A clinical trial supported by the National Institutes of Health (NIH) was stopped early after researchers found sufficient evidence that a drug called pomalidomide, which is used to treat bone marrow cancer and Kaposi sarcoma, is safe and effective in treating hereditary hemorrhagic telangiectasia (HHT), a rare bleeding disorder that affects 1 in 5,000 people worldwide. The double-blind, randomized trial, led by Keith McCrae, MD, director of benign hematology at Cleveland Clinic, demonstrated that HHT patients who were treated using pomalidomide experienced a significant reduction in the severity of nosebleeds, needed fewer blood transfusions and iron infusions than are generally required by individuals with HHT, and showed improved quality of life.
Even after finding a successful treatment for this rare disease, much is still unknown about the mechanisms of HHT itself. 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 commented.
McCrae and colleagues reported on the trial’s findings in NEJM, in a paper titled “Pomalidomide for Epistaxis in Hereditary Hemorrhagic Telangiectasia.”
HHT, also known as Osler-Weber-Rendu Syndrome, is the second most common inherited bleeding disorder, the authors noted. HHT is characterized by serious defects in the way the body’s blood vessels form. Instead of growing linearly, they become unusually tangled and twisted. The disordered blood vessels are fragile and prone to leaking, which causes excessive nosebleeds or bleeding along the gastrointestinal tract and other mucosal surfaces. These bleeding episodes, which worsen with age, can result in anemia and reduced quality of life. In severe cases, they can be life-threatening. “Gastrointestinal bleeding occurs in one-third of patients, and iron-deficiency anemia develops in most patients,” the investigators further stated. “HHT-associated bleeding usually worsens over the lifespan of affected patients and results in the need for frequent iron infusions, red-cell transfusions, or both.”
Current treatment options for HHT involve closing off the malformed blood vessels in the nose and gastrointestinal tract or prescribing off-label medications that temporarily stabilize blood clotting at sites of bleeding vessels, which in turn reduces bleeding. There are currently no FDA-approved medications for long-term management of HHT.
The motivation for the newly reported trial was a single patient. About 15 years ago McCrae saw the patient, then in his 50s, with symptoms of HHT, a disorder about which little information was available at the time. The patient was experiencing nosebleeds and severe gastrointestinal bleeding and 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.
McCrae began searching for new options and found that the cancer drug thalidomide had shown positive outcomes in a few patients with similar symptoms. When McCrae treated his patient with a low dose of the drug the bleeding almost completely stopped within two to three weeks. McCrae tried thalidomide with other patients who also showed similar HHT symptoms, and they also responded positively.
“It was amazing,” 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, McCrae used pomalidomide, a drug with a similar structure to thalidomide, and which is approved by FDA for the treatment of bone marrow cancer. He performed a pilot study with pomalidomide, and the drug appeared effective and safe. “Pomalidomide is structurally related to other drugs in the immunomodulatory imide family, particularly thalidomide,” the authors explained. “These agents share similar properties, including therapeutic efficacy in multiple myeloma. However, pomalidomide has a better safety profile than thalidomide, with a lower incidence of cytopenias and peripheral neuropathy.’
For the newly reported study, researchers enrolled 144 adults with HHT at 11 U.S. medical centers, between November 2019 and June 2023. All participants had moderate to severe nosebleeds requiring iron infusions or blood transfusions. Researchers gave 95 of the participants 4 mg of pomalidomide daily, though the dosage was reduced to 3 mg or 2 mg daily in patients with adverse reactions—mostly constipation, rashes, and lower-than-average white blood cell counts. The remaining 49 patients received placebo, in addition to their usual care.
At the start of the trial, researchers used a validated HHT-specific bleeding assessment tool to score each patient’s nosebleed severity. To establish a baseline in other areas, participants self-reported other data throughout the trial, particularly the severity of their nosebleeds and the effect of their HHT symptoms on everyday activities using a special scoring system. The number of units of red blood cells transfused or iron infused was also recorded. The primary trial outcome was the change from baseline through week 24 in the Epistaxis Severity Score. A key secondary outcome was the HHT-specific quality-of-life score.
In June 2023, 43 months into the scheduled four-year trial, an interim analysis found pomalidomide had met a prespecified threshold for efficacy, and the trial was closed to further enrolment. “This double-blind, randomized trial showed that treatment with pomalidomide resulted in a significant reduction in the Epistaxis Severity Score and appeared to substantially improve the disease-specific health-related quality-of-life score,” the team wrote. “The benefits of pomalidomide were most apparent over the course of the second 12 weeks of the trial, persisted during the four weeks after the end of the treatment period, and were not dependent on HHT genotype or baseline epistaxis severity.”
Although the researchers did not follow participants after the trial ended, McCrae noted that some of his patients from the study had gone four to six months without a recurrence of nosebleeds, even though they had stopped the medication. This suggests that pomalidomide may have potential as a long-term or intermittent treatment, although further study will be needed. Researchers speculate that pomalidomide works 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,” McCrae said.
Andrei Kindzelski, MD, PhD, a program officer at the NIH National Heart, Lung, and Blood Institute (NHLBI) Division of Blood Diseases and Resources, who was responsible for overseeing the study at the NIH level, but is not one of the reported study’s named authors, commented: “Finding a therapeutic agent that works in a rare disorder is highly uncommon, so this is a real success story. Before our trial, there was no reliable therapeutic to treat people with HHT.” The discovery will give people with HHT “a positive outlook and better quality of life,” Kindzelsi said. “These findings have broader implications for people with more severe forms of HHT. In those cases, malformed blood vessels can develop in organs such as the lung, liver, and brain, which can lead to hemorrhagic stroke, bleeding in the lungs, or heart failure. A treatment like this could be lifesaving for such patients.”
