Medicine for vascular abnormalities works just as effectively at a much lower dosage A low dose of sirolimus is found to be safe and effective with significantly fewer side effects

A low dose of sirolimus appears to be safe and effective with significantly fewer side effects in patients with a rare congenital vascular abnormality. It is also found that children respond more frequently and earlier to treatment than adults. These conclusions are based on a national study led by Radboud university medical center and provide insight into the optimal use of sirolimus.

Patients with a rare congenital vascular abnormality are born with abnormally developed vessels, such as blood or lymphatic vessels. They experience severe symptoms, including swelling, pain, fluid leakage, and thrombosis. Treatment typically involves compression stockings, pain relievers, radiological procedures, or surgery. If these measures prove insufficient or if the vascular abnormality is extensive, sirolimus is an option. A previous American study showed that high-dose sirolimus treatment effectively reduces pain and other symptoms, but also leads to severe side effects.

Diary

Researcher Veroniek Harbers, together with lead investigator Maroeska te Loo within the HECOVAN working group, investigated whether a low dose of sirolimus is also effective and causes fewer side effects. The study included 74 patients with complex vascular abnormalities who had no other treatment options. They received a low dose of sirolimus for six months. The researchers monitored the effects of the medication using a pain diary, questionnaires, and MRI scans to observe changes and the size of the vascular abnormalities.

The study reveals that treatment with a low dose of sirolimus improved pain symptoms, quality of life, and reduced the size of the vascular abnormalities in a significant portion of the patients. Children responded better to the treatment (90.6%) compared to adults (65.7%). Children also experienced fewer (severe) side effects. The effects were comparable to a high dose but with significantly fewer side effects.

Mosaic

Sirolimus works by inhibiting specific DNA mutations. In recent years, the DNA mutations responsible for these vascular problems have been identified. ‘The remarkable thing is that these are DNA mutations that are only present at the site of the vascular abnormality, in a mosaic pattern, and not in the rest of the body’, says Harbers. ‘These are often DNA changes that activate the cell through the so-called mTOR system, causing symptoms and overgrowth. There are increasingly more medications that inhibit these mutations, thereby reducing symptoms, including sirolimus.’

The research on a low dose of sirolimus was conducted in collaboration with other hospitals, including Erasmus MC, Amsterdam UMC, and UMC Utrecht. Te Loo says: ‘This first national clinical phase IIB study makes a significant contribution to our understanding of the optimal use of sirolimus in the treatment of patients with vascular abnormalities. Through pharmacologically targeted treatment, a new era of treatment possibilities is emerging for these patients.’

About the thesis defense

Veroniek Harbers dissertation defense took place on November 3 at 10:30. The thesis can be dowloaded here. The results of the clinical study have been published in Clinical and Translational Science: Clinical differences in sirolimus treatment with low target levels between children and adults with vascular malformations – A nationwide trial; Veroniek Harbers, Lilly Zwerink, Gerard Rongen, Willemijn Klein, Carine van der Vleuten, Ingrid van Rijnsoever, Linda Gerdsen-Drury, Uta Flucke, Bas Verhoeven, Paul de Laat, Chantal van der Horst, Leo Schultze Kool, Maroeska te Loo. The research was made possible by ZonMW, and Pfizer provided the study with sirolimus.

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