Canadian Consensus for Treatment of BRAF V600E Mutated Pediatric and AYA Gliomas

Abstract

Background: The treatment of BRAF V600E gliomas with BRAF inhibitors (BRAFis) and MEK inhibitors (MEKis) has been increasingly integrated into clinical practice for pediatric low-grade gliomas (PLGGs) and pediatric high-grade gliomas (HGGs). However, some questions remain unanswered, such as the best time to start targeted therapy, duration of treatment, and discontinuation of therapy. Given that no clinical trial has been able to address these critical questions, we developed a Canadian Consensus statement for the treatment of BRAF V600E mutated pediatric as well as adolescent and young adult (AYA) gliomas. Methods: Canadian neuro-oncologists were invited to participate in the development of this consensus. The consensus was discussed during monthly web-based national meetings, and the algorithms were revised until a consensus was achieved. Results: A total of 26 participants were involved in the development of the algorithms. Two treatment algorithms are proposed, one for the initiation of treatment and one for the discontinuation of treatment. We suggest that most patients with BRAF V600E gliomas should be treated with BRAFis ± MEKis upfront. Discontinuation of treatment can be considered in certain circumstances, and we suggest a slow wean. Conclusions: Based on expert consensus in Canada, we developed algorithms for treatment initiation of children and AYA with BRAF V600E gliomas as well as a discontinuation algorithm.

Keywords: BRAF V600E mutation; BRAF inhibitor; MEK inhibitor; glioma; high-grade glioma; pediatric low-grade glioma.

Figure 1

Treatment algorithm for pLGG and HGG with BRAF V600E mutation. a: including inability to receive weekly IV treatment due to long distance between home and hospital or high psychological impact of frequent visits for the child or family; b: consider resection or biopsy if progression despite optimal treatment; c: on clinical trial/study if possible; d: consider continuing BRAF inhibitors and MEK inhibitors concurrently with radiation therapy or standard chemotherapy in cases where rapid progression could be associated with neurological deterioration. Caution should be taken since these combinations have not been studied in the setting of a clinical trial for CNS tumors; e: please refer to the discussion section for specific discussion on HGG.

Figure 2

Discontinuation algorithm for PLGG and HGG with BRAFV600E mutation. Suggested surveillance MRI frequency during treatment: every 3 months for 2 years, and every 6 months after if stable and depending on clinical evolution. a: if the dose cannot be tapered by approximately 25% every three months due to tablet size/formulation. Consider alternate dosing (3 days on/one day off, 1 day on/1 day off, 1 day on/3 days off). b: MEKi could be tapered before BRAFi. c: taper 1 month prior to the next planned surveillance MRI. d: consider resection or biopsy if progression occurs.