Availability, Use, Efficacy and Safety of Bevacizumab in European HHT Centers

Availability, Use, Efficacy and Safety of Bevacizumab in European HHT Centers | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL British Journal of Clinical Pharmacology This is a preprint and has not been peer reviewed. Data may be preliminary. 11 June 2025 V1 Latest version Share on Availability, Use, Efficacy and Safety of Bevacizumab in European HHT Centers Authors : Pernille Darre Haahr 0009-0009-2562-127X [email protected] , Annette Fialla , Anette Kjeldsen , Anne-emmanuelle Fargeton , Alexandre Guilhem , Elisabetta Buscarini , Freya Droege , … Show All … , Guido Manfredi , Hans-Jurgen Mager , Jean-Christophe Saurin , Jens Kjeldsen , Josefien Hessels , Marco Post , Robert Mandic , Sanne Boerman , Stefan Kasper-Virchow , Sören Möller , Urban Geisthoff , and Sophie Dupuis-Girod Show Fewer Authors Info & Affiliations https://doi.org/10.22541/au.174963986.68576845/v1 330 views 202 downloads Contents Abstract Availability, Use, Efficacy and Safety of Bevacizumab in European HHT Centers Figure legends Supplementary Material References Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Introduction Bevacizumab, a VEGF inhibitor, is used off label for treatment of severe anaemia related to epistaxis, GI-bleeding and/or severe liver arteriovenous malformations (HAVM) and right sided cardiac failure in patients with Hereditary Haemorrhagic Telangiectasia (HHT) Aim To report the experience of treatment with bevacizumab within VASCERN centres. Method A retrospective analysis of the usage, availability, efficacy and safety in HHT patients treated with bevacizumab in the European VASCERN centres. Results A total of 151 patients received treatment with bevacizumab in European VASCERN centres. Most patients were treated in Denmark, France and the Netherlands. There was an improvement in haemoglobin with a mean increase of 2.9 g/dL and significant reduction in the number of red blood cells transfusions. Cardiac output was measured and improved in 85 % of patients treated for high output cardiac failure in relation to severe HAVM. No severe adverse events were recorded, however 70 patients experienced at least one side effect. Conclusion Although this is a retrospective study, we have shown convincing efficacy of bevacizumab in treatment of patients with HHT, with a good risk-benefit balance. Availability, Use, Efficacy and Safety of Bevacizumab in European HHT Centers Pernille D. Haahr MD a,b ; Anette D. Kjeldsen MD, PhD a ; Annette D. Fialla MD, PhD b ; Anne-Emmanuelle Fargeton MSc c ; Alexandre Guilhem MD c ; Elisabetta Buscarini, MD d ; Freya Droege, MD e ; Guido Manfredi, MD, PhD d ; Hans-Jurgen Mager, MD PhD f ; Jean-Christophe Saurin MD, PhD c ; Jens Kjeldsen MD, PhD b ; Josefien Hessels, MD f ; Marco C. Post, MD, PhD g,h ; Robert Mandic, MD i ; Sanne Boerman, MD f , Stefan Kasper-Virchow. MD, PhD j ; Sören Möller Cand.scient, PhD k ; Urban Geisthoff, MD i Sophie Dupuis-Girod, MD, PhD c a: VASCERN HHT Reference Centre and ENT Department, Odense University Hospital, University of Southern, Denmark b: VASCERN HHT Reference Centre and Gastroenterology and Hepatology Department, Odense University Hospital, University of Southern, Denmark c: VASCERN HHT Reference Centre and Genetic Department, Hospices Civils de Lyon, Lyon, France d: VASCERN HHT Reference Centre and Gastroenterology Department, ASST Maggiore Hospital, Crema, Italy e: VASCERN HHT Reference Centre and ENT Department, Essen University Hospital, Essen, Germany f: VASCERN HHT Reference Centre and Respiratory Department, St Antonius Hospital, Nieuwegein, The Netherlands g: VASCERN HHT Reference Centre and Cardiology Department, St Antonius Hospital, Nieuwegein, The Netherlands h: University Medical Center Utrecht, Utrecht, The Netherlands i: VASCERN HHT Reference Centre and ENT Department, Interdisciplinary Center for Vascular Anomalies Marburg, University Hospital Marburg, Philipps-Universität Marburg, Germany j: VASCERN HHT Reference Centre and Department of Medical Oncology, Essen University Hospital, Essen, Germany k: VASCERN HHT Reference Centre, OPEN and Department of Public Health, University of Southern Denmark Corresponding author: Pernille Darre Haahr, MD, PhD student [email protected] Keywords Hereditary Haemorrhagic Telangiectasia, VASCERN, Bevacizumab, Word count: 3738 Abstract: 180 Figures: 3 Tables: 4 What is already known about this subject: • HHT is a rare disorder, limiting large randomized controlled trials. • Bevacizumab shows potential in treating HHT-related anemia and high-output cardiac failure. • Bevacizumab is considered safe for clinical use. What this study adds: • European experience with bevacizumab use in HHT. • Χountry-specific challenges in prescribing bevacizumab. • Large cohort