Conference Coverage

Large cohort study: Bevacizumab safe, effective for severe HHT bleeds



Systemic bevacizumab is safe and highly effective for the management of chronic bleeding and anemia in patients with hereditary hemorrhagic telangiectasia (HHT), according to findings from an international observational study.

In 238 patients from 12 international centers who were treated with bevacizumab for a median of 12 months, mean hemoglobin levels increased by 3.2 g/dL (mean pre- and posttreatment levels, 8.6 vs. 11.8 g/dL), and epistaxis severity scores (ESS) decreased by a mean of 3.4 points (pre- and posttreatment scores, 6.8 vs. 3.4 points), Hanny Al-Samkari, MD, reported at the International Society on Thrombosis and Haemostasis virtual congress.

As established in prior studies, the minimal clinically important difference in the ESS, a well-validated 10-point bleeding score in HHT, is 0.71 points; the mean reduction seen in this study was 4.75 times that, noted Dr. Al-Samkari, a clinical investigator and hematologist at Massachusetts General Hospital, Boston.

Further, the median number of red blood cell units transfused during the first year of treatment decreased by 82%, compared with the 6 months prior to treatment (9.0 vs. 0 units), and median iron infusions decreased by 70% during the same period (8.0 vs. 2.0 infusions), he said, adding that these improvements occurred within the first 6 months of treatment and were maintained through 12 months.

Study subjects were adults with a mean age of 63 years who were treated with systemic bevacizumab, a vascular endothelial growth factor receptor (VEGF) monoclonal antibody, between 2011 and 2019 for the primary indication of moderate to severe chronic HHT-related bleeding and anemia. Treatment involved four to eight induction infusions – typically at a dose of 5 mg/kg and given 4 weeks apart – followed by bevacizumab maintenance, either as continuous or scheduled maintenance at 4-, 8-, or 12-week intervals regardless of symptoms, or on an as-needed basis, with 2-6 infusions for signs or symptoms of rebleeding.

Patients received a median of 11 infusions, and 181 received maintenance treatment, including continuous or scheduled maintenance in 136 patients and as-needed maintenance in 45 patients, Dr. Al-Samkari said.

The treatment was generally well tolerated; the most common adverse events during 344 patient-years of treatment were hypertension, fatigue, and proteinuria. No fatal treatment-related adverse events occurred, and no increase in adverse events occurred with longer treatment, he noted

Venous thromboembolism occurred in five patients, including two patients who had “provoked events immediately following joint replacement surgery,” he said.

Thirteen patients (5%) discontinued treatment – 11 for inadequate effect and 2 for side effects, he noted.

Subgroup analyses showed that outcomes were similar regardless of underlying pathogenic mutation, but among those receiving bevacizumab maintenance, the continuous approach, compared with as-needed maintenance, was associated with greater improvement in hemoglobin (10.8 vs. 12.3 g/dL) and ESS (mean, 4.96 vs. 2.88) during months 7-12 of treatment, “which is the time most reflective of the effect of maintenance,” he said.

HHT, also known as Osler-Weber-Rendu disease, is a “rare, genetic, progressive, multisystem bleeding disorder resulting from disorder of angiogenesis,” Dr. Al-Samkari explained, adding that the condition is characterized by severe, recurrent epistaxis and chronic gastrointestinal bleeding.

“Bleeding frequently leads to iron deficiency anemia, which may be severe and dependent on regular iron infusions and/or blood transfusions,” he said.

Though rare, it is the second most common bleeding disorder worldwide, with a prevalence about twice that of hemophilia A and six times that of hemophilia B.

“Despite this, it has no FDA-approved therapies,” he said. “The current mainstay of care is surgical or procedural local hemostatic intervention – which is usually temporizing – and hematological support in the form of blood and iron.”

However, given that the underlying genetic defects that cause HHT result in elevations in VEGF, targeting VEGF with existing antiangiogenic agents is a promising approach.

In fact, several centers have been using bevacizumab for several years as an off-label treatment for bleeding in this setting, and while scattered case reports and small case series suggest efficacy, no “large or definitive studies” have been conducted, and safety hasn’t been carefully evaluated, he said.

To that end, the International Hereditary Hemorrhagic Telangiectasia Intravenous Bevacizumab Investigative Team (InHIBIT) was formed. The current report, “the largest study of antiangiogenic therapy to date in HHT,” represents the results of the InHIBIT-Bleed study, the first completed by the team. The next study will address bevacizumab for the treatment of high-output cardiac failure in HHT (the InHIBIT-HF study), Dr. Al-Samkari said.

Though limited by its retrospective nature and lack of a unified treatment protocol, the InHIBIT-Bleed study provides important information and is strengthened by the large cohort size, especially given that HHT is a rare disease, and by other factors, such as the substantial number of patient-years of treatment.

“Bevacizumab was effective in the management of severe HHT-related epistaxis and GI bleeds,” he said, noting the “significant and striking improvements” on a variety of measures.

Questioned about the durability of treatment effects after treatment discontinuation, Dr. Al-Samkari said outcomes are variable, “highly patient dependent,” and “something that we really need to investigate thoroughly.”

As for the potential for anti-VEGF therapy for bleeding in certain non-HHT settings, session moderator Michael Makris, MD, professor of haemostasis and thrombosis at the University of Sheffield, England, said the possibilities are intriguing.

“I work with lots of patients with von Willebrand disease and angiodysplasia,” he said, adding that angiodysplasia-related bleeding in type 2A von Willebrand disease is a major issue.

Dr. Al-Samkari agreed that the possibility is worth exploring.

“We have looked at this in a small number of patients, and the jury is still out,” he said. “But there is a publication in Gastroenterology – Albitar et al. – that evaluated bevacizumab in patients without HHT [who had] angiodysplasias from other causes – not specifically in type 2 von Willebrand syndrome ... and did find that it was effective at causing the angiodysplasias to regress, hemoglobin to improve.

“So the non-HHT use of this agent is certainly an important one [and] we do have retrospective evidence in a small group of patients who don’t have HHT, who do have angiodysplasias and bleeding, that it may be effective as well.”

Dr. Al-Samkari reported receiving research support and/or consulting fees from Agios, Amgen, and Dova.

SOURCE: Al-Samkari H et al. ISTH 2020, Abstract OC 09.2.

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