Effect of systemic bevacizumab in severe hereditary hemorrhagic telangiectasia associated with bleeding
Authors: Narendranath Epperla, Jonathan T. Kapke, Matthew Karafin, Kenneth D. Friedman, Patrick Foy
Journal: American Journal of Hematology (2016)

To the Editor: Hereditary hemorrhagic telangiectasia (HHT) is a multisystem autosomal dominant vascular disorder characterized by severe and recurrent epistaxis and gastrointestinal (GI) hemorrhages from muco-cutaneous telangiectases 1. Other important features include development of arteriovenous malformations (AVM's), most commonly in the lung, liver, brain, and spine 1. Vascular endothelial growth factor (VEGF) levels in circulation are elevated in patients with HHT 2. Intravenous (IV) administration of bevacizumab, a VEGF inhibitor, has been shown to be effective in improving epistaxis and telangiectasias; reducing the need for packed red blood cell (PRBC) transfusions, and improvement in the high output cardiac failure 3-6. However, there have been no large scale studies demonstrating the effect of systemic bevacizumab with the primary goal of reducing bleeding complications in severe HHT. We conducted this study wherein we hypothesize that systemic bevacizumab reduces bleeding, transfusions, and hospitalizations in patients with severe HHT. Eleven HHT patients who received systemic bevacizumab during January 1, 2009 to December 31, 2014 were identified. Only five subjects were evaluable after exclusion of patients who were treated for high output cardiac failure (n = 2), with insufficient documentation (n = 2), and lost to follow up (n = 2). Demographic and clinical data collected for all subjects included age, gender, race, hemoglobin, and serum creatinine, history of epistaxis, melena, and hematochezia. Other variables obtained included number of PRBC transfusions and emergency room (ER) visits/hospitalizations up to 1 year before and after bevacizumab administration. Adverse events related to medication use (blood pressures, proteinuria, or any other grade III/IV side effects) were captured during and after IV bevacizumab treatment. Adverse events were recorded in four time blocks (each 3 months) following bevacizumab administration to capture early (first time block) or delayed (third and fourth time blocks) side-effects. Each course of bevacizumab consisted of six doses of IV bevacizumab (5 mg/kg body weight) administered every 2 weeks. The primary endpoint of the study was to determine the difference in the number of PRBC units transfused in the year before and after bevacizumab administration. Secondary endpoints included the number of ER visits and hospitalizations for the study patients during this time period, the average length of hospital stay, months following bevacizumab administration before repeat dosing, change in hemoglobin 60 days after bevacizumab administration, and the safety and tolerability of bevacizumab. The median age of the patients in our study was 54 years (range, 43–61 years) with (5/5 males and 0 females). The median baseline hemoglobin was 9 g/dL (range, 7.3–9.8 g/dL) at the time of bevacizumab administration. Anemia was related to epistaxis in four patients (cases 1–4), and GI bleeding in another patient (case 5). All patients were treated with oral and parenteral iron supplementation. All patients except for case 5 received antifibrinolytic agents and intranasal bevacizumab for control of epistaxis (Supporting Information Table). All patients required PRBC transfusions in the year prior to initiation of bevacizumab therapy. Total number of PRBC units transfused ranged from 2 to 471 in the year prior to bevacizumab administration. Five of five subjects (100%) had a decrease in transfusion requirements after bevacizumab, and one person became transfusion independent. The total number of units transfused in the year before and after bevacizumab decreased by 51%–100% (Table 1). Hemoglobin increase was seen early after the administration of bevacizumab and it was robust in all patients (Supporting Information Figure). Total number of ER visits and hospitalizations decreased by 78% (median reduction from 5 [range, 2–38] to 3 [range, 0–8]) in the year following administration of bevacizumab compared to the year prior to administration. The median length of hospital stay was 2 days both before and after bevacizumab treatment (Table 1). Two patients (cases 1 and 2) received a second course of bevacizumab after developing recurrent bleeding episodes. Treatment dosing and schedule was identical to the initial therapy (5 mg/kg every 2 weeks × 6 doses). The second courses of bevacizumab were given 16 and 14 months after initial course of bevacizumab in cases 1 and 2, respectively (Table 1). Case 5 received a total of 15 doses of bevacizumab due to ongoing bleeding but with a lag of 4 weeks between cycle 6 and 7. Two of the patients (cases 1 and 3) developed grade I hypertension and one patient (case 5) had grade I proteinuria. All the aforementioned adverse effects were early onset and transient. No delayed or other grade III/IV adverse effects were noted. mLOS (days) mLOS (days) To our knowledge, this is the first study that objectively demonstrates the decreased number of PRBC transfusions, interventions and hospitalizations in the year following administration of bevacizumab compared to the year prior to administration. Patients with epistaxis (cases 1–4) in our study initially had good responses to antifibrinolytic therapy with eventual resistance despite switching agents (EACA to tranexamic acid) or using combination agents (both EACA and tranexamic acid). Topical intranasal bevacizumab was also tried without sustained response. Patients were started on systemic bevacizumab with remarkable response as evidenced by the decreased transfusion needs and increased hemoglobin levels. The one patient (case 5) with profound GI bleeding related to AVM's also had decreased transfusion needs after initiation of systemic bevacizumab. We showed that initiation of systemic bevacizumab in severe HHT cases improves hemoglobin, and decreases the need for PRBC transfusions, hospitalizations/ER visits and invasive procedures (endoscopy, cautery). The drug was well tolerated with few adverse effects. Some patients benefitted from subsequent courses of therapy, raising the question about the best treatment timing, schedule, and dosing of systemic bevacizumab. Either a series of infusions as was performed in our study or a treatment option in which after an interval of induction therapy a maintenance course follows to prevent symptomatic recurrence need to be evaluated in a prospective fashion. The major limitation of our study is the small sample size and lack of quality of life data. In conclusion we feel that systemic bevacizumab is a viable and potentially safe option in patients with severe HHT refractory to other measures. Prospective randomized trial with longer follow-up is needed to validate our findings and suggest the duration of efficacy of therapy. The authors thank the Division of Hematology and Oncology for their support in manuscript preparation. Narendranath Epperla,1* Jonathan T. Kapke,2 Matthew Karafin,3 Kenneth D. Friedman,1 and Patrick Foy1 1Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin 2Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 3Division of Transfusion Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin Additional Supporting Information may be found in the online version of this article. Additional Supporting Information may be found in the online version of this article. Supporting Information Figure 1 Supporting Information Table 1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.