data on bevacizumab efficacy and adverse events. Abstract Introduction Bevacizumab, a VEGF inhibitor, is used off label for treatment of severe anaemia related to epistaxis, GI-bleeding and/or severe liver arteriovenous malformations (HAVM) and right sided cardiac failure in patients with Hereditary Haemorrhagic Telangiectasia (HHT) Aim To report the experience of treatment with bevacizumab within VASCERN centres. Method A retrospective analysis of the usage, availability, efficacy and safety in HHT patients treated with bevacizumab in the European VASCERN centres. Results A total of 151 patients received treatment with bevacizumab in European VASCERN centres. Most patients were treated in Denmark, France and the Netherlands. There was an improvement in haemoglobin with a mean increase of 2.9 g/dL and significant reduction in the number of red blood cells transfusions. Cardiac output was measured and improved in 85 % of patients treated for high output cardiac failure in relation to severe HAVM. No severe adverse events were recorded, however 70 patients experienced at least one side effect. Conclusion Although this is a retrospective study, we have shown convincing efficacy of bevacizumab in treatment of patients with HHT, with a good risk-benefit balance. Background Hereditary Haemorrhagic Telangiectasia (HHT) is a rare vascular disease, frequently caused by a loss-of-function mutation in one of three genes ( ENG , ACVRL1 and SMAD4 ) that are involved in the TGF-beta/ BMP signalling pathway, which controls angiogenesis 1-3 . The disease is autosomal dominantly inherited and has a prevalence of approximately 1/5,000-6,500, thus there are roughly 85,000 patients in Europe 4 . HHT is diagnosed using the Curaçao criteria, which consist of four criteria. The diagnosis is considered certain if three of the four criteria are met and possible if two criteria are met and unlikely if only one criterion is met. The criteria consist of the following: 1. Recurrent and spontaneous epistaxis, 2. Telangiectasia located in typical sites such as the skin of the face, lips or hands or in mucous membranes in the nose and/or oral cavity, 3. Visceral arteriovenous malformations in lungs, liver, brain or telangiectasias in the GI-tract and 4. Family history of HHT 5 . The severity of HHT varies widely, ranging from no or minimal symptoms to severe iron deficiency anaemia caused by bleeding, either from epistaxis or gastrointestinal (GI) bleedings, high output cardiac failure (HOCF), pulmonal hypertension (PH) due to hepatic arteriovenous malformations (HAVM), and/or cerebral abscesses, ischemic strokes and rarely severe shortness of breath, due to right-to-left shunts associated with pulmonary arteriovenous malformations (PAVM) 6-8 . Initial treatment is directed towards clinical manifestations and is performed by the corresponding specialty, in accordance with international guidelines 9 . However, in certain cases primary care is insufficient, urging the medical team to consider bevacizumab treatment, as recommended in the second international guidelines for the Diagnosis and Management HHT 9 . Bevacizumab is a humanized monoclonal antibody that binds to vascular endothelial growth factor (VEGF), thus inhibiting the formation of new blood vessels, and is recognized by European Medicines Agency for treatment of different cancers such as colorectal-, lung- and breast cancer and for local treatment of age-related macular degeneration 10,11 . Bevacizumab has now been used for over 15 years in HHT. The first prospective study included 25 patients with HHT and high cardiac output (CO) secondary to hepatic shunting, showing a significant reduction in CO and the duration and the number of epistaxis episodes in these patients 12 . Then, several studies and case reports have found similar results, both with improvements of CO, haemoglobin levels and frequency of blood transfusions 13-15 . In 2019 European HHT expert centers within the European Reference Network for Rare Multisystemic Vascular Diseases (VASCERN) made a retrospective evaluation of bevacizumab safety. Based on data thus far available, European experts suggested appropriate weighing of the toxicities which can arise in HHT settings and proposed recommendations for their prevention and management and in 2022 they issued a position document to propose the correct indications for use of intravenous bevacizumab in patients with HHT 16,17 . This study aims to present the first international VASCERN experience with the availability, use, efficacy and safety of bevacizumab for the treatment of HHT patients in Europe. Methods The study is a retrospective cohort study, reporting the results from use of bevacizumab, including 151 HHT patients who had received at least one dose of intravenous bevacizumab at or were under