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P13 Trametinib for chylothorax management in Noonan syndrome: discussion about efficacy, safety and tolerability
  1. Teresa Brooks,
  2. Sarah Whiteley,
  3. Stephen Morris,
  4. Alix Dunlop-Jones,
  5. Ines Hribernik,
  6. Jamie Bentham
  1. Leeds Children’s Hospital


Introduction Trametinib is a novel medicine that inhibits the mitogen-activated protein kinase enzyme (MEK), part of the mitogen-activated protein kinases (MAPK) signalling pathway. MAPKs regulates cell behaviour by controlling DNA transcription and subsequent protein production. It was developed to inhibit growth of cancers with an up-regulated MAPK signalling pathway. However, its role is expanding to other conditions which also have a link to MAPK pathways. Noonan syndrome is a genetic multisystem disorder which is linked to dysregulation of MAPK pathway.1 Lymphatic abnormalities, most commonly peripheral lymphoedema, are estimated to be present in up to 20% of individuals. There had been one case report in literature whereby a patient with Noonan’s syndrome was treated with MEK inhibitor (trametinib) with remodelling of lymphatic vasculature and complete resolution of symptoms.2

Situation A 3-year-old girl with previous intensive care admissions for chylothorax. Background issues included Noonan syndrome (RIT1 mutation), hypertrophic obstructive cardiomyopathy (HOCM), multiple congenital cardiac abnormalities, and spontaneous bowel perforation with a history of high output ileostomy. Previous failed treatments for the chylothoraces using conventional methods included medium-chained triglyceride (MCT) diet, parenteral nutrition (PN) and octreotide. Trametinib was accessed through Novartis’ compassionate scheme as a rescue treatment. Patients treated with MEK inhibitors are likely to encounter adverse effects including skin irritation, diarrhoea, hypertension, vision changes and pneumonitis. Dosage adjustment or withholding treatment is required if renal, hepatic or worsening cardiovascular impairment occurs. It was felt that this child needed a bespoke side effect management protocol due to their comorbidities. The protocol was devised by the pharmacist in consultation with the mother of the child, dietitian, cardiologist and general surgeon. It was important to particularly target the management of skin rashes, increased stoma losses, pneumonitis, hypertension and cardiac impairment. Tolerability and side effects were monitored and the protocol was followed and adjusted as clinically appropriate based on multidisciplinary team (MDT) and family discussions.

Lessons Learnt This medication is only routinely used in oncology patients in an outpatient setting. Therefore, the side effect management is based on practice within this patient cohort.3 In this situation the treatment was novel, using a theoretical pathway to guide its use. In addition, this child had comorbidities which complicated assessment of side effects. The side effects seen were skin irritation, increased stoma output and nausea, despite proactive management. Skin irritation was managed with short courses of steroid cream and regular emollients under guidance from a dermatologist. High stoma losses (>20 mL/kg) occurred despite maximum dose of loperamide and withholding most enteral nutrition, allowing small bites of fat-free food for comfort, and drinks of rehydration solution as part of a stoma losses replacement plan. In total, 12 weeks of treatment was given, with no chylothorax reoccurrence seen at 10 weeks post-treatment. In conclusion, 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.


  1. Roberts AE, Allanson JE, Tartaglia M, Gelb BD. Noonan syndrome. Lancet 2013;381(9863):333–342.

  2. Dori Y, Smith C, Pinto E, Snyder K, March ME, Hakonarson H, Belasco J. Severe lymphatic disorder resolved with MEK inhibition in a patient with Noonan syndrome and SOS1 mutation. Pediatrics 2020;146(6):e20200167. doi: 10.1542/peds.2020-0167. PMID: 33219052.

  3. O’Hare P, Ahmed M, Samrin-Balch L. Guideline for the prescribing of the MEK inhibitor trametinib for the treatment of oncology indications. Great Ormond Street Hospital for Children NHS Foundation Trust. Dec 2017.

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