Trametinib for the treatment of advanced stage patients with arterio-venous malformations.

Background: Arterio-venous malformations (AVMs) may lead to vessel aneurysms and thus to life-threatening bleeding or malperfusion of the extremities, causing recurrent ulceration. Possible therapies are embolisation and/or resection. This study investigates treatment options for patients with AVM Schobinger stage III and IV for whom embolisation and resection are no longer possible and medical treatment with trametinib, a mitogen-activated protein kinase inhibitor (MEK) was performed. Patients and methods: As part of the German guideline development process for the diagnosis and treatment of vascular malformations (AWMF register number 003-007), a systematic literature search was performed using a professional service provider, followed by a retrospective, exploratory analysis based on a consecutive local registry at an interdisciplinary tertiary care center for vascular anomalies. All patients with AVM Schobinger stage IIII - IV were included. Results: Of the 559 reports on specific medications for vascular malformations, only 4 (0.7%) included treatment with trametinib, and only 2 (0.4%) of them addressed its use in AVMs showing reduced blood inflow in the malformation or volume reduction. In our case series of 99 consecutive patients with AVM Schobinger stage III-IV, nine were treated with trametinib. Out of them, 6/9 (66%) had ulceration. 1/6 (20% of the patients with ulceration died, one patient required major amputation, and 4 (60%) were healed without recurrence through treatment. Three patients with chronic pain showed reduced symptoms without requiring additional analgesics. Conclusions: The single cases found in the literature and our small case series suggest that MEK1-inhibitors, such as trametinib, are an option for treating AVM Schobinger stage III - IV. Further large-scale studies are required to confirm these initial observations and to fully explore the potential of MEK1-inhibitors.