consultation of the respective HHT center. A logbook on how to collect and enter data was developed, on which all centers agreed (appendix 1). The indication for treatment and the evaluation of symptom severity was based on clinical evaluation. Follow up was defined as date of bevacizumab initiation to date of data entry, however adverse events (AE) were evaluated during active treatment. The data were entered in the secure OPEN REDCap database by each participating center. The data was pseudonymized so that only legitimized members of the patient’s center knew their identity. Each participating center also received a questionnaire on indications and availability for bevacizumab treatment in each center. The variables are listed in appendix 1. Ethics In all centers the local health authorities approved the study. The need for informed consent was waived in all centers due to the retrospective nature of the study. Recording of availability and use Availability was described by the HHT centre chief in each center. Data on usage of bevacizumab is collected by each center and includes all patients that have been treated with bevacizumab at the time of inclusion. Measurements of efficacy To evaluate the efficacy of treatment, haemoglobin levels, CO and cardiac index (CI) were noted immediately prior to treatment and six months after the treatment was initiated. The number of used red blood cell (RBC) units transfused was recorded in the 6-month period before the first dose of bevacizumab and again in a 6-month period from month 3 to month 9 after initiation of bevacizumab treatment. Measurements of safety Adverse events were recorded retrospectively, grading of these was not performed due to the retrospective nature of the study and limitations in recall bias. The timing of the event was not recorded. Setting All VASCERN centers in the HHT-working group (WG) were invited https://vascern.eu. The centers in Odense – Denmark, Lyon – France, Marburg – Germany, Essen – Germany, Crema – Italy, Nieuwegein – the Netherlands; all had experience with the usage of bevacizumab and data from these centers were included. Statistical method Presentation of variables at baseline was performed using descriptive statistics. Normally distributed continuous variables are presented with means and standard deviations. Non-normally distributed continuous data are presented with medians and inter-quartile ranges. Categorical data are presented as counts and proportions. Patient follow-up years are defined as date of first infusion to date of data collection or death. For analysis of continuous outcomes, multivariable linear mixed effects regression with a random intercept for each patient was used to estimate unadjusted and adjusted change between baseline and follow-up of covariates of interest. Model assumptions were assessed graphically. Two-sided p-values ≤0.05 were deemed as statistically significant. Results Availability of bevacizumab Treatment with bevacizumab for HHT patients is off-label and the VASCERN working group has tried to evaluate the availability and usage of the drug amongst its members from Denmark, France, Germany, Italy and the Netherlands. All the centers use a dose of 5mg/kg, administered intravenously. The costs of the treatment differ between countries (one dose costs between 350 and 1,900 €). Similar for all centers is that the treatment is initiated after clinical evaluation and multi-disciplinary team discussion. Bevacizumab treatment is an option in HHT-related digestive bleeding or epistaxis resistant to standard therapies, especially when it causes chronic severe anaemia despite iron supplement and/or RBC transfusions. For liver AVMs, the indication for bevacizumab is often seen when they are severe, complicated and refractory to medical management for patients over 65 years, or in those who are not candidates for liver transplant or as bridge to transplant 16 . All centers usually administer the treatment in the outpatient clinic. Table 1 depicts bevacizumab treatment protocols in the different VASCERN centers. Denmark In Denmark the treatment is available via the national HHT center in Odense, which has a general permission, and reimbursement is obtained by the local council for expensive medication. France In France treatment is available for all patients with severe disease. The indication is discussed and validated by the HHT-expert center, enabling reimbursement by the health insurance system. Germany In Germany the treatment is available for patients with severe disease. However, it can be difficult to get permission, as it requires individual assessment by the insurance company which usually initially only covers therapy induction (5 mg/kg every 2 weeks) for a total of six applications resulting in a period of usually 3 months. In