Introduction
In the last years, sirolimus, a well-established mTOR inhibitor, has
entered the therapeutic field of vascular anomalies [1] and is
currently administered for complicated vascular tumors, such as
kaposiform hemagioendothelioma (KHE), as well as for vascular
malformations refractory to standard therapy, including venous
malformations (VM) and lymphatic malformations (LM). Initial
observations of the effectiveness of sirolimus lead to a small case
series [2] followed by a clinical study in the US that included all
types of vascular anomalies refractory to previous therapy [3].
Several other studies followed analyzing the effect of sirolimus in
defined subgroups of vascular anomalies, such as VM, LM [4],
generalized lymphatic anomalies (GLA) [5], Gorham Stout disease
(GSD) [5], blue rubber bleb nevus syndrome (BRBNS) [6] or in KHE
with Kasabach-Merritt phenomenon (KMP) [7]. Taken together, the
therapeutic benefit of sirolimus could clearly be demonstrated, although
complete remission as a therapeutic end point was never reached.
In parallel to the clinical use of sirolimus, genetic testing has
elucidated the molecular mechanism of the activity of the mTOR inhibitor
in vascular anomalies. Somatic and germline mutations in the
tyrosine-kinase transmembrane receptor TEK were found in VM
[8], while the presence of PI3KCA mutations could be
demonstrated in tissue of VM and LM [9] as well as in endothelial
cells of LM [10]. Furthermore, PI3KCA mutations have been
described in overgrowth tissue leading to the description of thePI3KCA Related Overgrowth Spectrum (PROS) [11]. Both PIK3CA
and TEK have thus been identified [8] as a therapeutic targets and
are located upstream of mTOR in its signaling pathway.
Sirolimus has been used for many years as an immunosuppressive agent in
patients after organ transplantation, a population at high risk for
opportunistic infections. In patients with vascular anomalies, the
safety profile of the drug appears very favorable. However, two reports
with infectious complications due to sirolimus in this patient
population can be found in the literature: the first report is on a
child with KHE and KMP who developed pneumocystis jirovecii pneumonia
(PJP) while on sirolimus and a prednisolone taper [12]. The child
recovered under therapy with trimethoprim‐sulfamethoxazole (TMP‐SMX).
The second report is on two infants with KHE and KMP who both manifested
paroxysmal cough and tachypnea shortly after the onset of sirolimus
treatment and finally died [13]. Authors of both manuscripts advice
to administer prophylactic trimethoprim/sulfamethoxazole (TMP‐SMX) for
the prevention of pneumocystis jirovecii pneumonia (PJP) as implemented
in the US clinical trial. Furthermore, a trial with sirolimus for the
treatment of PROS-patients showed a surprisingly high incidence of
severe adverse events (SAE with >grade 3 severity in 26%
of patients), including infectious complications [14].
Here, we report the results of a survey on the nature of SAE in patients
treated with sirolimus in an off-label setting.