Long-Term Safety and Effectiveness of Pomalidomide for Bleeding in Hereditary Hemorrhagic Telangiectasia
Authors: Zhang Ellen , Hodges Pamela G , Rodriguez-Lopez Josanna , Al-Samkari Hanny 
Published: December 2024

Background
Hereditary hemorrhagic telangiectasia (HHT) is an important inherited vascular bleeding disorder that remains without licensed treatments. Severe, recurrent epistaxis and gastrointestinal (GI) bleeding in HHT cause iron deficiency anemia, substantial clinical and psychological suffering, and death. The PATH-HHT study, an RCT evaluating oral pomalidomide (POM) versus placebo in HHT, demonstrated the safety and efficacy of 6 months of POM for epistaxis. However, no data exists describing safety or effectiveness of POM in HHT for longer durations or its utility for GI bleeding.
Methods
We performed an observational study of patients with HHT treated with POM initially enrolled on PATH-HHT who continued POM via a post study POM access program. All patients were unblinded following PATH-HHT completion.
Data was extracted via manual chart review by HHT expert physicians. The primary endpoint was a durable epistaxis response (DER): an improvement of ≥0.71 [the minimal clinically important difference (MCID)] in the well-validated Epistaxis Severity Score (ESS, scored from 0-10) for ≥6 consecutive months. Secondary endpoints included superior DER (≥3x the MCID of the ESS), hematologic measures, and safety. Hematologic support (HS, RBC transfusions and IV iron infusions) was measured in RBC unit equivalents (RUEs, 1 RUE = 1 RBC unit or 250 mg IV elemental iron), and HS dependence was defined as a requirement for ≥6 RUEs in the 6 months prior to POM start.
Results
Patients & Dosing. 48 patients with HHT received POM. Median (range) age was 63 (31-87) years; 40% were female. All patients initiated at 4 mg daily. Mean treatment duration was 17.8 months and longest duration was 47 months. Dose reduction due to treatment-emergent adverse events (TEAEs) to 3 or 2 mg daily occurred in 16 patients and did not appear to impact effectiveness. POM was discontinued in 15 patients: 8 due to TEAEs and 7 due to ineffectiveness. 4 patients died during the observation period due to HHT complications unrelated to POM.
Bleeding Outcomes. DER was achieved in 84% and superior DER was achieved in 55%. Compared with pretreatment, mean ESS decreased by 2.83 (95% CI, 2.12-3.54) points [mean ESS 5.87 (5.33-6.41) vs 2.90 (2.31-3.49), P&lt;0.0001] at 1 year. Of 26 patients treated for &gt;12 months, 2 (8%) discontinued due to loss of response. POM was less effective for GI bleeding: of 14 patients with HS-dependent active chronic GI bleeding at treatment initiation [mean (range) 11.0 (6.1-34.6) RUEs in 6 months pretreatment], 4 achieved liberation from HS dependence; 7 discontinued POM; and 3 continue on POM despite ongoing HS dependence due to epistaxis improvement.
Hematologic Outcomes. There was no significant difference in mean hemoglobin pretreatment vs month 12 (11.2 vs 12.0 g/dL, P=0.44). Compared with 6 months pretreatment, HS required was significantly lower during months 7-12 of POM [mean RUEs 10.2 (6.9-13.4) vs 6.0 (2.7-9.3), P=0.02], driven primarily by reduced IV iron from improved epistaxis [mean milligrams elemental iron infused 1996 (1368-2624) vs 1188 (572-1804), P=0.04); there was no significant difference in RBC units transfused (primarily given to patients with GI bleeding).
Safety. 98% (N=47/48) of patients experienced ≥1 TEAE; most were grade 1 or 2. The most common TEAEs were neutropenia (56%), constipation (52%), rash (35%), and fatigue (35%). Venous thromboembolism occurred in 1 patient (2%); no arterial thromboses were observed. The thromboembolism rate was 1.66 per 100 patient-years, similar to the background rate in HHT. Discontinuation due to TEAEs occurred due to hypersensitivity rash (N=3), constipation (N=2), anorexia (N=1), edema (N=1), and infection (N=1); all discontinuations for TEAEs occurred in the first 4 months of POM administration and with the exception of a 54-year-old patient with a hypersensitivity rash, occurred in patients over age 60.
Conclusions
In this study, the largest of POM in HHT by patient exposure (&gt;60 patient-years) by a wide margin, POM was safe and highly effective in treating severe epistaxis in HHT for extended durations up to nearly 4 years; however, it was effective in only a minority of patients with chronic GI bleeding. TEAEs were common but mostly mild and led to discontinuation only in older adults. No emergent toxicities were identified with extended duration use. Compared with IV bevacizumab, POM may be inferior for GI bleeding but appears comparable or better for epistaxis.