Prenatal sirolimus treatment for rhabdomyomas In tuberous sclerosis

Daniel Ebrahimi-Fakhari MD, Gabrielle Stires FNP, Eunice Hahn MD, Darcy Krueger MD, PhD, David Neal Franz MD. Prenatal Sirolimus Treatment For Rhabdomyomas In Tuberous Sclerosis.  Pediatric Neurology, in press.

Abstract

Background

In tuberous sclerosis most cardiac rhabdomyomas regress spontaneously. In some cases, the tumors can cause life-threatening hemodynamic comprise requiring subsequent surgical resection. The mTOR inhibitors everolimus and sirolimus have shown to be effective treatments for multiple conditions. There are four cases reporting off-label treatment with transplacental sirolimus in tuberous sclerosis for fetal rhabdomyomas. The optimal dosing regimen is unknown. 

Methods

Retrospective chart review of all patients treated prenatally with sirolimus for rhabdomyomas. All fetuses had a clinical and molecular diagnosis of tuberous sclerosis (2012 Consensus Diagnostic Criteria, including a positive genetic test). Clinical history, mTOR inhibitor dosing and levels, outcome and adverse events were reviewed after initiation of sirolimus treatment. 

Results

Three fetuses were treated with maternal sirolimus. Dosing regimens and subsequent trough levels differed from 1 mg/day to 6 mg/day and <1.0 ng/mL to 12.2 ng/mL. Cardiac rhabdomyomas gradually shrunk in all patients. Growth restriction was noted in one patient. No severe adverse events occurred during the treatment period. 

Conclusions

Maternal sirolimus appears to be a safe treatment option in prenatally detected rhabdomyomas with possible need for intervention. Follow-up visits with fetal ultrasound, echocardiography and laboratory work should be performed weekly during the treatment period. The optimal dosing and trough level timepoints remain unclear. Based on our results we recommend a sirolimus starting dose of at least 2 mg/m 2 /day, preferably 3-3.5mg/m 2 /day to achieve a target trough level of 10-12 ng/mL.