I-SWITCH: Changes in Immune profiles after SWITCH to a different factor VIII product

Hemophilia A is a serious bleeding disorder characterized by a deficiency of
factor VIII (FVIII). Treatment traditionally consists of administration of the
deficient coagulation protein. The past decennia a lot of progress has been
made in the development and improvement of many different types of FVIII
concentrates.
Nowadays the most serious complication in the treatment of hemophilia A is the
development of so called *inhibitors*, neutralizing antibodies against factor
VIII, which occurs in almost 30% of all patients with severe hemophilia A. As a
consequence of these inhibitors traditional replacement therapy becomes
ineffective, making it necessary to switch to alternative hemostatic therapies
by using bypassing agents, which are less efficient, more costly and moreover
require a lot of intravenous injections because of a very short half-life. This
all causes a high morbidity and negatively influences patients* quality of
life3.

Since the important negative impact of inhibitors a lot of attention is paid to
the prevention of inhibitor formation as well as the elimination of inhibitors,
once they are formed. Considering prevention of inhibitor formation many
different risk factors are described, both patient-related and
treatment-related. An ongoing and still unresolved issue in the risk of
inhibitors is the role of the different FVIII products, whereby there is some
evidence that recombinant FVIII is associated with a higher risk of inhibitor
formation compared to plasma derived Von Willebrand Factor containing products
(pd-VWF/FVIII) FVIII (pd-FVIII).

Another interesting issue is the recent introduction of FVIII products with an
extended half-life, for example rFVIII-Fc, which is a fusion protein of rFVIII
and the Fc domain of IgG1. The approximately 1.5-fold longer half-life of
rFVIII-Fc is caused by the possibility of the Fc-domain to bind to the neonatal
Fc receptor (FcRn), which is expressed in many cell types and protects IgG1 and
Fc-fusion proteins from lysosomal degradation. The main advantage of this new
rFVIII-Fc product is that it requires less intravenous injections, making the
treatment of hemophilia less invasive and burdensome. Moreover there are some
previous reports that fusion of FVIII (or other haptens) to the Fc-region of
IgG has immunomodulatory properties and may induce tolerance. Therefore
rFVIII-Fc could have a protective role in the prevention and treatment of
inhibitors. Recently this has been confirmed in a hemophilia A mouse study.

Due to national regulations the prescription of coagulation products will
change this year and for hemophilia A the number of FVIII products will be
limited to the use of three preferred medications, of which two short-acting
rFVIII products and the abovementioned rFIII-Fc. Therefore many patients with
hemophilia A will have to switch to a different FVIII product.
For some people, both patients and doctors, there is still some reluctance to
change FVIII products because of the fear of inhibitor formation. However this
is mainly based on some older reports and is not confirmed in more recent
studies.

Since hemophilia A is still a relatively rare disease it*s not easy to perform
large randomized controlled trials. Instead information to a large extent is
still derived from case reports, case series and retrospective cohorts. Due to
the abovementioned change in prescription regulations a large cohort of
patients will have to switch to a different FVIII product. This switch offers
an unique opportunity to prospectively follow these patients and to perform an
immunologic analysis, which can provide essential information regarding
possible changes in the immunologic profile after switch to a different FVIII
product and if there is a difference between the various types of FVIII product
(ie pd-VWF/FVIII vs. rFVIII vs. rFVIII-Fc).
Moreover also the incidence of inhibitor formation will be determined. This all
is very valuable information regarding the treatment of hemophilia A.

1. Evaluation of the change in immunologic profile after switch to a different
FVIII product, ie analysis of (FVIII specific) B- and T-cell subtypes, amount
and function of regulatory T cells (Tregs) and cytokine production.

2. Determining the risk of inhibitor formation after switch to a different
FVIII product and evaluating if there is a difference in type of FVIII used
4 different comparisons:
- Switch of pd-FVIII to rFVIII
- Switch of rFVIII to other type of rFVII
- Switch of pd-FVIII to rFVIII-Fc
- Switch of rFVIII to rFVIII-Fc

We hypothesize that switch to a different FVIII product is not associated with
an increased risk of inhibitor formation. With this prospective cohort study we
expect to confirm this hypothesis in order to reduce the fear of changing FVIII
products. Moreover the comparison between the different FVIII products and the
immunologic analyzes will provide valuable informating regarding the ongoing
debate about possible differences in the type of FVIII and the risk of
inhibitor formation.

Prospective cohort study.

For participation in the study patients will be subjected to the withdrawal of
blood at 3 time points (before switch, 4-6 months after switch and 1 year after
switch). At all time points the bloodwithdrawal will be combined with a regular
outpatient clinic visit and scheduled venipuncture as part of standard of care.
So the additional burden due to participation of the study will be the
withdrawal of a larger volume of blood than usual. For patients aged 6-12 years
this will be 3 time 11 ml extra, for patients aged 12 years and older this will
be 3 times 22.5 ml extra. These quantities are so small that no adverse events
are expected.