Clinical trial demonstrates success in treating rare blood disease

A clinical trial has shown that the cancer drug pomalidomide is safe and effective in treating hereditary hemorrhagic telangiectasia (HHT), a rare bleeding disorder that affects more than 1 in 5,000 people worldwide.

The trial, led by Dr. Keith McCrae of the Cleveland Clinic, was stopped early because of these positive results and was published in New England Journal of Medicine.

The idea for the trial came from a single patient. About 15 years ago, Dr. McCrae, the director of benign hematology at the Cleveland Clinic and the study’s lead author, saw a patient with symptoms of the disease. At the time, there was little information about the disease, according to Dr. McCrae, a hematologist and scientist.

HHT is a condition in which blood vessels become tangled and twisted in unusual ways. This can lead to the excessive nosebleeds that characterize the condition. HHT also causes bleeding in the digestive tract and can lead to serious complications in the lungs, liver, and brain. Bleeding episodes worsen with age, affect quality of life, and can lead to anemia and other life-threatening conditions. There are no FDA-approved medications for the long-term management of HHT.

The patient, who was in his 50s at the time, suffered from nosebleeds and severe gastrointestinal bleeding. He required multiple blood transfusions and multiple doses of clotting factors concentrated in blood plasma each week. He was told his only option was surgery to remove his diseased intestine, which would have significantly affected his quality of life.

Dr. McCrae began looking for new options and discovered that the cancer drug thalidomide had shown positive results in a few patients with similar symptoms. He treated his patient with a low dose of the drug and the bleeding almost completely stopped within two to three weeks. Dr. McCrae tried thalidomide with other patients who also had similar symptoms of HHT, and they also responded positively.

“It was amazing,” Dr. McCrae said. “I had rarely seen anything like it in my clinical experience, and I thought it was important that we study this.”

Thalidomide is primarily used to treat multiple myeloma, but it can have serious side effects. So instead of conducting large-scale research on thalidomide, Dr. McCrae used a drug with a similar chemical structure, pomalidomide, an FDA-approved drug for treating bone marrow cancer. He conducted a pilot study on pomalidomide, and the drug was found to be effective and safe.

To test pomalidomide, researchers enrolled 144 adults with HHT at 11 U.S. medical centers between November 2019 and June 2023. CureHHT, a patient advocacy organization, actively supported enrollment in the clinical trial.

All participants had moderate to severe nosebleeds requiring iron infusions or blood transfusions. RTI International in North Carolina was the study’s data coordinating center, and C5Research, the Cleveland Clinic’s academic research organization (ARO), was the clinical coordinating center.

Researchers observed that HHT patients taking pomalidomide saw significantly reduced severity of nosebleeds, required fewer blood transfusions and iron infusions, and had a better quality of life. In June 2023, an interim analysis found that pomalidomide was effective, and the trial was closed.

Researchers think pomalidomide works by blocking the growth of abnormal blood vessels. “The drug may give blood vessels a more normal structure or thicker walls, making them less fragile,” Dr. McCrae said, but more study is needed.

“It’s very rare to find a therapeutic agent that’s effective in treating a rare disease, so this is a real success story,” said Andrei Kindzelski, MD, PhD, a program officer in the Division of Blood Diseases and Resources at the National Heart, Lung, and Blood Institute, part of the National Institutes of Health. “To date, there have been no positive trials of a treatment for HTH.”

Dr. Kindzelski said the discovery has broader implications and could save lives for people with more severe forms of the disease. In these cases, malformed blood vessels can also develop in organs such as the lungs, liver and brain, which can lead to hemorrhagic stroke, bleeding in the lungs or heart failure.

Although the researchers did not follow up with participants after the trial ended, Dr. McCrae said some of his patients in the study did not have nosebleeds for six months, even after they stopped taking the drug. That suggests the drug may hold promise as a long-term or intermittent treatment, he said.

Although an effective treatment for this rare disease has been found, the mechanisms of HHT remain poorly understood. Dr. McCrae hopes to secure additional funding to continue studying HHT, clarifying the mechanisms behind the disease and how pomalidomide and other drugs influence them.

“I am optimistic that learning more about the mechanisms of how this treatment works will have a significant impact on the treatment of HHT and our understanding of vascular malformations,” he says.