case of subsequent clinical deterioration, insurance companies must be contacted again for new permissions. Italy In Italy the treatment is available for HHT patients, with a general approach to reimbursement, based on the indication of the HHT-expert center. Netherlands In the Netherlands the treatment is available for all patients with severe disease insufficiently responsive to conventional therapy, after individual assessment, but with a more general approach to reimbursement if the treatment is initiated and monitored by the HHT-expert center. Use of bevacizumab in VASCERN centres A total of 151 patients with HHT reportedly have received bevacizumab at a VASCERN center or under their consultation. Table 2 summarizes the usage of bevacizumab depending on the different VASCERN centers. Treatment is more widely used in France, Denmark and the Netherlands, compared to Italy and Germany. The average number of treatments per patient is 13, with higher number of treatments performed per patient in the Netherlands and Italy compared to the other centers. Furthermore, 48.0 % of the patients included in this study, are still treated with bevacizumab. All patients on maintenance therapy had received induction therapy prior to initiation of the maintenance protocol. The baseline data according to the indication of the treatment is illustrated in table 3. Mean age of the patients is 64 years, however the patients treated for complicated HAVM are on average younger (mean age 58 years), than patients treated due to bleeding (mean age 65 years). 100 patients (66 %) were alive at the time of data entry into the database. Efficacy on anaemia Of the 151 patients included in this study, 119 patients were treated for HHT-related bleeding. Mean haemoglobin improved from 8.6 g/dL to 11.5 g/dL, resulting in a mean increase of 2.9 g/dL (95 % Confidence Interval (CI) 2.4-3.6, p= 0.0001). Haemoglobin levels are shown in figure 1. Of the 119 patients treated for bleeding 78 (66 %) achieved haemoglobin levels higher than 11 g/dL. A multivariable linear mixed effects regression was used to adjust for confounders such as age, gender, mutation type, dosage of bevacizumab, iron treatment prior to and during bevacizumab treatment and RBC units used before and during bevacizumab treatment. Only RBC units during bevacizumab treatment was correlated to higher haemoglobin levels. None of the remaining variables had significant influence on the haemoglobin. When specifically focusing on the number of transfused units of red blood cells in patients with anaemia, a total of 81 patients needed 1768 units in the 6 months before treatment with bevacizumab, whereas 44 patients used 408 units in the period between 3 and 9 months after bevacizumab initiation. Complete RBC data was reported in 98 patients, of these 56 (57 %) patients did not need RBC units after bevacizumab was initiated, compared to 20 (10 %) patients prior to bevacizumab treatment. Mean difference between units used was -10.1 units (95 % CI: -13.9 to -6.4, p=0.0001). Of the 98 patients, 69 (70 %) patients experienced reduced need of RBC units, whereas 7 (7.1 %) patients had increased use of RBC units, as illustrated in figure 2. A multivariable linear mixed effects regression model accounting for confounding factors, including age, mutation type, bevacizumab dosage, iron treatment (both prior to and during bevacizumab therapy), and haemoglobin levels, confirmed this finding. Interestingly, the regression showed that iron usage after bevacizumab induction was related to an increased need for transfusions (p=0.02). Of all the patients treated, 140 patients had data on their perceived effect. Of these 120 (85.7 %) patients reported that they experienced that their symptoms improved during treatment. This is comparable to the clinicians who reported positive outcomes in 95.2 % of patients Efficacy on cardiac output Of the 151 patients treated in this study, 68 (45%) were treated for complicated HAVM. CO and CI were used as outcome. CO was reduced from mean 8.5 L/min to 6.6 L/min, thus a reduction of 1.9 L/min (95 % CI: 1.5 to 2.3, p=0.0001). The CO reduction was highest in patients from The Netherlands (-3.1 L/min, baseline CO 9.5 L/min), and lowest in French patients (-1.2 L/min, baseline CO 7.9 L/min). CO was reduced in 42 out of 49 patients (85%), in seven patient there was no change in CO, there was missing data in 19 patients. CI was reduced by 1.1 L/min/m 2 (95 % CI: 0.8 to 1.3, p=0.0001), from mean 5.0 L/min/m 2 to mean 3.9 L/min/m 2 . A multivariable linear mixed effects regression model, adjusting for age, gender, mutation type, dosage of bevacizumab, haemoglobin levels and iron treatment showed that only haemoglobin levels after initiation had a significant correlation to CO, where a lower haemoglobin level, increased