P13 Trametinib for chylothorax management in Noonan syndrome: discussion about efficacy, safety and tolerability

Abstract

Background and Aim: 3 year old with recurrent chylothoraces. Background of Noonan syndrome (RIT1 mutation), hypertrophic obstructive cardiomyopathy, multiple congenital cardiac abnormalities, and spontaneous bowel perforation with ileostomy. Previous failed treatments for the chylothoraces included medium-chain triglyceride diet, parenteral nutrition (PN) and octreotide. Noonan syndrome is linked to dysregulation of the mitogen-activated protein kinase (MAPK) pathway (1). Mitogen-activated protein kinase enzyme (MEK) inhibitors disrupt theMAPKsignalling pathway. One case demonstrated lymphatic vasculature remodelling and resolution of recurrent chylothoraces with the provision of MEK inhibitor, trametinib, in a patient with Noonan's syndrome (2). Method: Trametinib was accessed through Novartis' compassionate scheme with dosing based on oncology (0.032mg/Kg/day), for 12 weeks of treatment (3). A side-effect management protocol was designed targeting the most common side effects: skin rashes, increased stoma losses, pneumonitis, hypertension and cardiac impairment. Baseline assessment included: blood testing, tibial growth plate and left wrist X-ray, ophthalmology assessment, physical examination. Throughout treatment monitoring included; weekly bloods and daily physical examination, stoma output measurement and weight. A skin emollient regime was proactively initiated. All baseline tests were normal. Results: Skin irritation worsened within 4 weeks of treatment. It was managed with steroid creams and dressings under dermatology guidance. Stoma output escalated within 24hrs of starting treatment, to a maximum 45mL/kg, normalising 14days post-treatment. Stoma losses remained high (>20mL/kg) despite loperamide and withholding most enteral nutrition, moving to PN to meet nutritional needs. Enteral intake was limited to small bites of fat-free food, and rehydration solution for stoma loss replacement. Diuretics and weight were reviewed daily, ensuring a neutral fluid balance, appreciating large insensible losses. Nausea and vomiting were seen throughout, leading to the provision of anti-emetics and proton pump inhibitors. ALT and serum triglycerides increased, improving with a reduction inPN lipid provision and infusion time. GammaGT increased within 1 week of treatment and were not back to baseline at discharge. There has been no chylothorax reoccurrence 31 weeks posttreatment. Conclusions: Our experience has demonstrated that it is possible to manage the side effects of trametinib in a patient with multiple comorbidities using a patient centred and MDT approach.