Long-Term TIE2 Inhibition in a TEK-Mutated Venous Malformation: A 3-Year Clinical Experience

Venous malformations (VMs) are slow-flow vascular anomalies frequently driven by somatic activating mutations in TEK/TIE2 receptor. Medical treatment options remain limited; while mTOR inhibition with sirolimus has shown moderate benefit, direct TIE2 inhibition has a strong biological rationale and emerging clinical evidence.

We report a 51-year-old patient with a diffuse VM involving the right cervical region, thorax, and upper extremity, associated with a somatic mosaic TEK (L914F) variant. The disease was refractory to conventional therapies and complicated by chronic coagulopathy. Compassionate-use treatment with the selective TIE2 inhibitor rebastinib was initiated based on a previously reported patient. Over 3 years of follow-up, the patient experienced sustained clinical benefit with decreased pain and inflammation, partial volume reduction, functional improvement, and stabilization of coagulopathy with manageable toxicity. Unfortunately, the interruption in the production of the drug made it necessary to try other less specific alternatives like PI3K inhibitor alpelisib.

This second long-term clinical experience supports the sustained efficacy and safety of TIE2 inhibition in selected TEK-mutated VMs and highlights the therapeutic gap arised from drug discontinuation, underscoring the need for alternative targeted strategies and prospective evaluation.