Pomalidomide in Hereditary Hemorrhagic Telangiectasia: Interim Results of a Phase I Study

Background Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by telangiectasias on mucocutaneous surfaces and arteriovenous malformations in visceral organs. Most patients present with epistaxis and gastrointestinal (GI) bleeding requiring iron supplementation and blood transfusion. There is no accepted medical treatment for HHT, although several studies suggest the potential efficacy of thalidomide. However, thalidomide is not available for treatment of patients with HHT. To address this, we initiated a Phase I trial of pomalidomide, a third generation thalidomide analogue with a lower incidence of cytopenias and neuropathy than thalidomide, in patients with HHT and dependence on iron infusion or blood transfusion. The aim of this phase 1 trial is to investigate the safety and efficacy of pomalidomide in HHT related epistaxis and GI bleeding. Methods Adult HHT patients with GI bleeding requiring at least 4 units transfusion or four doses of intravenous iron in the preceding four months, and patients with epistaxis requiring 2 units transfusion or 500 mg of intravenous iron in the preceding four months, and with an epistaxis severity score (ESS) ≥ 4 were enrolled. Pomalidomide was initiated at a 1 mg daily dose, which was increased by 1 mg/month to a maximal dose of 5 mg/day if bleeding did not entirely stop as judged by clinical evaluation. If bleeding stopped, patients were maintained on the dose of pomalidomide they were taking at the time of bleeding cessation for an additional 4 months. If bleeding did not stop, but improved, and patients escalated to the 5 mg/daily dose, they were maintained on this dose for an additional 4 months. After treatment with a stable dose of pomalidomide for 4 months, it was tapered by 1 mg/month until discontinued. The primary endpoint was a 50% reduction in the need for transfusion or parenteral iron therapy. A secondary endpoint was a reduction in the ESS of at least 1 point. Results The trial was designed for 9 patients and is continuing to accrue. Six patients, 5 males and 1 female, aged 48-70 with clinically diagnosed HHT provided informed consent. One patient withdrew consent before initiating therapy due to valvular heart disease requiring surgery. One patient had a drug-related adverse event (rash) soon after starting pomalidomide, which required removal from the study. Two patients (brothers) had non-drug related adverse events (diagnosis of a neuroendocrine tumor and recurrence of a perianal abscess requiring surgery) and were removed from the study within 5-7 months after initiation. One of these also had significant cramping after 7 months of treatment. Both of these siblings had presented with epistaxis and GI bleeding and reported a decrease in frequency of melanotic stools. Both required one course of IV iron soon after entering the study (prior to pomalidomide, they received iron every 2-3 months), however both maintained hemoglobin levels at least 1 gm higher than their previous baseline during study, and iron studies remained in the normal range after initiation of therapy. Two patients had primarily epistaxis. Both responded to pomalidomide within 1-2 months with decreases of > 50% (2-3 points) in the ESS; this was associated with an increase in quality of life. One of these patients required weekly iron infusions as well as red blood cell transfusions every 3-6 weeks before study; however, she has currently been on study for more than 6 months with a hemoglobin of 10-11 gm/dl, has not required blood transfusion, and has not received intravenous iron for more than 3 months with iron studies remaining normal. An additional patient has recently entered the study at the time of this abstract preparation. Pre- and post-treatment blood sampling has been performed and will be analyzed for biomarker changes prior to the ASH meeting. Toxicity has consisted primarily of grade 1-2 fatigue (n = 2), and cramps (n = 2), but these were not felt to be of sufficient severity to stop pomalidomide. Conclusions Preliminary interim findings from this phase I study provide an efficacy signal for patients with HHT and refractory bleeding. As with thalidomide, we speculate that pomalidomide causes remodeling of abnormal vasculature leading to decreases in AVMs and improvements in vessel stability. These findings support the development of a larger, multi-institutional HHT study. (NCT02287558) Disclosures No relevant conflicts of interest to declare.