Oral Sirolimus: An Option in the Management of Neonates with Life-Threatening Upper Airway Lymphatic Malformations

Abstract

Background: Mechanistic target of rapamycin (mTOR) inhibitors are being used off-label showing promising results in patients with vascular anomalies. Children with lymphatic malformations (LMs) involving the airway benefit from sirolimus therapy soon after birth, reducing the need of tracheostomy. Available information about efficacy and side effects in neonates remains poor. We present seven newborns with severe head and neck LM showing response to sirolimus with no significant toxicity. Methods and Results: We performed a retrospective review of neonates with head and neck LM who received sirolimus between January 2014 and May 2018 with upper airway involvement needing ventilatory support. We analyzed type of LM, involved anatomical area, symptoms and response to sirolimus, including dosage, blood levels, response, side effects, and complications. Seven neonates received primary treatment with sirolimus in the context of cervical LM. Sirolimus was started at the recommended dose of 0.8 mg/m 2 /12 h and adjusted to maintain blood levels between 4 and 12 ng/mL. Median follow-up was 32 months (4-43) with a median treatment duration of 12 months (3-43). One patient had complete resolution of the malformation, one had complete resolution of symptoms, and five had partial resolution of the malformation with significant improvement in their respiratory conditions. Two patients required additional subtotal surgical resection and one tracheostomy. Four patients remain under treatment. Toxicity was not observed. Conclusions: Sirolimus is a safe drug in neonates and can be considered the first therapeutical option in newborns at high risk of respiratory failure before sclerosis or surgery. Close follow-up is mandatory to identify side effects at long-term use.

Early Adjuvant Medication With the mTOR Inhibitor Sirolimus in a Preterm Neonate With Compressive Cystic Lymphatic Malformation

“…Sirolimus seems to be helpful in the management of cystic lymphatic malformations but without the necessary hindsight to define its place in the therapeutic strategy as well as its dosage and duration. Our observation along with a few other ones (6,7,10,12) suggest that it could be considered as an adjuvant therapy in first line because it is a feasible therapy with an acceptable safety. This is particularly interesting in preterm neonates for whom surgery and sclerotherapy procedures can expose to severe complications.…”

“…The choice of this therapeutic target was made in concentration with the local referring center for vascular malformations. However in the literature, the usual therapeutic target is frequently lower ( 2 , 7 , 10 , 17 ). We can hypothesize that a lower serum level of sirolimus could have prevented from those adverse events in our patient.…”

“…However, there are no guidelines concerning the treatment that is therefore individualized for each patient and situation (5). In the recent literature, off-label administration of sirolimus has been reported in such indication and could constitute an effective treatment (6,7).…”

Lymphatic and Mixed Malformations

“…Rare reports of Pneumocystis carinii pneumonia while on sirolimus support prophylaxis with trimethoprimsulfamethoxazole. 36 Sirolimus and additional inhibitors of the PI3K/AKT/mTOR signaling pathway used in treatment of LMs 37 can be reviewed in Figure 5.…”

Efficacy of Initial Sirolimus Therapy for 27 Patients with Intractable Lymphatic Malformations

“…3,4 LMs can cause adjacent structures compromise leading to life threatening airway obstruction, cosmetic deformity, swallowing impairment, infection, or naturally diffuse. 1,[5][6][7][8] Current treatment strategies include observation; sclerotherapy; radiofrequency ablation; laser therapy; and/or surgical interventions, including debulking of symptomatic regions or total resection, but it is often technically challenging-especially for LMs located close to vital structures. 6,9 Sclerotherapy has been reported to be as effective as initial surgery on treatment of LMs.…”