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SAN DIEGO -- In a randomized trial, pomalidomide (Pomalyst) significantly reduced severe nosebleeds in patients with hereditary hemorrhagic telangiectasia (HHT), a condition with no approved therapy.

From baseline to 24 weeks, daily treatment with the multiple myeloma drug demonstrated a 0.95-greater reduction in patients' Epistaxis Severity Score (ESS) compared with placebo (95% CI -1.58 to -0.32, P=0.003), a difference shown to be clinically meaningful on the validated scale, reported Keith McCrae, MD, of the Cleveland Clinic's Taussig Cancer Institute.

Treatment at the 4-mg dose of pomalidomide also significantly improved quality of life (QOL) and increased hemoglobin, hematocrit, and mean corpuscular volume, he said during a late-breaking presentation at the American Society of Hematology (ASH) annual meeting.

HHT is characterized by the formation of telangiectasia, or spider veins, along with arteriovenous malformations (AVMs) on mucosal surfaces and in the lungs, brain, liver, and spinal cord. Recurrent and often severe epistaxis is the most common clinical manifestation of HHT -- occurring in more than 95% of patients -- and can lead to iron deficiency anemia, visits to the emergency department, hospitalization, and negative effects on QOL.

The disorder is the second most common inherited bleeding disorder behind von Willebrand disease, with an approximate incidence of one in every 5,000 individuals. HHT may also be the most clinically significant bleeding disorder in women, according to presented this year at ASH.

'I Went to the Literature'

"My interest in this disease began a long time ago," said McCrae.

He detailed a 2009 case involving a 45-year-old man with type 2A von Willebrand disease and severe epistaxis and gastrointestinal (GI) bleeding. Each week the patient required multiple packed red blood cell transfusions and three doses of antihemophilic factor/von Willebrand factor complex (Humate-P), and was "advised by surgeons that his only chance was to actually have his whole bowel resected."

Genetic testing revealed the man to be an ACVRL1 mutation carrier, and he was diagnosed with HHT. Pathogenesis of HHT involves altered TGF-β signaling, with mutations in ENG, ACVRL1, and SMAD4 associated with the condition in more than 90% of cases.

"I went to the literature and found an anecdotal report of using thalidomide in this disorder, and started him on low-dose thalidomide," said McCrae. "His bleeding had almost stopped within 3 weeks."

Why Pomalidomide?

Thalidomide and pomalidomide are immunomodulatory drugs (IMiDs), a class of agents used in treating multiple myeloma that also includes lenalidomide (Revlimid). HHT is considered a systemic vascular dysplasia of dysregulated angiogenesis, and pomalidomide has been shown to have anti-angiogenic activity, said McCrae.

Responding to a question from the audience, he noted that the choice of pomalidomide rather than another IMiD was in part due to convenience -- it was offered -- but also due to its favorable safety profile and the fact that thalidomide and is difficult to access.

"Might all the IMiDs work in the same manner? It's certainly possible," he said.

Session co-chair Jean Connors, MD, of Dana-Farber Cancer Institute in Boston, noted the limited duration of treatment in the study.

"You gave 6 months of treatment, do you see a sustained effect?" she asked. "How do you manage [patients] once you stop treatment?"

McCrae noted that access to pomalidomide post-study has not been without challenges. Even during the trial, he said, investigators were required to go through the drug's risk evaluation and mitigation strategies (REMS) program, which occasionally caused short gaps in treatment.

But in one of his patients from the study, "bleeding only began to recur about 6 months after therapy, so in some patients anyway there are certainly prolonged responses," said McCrae.

Study Details

From 2019 to 2023, the double-blind trial randomized 144 patients with HHT in a 2:1 ratio to 24 weeks of daily treatment with pomalidomide (4 mg) or matched placebo -- after screening some 4,700 patients across more than a dozen U.S. sites.

Main enrollment criteria included a confirmed HHT diagnosis per Curaçao Diagnostic Criteria, documented anemia, and an ESS ≥3 over the prior 3 months. Higher scores on the 0 to 10 ESS scale indicate worse severity (a score of 2 to 6 represents mild to moderate epistaxis and 4 to 10 represents moderate to severe epistaxis).

The study population had a mean age of 59 years, and 48% were female, with 11% of non-white race and 3% of Hispanic ethnicity. In the 134 patients who agreed to genetic testing, ENG mutations were detected in 37%, ACVRL1 in 51%, and SMAD4 in 1%.

At baseline, patients had a mean ESS of 5 and a mean daily epistaxis duration of 16 minutes. In the preceding 6 months, 84% had required iron infusions and 19% blood transfusions. More than a third of the participants also had GI bleeding, and 40% had pulmonary AVMs.

The study's primary endpoint was change in ESS from baseline to 24 weeks, and the benefits with pomalidomide were seen as early as week 12 and sustained through the end of study (4 weeks post-treatment).

A key secondary endpoint was change in HHT-specific QOL score. Here as well, the pomalidomide-treated group experienced significantly greater and sustained improvements in QOL versus the placebo group, both at 24 weeks (P=0.015) and at the end-of-study follow-up (P=0.017).

Neutropenia represented the major toxicity of pomalidomide in the trial and was managed by dose reductions, said McCrae, who added that lowering the dose did not appear to decrease the beneficial effect of the agent. He noted that in a small pilot study involving nine patients, some did respond well at lower doses.

Fourteen percent of patients assigned to pomalidomide discontinued treatment due to toxicity. Adverse events (AEs) significantly more common with the IMiD included neutropenia (45% vs 10% with placebo), rash (36% vs 10%), constipation or diarrhea (60% vs 37%), and mild tremor (8% vs none). Serious AEs occurred at a numerically higher rate for patients on pomalidomide (23% vs 16% with placebo).

Investigators observed no thrombosis signal and no opportunistic infections with pomalidomide, said McCrae, side effects that have been reported in myeloma patients.

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