' body weight). Based on an
average duration of ITI of 1-2 years (in which during the first half year blood
samples will be taken every month and thereafter every 3 months) and a 2 year
follow-up after termination of ITI (in which blood samples will be taken 2
times a year), in totaal about 10-20x 8-27 ml blood will be withdrawn for study
purposes.
Hereby the volume of blood is small enough and the interval between the
venipunctures long enough that we don't expect any adverse events or other
risks.