Clinical trial successfully repurposes cancer drug for hereditary bleeding disorder

A drug approved for treating the blood cancer multiple myeloma may offer a safe and effective way to reduce the risk of severe nosebleeds from a rare but devastating bleeding disorder. Hereditary hemorrhagic telangiectasia (HHT), the world's second-most-common inherited bleeding disorder, affects approximately 1-in-5,000 people and can have life-threatening complications, but there are currently no U.S. FDA-approved drugs to treat HHT. The PATH-HHT study, the first-ever randomized, placebo-controlled U.S. clinical trial, evaluated the oral drug pomalidomide, currently approved to treat multiple myeloma, to treat bleeding and disease manifestations in HHT. The trial, which enrolled more than 50 patients at Massachusetts General Hospital (MGH), a founding member of the Mass General Brigham healthcare system, found that the drug resulted in a significant, clinically relevant reduction in the severity of nosebleeds and improved quality of life. Results of PATH-HHT are published in the New England Journal of Medicine.

"The results of our trial demonstrate the clear safety and efficacy of pomalidomide to treat bleeding in HHT, giving these patients a much-needed effective treatment option,” said first author Hanny Al-Samkari, MD, the Peggy S. Blitz Endowed Chair in Hematology/Oncology at Massachusetts General Hospital, Associate Professor of Medicine at Harvard Medical School, classical hematologist and principal investigator at the Mass General Cancer Center. “While much work is still needed to develop additional treatments for HHT, the PATH-HHT study serves as proof of principle that we can develop effective drugs to treat this awful disease."

Patients with HHT suffer from severe, recurrent nose bleeding that severely reduces their health-related quality of life and results in unemployment and social isolation. They also endure chronic gastrointestinal bleeding, which results in severe anemia and dependence on intravenous iron infusions and blood transfusions.  They can additionally suffer from vascular malformations in internal organs, like the brain, lungs, and liver, that can cause life-threatening bleeding, strokes, and heart complications.

The PATH-HHT study is a National Institutes of Health-sponsored clinical trial that enrolled patients at 11 centers, including MGH. The trial evaluated pomalidomide to treat disease manifestations in HHT, focusing on the severe nosebleeds that affect almost all patients with this disease. The primary outcome achieved significant improvements in longitudinal nosebleed severity over time in the pomalidomide group versus the placebo group. Additionally, the investigators found substantial improvements in HHT-specific quality of life in patients receiving pomalidomide compared with those receiving placebo.

The PATH-HHT study was intended to enroll 159 participants but because it eclipsed its prespecified threshold for efficacy, it was closed to enrollment early.

"When you do a clinical trial, closing early for efficacy is the best possible outcome," said Al-Samkari.

The most common side-effects of pomalidomide were neutropenia, constipation, and rash, but these were mostly mild and manageable. The authors note that additional studies will be needed to define the mechanisms of action of pomalidomide in HHT—that is, why the drug works for this condition. Future studies will also be needed to determine if the drug could have similar effects in patients with gastrointestinal bleeding or other HHT complications.

Massachusetts General Hospital is a HHT Center of Excellence, as certified by the Cure HHT Foundation, and serves over 500 families with HHT throughout Massachusetts and the rest of New England, plus upstate New York. People additionally travel from far and wide to participate in clinical trial opportunities within the MGH HHT Center. The Center is co-directed by Al-Samkari and Josanna Rodriguez-Lopez, MD, from the Division of Pulmonary and Critical Care Medicine.

"As you can imagine, for a neglected but serious disease with no approved therapies, we had great interest in the PATH-HHT study from patients, and enrolled over 50 patients into this important trial," Al-Samkari said. "This success would not have been possible without the efforts of Pamela Hodges, NP, PhD and the incredible research nurses, coordinators, and associates within the Mass General Cancer Center, as well as my colleagues throughout MGH HHT Center. It has also been my great pleasure to work with Dr. Keith McCrae at the Cleveland Clinic to contribute to this multicenter effort. As a multisystem disease, HHT is very much a team sport."

Authorship: Additional authors include Raj S. Kasthuri, Vivek N. Iyer, Allyson M. Pishko, Jake E. Decker, Clifford R. Weiss, Kevin J. Whitehead, Miles B. Conrad, Marc S. Zumberg, Jenny Y. Zhou, Joseph Parambil, Derek Marsh, Marianne Clancy, Lauren Bradley, Lisa Wisniewski, Benjamin A. Carper, Sonia M. Thomas, and Keith R. McCrae.

Disclosures: Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Funding: Funded by the National Heart, Lung, and Blood Institute (UG3HL140097, U24HL140090, and 1K23HL159313).

Paper cited: Al-Samkari H et al. “Pomalidomide for Epistaxis in Hereditary Hemorrhagic Telangiectasia” New England Journal of Medicine DOI: 10.1056/NEJMoa2312749

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