Treatment with systemic bevacizumab reduced bleeding and significantly increased hemoglobin levels in patients with the rare bleeding disorder hereditary hemorrhagic telangiectasia (HHT), according to results from the InHIBIT-Bleed study presented at EHA25 Virtual, the virtual edition of the 25th European Hematology Association Annual Congress. Bevacizumab is a monoclonal IgG1 antibody that neutralizes circulating vascular endothelial growth factor (VEGF) and is often used off-label as an anti-angiogenic treatment in HHT.
“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, we expect that these findings will establish systemic bevacizumab as a treatment option for moderate-to-severe HHT-associated bleeding,” said study author and presenter Hanny Al Samkari, MD, of Massachusetts General Hospital.
The current standard of care for the management of bleeding in HHT is local hemostatic procedural interventions, such as argon plasma coagulation for gastrointestinal tract telangiectasias, or laser cautery treatments for nasal telangiectasias, Dr. Al-Samkari explained. He noted that these interventions can improve local 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 recurrent bleeding.”
Dr. Al-Samkari added, “It is quite common for patients with HHT to have had dozens and dozens of these procedures over time,” he said, “and in severe cases of recurrent nose bleeding, patients may resort to a nasal closure procedure, sacrificing their sense of taste, smell, and their ability to breathe through their nose.” In addition, standard care rarely leads to resolution of patients’ iron-deficiency anemia, which results from recurrent bleeding.
The InHIBIT-Bleed study was an international retrospective analysis of 238 patients from 12 centers with a clinical diagnosis of suspected or definite HHT, defined by the presence of at least 2 of the following criteria:
- spontaneous and recurrent epistaxis
- telangiectasias at characteristic sites
- visceral arteriovenous malformations
- first-degree relative with HHT
Participants also had red blood cell (RBC) transfusion dependence and/or iron infusion dependence.
Treatment consisted of an induction phase that comprised 4 to 6 intravenous infusions of bevacizumab 5 mg/kg administered every 2 weeks for up to 12 weeks. In the maintenance period following induction phase, bevacizumab 5 mg/kg was administered every 4 to 12 weeks.
During a median treatment period of 12 months (range = 1-96), patients in the retrospective cohort received a median of 11 bevacizumab infusions (range = 1-74). The mean age of the HTT population was 63 years (range = 29-91), and a slight majority of the patients (62%) were women.
Primary bleeding sources across all patients included:
- epistaxis (42%)
- gastrointestinal (GI) bleeding (19%)
- epistaxis and GI bleeding (39%)
In a safety analysis that included 340 patient-years, 38% of patients treated with bevacizumab experienced adverse events (AEs), such as:
- hypertension (18%)
- fatigue (10%)
- proteinuria (9%)
- myalgia/arthralgia (6%)
Approximately 5% of patients discontinued bevacizumab because of AEs. All 5 patients (2%) who experienced venous thromboembolism were anticoagulated without bevacizumab interruption or increased bleeding incidence. There were no fatal AEs and no increase in treatment-related AEs in those treated with the agent for a longer duration, Dr. Al-Samkari reported.
In the efficacy analysis, researchers examined the change in HSS from pretreatment to maintenance during a designated timeframe of up to 36 weeks, as well as changes in the individual patient mean hemoglobin, average maintenance epistaxis severity score (ESS), individual RBC transfusion requirements, and individual patient intravenous iron infusion requirements.
In the year following bevacizumab administration, patients achieved significantly higher mean hemoglobin levels, which increased by 3.2 g/dL from pre- to post-treatment (8.6 g/dL vs. 11.8 g/dL, respectively; p<0.0001). In addition, bevacizumab was associated with a significant 3.4-point reduction in the mean ESS (6.8 vs. 3.4; p<0.0001).
Bevacizumab also led to an 82% reduction in the median number of transfused RBC units, from 9 units during the 6 months before treatment to 0 units during the first 6 months of treatment (p<0.0001). Participants experienced a similar reduction in the need for iron transfusions, from 8 to 2 units in the first 6 months of treatment (p<0.0001). No difference was found between disease severities or underlying pathogenic gene mutation (ENG vs. ACVRL1) in terms of treatment efficacy or outcomes.
Overall, Dr. Al-Samkari said, approximately two-thirds of patients who were anemic at baseline achieved freedom from anemia following treatment with bevacizumab. These “significant and striking improvements” were observed in a “cohort of patients with a rare disease treated with a biologic therapy,” he added, “and [the study] had the size and scope capable of doing subgroup analyses to compare maintenance strategies and treatment effects by underlying genotype.”
However, he noted that the study was limited by its lack of a control group, retrospective design, and the lack of assessment of patient-reported quality of life both before and after bevacizumab treatment.
The authors report relationships with Agios, Dova, and Amgen.
Al-Samkari H, Kasthuri R, Albitar H, et al. An international multicenter study of systemic bevacizumab for bleeding in hereditary hemorrhagic telangiectasia: The InHIBIT-Bleed study. Abstract S320. Presented as part of EHA25 Virtual, June 12, 2020.