An international, multicenter study of intravenous bevacizumab for bleeding in hereditary hemorrhagic telangiectasia: the InHIBIT-Bleed study

Abstract

Hereditary hemorrhagic telangiectasia (HHT, Osler-Weber-Rendu disease) is a rare multisystem vascular disorder causing chronic gastrointestinal bleeding, epistaxis, and severe anemia. Bevacizumab, an anti-vascular endothelial growth factor antibody, may be effective to treat bleeding in HHT. This international, multicenter, retrospective study evaluated the use of systemic bevacizumab to treat HHT-associated bleeding and anemia at 12 HHT treatment centers. Hemoglobin, epistaxis severity score, red cell units transfused, and intravenous iron infusions before and after treatment were evaluated using paired means testing and mixed-effects linear models. 238 HHT patients received bevacizumab for a median of 12 (range, 1-96) months. Compared with pretreatment, bevacizumab increased mean hemoglobin by 3.2 g/dL (95% CI, 2.9-3.5 g/dL) [mean hemoglobin 8.6 (8.5, 8.8) g/dL versus 11.8 (11.5, 12.1) g/dL, p<0.0001)] and decreased the epistaxis severity score (ESS) by 3.4 (3.2-3.7) points [mean ESS 6.8 (6.6-7.1) versus 3.4 (3.2-3.7), P<0.0001] during the first year of treatment. Compared with 6 months pretreatment, RBC units transfused decreased by 82% [median of 6.0 (IQR 0.0-13.0) units versus 0 (IQR, 0.0-1.0) units, P<0.0001] and iron infusions decreased by 70% [median of 6.0 (1.0-18.0) infusions versus 1.0 (0.0-4.0) infusions, P<0.0001] during the first 6 months of bevacizumab treatment. Outcomes were similar regardless of underlying pathogenic mutation. Following initial induction infusions, continuous/scheduled bevacizumab maintenance achieved higher hemoglobin and lower ESS than intermittent/as needed maintenance but with more drug exposure. Bevacizumab was well tolerated: hypertension, fatigue, and proteinuria were the most common adverse events. Venous thromboembolism occurred in 2% of patients. In conclusion, systemic bevacizumab was safe and effective to manage chronic bleeding and anemia in HHT.

Figure 1.

Box-and-whisker plots showing the effect of intravenous bevacizumab on hematologic parameters and epistaxis severity. A box represents the median and interquartile range and tails represent minimum and maximum values. Numbers at each time-point reflect the number of hereditary hemorrhagic telangiectasia (HHT) patients in a given analysis treated for at least that duration with complete data. (A) Effect on hemoglobin in HHT patients with baseline anemia (n=185). (B) Effect on Epistaxis Severity Score in patients treated for epistaxis (n=146). (C) Effect on red blood cell (RBC) transfusions in patients receiving transfusion in the 6 months prior to bevacizumab initiation (n=137). (D) Effect on iron infusion events in patients receiving intravenous iron in the 6 months prior to bevacizumab initiation (n=155). RBC: red blood cell; Mo: months; Tx: treatment.

Figure 2.

Red blood cell transfusions and iron infusions pretreatment and on-bevacizumab treatment by hematologic support requirements in the 6 months prior to bevacizumab initiation. (A) All patients requiring red blood cell (RBC) transfusion before treatment (n=137) were divided into quartiles (Q1-Q4) according to their pretreatment RBC transfusion requirements. Reductions in RBC transfusions were observed following bevacizumab treatment regardless of the pretreatment disease severity. (B) All patients requiring iron infusion pretreatment (n=155) were divided into quartiles according to their pretreatment iron infusion requirements. Reductions in iron infusions were observed following bevacizumab treatment regardless of the pretreatment disease severity. Mo: months; PreTx, pretreatment; OnTx, on treatment.