Discussion
Sirolimus is a relatively old drug, that has successfully been used as
an immunosuppressive agent in the context of solid organ transplantation
[15]. The possibility to measure sirolimus serum trough levels makes
the therapy well controllable. There is, however, no recommendation for
an effective and safe serum level for pediatric patients [16].
Furthermore, data on safety of sirolimus therapy in children for its use
in the approved indications is scarce. In a clinical study on children
with autoimmune lymphoproliferative syndrome, no major side effects in
the 30 patients with a median age of 11 years treated with sirolimus
were reported [17].
In the context of vascular anomalies, sirolimus has been administered
for the last several years. In the phase II trial from the U.S. for
patients with complicated vascular anomalies 57 patients were treated
with a median age of 8.1 years at start of therapy [3]. The most
common toxicities (grades 3 or 4) attributed to sirolimus included
blood/bone marrow (27% of patients), metabolic/laboratory (3%),
gastrointestinal (3%), infectious (2%), lymphatic (2%), and/or
pulmonary/upper respiratory (2%) complications. Dose reduction was
required in 2 patients, one associated with possible laryngospasm and
the second related to hypertriglyceridemia. Two patients were taken off
study secondary to toxicity: One patient had persistent grade 2 nausea
and the second grade 3 lymphedema. No toxicity-related deaths were
observed. Interestingly, no SAEs were reported in 6 patients reported
from the University Hospital in Graz, Austria, who had started sirolimus
therapy under the age of 2 years (4x at birth, and at 10 and 13 months)
and continued therapy for 3 to 56 months [18].
Most of the SAEs in this survey were infections that could be managed by
hospitalization, antibiotics and supportive care. The most frequent
cause of the respiratory infections were viruses demonstrating that a
prophylactic antibiotic therapy during sirolimus cannot mitigate the
risk of all infectious complications. Unfortunately, results on immune
status (lymphocytes, immunoglobuline level, etc.) from the affected
patients were not available. Risk factors of the underlying vascular
malformations appear important, e.g. in GSD osteosynthesis material in
fractured bones can easily be infected. Furthermore, lung and/or bowel
involvement as well as spleen involvement may be a predisposing factor
for severe infections, because most patients with SAEs in this survey
suffered from LM and especially complex lymphatic anomalies such as GLA
and GSD.
There are 3 fatal cases of SAEs during sirolimus therapy in the
literature: The first case is due to pneumocystis jirovecii pneumonia
(PJP) leading to respiratory failure, which required extracorporeal
membrane oxygenation. Importantly, sirolimus was administered in
combination with steroids, which might have contributed to the
development of PJP [12]. The other two fatal cases had respiratory
failure as well; however, an infectious agent could not be identified
[13]. Additionally, Parker et al. reported SAEs in a pilot study on
39 patients with PROS and progressive overgrowth treated with sirolimus
[14]: 23 SAEs occurred among 12 participants of the study leading to
discontinuation of sirolimus in seven patients. The most common class of
adverse effects (AEs) was infection in 41% patients, followed by blood
or lymphatic disorders in 21%. Clinically important AEs included grade
4 neutropenia (neutrophil count 0.02 × 109/L),
interstitial pneumonitis, and a sirolimus hypersensitivity syndrome with
prolonged fever. Sirolimus was withdrawn in all three participants, all
of whom subsequently made full recoveries.
Most SAE reported in our retrospective survey were observed during the
first year of sirolimus therapy. However, some patients experienced SAE
with sirolimus therapy after several years. Two SAEs in our cohort lead
to death in young infants. Presence of further risk factors, i.e. of the
underlying vascular anomaly could play a role, as it was the case in the
GLA patient with lung and bowl involvement (P03). Viral infections like
metapneumovirus, rhinovirus, parainfluenca viurs and adenovirus must be
added to the list of possible opportunistic infections next to the
already known risk for PJP.
The major limitation of this retrospective study is the “off-label”
setting. There was no harmonized treatment protocol, and “low-dose” as
well as “high-dose” sirolimus has been administered. Interestingly,
the occurrence of SAEs did not seem to be dependent on the sirolimus
blood level. Furthermore, anti-infectious prophylactic measures were not
standardized. Moreover, we cannot calculate the true frequency of SAEs
during sirolimus therapy from our data because the number of patients
with vascular anomalies treated with sirolimus cannot accurately be
estimated, since some patients for whom sirolimus treatment was
recommended then received therapy at another hospital. Calculating the
incidence of SAEs of sirolimus with the number of patients treated with
sirolimus at the participating centers would thus overestimated the true
incidence. In addition, it would be helpful to have more detailed
information on the immune status of the reported patients to exclude
underlying risk factors.
Nevertheless, we suggest that patients treated with sirolimus for
vascular lesion may be at a significant risk for severe adverse events
and should be monitored carefully, even when they are maintained at a
low sirolimus trough levels. Furthermore, all recommended vaccinations
should be realized before start of sirolimus therapy and dead vaccines
should be continued to be administered according to recommendations
during sirolimus therapy. Finally, experienced investigators should only
administer sirolimus for vascular anomalies, preferably in the setting
of a clinical study.
Most recently, inhibitors of PI3KCA are under clinical evaluation in
patients with vascular anomalies. A first case series of 20 patients
showed preliminary results with efficacy and few mild side effects
[19]. Hopefully, this more selective therapeutic approach will
provide better therapy for patients affected with these rare and
heterogeneous disorders.