Pomalidomide Found Safe, Highly Effective for Epistaxis in HHT

An observational study that was presented in an oral abstract session at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition suggested the utility of pomalidomide for long-term treatment of epistaxis in patients with hereditary hemorrhagic telangiectasia (HHT), although it may only benefit a minority of patients with chronic gastrointestinal (GI) bleeding.¹

The inherited bleeding disorder HHT is characterized by extensive telangiectasias and arteriovenous malformations. It is characterized by recurrent epistaxis and GI bleeding, leading to iron deficiency anemia, reduced quality of life, and even death. Bleeding events from HHT often become more frequent and severe with age, ultimately requiring frequent iron infusions, red blood cell transfusions, or both.²

No therapies are officially approved by the U.S. Food and Drug Administration for HHT, but some anti-angiogenic agents have shown benefit off-label. Thalidomide, an immunomodulator with anti-angiogenic properties, has shown positive prospective results, but potential toxicities such as thromboembolism and peripheral neuropathy have limited its utility.^2,3

Bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, has shown some effectiveness in treating HHT-related bleeding, including GI bleeding, but its cost and intravenous administration are drawbacks to use.⁴

Researchers on the randomized, placebo-controlled PATH-HHT study explored the safety and efficacy of a chemical cousin of thalidomide, pomalidomide, hoping it would prove efficacious but less toxic. In results initially reported at the 2023 ASH annual meeting, oral pomalidomide was shown to reduce epistaxis in a clinically significant way over a six-month period.^2,5

Ellen Zhang, MD, of Stanford University in Palo Alto, California, presented follow-up observational data from 48 HHT patients who were initially enrolled in PATH-HHT and continued taking pomalidomide (unblinded) after completion. To date, it is the largest study of pomalidomide for HHT in terms of total years of patient exposure (mean duration over 17 months, with a maximum of almost four years).¹

Of the participants, 84% achieved a durable epistaxis response, defined as the minimal clinically important difference via the Epistaxis Severity Score (ESS) for at least six months; 55% achieved a superior durable epistaxis response (at least three times the minimal clinically important difference). Mean ESS decreased by 2.83 points at one year, an improvement on results initially reported.^1,2,5

However, effects were less impressive for GI bleeding. Of the 14 patients with active chronic GI bleeding, only four were able to stop receiving iron or red blood cell transfusions; seven chose to discontinue pomalidomide; and three continued the drug due to improvement in their epistasis.¹

Although 98% of participants experienced a treatment-emergent adverse event, most were only grade 1 or grade 2, most commonly neutropenia (56%), constipation (52%), rash (35%), or fatigue (35%). Almost all discontinuations occurred in people over age 60. Thromboembolism occurred in only one patient, on par with the expected background rate in HHT.¹

Dr. Zhang acknowledged the relatively high failure rate, as 15 patients (31%) discontinued the drug because of adverse events or ineffectiveness. However, she also noted that as an oral agent, pomalidomide may decrease access barriers for some patients.

“The result of this study suggests that oral pomalidomide may be inferior for GI bleeding when compared with intravenous bevacizumab, but pomalidomide appears comparable or better for epistaxis treatment,” said Dr. Zhang, although she also noted the importance of future head-to-head trials. “Overall, our study provides evidence of the safety and effectiveness of pomalidomide for long-term use in patients with HHT, which may lead to an improved quality of life in this population.”

Any conflicts of interest declared by the authors can be found in the original abstract.

References

1. Zhang E, Hodges PG, Rodriguez-Lopez J, er al. Long-term safety and effectiveness of pomalidomide for bleeding in hereditary hemorrhagic telangiectasia. Abstract 558. Presented at the 66th American Society of Hematology Annual Meeting and Exposition; December 8, 2024; San Diego, California.
2. Al-Samkari H, Kasthuri RS, Iyer VN, et al. Pomalidomide for epistaxis in hereditary hemorrhagic telangiectasia. N Engl J Med. 2024;391(11):1015-1027.
3. Ugur MC, Baysal M, Umit EG. The role of thalidomide and its analogs in the treatment of hereditary hemorrhagic telangiectasia: a systematic review. J Clin Med. 2024;13(18):5404.
4. Al-Samkari H, Kasthuri RS, Parambil JG, et al. An international, multicenter study of intravenous bevacizumab for bleeding in hereditary hemorrhagic telangiectasia: the InHIBIT-Bleed study. Haematologica. 2021;106(8):2161-2169.
5. Al-Samkari H, Kasthuri RS, Iyer V, et al. PATH-HHT, a double-blind, randomized, placebo-controlled trial in hereditary hemorrhagic telangiectasia demonstrates that pomalidomide reduces epistaxis and improves quality of life. Blood. 2023;142(Suppl. 2):LBA3-LBA5.