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.