Bleeding Complications of BRAF Inhibitors

Targeted inhibition of the mitogen-activated protein kinase (MAPK) pathway with BRAF inhibitors has been crucial in improving outcomes for BRAF-variant melanoma. However, clinically significant bleeding has recently been reported in the literature. Bleeding on BRAF inhibitors is uncommon but heterogeneous. Across trials, any-grade bleeding has been reported. Grade ≥3 events and fatal intracranial haemorrhage are rare but noted. Mechanistically, BRAF inhibitors can paradoxically activate MAPK signalling in the normal endothelium. This destabilises junctions and promotes microvascular leak. In addition, BRAF inhibitors may reduce tissue factor (TF)-dependent procoagulant activity. Management should focus on regimen-specific labelling with general haemorrhage principles. A baseline appraisal of bleeding risk, assessing for central nervous system (CNS) disease and concomitant antithrombotics use, should be undertaken prior to therapy initiation. Patients should be counselled on bleeding symptoms. There is a paucity of evidence in the literature to guide BRAF therapy use in bleeding events. In general, prompt intervention for bleeding events includes local haemostasis control and continuation for low-grade mucosal bleeds. Therapy should be suspended and multidisciplinary care input sought for major and intracranial haemorrhage. Evidence to guide rechallenge is sparse. Resumption after minor events may be reasonable with dose modification and close monitoring, whereas major or intracranial bleeding generally warrants discontinuation unless a compelling oncologic indication exists and multidisciplinary consensus supports cautious reinitiation after shared-decision making.