The effect of systemic bevacizumab treatment of chronic bleeding and anemia on prognosis and quality of life in hereditary hemorrhagic telangiectasia: A retrospective cohort

Authors

Abstract

Aim Anti-angiogenic therapy using bevacizumab has been tested on Hereditary Hemorrhagic Telangiectasia (HHT), but the evidence in the literature is not high-level. In this retrospective cohort analysis, we aimed to evaluate bleeding frequency, severity, and the need for blood transfusion and iron replacement in patients with HHT receiving intravenous bevacizumab. We also examined the effect of bevacizumab on quality of life.
Materials and Methods The study included 8 patients who were started on bevacizumab with the diagnosis of HTT. Epistaxis Severity Score (ESS) and SF-36 were used to assess disease severity and health-related quality of life (HRQOL), respectively. The study was approved by the Tekirdağ Namık Kemal University Medical Faculty’s Ethics Committee. Mainly, descriptive statistical analysis was performed, and SPSS 25.0 was used.
Results Five patients were female, and three were male. Median follow-up time was 30 months. The mean age was 65 (range: 44-70). The median ESS score before treatment was 7.75 ± 2.7 (range, 2-8), and after treatment, it was 1.4 ± 1.2 (range, 1-5). The median transfusion requirement in the last 3 months before bevacisumab use was 5. After treatment, there was no requirement in the first 6 months, in the second 6 months, and also in the second year. The median baseline hemoglobin value was 9.5 g/dL. The median values at 3, 6, 12, and 24 months after treatment were 13.1 g/dL, 14.55 g/dL, 12.95 g/dL, and 12.5 g/dL, respectively. A headache and an increase in the systolic blood pressure level were observed in two patients each. All SF-36 item scores were found to be significantly increased after the treatment.
Discussion We found that bevacizumab was an effective and safe treatment method in patients with HHT. In our long-term follow-up, efficacy was sustained, and no additional toxicity was observed. Bevacizumab treatment also positively affected the HRQOL.

Keywords

Introduction

Hereditary hemorrhagic telangiectasia (HHT; Osler-Weber- Rendu disease) is an autosomal dominant inherited genetic disorder characterized by dysregulated angiogenesis with an estimated prevalence of 1 in 5000 [1, 2]. HHT causes clinically significant malformations of the vasculature. Telangiectasias in the mucous membranes of the nose and gastrointestinal tract cause bleeding, as well as arteriovenous malformations (AVMs) in the central nervous system, pulmonary, and hepatic systems. Telangiectasias of the nasal mucosa are present in >68% of HHT patients, and epistaxis is the most common symptom of the disease [3]. Frequent anemia due to repeated nasal or gastrointestinal bleeding is the most common complication and can sometimes be very severe [4]. It may require iron supplementation and sometimes erythrocyte suspension (RBC) transfusions. The impact on quality of life is significant. Sometimes fatal bleeding can develop [5].
The diagnosis is based on Curaçao criteria (recurrent epistaxis, telangiectasia, family history, and visceral lesions) and is considered definitive if at least three criteria are met [6].
It is known that the disease is often caused by mutations in three genes: Endoglin (ENG), Activin A Receptor-Like Type 1 (ACVRL1), and SMAD family member 4 (SMAD4). In addition, rare families may have mutations in Growth Differentiation Factor 2 (GDF2) or RAS Protein Activator 1 (RASA1) [7]. The presence of these mutations causes dysregulation of the angiogenic balance. Excessive angiogenic proliferation and/ or impaired control of maturation are thought to lead to the formation of numerous problematic new vessels [8].
Vascular endothelial growth factor (VEGF) is one of the key factors in the activation phase of angiogenesis. Thalidomide, lenalidomide, and pomalidomide, which exhibit immunomodulatory and antiangiogenic characteristics, have been evaluated in smaller studies involving HHT patients and shown to be effective [9, 10]. Since 2010, bevacizumab, a humanized monoclonal antibody that selectively binds to human VEGF and neutralizes its biological activity, has been tested on HHT patients [11]. A case report, study, and case series have been published [12, 13].
In this retrospective cohort analysis, we aimed to evaluate bleeding frequency, severity, the need for blood transfusion, and iron replacement in patients with HHT receiving intravenous bevacizumab compared to the pretreatment period. We also examined the effect of intravenous bevacizumab use on quality of life in patients with severe disease symptoms.