CO (p=0.015). Figure 3 illustrates the overall trend of CO, prior and 6 months after bevacizumab initiation. Safety Of the 151 patients included in this cohort, 81 patients (53.6 %) experienced no side effects during bevacizumab treatment. The remaining 70 experienced at least one; 48 (31.8 %) experienced one AE, 14 (9.3 %) experienced two AE, seven (4.6 %) had three AE and one (0.6 %) experienced four AE. A total of 101 AEs were reported in 151 patients, causing a frequency of 0.67 AE per patient. The most common AE included hypertension, proteinuria, headache, and joint pain. Amongst the more severe AE are thrombosis (DVT and mesenteric) (3). These adverse events are however not suspected to be directly related to the bevacizumab treatment. Regarding the mesenteric thrombosis, the case was discussed within the VASCERN group, possibly related to treatment. Table 4 depicts the type of adverse event and the number of events in total. In 16 (10.5 %) patients, adverse events were the reason of stopping bevacizumab treatment. The data furthermore illustrated that 51 patients died during follow-up, at mean 71 age (IQR 67-78 years). Of these, 5 (10.0%) died from bleeding related to HHT, 14 (28.0 %) of complicated HAVM (HOCF), and the remaining of infection, comorbidity, cancer, stroke, organ failure, non-HHT GI bleeding, see appendix 2. The treating physicians did not attribute any of the deaths directly to the treatment with bevacizumab. In most cases, the death was related to the progression of the disease or other associated illnesses. In one case of mesenteric ischemia, the case was reviewed during a European meeting, and we concluded that it was possibly related to bevacizumab, but in the absence of a therapeutic alternative and due to the severity of the disease, the treatment seemed to be justified in all cases. Discussion Availability and use in European countries This work explores the variability in availability of bevacizumab within the VASCERN working group. The nations e.g. Denmark, France and the Netherlands, where reimbursement is established are treating more HHT patients with bevacizumab, compared to Germany, where reimbursement is dependent on insurance coverage. Indications for treatment are in line with European VASCERN position document, and similar to those described in the InHIBIT-Bleed study 15,16 . The InHIBIT-Bleed study included patients from 9 centers in the USA and one center each in Argentina, Israel, and France, with severe epistaxis, frequent local nasal procedures to maintain epistaxis control or a significant reduced quality of life due to epistaxis 15 . Furthermore, patients with GI bleeding leading to hospitalisation for GI bleeding, need for frequent endoscopic procedures or persistent anaemia were included. This corresponds well to the VASCERN experience with bevacizumab. In contrast to the InHIBIT-Bleed study, our data also includes patients treated for complicated HAVM, refractory to medical management for patients over 65 years, or in those who are not candidates for liver transplant or as bridge to transplant 16,19 . Overall, the centers apply similar therapeutic regimens, with 3-6 induction infusions of 5 mg/kg bevacizumab administered every 2-3 weeks. The majority of patients (68%) received maintenance after 2015, which each center individualises to the patient. However, data indicates that the German centers, thus far primarily administer induction protocols, mainly because of the difficulties with coverage by health insurances. Thus, bevacizumab treatment for HHT diagnosis is used, as off label treatment, in 151 patients at the VASCERN centers. This treatment relies on national approvals, which differ between the countries. The data suggest that there a majority of patients are treated for HHT related bleeding (epistaxis, GI-bleeding or a combination of these). Like previous studies suggest, these results show that most patients treated for severe HAVM (HOCF) are younger females (age around 50) with AVCRL1 mutations 20,21 . Effect on anaemia This study found that bevacizumab significantly increases haemoglobin levels and decreases the need of blood transfusions for HHT patients treated because of either epistaxis and/or GI- bleeding. This is consistent with other data published in the literature 12,15,22-26 . Furthermore, the study found a significant decrease in usage of RBC units in the 6 months period after bevacizumab initiation 15 . The subgroup analysis showed, as expected, that the patients needing blood transfusions had lower haemoglobin levels, but there was no significant correlation to either age, gender, mutation type, or bevacizumab dosage. The results of this study show a high reduction of RBC unit requirements with 12 units decrease; this is higher than the decrease of 6 RBC units reported 