Drug Shows 'Striking' Efficacy in Hereditary Bleeding Disorder

Nancy A. Melville

June 18, 2020

Bevacizumab has shown efficacy in the treatment of hereditary hemorrhagic telangiectasia (HHT), a rare, progressive bleeding disorder for which there are currently no approved therapies.

The finding comes from the InHIBIT-Bleed trial, results from which were presented as part of the Virtual Edition of the 25th European Hematology Association (EHA) Congress.

"This is the largest study of an anti-angiogenic therapy to date on hereditary hemorrhagic telangiectasia," said first author Hanny Al-Samkari, MD, from Massachusetts General Hospital and Harvard Medical School, Boston.

"Given the striking effectiveness observed in the InHIBIT-Bleed study coupled with the fact that there are no FDA-approved medications to treat the manifestations of HHT, including bleeding, we expect that these findings will establish systemic bevacizumab as a clear standard-of-care treatment option for moderate-to-severe HHT-associated bleeding," Al-Samkari told Medscape Medical News.

HHT, though rare, is highly underrecognized, Al-Samkari said. The condition, also known as Osler-Weber-Rendu disease, is in fact the second most common hereditary bleeding disorder worldwide, with a prevalence that is approximately twice that of hemophilia A and 6-times that of hemophilia B, he noted.

An expert approached for comment said the new results with bevacizumab represent an important advancement in the management of a highly challenging syndrome.

"This is an important study because it has a large number of patients, with a multicenter, international population that has been well-characterized," Riitta Lassila, MD, PhD, head of coagulation disorders at Helsinki University Hospital and professor in coagulation medicine at Helsinki University, Finland, told Medscape Medical News.  

"What they demonstrate here is with this treatment, you can maintain hemostasis by improving red blood cell numbers and hemoglobin," she said. "So it's a great achievement in helping to alleviate the anemia with HHT and reduce the need for infusions."

Lassila commented that she has seen first-hand how devastating the bleeding can be for patients with HHT. "When I was in medical school, one of the first nights on-call, we had a patient who bled to death as a result of this syndrome, and I learned how severe it can really get," she said.

"The patient was elderly and had other issues, but the bleeding was so heavy that it couldn't be managed in the emergency situation," she recalled. "So this is an important syndrome that needs to be managed well."

Lassila noted that bevacizumab already has become established in the field of gastroenterology.

"Now, it can be considered an evidence-based treatment in HHT, and I agree that it could become the standard of care for these patients," she told Medscape Medical News.

Multisystem Bleeding Disorder

HHT, a multisystem bleeding disorder, involves abnormal vessel formation that results in severe recurrent epistaxis (nosebleeding) in nearly all patients, as well as chronic gastrointestinal hemorrhage and potentially severe iron-deficiency anemia.

Symptoms can be so severe that patients require monthly or weekly infusions of iron or blood, Al-Samkari noted.

Bevacizumab was investigated because it is an antibody that targets vascular endothelial growth factor (VEGF), which is elevated in patients with HHT because of the underlying genetic defects.

The multicenter, international InHIBIT-Bleed trial involved 238 patients with HHT and moderate-to-severe bleeding (mean age 63 years, range 29-91). They were recruited at 12 international centers and treated with bevacizumab infusions for a median of 12 months (range 1-96 months), receiving a median of 11 (range 1-74) infusions of bevacizumab.

These patients had epistaxis (42%), gastrointestinal bleeding, (19%) or both (39%).

Compared with pretreatment levels, patients had mean increases in hemoglobin of 3.2 g/dL (mean hemoglobin 8.6 g/dL vs 11.8 g/dL, P < .0001) during the first year of treatment.

During the period, they also had a mean decrease in the epistaxis severity score (ESS) of 3.4 points (mean ESS 6.8 vs 3.4; P < .0001) during the first year of treatment, or about 50%.

"The minimal clinically important difference in ESS score, determined from previous studies, is a reduction of 0.71 points, so the mean reduction in the study of 3.4 points is about 4.75 times the minimal clinically important difference," Al-Samkari said.

In addition, compared with 6 months pretreatment, patients' red blood cell transfusions decreased by 82% (median of 9.0 units vs 0 units, P < .0001) during the first 6 months of bevacizumab, and infusions of iron decreased by 70% (median of 8.0 infusions vs 2.0 infusions, P < .0001).

There were no significant differences in bevacizumab efficacy based on disease severity, and outcomes were similar regardless of underlying pathogenic gene mutation, such as ENG vs ACVRL1.

In terms of dosing regimens, patients were treated with initial induction of 4 to 6 infusions of bevacizumab 5 mg/kg administered every 2 weeks.

A continuous maintenance regimen administered every 4 to 12 weeks was associated with slightly higher hemoglobin and lower ESS scores compared with the alternative approach of intermittent/as needed maintenance; the continuous approach involved more drug exposure.

Bevacizumab was well tolerated, with adverse events (AEs) occurring in 38% of patients, including hypertension (18%), fatigue (10%), proteinuria (9%) and myalgia/arthralgia (6%). Only 5% of patients discontinued treatment because of AEs and there were no fatal AEs.

"The effect of bevacizumab treatment," Al-Samkari explained, "was that 67% of patients who were anemic at baseline achieved freedom from anemia and 92% of those treated for epistaxis achieved a clinically meaningful reduction in ESS.

"In addition, 80% of patients requiring red blood cell transfusion in the 6 months pretreatment were RBC transfusion-free after 6 months of treatment. And 61% of patients requiring iron infusions in the 6 months pretreatment were iron infusion-free after 6 months of treatment."

No Approved Treatments

In the absence of a treatment for HHT that has US Food and Drug Administration (FDA) approval, the current standard of care has for many decades been local hemostatic procedural interventions, including argon plasma coagulation for gastrointestinal tract telangiectasias or laser cautery treatments for nasal telangiectasias.

"These procedures often improve bleeding but do not address the underlying disease pathophysiology the way that a systemic anti-angiogenic agent like bevacizumab does, so their effects usually wear off after a few months and the patient has bleeding again," Al-Samkari explained.

In some severe cases of recurrent nosebleeding, patients may resort to a nasal closure procedure, "which can sacrifice their sense of taste, smell, and the ability to breathe through their nose to get the bleeding to stop," he added.

"Given that our study found that bevacizumab is safe and effective to treat both nasal and gastrointestinal bleeding in HHT, it clearly compares quite favorably to procedural interventions."

Although the study did not include quality-of-life assessments, Al-Samkari said he has observed them first-hand. "In HHT patients whom I have treated with bevacizumab, it is very common for them to state that their lives have been dramatically changed for the better after initiating this agent."

Al-Samkari disclosed relationships with Agios, Dova, and Amgen. Lassila has disclosed no relevant financial relationships.

25th European Hematology Association (EHA) Congress (virtual): Abstract S320. Presented June 12, 2020.

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