Treatment of congenital vascular malformations using Sirolimus: improving quality of Life

Congenital vascular anomalies are uncommon and belong to the group of rare
diseases. In 1996, the International Society of the Study of Vascular Anomalies
adopted a new classification, distinguishing vascular malformations from
vascular tumors. This classification was revised in 2014 and newly identified
genetic features were taken into account. Vascular malformations feature
dysplastic malformed vessels and are a consequence of a defective development
of the embryonic vascular system. Vascular malformations can involve lymphatic
vessels, capillaries, veins and arteries or even combinations. These vascular
malformations are present at birth and grow with the child. Treatment options
range from conservative to
surgical extirpation or intralesional embolisation/sclerosis . Unfortunately,
this is often not enough. Many patients still have complaints like severe pain
and invalidation due to the lymphatic or venous malformation making a normal
functional life impossible. These vascular malformations can cause serious
complications including obstruction of vital organs and their function,
recurrent infection and significantly reduced quality of
life of persons affected. As the natural course of the disease affects multiple
body systems, the therapeutic management is challenging. To date, no other
medical treatment options are available. Although standard pain medication is
given according the (inter) national pain protocols, patients still suffer pain
and are not able to function normally in daily life. Majority (60-70% percent
of the patients) of the patients is not able to
have a normal life, with a normal job and normal social activities. Children
are often not able to go to school normally, cannot play outside and have pain
at the site of the malformation. The vast majority of literature reporting
medical therapies for vascular anomalies consists of case reports and small
series and is complicated by publication bias (negative findings are often not
published), inconsistent use of nomenclature, and the absence of clinical
trials. Recent case reports mention the positive effects of refractory patients
with Sirolimus. Sirolimus, also known as rapamycin, is currently the only
FDA-approved mTOR inhibitor, indicated for prevention of kidney allograft
rejection in adults and children 13 years or older,
but is commonly used to manage organ rejection in younger children. mTOR is a
serine/threonine kinase that is regulated in the cell by
phosphoinositiede-3-kinase (PI3K) and Akt.In patients with vascular
malformations mutations in the mTOR pathway occur leading to increased
activation of mTOR. For example, in patients with venous malformations
mutations in the gene encoding for TIE2 (=endothelial cell tyrosine kinase
receptor 2) occur in almost 50% of cases leading to a chronic activation of
AKT. In patients with lymphatic malformations similar mutations can be found
leading to the same activated pathway. Inhibition of this pathway in patients
with vascular malformations seems therefore very rational.
In the literature more than 85 cases of all kind vascular malformations have
been published so far. All showing a positive effect of Sirolimus in the
treatment of vascular malformations. Based on all these case reports it seems
Sirolimus is a panacea, however, we believe this is most probably caused by a
publication bias i.e. we think that failures of treatment are not reported.
Although the number of patients treated in our hospital center is still small
(n=8), one patient did not respond to Sirolimus treatment underlining this
hypothesis. For this reason we want to perform an open label study with
Sirolimus in patients that have congenital vascular malformations that cannot
be treated by other conventional techniques.

As patients with congenital vascular malformations often suffer from severe
pain and morbidity due to the vascular malformation, quality of life is often
signifcantly impaired. The primairy objective of the present study is to reduce
pain complaints and in this way improving the quality of life of the patients.

The diagnosis of vascular anomaly has been made previously based on clinical,
radiographic and//or histological criteria. mTOR inhibitors, such as Sirolimus,
have been postulated to be beneficial in the treatment of these complex
vascular anomalies were no other conventional treatment options are present.
Sirolimus is currently the only FDA and EMA-approved mTOR inhibitor. To make
sure that only patients that have no other treatment options will be included,
a independent committee will evaluate the patient whether he/she is eligible
for the present study. All patients will be treated for six months with
Sirolimus, followed by at time period without treatment . If pain complaints
return a second phase of one year with treatment of Sirolimus will start
(rechallenge).
As control, the chronic history as has been documented in the medical records
of the patients will be used. Before start of the study the chronic history of
the patients will be documented and data will be entered in a GCP certified
data-management system (Castor) that is already operational. In addition, for
start of the study all patients will have an assessment regarding quality of
life and a recent MRI of the vascular malformation. Furthermore, patients will
be asked to keep a diary in two months before start with Sirolimus to monitor
complaints of pain (using the VAS score). The quality of life assessments are
being performed to gain insight in the burden of the disease in daily life and
the influence of pain experienced by patients in daily life. After six months
of treatment the possible effect of Sirolimus on the vascular malformation is
being evaluated by MRI. In addition, Quality of Life assessments will be
performed again at, six and at the end of the study (12 months). Total duration
of inclusion of patients in the study will be 2.5 years. All patients will have
at least one year follow up after the six months treatment meaning that the end
of study will be after 4.0 years. The study will be performed according the GCP
guidelines.
All patients will be included and start the trial in Nijmegen, as regular
controls will take place also in Nijmegen . Sirolimus has been provided for all
patients, however, is only send and stored at the Radboudumc. However, if
necessary, controls in between for example in case of fever, will be done as
close as possible to the place where patients live.

The intervention is treatment with Sirolimus

The agent Sirolimus is extensively known from the treatment of patients with
kidney transplants. For this reason the side effects of Sirolimus are well
known, although Sirolimus in renal transplant patients is always given in
combination with other agents such as cyclosporine and corticosteroids. As
these drugs are converted through the same pharmacological pathway you can
expect this to affect the risk of side effects. Given the fact that patients
with vascular malformations will receive Sirolimus as a single agent (if any
pain medication except acetaminophen is stopped prior study in order to
adequately assess the effect of sirolimus on the pain), it is expected that
the risk of side effects is much lower. In the 12 patients who have been
treated at our center , 1/3 of patients developed after start of Sirolimus
aphthous lesions in the mouth that mostly disappeared within 2 weeks, one
patient had passagere hepatic impairment, one patient had had a passagere
hypertriglyceremie and one patient developed hypophosphatemia when Sirolimus
levels were higher. After lowering the Sirolimus is this side effect
disapeared. In our view, all side effects associated with a low risk profile.
The burden that exist for the patients, in particular for those that have to
travel for a larger distance, are the regular visits that have to take place in
Nijmegen, including blood withdrawal each time that they have a control
appointment. Although this burden is present, especially for those patients who
come from further, there is no increased risk associated with them and the
burden is in our opinion minimal. Furthermore, the patient will have at start
of the study as well as after six months a MRI of the vascular malformation.
All children participating in the study will be adequately accompanied
pedagogical staff to minimize the burden of having MRI.
Finally, questionnaires are completed with respect to quality of life for both
children and parents and for the adult participants. The burden of this is
mainly the time it costs. Some of the patients are already known to the medical
psychologist and have already completed the questionnaires. Depending on how
long ago this have been done, these questionnaires will be filled again.

In conclusion, the estimate of the risk and burden of the present study is in
our opinion acceptable with minimal risk (e.g. possible side effects of
Sirolimus)