Extensive venous malformations (VM) involving limbs severely impact quality of life, mostly due to chronic pain and functional limitations. Patients can also display coagulopathy with associated risks of life-threatening thromboembolism and bleeding. Current pharmacological VM treatments (e.g. sirolimus) are not universally effective as 10% of patients present intractable debilitating and/or critical disease. Novel therapies are therefore highly needed for treatment-resistant VM. Over 70% of sporadic VM are attributed to activating mutations in the TEK gene, encoding the receptor tyrosine kinase TIE2 expressed by venous endothelial cells. Despite in vitro studies showing the superiority of alpelisib over sirolimus in inhibiting TIE2 signalling pathway and vein remodelling, there are currently no clinical reports of alpelisib use in VM. Our aim was therefore to assess the effect of alpelisib in TIE-2 mutated VM and to assess its pharmacokinetics.
Three patients with a VM harboring the TEK L914F mutations were treated with alpelisib in an open-label compassionate use study. All patients experienced significant improvement. Pain was controlled, gait improved, size of the abnormal venous network decreased, and coagulopathy showed dramatic improvement. Drug exposure was highly variable despite similar weight-adjusted doses, suggesting that alpelisib dosing should be individualized to patient’s characteristics and guided by therapeutic drug monitoring to improve clinical response.