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.