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

Summary: 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.