2021 in the study by Al-Samkari et al 22 . When only focusing on the usage of RBC units, it is evident that the number of treatments has a positive impact, thus the more treatments with bevacizumab the patient receives the fewer RBC units the patient requires. This could be because the patients with no or little effect of bevacizumab, ended the treatment earlier, and thus both had more severe symptoms and had fewer treatments. Effect on cardiac output The results of this study support those of several previous, however, smaller studies, which state that bevacizumab has a significant effect on the reduction of both, the CO and the CI 12,14 . The average CO prior to treatment was 8.5 L/min and average CI prior was 5.0 L/min/m 2 . This correlates well to the definition of HOCF, which is defined as CO >8.0 L/min, CI >4 L/min/cm 2 and symptoms of cardiac failure, such as dyspnoea or oedema 27 . In this study the CO varies between the centers, which may be due to the diagnostic methods, as the Dutch and Danish centers use right heart catheterisation, whereas the French, German and Italian centers use transthoracic echocardiography, which tends to give lower and less reliable CO/CI values. The data can therefore not be compared between centres, they are only used as an indication of improvement for the individual patient In 2014, a study from Singh et al, showed that the five-year survival in HHT patients with symptomatic HAVM was 71 %. As the criteria for treatment with bevacizumab, in all participating centers, were that patients presented symptoms of severe HAVM, it is assumed that these patients are in the category of the most severely ill patients with HHT, and thus have a lower rate of 5-year survival 28 . Overall, this study takes into consideration primarily the patients with high output cardiac failure, however, HAVM can cause shunting between the hepatic artery and portal vein, causing symptoms arising from portal hypertension with ascites and oesophageal varices 19,29,30 . Patients with these symptoms may have similar positive effects of bevacizumab. Safety The current data show relatively few severe adverse events. However, 16 patients (10.6%) stopped treatment due to side effect. In total, 46.4 % of patients experience some kind of adverse event. Most events are mild, with hypertension and headache being the most common ones. When treatment was terminated due to side effects, it was a clinical decision based on efficacy treatment versus severity of side effect and taking the patients choice into account. In this study, the adverse events are not grouped according to relation to treatment, thus it includes all possible adverse events, even if the event may not be attributed to the treatment. This may cause to uncertainty regarding the severity and number of adverse events. This study has a slightly higher percentage of adverse events and number of patients who ended treatment due to adverse events than the results of the InHIBIT-Bleed study. However, lower number of AEs per patient in comparison to the prospective trial of Dupuis-Girod from 2019, possibly due to the fact that data collection is less exhaustive in retrospective studies than in prospective studies 15 . In 2019, Buscarini authored a work specifically focusing on AEs relating to bevacizumab, this work showed 1.18 events per patient, compared to 0.68 events per patient in this study 17 . When comparing to other studies, this study displays fewer both mild and severe adverse events in a larger population 17,22 . When analysing the total effect, with high satisfaction and perceived effect in most patients, and the few severe adverse events, bevacizumab is deemed a relatively safe treatment option in cautious hands for this population. The number of deaths due to HHT highlights the severity of the patient group who are candidates for bevacizumab, as it is currently used as one of the last options after local treatment or in case of complicated HAVM. Furthermore, one should notice that 27 % of deaths during this study are due to complicated HAVM, underlining the clinical impact of this manifestation of the HHT disease, which is probably underdiagnosed and insufficiently treated. Appendix 2 illustrates the causes of deaths in this work. Limitation The primary limitation of this study is its retrospective nature, causing recall bias. Furthermore, patients are treated in various therapeutic protocols, which may affect the comparability of the results although all participants do their best to follow the agreed indications published 16 . Conclusion In this retrospective study we have demonstrated high variability in the use and accessibility of bevacizumab treatment across different European countries among HHT patients with severe complications. Furthermore, the majority of HHT