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A. Kritharis et al.
ity scores and RBC transfusion requirements, although 4 patients developed new-onset or worsened hypertension. Most published studies have used bevacizumab at a dose of 5-10 mg/kg every 2-4 weeks for up to 6 cycles. A lower dose may be sufficient based on pharmacokinetic data showing VEGF suppression at 0.3 mg/kg.71 Adverse effects of bevacizumab may include hypertension, proteinuria, venous thromboembolism, intestinal perforation, and poor wound healing. Interestingly, epistaxis, which is often cited as a side effect in non-HHT patients, has not been a major complication in published studies or in our center’s extensive experience. Bevacizumab may have an impact on high output states in reducing cardiac output. In one study,48 25 patients with severe hepatic vascular AVMs were treated with bevacizumab 5 mg/kg every 14 days for 6 cycles and showed an improvement in cardiac index at three months, reduced epistaxis, and improved
quality of life. Bevacizumab nasal spray has been studied as a treatment for epistaxis. In a randomized phase I study (the ELLIPSE study), 40 patients received a single day treatment of 0.05-0.1 mL of (dose escalated) bevacizumab nasal spray into each nostril for a total dose of 12.5-100 mg.72 Initial results suggested that intranasal treatment was safe but not effective.
Use of anticoagulation in patients with thrombosis
Patients who develop thrombotic complications present a difficult therapeutic dilemma given the inherent bleed- ing of the disease. The low serum iron levels in HHT patients have been associated with elevated factor VIII levels, along with a 2.5-fold increased risk of VTE events.67 In those patients who develop a VTE, therapeutic antico- agulation can be administered. This should be managed with caution and the patient should be screened for pul-
Figura 4. Bevacizumab treatment course in a 71-year-old woman with hereditary hemorrhagic telangiec- tasia (HHT) and chronic gastroin- testinal bleeding and epistaxis. For years, the patient was only able to maintain her hemoglobin with 1-2 units of packed red blood cell (RBC) transfusion weekly plus darbepoet- in alfa 300 mcg every other week. After beginning bevacizumab 5 mg/kg at time 0, she became trans- fusion independent immediately and her hemoglobin normalized within two weeks. Bevacizumab was administered every other week for the first 4 infusions, then month- ly as maintenance. Duration of maintenance therapy is patient- dependent and optimal dose and duration is not known.
Table 3. Published data using bevacizumab to treat chronic bleeding in hereditary human telangiectasia are patients.
Study
Bose 200977
Oosting 200978
Brinkerhoff 201179
Thompson 201480
Epperla 201681
Guilhem 201782
Iyer20188
Country
U.S.
the Netherlands
U.S.
U.S.
U.S.
France
U.S.
Patient number
1
1
1
9
5
36 treated for bleeding
34
Dosing
10 mg/kg every 2 weeks x 2 cycles then 5 mg/kg every 2 weeks x 2 cycles
5 mg/kg every 2 weeks or 7.5 mg/kg
every 2 weeks
5 mg/kg every 2 weeks x 4 cycles 0.125 mg/kg IV every 4 weeks x 6 cycles
5 mg/kg every 2 weeks x 6 cycles
5 mg/kg
every 2 weeks x 6 cycles
5mg/kgevery2weeksx4cycles, with modification of dosing depending on response
Duration of efficacy
12 months
12 months
12 months
6 months
12 months
6 months (median)
Effect on epistaxis
Immediate improvement
Immediate improvement
Resolution after 4 cycles
Improvement in frequency and severity after 3 cycles on average
Reduced need for nasal cautery procedures
78% of patients had improved bleeding by physician assessment
6.4months(median), Significantimprovement intermittent treatment in epistaxis severity
scores
HHT: hereditary hemorrhagic telangiectasia; IV: intravenous.
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