Pomalidomide: A Step on the PATH Forward for Treatment of Hereditary Hemorrhagic Telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is the second most common inherited bleeding disorder, usually caused by pathogenic variants in ENG, ACVRL1, and SMAD4. It is characterized by abnormal blood vessel formation, resulting in the presence of mucocutaneous telangiectasias and visceral arteriovenous malformations involving the lungs, liver, brain, and other organs.^1,2  Patients with HHT frequently report debilitating epistaxis, often resulting in iron deficiency anemia with significant impact on quality of life.

Currently, there are no approved therapies for the treatment of HHT, with the Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia recommending both surgical and non-surgical approaches for the management of epistaxis.³  Those with severe symptoms not responding to topical therapies and antifibrinolytic agents may require more extensive surgery and systemic anti-angiogenic agents.³  In an international, multicenter, retrospective study, bevacizumab (a humanized monoclonal antibody against vascular endothelial growth factor) was shown to increase mean hemoglobin, decrease Epistaxis Severity Score (ESS), and reduce red blood cell transfusions and iron infusions.^4,5  In a phase II, single center, non-randomized study, the immunomodulatory drug thalidomide demonstrated efficacy in the management of severe epistaxis.⁶ 

Pomalidomide, a thalidomide derivative, is currently approved by the U.S. Food and Drug Administration for patients with multiple myeloma. Published evidence suggests an improved side-effect profile compared to thalidomide, thus making it an attractive potential therapeutic option for HHT. The double-blind, randomized, placebo-controlled PATH-HHT trial investigated the safety and efficacy of pomalidomide for epistaxis in HHT.⁷  The study included patients who met the Curaçao diagnostic criteria for HHT, with anemia, an ESS of 3 or higher in the preceding three months, or a need for red cell transfusions or iron infusions in the preceding six months. The study randomized 144 patients in a 2:1 ratio to receive either 4 mg daily of pomalidomide or placebo. Oral antifibrinolytic agents taken at a stable dose at the time of study entry were continued.

The primary outcome was change in ESS after a 24-week treatment period, with a statistically significant greater reduction in ESS reported in the pomalidomide group than in the placebo group (-1.84 points vs. -0.90 points; p=0.004). Improvement in ESS was first noted at 12 weeks and persisted for four weeks post-treatment. Dose reduction was permitted down to 3 mg and 2 mg, with impact still evident. Patients in the pomalidomide group had improved hemoglobin despite decreased needs for iron infusion and blood transfusion. The HHT-related quality-of-life score change from baseline was -2.7 points in the pomalidomide group and -1.2 points in the placebo group; however, this outcome did not meet statistical significance.

Dose-dependent reversible neutropenia was a major toxicity occurring in 44% of patients. However, no infections were noted, and counts improved with dose changes or temporary discontinuation of pomalidomide. Other common side effects included rash and constipation. Four patients (4%) in the pomalidomide group experienced venous thromboembolism, compared with one (2%) in the placebo group.

Overall, this trial demonstrated that pomalidomide led to improvement in epistaxis severity, with a trend towards improvement in quality of life. Patients on treatment also trended towards improved hemoglobin and required less iron infusions. While pomalidomide led to more adverse events that required dose reduction or interruptions, efficacy persisted in those requiring dose reductions.