patients with severe bleeding and/or severe complicated HAVM, significantly benefitted from treatment with bevacizumab. Side effects were sufficiently manageable in most cases and the treatment was stopped due to side effects in 11%. Acknowledgement We thank VASCERN for their support and the HHT patients across Europe for their invaluable participation. Conflict of Interest Statement Anette D. Kjeldsen: participating in advisory board meeting Pharmacosmos 2024 Freya Droege: Advisory board meeting Pharmacosmos (2024), Advisory board Delbert Pharma (2024/2025). Research funding for HHT: German Research Foundation (DFG, 2024 - 2027), Foundation of the University Medicine Essen (2023 -2024), Essen Training Programme ”Laboratory and Science” for Young Physicians (ELAN, 2022 - 2023) Josefien Hessels: research funding to institution from Vaderis Therapeutics Marco C. Post: Research funding from: ZonMw, Research fund St. Antonius Hospital, Johnson & Johnson. Member of the advisory board of MSD and J & J. Stefan Kasper-Virchow Roche: personal advisory, institutional: research funding Urban Geisthoff: is deputy vice president of the German HHT self-help group (www.morbus-osler.de), president of the board of trustees of the German HHT foundation (www.osler-stiftung.de), member of the Global Research and Medical Advisory Board of CureHHT (www.curehht.org), member of the board of trustees of the booster club for unrecognized and rare diseases in Hesse (www.fuse-hessen.de). The remaining authors have no conflicts of interests. Funding This project received no specific funding. Publication costs will be covered by VASCERN. Data availability statement Data is unavailable due to the rarity of the disease, where patients are easily recognizable. Tables Odense, DK 1, 2 and 3 5 mg/kg every 3 weeks Individual time interval between 2-4 months 700 39 Lyon, FR 1, 2 and 3 5 mg/kg every 2 weeks Individual time interval between 1-4 months 1200 57 Marburg, DE 1, 2 and 3 5 mg/kg every 2 weeks Not administered at regular basis 400 8 Essen, DE 1, 2 and 3 5 mg/kg every 2 weeks Individual time interval between 1-3 months 600 5 Crema, IT 1, 2 and 3 5 mg/kg every 3 weeks Individual time interval between 1-4 months 1400 8 Nieuwegein, NL 1, 2 and 3 5 mg/kg every 2 weeks Individual time interval every 4-8 weeks 1400 34 Table 1 Bevacizumab treatment protocols in the different VASCERN centers. † Causing severe anaemia. ‡ Causing HOCF Total n (%) Denmark 39 (25.8) France 57 (37.7) Marburg (DE) 8 (5.3) Essen (DE) 5 (3.3) Italy 8 (5.3) The Netherland 34 (22.5) Total 151 (100) Age of first treatment (mean + SD) 65 (10.4) 65 (11.2) 57 (10.8) 62 (6.0) 70 (6.0) 62 (11.0) 64 (10.8) Number of treatments pr patient (median + Q1-Q3) 9 (6-19) 12.5 (6-30) 12 (6.5-17.5) 6 (5-13) 28 (11-43) 22 (13-43) 13 (7-27) Type of treatment Induction alone Incomp ind Ind + maint n (%) 6 (15.4) 9 (23.1) 24 (61.5) 19 (33.5) 3 (5.3) 35 (61.4) 2 (25.0) 1 (12.5) 5 (62.5) 3 (60.0) 0 (0) 2 (40.0) 1 (12.5) 0 (0) 7 (87.5) 1 (3.3) 1 (3.3) 28 (93.3) 33 (22.3) 14 (9.5) 101 (68.2) Initial dose † 2.5 mg/kg 5 mg/kg n (%) 0 (0) 39 (100) 0 (0) 57 (100) 0 (0) 8 (100) 2 (40) 3 (60<) 0 (0) 8 (100) 0 (0) 32 (100) 2 (1.3) 147 (98.7) Dosage changes during treatment n (%) 8 (21.1) 7 (12.3) 0 (0) 1 (20.0) 0 (0) 0 (0) 16 (11.0) Reason for changing dosage No efficacy Side effect n (%) 7 (87.5) 1 (12.5) 7 (87.5) 0 (0) 0 (0) 0 (0) 0 (0) 1 (100.0) 0 (0) 0 (0) 0 (0) 0 (0) 14 (87.5) 2 (12.5) Ongoing treatment n (%) 17 (43.6) 23 (40.4) 0 (0) 4 (80.0) 2 (25.0) 25 (80.6) 71 (48.0) Reason for ending treatment † Clinical improvement End of therapeutic protocol No efficacy Patients’ choice Contraindication Other treatment Side effects Drug no longer efficient Death due to HHT Death from other reasons Other n (%) 3 (7.7) 0 (0) 4 (10.3) 6 (15.4) 0 (0) 1 (2.6) 5 (12.8) 2 (5.1) 2 (5.1) 5 (12.8) 1 (2.6) 9 (15.8) 13 (22.8) 4 (7.0) 1 (1.8) 3 (5.3) 0 (0.0) 5 (8.8) 5 (8.8) 0 (0) 2 (3.5) 3 (3.5) 0 (0) 3 (37.5) 2 (25.0) 1 (12.5) 0 (0) 0 (0) 1 (12.5) 0 (0) 0 (0) 0 (0) 1 (12.5) 1 (20.0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (20.0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 4 (50.0) 0 (0) 1 (12.5) 0 (0) 0 (0) 0 (0) 1 (2.9) 2 (5.9) 0 (0) 0 (0) 0 (0) 1 (2.9) 1 (2.9) 1 (2.9) 3 (8.8) 0 (0) 13 (8.6) 17 (11.3) 12 (7.9) 8 (5.3) 3 (2.0) 1 (0.7) 16 (10.6) 8 (5.3) 4 (2.6) 10 (6.6) 5 (3.3) Table 2: Use of bevacizumab in VASCERN centers and bevacizumab characteristics (n=152). Standard deviation (SD), interquartile range (Q1-Q3), number (n), † missing data Total n=151 n (%) Epistaxis 40 (26.5) GI-bleeding 18 (11.9) Epistaxis + GI bleeding 25 (16.6) Complicated HAVM 32 (21.2) Complicated HAVM + bleeding 36 (23.8) Gender F n (%) 17 (42.5) 9 (50.0) 16 (64.0) 28 (87.5) 29 (80.6) 100 (66.2) Mutation n (%) († =1) ALK1 ENG SMAD4 No gene known 21 (52.5) 18 (45.0) 