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Case Report

Angiographic Evidence of Response to Trametinib Therapy for a Spinal Cord Arteriovenous Malformation

Cooke, Daniel L.a; Frieden, Ilona J.b; Shimano, Kristin A.c

Author Information
Journal of Vascular Anomalies: September 2021 - Volume 2 - Issue 3 - p e018
doi: 10.1097/JOVA.0000000000000018
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Abstract

Introduction

The majority of arteriovenous malformations (AVMs) are sporadic and without known underlying germline gene defects. Recently, there have been several publications implicating RAS and the RAS-related gene family (eg, BRAF, KRAS, and MAPK) in these sporadic cases,1 with 50%–60% of cases demonstrating somatic gene mutations. Based on these results, targeted biologic agents are being used for complex AVM cases.2 MEK-inhibition has recently been reported as a beneficial treatment for KRAS-positive chest wall AVMs.3,4 We previously reported on one of these cases demonstrating significant reduction in the cardiac output after 6 months of treatment.3 We now provide further evidence of MEK-inhibition’s benefit in dramatically reducing flow in the central nervous system (CNS) component of this AVM.

Case report

As previously described,3 the patient had a congenital vascular birthmark on his back and was asymptomatic until age 7 at which time he had flank pain and bruising. Magnetic resonance (MR) revealed a metameric AVM in the left chest wall spanning levels T5 to T9 with cutaneous, soft tissue, and intramedullary (T5) components, consistent with spinal arteriovenous malformation syndrome (aka Cobb’s syndrome). Over the next 7 years, he developed a number of complications secondary to the AVM, including kyphoscoliosis and associated restrictive lung disease and failure to thrive. He developed a progressive spastic paraparesis due to recurrent thoracic spinal cord intramedullary hemorrhages in 2012 and 2017. As part of paraspinal rod placement for scoliosis, a cutaneous sample from his birthmark was taken for genetic testing. No treatment was performed on nor tissue taken from the spinal cord. This skin biopsy revealed a KRAS mutation. Based on this genetic finding and because of his recurrent hemorrhages, at 15 years of age, the patient began oral trametinib 1 mg/d in 2018 and was treated continuously for ~2.5 years, with elective drug holidays in summer of 2020 and winter of 2021 due to family preference. The patient experienced recrudescence of symptoms related to the chest wall component during his drug holiday, though manifested no new neurological deficits while on trametinib. At the time of spinal angiography, the patient had restarted the medication for 12 days after a 6-week drug holiday. To serve as a reference for comparison with prior systemic response, the patient underwent quantitative MR flow assessment, as previously described,3 the day before the scheduled catheter angiogram. Quantitative MR flow imaging of his aorta was 1.0 L/min (2.2 L/min pretherapy in 2018; 0.5 L/min on therapy after 6 months 2019). The spinal angiogram was performed under general anesthesia, using 4-F transfemoral access and a 4-F C2 glide catheter. Intercostal arteries of interest were selected for planar and 3D rotational angiography. As compared to the 2017 angiogram, the patient’s intramedullary AVM had qualitatively decreased in both flow and size (Figure 1). The supply from the left T7 and T10 intercostal arteries had significantly diminished to the thoracic wall AVM (Figure 2), and the supply to the medullary AVM from the left T10 intercostal was not seen at all.

F1
Figure 1.:
Composite image detailing left T7 intercostal angiographic and flat panel CT changes from 2017 (A–C) to 2021 (D–F). The black arrows (A, D) denote the AVM nidus with absence of the lesion (D) seen in a comparable arterial phase in 2021. The inset image in (D) notes the trace residual nidus (small black arrow) best seen in the venous phase. This finding corroborates with CT images (axial: B, E; sagittal: C, F) performed during the angiogram via selective T7 intercostal injections. Despite the metallic artifact, the nidus (white arrow) is significantly smaller. AVM, arteriovenous malformation; CT, computed tomography.
F2
Figure 2.:
Composite image detailing left T7 and T10 intercostal angiographic changes from 2017 (A and B) to 2021 (C and D). The T7 injection (A and C) demonstrates gross reduction in the thoracic wall AVM and its afferents (thin black arrows). This is similarly seen with the T10 injection (B and D) denoted by the black star, as well as absence of the medullary AVM (thick black arrow) as previously supplied by the anterior spinal artery. AVM, arteriovenous malformation.

