Cleveland Clinic Study Is First to Show Success in Treating Rare Blood Disorder

A clinical trial has demonstrated that the cancer drug pomalidomide is safe and effective in treating hereditary hemorrhagic telangiectasia (HHT), a rare bleeding disorder that impacts more than 1 in 5,000 people worldwide. The trial, led by Keith McCrae, M.D., of Cleveland Clinic and supported by the National Institutes of Health, was stopped early because of these successful findings, and has been published in the New England Journal of Medicine.

The impetus for this trial was a single patient. About 15 years ago, Dr. McCrae, director of Benign Hematology at Cleveland Clinic, and the study’s senior author, saw a patient with HHT symptoms. There was little information about the disease at the time, according to Dr. McCrae, a hematologist and scientist.

HHT is a condition in which blood vessels become unusually tangled and twisted. This can lead to excessive nosebleeds that hallmark the disease. HHT also causes bleeding in the digestive tract and can produce 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 long-term management of HHT.

The patient, who was in his 50s at the time, was experiencing nosebleeds and severe GI bleeding. He required several blood transfusions and multiple doses of concentrated blood plasma clotting factors every week. He had been told that his only option was surgery to remove his diseased bowel, which would have significantly affected his quality of life.

Dr. McCrae began searching for new options and found that the cancer drug thalidomide had shown positive outcomes 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 showed similar HHT symptoms, and they also responded positively.

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

Thalidomide primarily treats multiple myeloma, but can have serious side effects, so instead of pursuing large-scale research with thalidomide, Dr. McCrae used a drug with a similar chemical structure called pomalidomide, an FDA-approved drug for the treatment of bone marrow cancer. He performed a pilot study with pomalidomide, and the drug appeared 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 data coordinating center for the study, and C5Research, Cleveland Clinic's Academic Research Organization (ARO), was the clinical coordinating center.

Researchers observed that patients with HHT taking pomalidomide saw a marked decrease in nosebleed severity, required fewer blood transfusions and iron infusions and experienced an improved quality of life. In June 2023, an interim analysis found pomalidomide to be effective and the trial was closed.

Researchers speculate that pomalidomide worked by blocking the growth of abnormal blood vessels. “The drug may cause the blood vessels to have a more normal structure or thicker walls, so they are less fragile,” Dr. McCrae said, but further study is needed.

“Finding a therapeutic agent that works in a rare disorder is highly uncommon, so this is a real success story,” said Andrei Kindzelski, M.D., Ph.D., 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 has been no positive trial of a therapeutic for treating HHT.”

Dr. Kindzelski said the finding has broader, life-saving implications for people with more severe forms of HHT. In those 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.

Though researchers did not follow participants after the trial ended, Dr. McCrae said some of his patients who were enrolled in the study have gone up to six months without nosebleeds recurring, even though they had stopped the medication. This suggested that the drug may have promise as a long-term or intermittent treatment, he said.

Even after finding a successful treatment for this rare disease, much is still unknown about the mechanisms of HHT itself. Dr. McCrae is hoping to obtain additional funding to continue studying HHT, clarifying the mechanisms behind the disease and how pomalidomide and other drugs influence them.

"I'm optimistic that learning more about the mechanisms of how this treatment works will make a great impact in treatment of HHT hematology and our understanding of vascular malformations," he says.

This study was supported by NHLBI grants 1U24HL140090-01A1 and 1UG3HL140097-01A1.