Fewer nosebleeds with pomalidomide for HHT

Daily treatment with the immunomodulatory agent pomalidomide for 6 months significantly reduced severe nosebleeds in patients with hereditary haemorrhagic telangiectasia (HHT) in the double-blind, randomized, placebo-controlled PATH-HHT trial.

HHT, also called Osler-Weber-Rendu syndrome, is potentially life-threatening and equally affects men, women, and children of different backgrounds. People with HHT develop small lesions (telangiectases) that can burst and bleed.  Over 90 percent of individuals affected by HHT will develop chronic nosebleeds. 

There is no cure for HHT, but treatments can improve symptoms and reduce the risk of serious complications. 

Reduction in epistaxis score

In the PATH-HHT trial, there was a 0.95-greater reduction in patients’ Epistaxis Severity Score (ESS) – a tool for tracking nosebleeds – with pomalidomide at 6 months compared with placebo (95 percent confidence interval [CI], -1.58 to -0.32; p=0.003), a difference that was clinically meaningful, according to study investigator Dr Keith McCrae from the Cleveland Clinic’s Taussig Cancer Institute in Cleveland, Ohio, US, during his presentation at ASH 2023. [ASH 2023, abstract LBA-3]

“Quality of life [QoL] also improved with pomalidomide, as well as haemoglobin and haematocrit levels, and mean corpuscular volume,” he added.

McCrae said his interest in HHT started in 2009 when a male patient of him presented with a type 2A von Willebrand disease, with severe epistaxis and gastrointestinal (GI) bleeding. The patient was administered packed red blood cell transfusions and antihaemophilic factor/von Willebrand factor complex (Humate-P) every week. “Surgeons told him his only chance of survival was to have his entire bowel resected.”

Anecdotal evidence

The patient was identified as an activin receptor-like kinase-1 (ACVRL1) mutation carrier and was eventually diagnosed with HHT.

“HHT involves altered TGF-β signalling, with mutations in ENG, ACVRL1, and SMAD4 associated with the condition in over 90 percent of cases,” said McCrae.

“I went to the literature and found an anecdotal report on the use of thalidomide for HHT, so I started him on low-dose thalidomide,” he added. “His bleeding had almost stopped in 3 weeks.”

6 months of pomalidomide

Pomalidomide, just like thalidomide, is an immunomodulatory drug with known antiangiogenic activity, said McCrae. Why pomalidomide was used in the PATH-HHT trial over other immunomodulatory drug was because of its safety profile and convenience of use.

In the trial, 144 patients with HHT were randomly assigned in a 2:1 ratio to pomalidomide 4 mg daily or a matching placebo for 6 months.

The patients also had anaemia and an ESS score of ≥3 in a scale of 0–10 scale (0-1 means no epistaxis, 2–6 suggests mild-to-moderate epistaxis, 4–10 means moderate-to-severe epistaxis). Mean age was 59 years, 48 percent were female. In 134 patients who underwent genetic testing, 37 percent had mutations in ENG, 51 percent had ACVRL1, and 1 percent had SMAD4.

Mean ESS at baseline was 5. Mean epistaxis duration daily was 16 minutes. Six months prior, 84 percent had iron infusions and 19 percent had blood transfusions. More than a third of the participants had GI bleeding; 40 percent had pulmonary arteriovenous malformations.

Early benefits

The benefits with pomalidomide were evident as early as 3 months and were sustained 1 month after treatment.

As for the change in HHT-specific QoL score, the pomalidomide-treated group had greater and sustained improvements in QoL vs the placebo group, both at 6 months and at the end of follow-up (p=0.015 and p=0.017, respectively).

Constipation or diarrhoea (60 percent) and neutropenia (45 percent) were the most common adverse events seen with the drug, followed by rash (36 percent) and mild tremor (8 percent). There were no reports of opportunistic infections nor thrombosis signal with pomalidomide, said McCrae.