Discussion

This report is the first to document objective reduction of a CNS AVM following treatment with medical therapy. Importantly, in addition to the angiographic change, the patient had no new neurological signs or symptoms referable to the cord AVM. There are other reports of medical interventions for brain AVMs using doxycycline and bevacizumab,5 though these did not demonstrate reduction in the size or flow of the lesions. There are also reports of spontaneous thrombosis of spinal AVMs particularly following hemorrhage.6,7 We cannot exclude the possibility of such a phenomenon, though would note that the nidus was seen on catheter angiography within days of both hemorrhagic events. With respect to the mechanism of drug action, we noted that all afferent vessels subjectively decreased in size and tortuosity reflecting a reduction in shunt flow and subsequent arterial caliber change. This may suggest that the nidus is the locus of action, an encouraging premise as there is an understandable concern for AVM hemorrhage should the venous outflow be preferentially affected. The authors chose a low dose and the patient experienced minimal side effects during treatment. Future studies will need to evaluate dose effect and duration for both potential primary and adjuvant treatment applications.

A planned trial will evaluate this strategy for patients with non-CNS AVMs in the near future (NCT04258046). For CNS cases, there may be a role for trametinib for patients with inoperable lesions and/or larger lesions that could be downsized to improve radiosurgical or microsurgical treatments. Should the genetic identity of the AVMs prove consequential in the safety and efficacy of such targeted molecular therapies, tissue collection becomes central to management. For peripheral AVMs, this may be problematic due to bleeding concerns, but manageable with conventional biopsy methods, while for CNS AVMs such open surgical biopsy is not possible due to the risk of stroke. As such, investigators at the University of California, San Francisco, have demonstrated a method to safely and accurately collect cells using endovascular means for AVM-specific genetic diagnosis.8 This technique may prove instrumental in determining which cases will most favorably respond to certain therapies, medical, or otherwise, in addition to more generally expanding our understanding of the molecular genetics of secondary vascular disorders.

Conclusion

This case report of a CNS AVM responding to targeted medical therapy indicates the potential therapeutic benefit for patients with life-threatening AVMs that are currently considered incurable.

References

1. Nikolaev SI, Fish JE, Radovanovic I. Somatic activating KRAS mutations in arteriovenous malformations of the brain. N Engl J Med. 2018; 378:1561–1562
2. Fish JE, Flores Suarez CP, Boudreau E, et al. Somatic gain of KRAS function in the endothelium is sufficient to cause vascular malformations that require MEK but not PI3K signaling. Circ Res. 2020; 127:727–743
3. Edwards EA, Phelps AS, Cooke D, et al. Monitoring arteriovenous malformation response to genotype-targeted therapy. Pediatrics. 2020; 146:e20193206
4. Lekwuttikarn R, Lim YH, Admani S, Choate KA, Teng JMC. Genotype-guided medical treatment of an arteriovenous malformation in a child. JAMA Dermatol. 2019; 155:256–257
5. Muster R, Ko N, Smith W, et al. Proof-of-concept single-arm trial of bevacizumab therapy for brain arteriovenous malformation. BMJ Neurology Open. 2021;3:e000114.
6. Gupta V, Rizvi T, Garg A, Gaikwad SB, Mishra NK. Postangiographic thrombosis of a spinal arteriovenous malformation: case report. J Neurosurg Spine. 2005; 2:486–490
7. Chun JY, Gulati M, Halbach V, Lawton MT. Thrombosis of a spinal arteriovenous malformation after hemorrhage: case report. Surg Neurol. 2004; 61:92–94
8. Cooke DL, McCoy DB, Halbach VV, et al. Endovascular biopsy: in vivo cerebral aneurysm endothelial cell sampling and gene expression analysis. Transl Stroke Res. 2018; 9:20–33
Keywords:

AVM; Trametinib; Angiography; Spine

Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Society for the Study of Vascular Anomalies.