Materials and Methods

The study included 8 patients who were started on bevacizumab with the diagnosis of HTT according to Curacao criteria at Tekirdağ Namık Kemal University Hospital and Tekirdağ Fehmi Cumalioglu City Hospital. Patients resistant to conservative treatments with severe disease symptoms (history of recurrent and severe bleeding, frequent need for transfusions, and frequent visits to the emergency room) were included in the study. Thoracic CT, pulmonary CT angiography, esophagogastroduodenoscopy, colonoscopy, whole abdomen USG, and liver Doppler USG were routinely performed in all patients to detect visceral AVMs. Brain MRI was also performed for symptomatic patients. In addition, all patients were referred for cardiologic examination before treatment.
Patients who were started on bevacizumab continued treatment for at least 18 months from the start of treatment. According to the standard protocol, 5 mg/kg bevacizumab was given as 6 cycles at 14-day intervals followed by 5 mg/kg every 2 months. After one year of treatment, one patient’s epistaxis completely resolved, and was continued with observation without maintenance treatment. The 5 patients who responded were switched to maintenance treatment at a dose of 5 mg/ kg every 3 months. In 2 patients, the treatment interval was continued as 5 mg/kg every 4 months due to transportation difficulties. Patients were observed for efficacy and side effects. Hemogram, liver function tests, renal function tests, complete urinalysis, ECG, and blood pressure were measured at each visit. Hemogram values and the need for erythrocyte transfusion and iron replacement were recorded. Patients with nosebleeds were advised to use a nasal moisturizer morning and evening. The epistaxis severity score, which is routinely evaluated in HHT practice before treatment, was recalculated at the 3rd, 6th, 12th, and 18th months of bevacizumab treatment.
Epistaxis Severity Score
The Epistaxis Severity Score (ESS) is a standardized, reproducible, and validated patient-reported outcome measure of epistaxis control over the previous 3 months and has been used in many studies of HHT-related epistaxis. It is a weighted model consisting of 6 factors scored from 0 to 10 that are independent predictors of epistaxis severity. In this study, we used an adapted version to specifically query symptom outcomes before treatment and at 3-month follow-up intervals after treatment. Scoring was done by the physician asking questions to the patient with the online calculator at curehht. org. The minimum clinically important difference (MCID) of ESS was reported as 0.71 [14].
Since HHT severely affects the quality of life of patients with symptoms, SF-36 scales were administered to patients at regular intervals as part of routine practice in both clinics. SF- 36 scales administered before treatment and at 6 months of treatment were included in the analysis to assess treatment response in patients receiving bevacizumab.
SF-36
The quality of life of the patients was assessed using the short form of the 36-item (SF-36) scale, one of the most commonly used surveys [15]. It consists of two main subdimensions: a physical component, including physical function, physical role, pain, and general health status, and a mental component, including social functioning, emotional role, and mental health. The scale is a self-assessment tool and is completed by the patient. The Turkish adaptation study of SF-36 was conducted by Koçyiğit et al. [16].
Informed Consent
Written informed consent was obtained from all patients.
Ethical Approval
This study was approved by the Ethics Committee of Tekirdağ Namık Kemal University, Medical Faculty (Date: 2024-09-24, No: 2024.258.09.08). Mainly, descriptive Statistical calculations were performed using SPSS 25 for PC (IBM Corp., USA).

Results

Five patients were female and three were male. Median follow- up time was 30 months. The mean age was 65 (range: 44- 70). Characteristics of patients and response to bevacizumab treatment are given in Table 1.
The median ESS score before treatment was 7.75 ± 2.7 (range: 2-8), and after treatment it was 1.4 ± 1.2 (range: 1-5). The difference was statistically significant (p = 0.012).
The median transfusion requirement in the last 3 months before bevacisumab use was 5. After treatment, it was 0 in the first 6 months and 0 in the second 6 months. In the second year, the median was 0.
The median baseline hemoglobin value was 9.5 g/dL. The median values at 3, 6, 12, and 24 months after treatment were 13.1 g/dL, 14.55 g/dL, 12.95 g/dL, and 12.5 g/dL, respectively. The change in hemoglobin values in patients is given in Table 2. All SF-36 item scores were found to be increased significantly after the treatment, which may be regarded as an improvement in quality of life with bevacizumab treatment. Quality of life assessment scores before and after bevacizumab are given in Table 3.
Two patients reported a headache, and two patients reported an increase in the systolic blood pressure level. Each patient tolerated the drug well.