0 (0.0) 1 (2.5) 4 (22.2) 10 (55.6) 0 (0.0) 4 (22.2) 11 (44.0) 11 (44.0) 0 (0.0) 3 (12.0) 21 (67.7) 3 (9.7) 2 (6.5) 5 (16.1) 30 (83.3) 4 (11.1) 0 (0.0) 2 (5.6) 87 (58.0) 46 (30.7) 2 (1.3) 15 (10.0) Age at first treatment (mean) (SD) 64 (11.8) 67 (7.0) 64 (7.6) 58 (11.6) 68 (10.2) 64 (10.7) Alive at data entry n (%) 27 (67.5) 15 (83.3) 15 (60.0) 21 (67.7) 22 (61.1) 100 (66.2) Epistaxis severity No Moderate Severe n (%) 0 (0.0) 0 (0.0) 40 (100.0) 3 (16.7) 14 (77.8) 1 (5.6) 0 (0.0) 8 (32.0) 17 (68.0) 11 (36.7) 19 (61.3) 1 (3.2) 1 (2.9) 5 (14.3) 30 (83.3) 15 (10.0) 46 (30.7) 90 (59.3) GI-bleed severity ( † =1) No Moderate Severe n (%) 30 (75.0) 9 (22.5) 1 (2.5) 0 (0.0) 0 (0.0) 18 (100) 0 (0.0) 8 (32.0) 17 (68.0) 27 (87.1) 4 (12.9) 0 (0.0) 22 (61.1) 7 (19.4) 7 (19.4) 79 (52.7) 28 (18.7) 43 (28.7) HAVM severity No Moderate Severe n (%) 37 (92.5) 3 (7.3) 0 (0.0) 13 (72.2) 4 (22.2) 1 (5.6) 22 (88.0) 2 (8.0) 1 (4.0) 0 (0.0) 0 (0.0) 32 (100.0) 0 (0.0) 1 (2.8) 35 (97.2) 72 (47.7) 10 (6.6) 69 (45.7) Table 3 Baseline characteristics. F: female, n: number, † missing data Type of side effect n (%) Hypertension 20 (19.8) Proteinuria 4 (4.0) Headache 11 (10.9) Joint pain 16 (15.8) DVT 1 (1.0) Haemorrhage 2 (1.9) Cardiac failure 1 (1.0) Skin ulceration 5 (4.9) Infection 3 (3.0) Osteonecrosis 0 (0.0) Fragility of nails 3 (3.0) Thinning of hair 1 (1.0) Exhaustion 3 (3.0) Other side effect ‡ 31 (30.7) Table 4: Adverse event table, showing data from 70 patients who had experienced adverse events. 101 adverse events were reported during the study period. ‡ Other side effect includes leucopoenia, dyspnoea, skin affection, gastrointestinal symptoms, and thrombosis. Figure legends Figure 1: Frequency of patients within each haemoglobin (g/dL) level grouped. Haemoglobin levels before bevacizumab treatment was measured immediately prior to treatment. Haemoglobin levels are grouped into categories. Figure 2: Graph illustrating number of RBC units used, in the patients treated for bleeding (epistaxis and/or GI bleeding). Blue shows RBC data from a six-month period immediately prior to bevacizumab initiation. Orange shows number of RBC units used in a six-month period from month 3 to month 9 after bevacizumab initiation. Figure 3: Blue bars: CO before bevacizumab treatment, orange bars: 6 months after first bevacizumab treatment. Standard range of CO is 4-8 L/min and CI 2-4 L/min/cm 2. 18 Supplementary Material File (figure 1.docx) Download 19.35 KB File (figure 2.docx) Download 19.59 KB File (figure 3.docx) Download 22.03 KB References 1. 1. McAllister KA, Grogg KM, Johnson DW, et al. Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet 1994;8(4):345-51. Johnson DW, Berg JN, Gallione CJ, et al. A second locus for hereditary hemorrhagic telangiectasia maps to chromosome 12. Genome Res 1995;5(1):21-8. Gallione CJ, Repetto GM, Legius E, et al. 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Collection British Journal of Clinical Pharmacology Keywords clinical pharmacology clinical pharmacy drug utilization patient safety therapeutics Authors Affiliations Pernille Darre Haahr 0009-0009-2562-127X [email protected] Odense University Hospital View all articles by this author Annette Fialla Odense University Hospital View all articles by this author Anette Kjeldsen Odense University Hospital View all articles by this author Anne-emmanuelle Fargeton Hospices Civils de Lyon View all articles by this author Alexandre Guilhem Hospices Civils de Lyon View all articles by this author Elisabetta Buscarini Maggiore Hospital Crema View all articles by this author Freya Droege University Hospital Essen View all articles by this author Guido Manfredi Maggiore Hospital Crema View all articles by this author Hans-Jurgen Mager St Antonius Hospital View all articles by this author Jean-Christophe Saurin Hospices Civils de Lyon View all articles by this author Jens Kjeldsen Odense University Hospital View all articles by this author Josefien Hessels St Antonius Hospital View all articles by this author Marco Post St Antonius Hospital View all articles by this author Robert Mandic University Hospital of Giessen and Marburg Campus Marburg View all articles by this author Sanne Boerman St Antonius Hospital View all articles by this author Stefan Kasper-Virchow University Hospital Essen View all articles by this author Sören Möller University of Southern Denmark View all articles by this author Urban Geisthoff University Hospital of Giessen and Marburg Campus Marburg View all articles by this author Sophie Dupuis-Girod Hospices Civils de Lyon View all articles by this author Metrics & Citations Metrics Article Usage 330 views 202 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Pernille Darre Haahr, Annette Fialla, Anette Kjeldsen, et al. 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