Page 134 - 2021_06-Haematologica-web

H. Al-Samkari et al.
Introduction
Hereditary hemorrhagic telangiectasia (HHT, Osler- Weber-Rendu disease) is an autosomal dominant multi- system disease of disordered angiogenesis.1 It occurs due to mutations in genes encoding proteins that mediate sig- naling via the transforming growth factor-b superfamily.2 The vast majority of patients with HHT have mutations in endoglin (ENG) or activin receptor-like kinase 1 (ACVRL1/ALK1), resulting in angiogenic dysregulation, formation of telangiectasias on mucocutaneous surfaces, local hyperfibrinolysis within telangiectasias, and devel- opment of arteriovenous malformations in visceral organs.3-5 Fragile mucocutaneous telangiectasias in the nasal mucosa (>95% of patients) and throughout the gas- trointestinal tract (75% of patients) lead to severe, recur- rent epistaxis and chronic gastrointestinal bleeding, with consequent severe iron deficiency anemia that is often transfusion-dependent.6-8 Severe recurrent epistaxis, which may last for hours per day, also results in psy- chosocial morbidity, social isolation, and challenges with employment, travel, and routine daily activities.9 Visceral arteriovenous malformations may involve the liver, lung, and central nervous system and can result in severe com- plications including high-output cardiac failure, liver fail- ure, pulmonary hemorrhage, stroke and intracerebral hemorrhage.10 Thus, chronic bleeding and visceral arteri- ovenous malformations in HHT are associated with con- siderable morbidity and mortality.10,11
With a prevalence of one case in 5,000 people, HHT is classified as a rare bleeding disorder by the Centers for Disease Control and Prevention, but is actually the sec- ond most common hereditary bleeding disorder in the USA and worldwide (following only von Willebrand dis- ease in prevalence). Despite this, there are no United States Food and Drug Administration or European Medicines Agency-approved treatments for HHT-associ- ated bleeding. The current standard of care for bleeding in HHT includes supportive red blood cell (RBC) transfusion and intravenous iron infusion to treat anemia and local nasal and endoscopic hemostatic procedures to reduce bleeding symptoms. Systemic non-specific hemostatic therapies, such as antifibrinolytic agents, are of limited benefit.12 Most importantly, none of these modalities addresses the underlying pro-angiogenic pathophysiolo- gy, and the natural history of HHT in many patients is of unremitting telangiectasia formation and progressively worsening bleeding over the lifespan.9,13-15
Although several angiogenic proteins are dysregulated in HHT,5,16 the raised level of vascular endothelial growth factor (VEGF)17 is of particular clinical interest due to the availability of targeted anti-VEGF agents. Bevacizumab (Avastin®), a recombinant, humanized monoclonal IgG1 antibody that binds to and neutralizes circulating VEGF, is one such agent and is widely used to treat malignancies and age-related macular degeneration.18,19 After promising case reports were published describing successful use of systemic bevacizumab to manage bleeding and anemia in HHT,20-22 several HHT Centers of Excellence worldwide began using this agent off-label to treat HHT patients, given the profound unmet clinical need. Currently, data describing effectiveness and safety of systemic beva- cizumab to treat chronic bleeding and anemia in HHT is limited to case reports and small, retrospective, single- center case series.23-28 The International HHT Intravenous
Bevacizumab Investigative Team study of Bleeding (InHIBIT-Bleed) was therefore designed as an internation- al collaboration of 12 HHT centers seeking to better define the safety and effectiveness of systemic beva- cizumab in the treatment of moderate-to-severe HHT- associated bleeding.
Methods
Patients and data collection
This study was approved by the Institutional Review Board of Partners Healthcare (approval 2016P002753/PHS). Nine centers in the USA and one center each in Argentina, Israel, and France participated in the study. All patients aged >18 years treated with systemic (intravenous) bevacizumab for HHT-associated bleeding (epistaxis, gastrointestinal bleeding, or both) from January 1, 2011 until May 1, 2019 were identified at each partic- ipating institution. General criteria used by centers to offer sys- temic bevacizumab for HHT-associated bleeding are detailed in Online Supplementary Table S1. Additional data collection infor- mation is given in the Online Supplementary Methods.
Effectiveness measures
Hemoglobin
Anemia was defined as a baseline hemoglobin (Hb) <11 g/dL regardless of gender. Baseline hemoglobin was calculated as the average of all measured hemoglobin values in the 6 months prior to bevacizumab initiation (at least 2 values required) and com- pared with mean on-treatment hemoglobin (mean of values col- lected at 3, 6, 9, and 12 months depending on treatment dura- tion).
Epistaxis Severity Score
Background information regarding the Epistaxis Severity Score (ESS) is provided in the Online Supplementary Methods. The baseline ESS at initiation of bevacizumab was compared with the mean on-treatment ESS (mean of values collected at 3, 6, 9, and 12 months depending on treatment duration).
Red blood cell transfusion and iron infusion
The number of red blood cell (RBC) units transfused in the first 6 months on treatment was compared with the number of units transfused in the 6 months prior to treatment. Additionally, events in the second 6 months on treatment were compared with those in the first 6 months on treatment to eval- uate ongoing response. The same analysis was performed for the number of intravenous iron infusions administered.
To be included in effectiveness analyses, patients needed to receive ≥3 months of treatment (Hb and ESS) or ≥6 months of treatment (RBC transfusion and iron infusion).
Subgroup analyses
Subgroup analyses for each effectiveness outcome were per- formed by genotype (ENG vs. ACVRL1 mutation) as well as by maintenance dosing method (continuous vs. intermittent beva- cizumab maintenance following an initial series of induction infusions).
Receipt of concurrent bleeding and anemia-directed therapies
Rates of freedom from hemostatic procedures and medical treatments (antifibrinolytic or erythropoiesis-stimulating agents) in the year following bevacizumab initiation were calculated, and effectiveness outcomes in patients who received these con-
2162
haematologica | 2021; 106(8)