Efficacy of Thalidomide in the Treatment of Severe Recurrent Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT): Preliminary Results of an Ongoing Study

Hereditary hemorrhagic telangiectasia (HHT; OMIM 187300 and 600376), also known as Rendu-Osler-Weber syndrome, is an autosomal dominant disease that leads to multiregional angiodysplasia. It affects approximately one in 5000 people. Recurrent and severe epistaxis, due to the presence of telangiectasias in nasal mucosa, is the most common presentation of HHT, frequently leading to severe anemia requiring iron supplements and blood transfusions. Multiple approaches, including surgical options, have been tried In the management of HHT epistaxis, but all of them are largely palliative with variable and temporary results. As a consequence, most patients require repeated interventions. Recently, angiogenesis has been implicated in the pathogenesis of HHT and, therefore, it has been suggested that anti-angiogenic substances may be effective in the treatment of vascular malformations. A recent study (Nat Med 2010; 16:420–428) found that oral administration of 100 mg of thalidomide daily lowered the frequency of epistaxis in six of seven treated subjects. The aim of our prospective, non-randomized, phase II, open-label trial is to confirm the effectiveness of this drug in reducing epistaxis and to identify the lowest effective dose in patients with HHT refractory to standard therapy (ClinicalTrials.gov Identifier: NCT01485224).

HHT patients with at least one episode of overt bleeding/week requiring at least one blood transfusion during the last three months and refractory to mini-invasive surgical procedures are enrolled. Thalidomide is administered at a starting dose of 50 mg/day orally. In the event of no response, thalidomide dosage is increased by 50 mg/day every 4 weeks until complete (cessation of nose bleeding) or partial response (reduction in the severity of epistaxis less than complete response) to a maximum dose of 200 mg/day. After the achievement of complete/partial response patients are treated for 16 additional weeks. Monthly follow-up evaluates the epistaxis severity score and the transfusion need, with adverse events being reported. The study, which wants to enroll 34 patients, is currently recruiting participants.

Eleven patients, 7 M and 4 F, aged 45–80 years (median 67), with mutations in either ACVRL1 (8 cases) or ENG gene (3 cases) have been enrolled so far and 5 have completed at least 16 weeks of treatment (median follow-up 11 weeks, range 1–28). Treatment was effective in all 9 evaluable patients. Five patients responded within 4 weeks of starting the drug: cessation of nose bleeding was observed in one case, and a large reduction of nose bleeding measured according to a well defined epistaxis severity score (Am J Rhinol Allergy 2009;23:52–58) has been obtained in 4 cases. Four patients achieved a good, partial response after 8 weeks of treatment. As a consequence, thalidomide therapy significantly increased hemoglobin levels and abolished or greatly decreased the need for red blood cell transfusions. Only nonserious, drug-related adverse effects were observed during treatment, including constipation and drowsiness. Three patients completed the treatment and remained stable, off of thalidomide, without the loss of response during the immediate follow-up period.

These preliminary results strongly support the hypothesis that low-dose thalidomide is very effective for the treatment of epistaxis in patients with severe HHT who did not benefit from other available modalities of treatment.

Off Label Use: Thalidomide is used off-label for tretment of hereditary hemorrhagic telangiectasia.