Endocrine effects of MEK and BRAF inhibitor therapy in paediatric patients: a tertiary centre experience.

Purpose: BRAF and MEK inhibitors are used to treat a range of paediatric tumours including low-grade gliomas. The ubiquitous nature of the BRAF/MAPK/MEK pathway means such treatments are not without side effects such as renal tubulopathies and hyperglycaemia. This study aims to describe the endocrine dysfunction observed in a cohort of children treated with BRAF and MEK inhibitors at the largest paediatric centre in the UK utilising these treatments.

Methods: Electronic data for patients treated with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) from January 2019 to May 2022 were retrospectively reviewed. Outcomes included diagnosis of glucose dysregulation, the presence of hyponatraemia (< 135 mmol/l) and sodium nadir during treatment.

Results: A total of 55 patients were included for analysis. Nine patients had at least one hyponatraemic episode during treatment of whom three had coexisting central diabetes insipidus. A statistically significant difference (p-value = 0.037) with regards to the plasma sodium nadir during treatment was observed between patients with diabetes insipidus (median = 134 (132-137) mmol/l) and patients without (median = 137 (127-141 mmol/l). Six patients were diagnosed with a form of glucose dysregulation (e.g. insulin resistance, type 2 diabetes), of whom four were diagnosed during treatment with dabrafenib, all with hypothalamo-pituitary lesions.

Conclusion: Clinicians using such treatments need to be aware of these potential effects, particularly the risk of hyponatraemia in patients with pre-existing central diabetes insipidus and monitor for these accordingly, including performing measurements of sodium and glucose prior to, during and after treatment.