Severe adverse events during sirolimus “off label” therapy for
Objectives: Clinical studies have shown low toxicity and a favorable
safety profile for sirolimus in vascular anomalies. Here, we describe
severe adverse events (SAEs) observed during “off-label use”. Methods:
We performed a retrospective, multicenter chart review for SAEs during
“off-label” sirolimus therapy for vascular anomalies and analyzed
these cases by a pre-designed workflow. Results: We identified 17 SAEs
in 14 patients diagnosed with generalized lymphatic anomaly (n=4),
Gorham-Stout disease (n=2), central conducting lymphatic anomaly (n=1),
lymphatic malformation (n=4), tufted angioma (n=1), kaposiform
hemangioendothelioma (n=1), and venous malformation in a CLOVES syndrome
(n=1). Three patients presented two SAEs. The age at initiation of
sirolimus therapy was under the age of 2 years (5x), 2 to 6 years (5x)
and older than 12 years (4x). SAEs occurred during the first 3 months of
sirolimus therapy (7x), between 3 and 12 months (7x) and after one year
of therapy (3x). The most frequent SAE was viral pneumonia (8x)
resulting in death due to a metapneumovirus infection in a 3 months old
and generalized adenovirus infection in a 28 months old child. Sirolimus
blood level at the time of SAEs ranged between 2.7 and 21 ng/L. Five
patients were on antibiotic prophylaxis during sirolimus therapy.
Conclusions: Most SAEs are observed in the first year of sirolimus
therapy; however, SAEs can also occur after a longer treatment period.
SAEs are potentially life threatening, especially in early infancy.
Presence risk factors, i.e. underlying vascular anomaly or immune
status, may contribute to the risk of SAEs.