Pomalidomide: A Game-Changer in Treating Hereditary Hemorrhagic Telangiectasia

Pomalidomide, a cancer medication, has been revealed in a clinical trial to be safe and efficacious in treating hereditary hemorrhagic telangiectasia (HHT). This rare bleeding disorder affects more than 1 in 5,000 individuals globally.

Dr. Keith McCrae of Cleveland Clinic directed the trial funded by the National Institutes of Health. The trial was halted early because of the positive results published in the New England Journal of Medicine ().

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Bleeding disorder is a rare condition that impairs how the body regulates blood coagulation. In case of an injury, bleeding can occur in the organ internally or externally. Under normal circumstances, the blood vessels constrict ...

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A single patient sparked this trial. They observed a patient with signs of HHT approximately 15 years ago. There was very little knowledge about the illness.

A disorder known as HHT causes blood vessels to become abnormally twisted and knotted. This can lead to excessive nosebleeds that hallmark the disease.

HHT can result in major problems in the liver, brain, and lungs, in addition to causing bleeding in the digestive system. Bleeding episodes deteriorate with age, impair quality of life, and may result in anemia and other potentially fatal illnesses.

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For the long-term treatment of HHT, there are no FDA-approved drugs.

The patient, who was in his 50s, was suffering from significant gastrointestinal bleeding and nosebleeds. Every week, he needed numerous blood transfusions and high dosages of concentrated blood plasma clotting factors.

The doctor informed him that the only option available was to undergo surgery to remove his diseased colon, which would severely affect 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.

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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 to Pomalidomide: A Safer Option Emerges

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.

A patient advocacy organization actively supported enrollment in the clinical trial. All participants had moderate to severe nosebleeds requiring iron infusions or blood transfusions.

How Pomalidomide Works

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 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. “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, some of the patients who were enrolled in the study had 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.

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 the treatment of HHT hematology and our understanding of vascular malformations," he says.

Reference:

Pomalidomide for Epistaxis in Hereditary Hemorrhagic Telangiectasia - (https://www.nejm.org/doi/10.1056/NEJMoa2312749)

Source-Eurekalert