A drug approved to treat the blood cancer of multiple myeloma may offer a safe and effective way to reduce the risk of serious nosebleeds from a rare but devastating bleeding disorder. Hereditary hemorrhagic telangiectasia (HHT), the second most common inherited bleeding disorder in the world, affects about 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 randomized, placebo-controlled clinical trial in the U.S., evaluated the oral drug pomalidomide, currently approved to treat multiple myeloma, to treat bleeding and disease manifestations in HHT. The trial, which involved more than 50 patients at Massachusetts General Hospital (MGH), a founding member of the Mass General Brigham health care system, found that the drug resulted in a significant and clinically relevant reduction in the severity of nosebleeds and improved quality of life. The results of PATH-HHT are published in he New England Journal of Medicine.
“The results of our trial demonstrate the clear safety and efficacy of pomalidomide for treating bleeding in HHT, offering these patients a much-needed, effective treatment option,” said first author Hanny Al-Samkari, MD, Peggy S. Blitz Chair in Hematology/Oncology at Massachusetts General Hospital, Associate Professor of Medicine at Harvard Medical School, a classical hematologist, and principal investigator at the Massachusetts General Cancer Center. “While there is still much work to be done to develop additional treatments for HHT, the PATH-HHT study serves as proof of principle that we can develop effective drugs to treat this terrible disease.”
Patients with HHT suffer from severe and recurrent nosebleeds that severely reduce their health-related quality of life and lead to unemployment and social isolation. They also suffer from chronic gastrointestinal bleeding, leading to severe anaemia and dependence on intravenous iron infusions and blood transfusions. In addition, they may suffer from vascular malformations in internal organs, such as the brain, lungs and liver, which can lead to life-threatening bleeding, strokes and cardiac 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 for treating disease manifestations in HHT, focusing on severe nosebleeds that affect nearly all patients with the disease. The primary outcome was significant improvements in longitudinal nosebleed severity over time in the pomalidomide group versus the placebo group. Additionally, investigators found substantial improvements in HHT-specific quality of life in patients who received pomalidomide compared with those who received placebo.
The PATH-HHT study was planned to enroll 159 participants, but because it exceeded its pre-specified efficacy threshold, enrollment was closed early.
“When you conduct a clinical trial, the best possible outcome is to close it early for reasons of efficacy,” Al-Samkari said.
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 pomalidomide’s mechanisms of action in HHT—that is, why the drug works for this condition. Future studies will also be needed to determine whether the drug could have similar effects in patients with GI bleeding or other complications of HHT.
Massachusetts General Hospital is a Cure HHT Foundation-certified HHT Center of Excellence and serves more than 500 families with HHT throughout Massachusetts and the rest of New England, as well as upstate New York. Additionally, people travel from far away to participate in clinical trial opportunities within the MGH HHT Center. The Center is co-directed by Al-Samkari and Josanna Rodriguez-Lopez, MD, of the Division of Pulmonary and Critical Care Medicine.
“As you can imagine, for a neglected but serious disease for which there are no approved therapies, patients showed great interest in the PATH-HHT study, and we recruited more than 50 patients for 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 at the Mass General Cancer Center, as well as my colleagues across the 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.”