The antiangiogenic properties of thalidomide that caused birth defects when the drug was given to pregnant women have led to an interest in its potential therapeutic applications. Researchers at the de Duve Institute, Université catholique de Louvain, reported promising results from a case study of thalidomide therapy in patients with severe arteriovenous malformations (AVMs). The study demonstrated a striking reduction in symptoms, and improved quality of life for patients treated using thalidomide.

The study results were presented at the annual conference of the European Society for Human Genetics by Miikka Vikkula, PhD, professor, de Duve Institute, and were also reported in Nature Cardiovascular Research, in a paper titled, “Case report study of thalidomide therapy in 18 patients with severe arteriovenous malformations.” Vikkula stated, “We had hypothesized that thalidomide should work in these patients, so our results did not come as a surprise, but it was great to have clinical confirmation that we were right. In our view, this is a breakthrough finding and provides a solid basis for the development of molecular treatments for AVMs.” Alexandre Reymond, chair of the conference, said: “This study shows not only the healthcare and economic benefits of repurposing drugs—even the most maligned—but also how genetic research can lead to real breakthroughs in therapies for difficult to treat, distressing conditions.”

AVMs are abnormal tangles of the blood vessels connecting arteries and veins, which alter normal blood flow. “AVMs are vascular anomalies with abnormal connections between high-pressure arteries and low-pressure veins that replace the normal intervening capillary network,” the team explained. AVMs can occur anywhere in the body. They are very painful and may cause bleeding and deformation of the affected body part, as well as potential cardiac problems. “The resulting shunting and venous hypertension can lead to swelling, local tissue ischemia with pain, ulceration and bleeding, and cardiac overload,” the team continued.

Usually congenital, AVMs are often only noticeable in adolescence or adulthood as the person grows. Treatment of severe cases is usually through surgery or embolization (the injection of an agent that destroys the blood vessels locally, thus inducing scarred tissue), though this is rarely totally effective and can worsen the AVM. “Complications of therapy such as cutaneous necrosis, peripheral nerve injuries, and even death can occur,” the authors stated. “Partial resection and improper embolization often worsen an AVM.”

Some people with AVMs can live relatively normal lives, but even in less severe cases there is always the risk that the abnormal tangles of blood vessels can burst and may cause a stroke when in the brain. About one in every hundred AVM patients suffers a stroke each year. As the investigators noted, “ … there is a pressing need for novel therapies … The international community is desperately looking for options to control AVMs that are refractory to conventional therapies.”

Thalidomide, used as a sedative drug for pregnant women in the 1950s, is infamous for its teratogenic properties (phocomelia), which were later shown to be due to inhibitory effects on angiogenesis. This antiangiogenic property resulted in new interest in the potential use of thalidomide for the treatment of age-related macular degeneration, and for treating bleeding in patients with hereditary hemorrhagic telangiectasia. “Thalidomide was also effective for the treatment of cerebral AVM in a mouse model,” the authors noted.

“Our group has been studying the causes of vascular abnormalities for 30 years,” commented Vikkula. “We have identified several genetic causes and have been able to show that certain mutations activate the signaling inside the blood vessel wall cells and this promotes the abnormal formation of blood vessels (angiogenesis). This led us to wonder about the possibility of using thalidomide to inhibit abnormal blood vessel formation.”

After showing that a vascular malformation could be corrected in a mouse model, Laurence Boon, PhD, from the Centre for Vascular Anomalies at Saint Luc University Hospital, Brussels, who has been working in collaboration with Vikkula for 30 years, recruited 18 patients with AVMs into a study of thalidomide as a potential treatment for their condition. The participants were aged 19–70 years, had severe malformations that could not be treated by conventional approaches, and had all agreed to use contraception for at least four weeks before starting thalidomide and to continue for four weeks after the cessation of treatment.

The participants then received 50 mg, 100 mg, or 200mg of thalidomide per day for between two months and 52 months. Describing the results in their paper, the team reported, “Thalidomide was rapidly effective, within 1–5 months, in relieving chronic pain … It also reduced bleeding in extensive stage III and stage IV AVMs for which conventional therapies had failed.”

Vikkula further stated: “All the patients experienced a rapid reduction of pain, together with cessation of bleeding and the healing of ulcers where these were present.” The three patients with cardiac failure also saw their problems resolved, and one AVM appeared to be completely cured after 19 months of thalidomide and an eight-year follow-up.

The investigators continued, “Eight AVMs were stable after a mean thalidomide cessation of 58 months, and four recurred after a mean duration of 11.5 months. In three patients (patients 4, 5, and 12) receiving thalidomide therapy, the AVM reduced in size and vascularization on arteriography.”

Combining treatment with embolization allowed a reduction in thalidomide dose to 50 mg per day in five patients. Reducing the dose where possible was important, said Vikkula, because a higher dose was associated with side effects, particularly tiredness and peripheral neuropathy, damage to the nerves located outside the brain and spinal cord that causes weakness and numbness, particularly in the hands and feet. “Adverse side effects were completely reversible when thalidomide was stopped,” the investigators stated.

They further concluded, “The results suggest that thalidomide is efficacious in the management of chronic pain, bleeding, and ulceration of extensive AVMs that are refractory to conventional therapy. Further clinical study is needed to confirm the safety and efficacy of thalidomide treatment in AVM.”

Vikkula noted, “We know that thalidomide acts through vascular endothelial growth factor (VEGF), a signaling protein that promotes the growth of new blood vessels. VEGF levels are high in vascular abnormalities such as AVMs and is therefore likely that thalidomide reduces signaling via the angiogenesis-promoting pathways. Although our study is only small, the results are convincing, and we hope that they will be confirmed by larger trials.”

A further advantage of the use of thalidomide in the treatment of AVMs would be one of cost. Two other drugs, recently developed for use in oncology and being tested for treating AVMs, cost up to twelve times as much, as well as have numerous side effects.