Discussion

In our cohort study, we assessed the effectiveness and side effects of long-term systemic treatment with bevacizumab in our patients with HHT experiencing severe anemia and epistaxis. These patients frequently required hospitalizations for transfusions, and their work and social lives were significantly affected. Our findings revealed significant improvements in both bleeding and anemia among patients receiving bevacizumab. We found that the health-related quality of life of patients also increased with bevacizumab treatment. No serious drug toxicity was observed despite long-term follow-up.
Although there are numerous studies in the literature evaluating the efficacy and safety of bevacizumab in the treatment of HHT, data on efficacy and safety under treatment for more than one year are limited. Although InHIBIT-Bleed is one of the largest clinical trials of HHT [17], patients were followed for a median of 12 months (range 1-96 months). In our study, the median follow-up period was 30 months with a range of 36-24 months, which, to our knowledge, has the longest duration of maintenance therapy and follow-up among the studies in the literature.
Most of our patients had extensive disease burden, and they had first-degree relatives with bleeding-related deaths. Patients were treated with alternative local and systemic therapies (refractory epistaxis in five patients; hematuria, hematochezia, tongue and fingertip bleeding in one patient each), but no bleeding control was achieved with any of the methods. The longest follow-up with bevacisumab treatment in our study was 100 months, and the shortest was 18 months. Treatment was continued at individualized intervals and doses in all but one patient. The patient with intense nosebleeds, whose nosebleeds were under control as of the 3rd month of treatment and whose iron deficiency never developed during the treatment period, was discontinued at the 18th month, and the patient was followed up without treatment. After six months of treatment- free follow-up, the patient’s bleeding did not recur, and the Hgb level remained stable. This suggests that treatment can be discontinued in patients with nasal mucosal bleeding who have a rapid and persistent response after bevacizumab. On the other hand, although good results with bevacizumab for gastrointestinal bleeding were reported in an expert opinion [18] in which more than 100 patient experiences were presented, the least success in our study was seen in patients with gastrointestinal bleeding. We think that this difference may be related to the severity of gastrointestinal involvement. According to the literature, the most common side effects in patients given bevacizumab are hypertension (18%), fatigue (10%), proteinuria (9%), myalgia and/or arthralgia (6%), headache (4%), and venous thromboembolism (VTE, 2%) [17]. Two of the patients we followed up with complained of headache, and no pathology was detected in neurologic evaluation in both patients. The headache was controlled with paracetamol. In patients with headache, individualized doses were continued as 4 mg/kg every 3 months. Reduced doses resulted in a decrease in headache complaints, and treatment efficacy was maintained. This may be a rationale for planning prospective controlled studies to determine whether lower doses of bevacizumab would be effective in the treatment of HHT. In both of the 2 patients with known hypertension, the increase in blood pressure was controlled with the addition of amlodipine 5 mg. On the other hand, in a retrospective study involving 14 centers and 46 patients, infection was reported as the most common side effect in treated patients (22% of patients), and 15 patients died during treatment [19]. In the follow-up of our patients, no infectious side effects were observed, and no patient died during treatment. The difference between the studies may be related to the existing comorbidities of the patients.
The treatment interval was individualized according to social reasons in patients with good response and good drug tolerance, 1 year after treatment initiation. In six patients, the treatment interval was continued for 3 months. Two patients were able to come to the controls every 4 months because they lived in a rural area, and the treatment continued as 5 mg/kg every 4 months. The frequency and amount of bleeding increased with increasing treatment intervals. This was inconsistent with the data reported in a case report that bleeding in the gastrointestinal tract was controlled even after discontinuation of treatment [18]. However, treatment success was regained when the treatment frequency was increased again. This suggests that efficacy may be restored when the treatment interval is prolonged for various reasons and the original dosing regimen is reinstated. According to our experience, long-term follow-up with bevacizumab maintained an improvement effect on the hemogram. Patients did not develop intolerable side effects.
When the maintenance treatment dose was reduced to 3 mg/kg after one year, the efficacy was still maintained on both epistaxis and bleeding from other sites. In another study conducted on 6 patients, IV bevacizumab infusion was administered at a dose of 0.125 mg/kg every 4 weeks, and a total of six treatment cycles were performed. The severity and frequency of epistaxis decreased in all patients [20]. In our study, no loss of efficacy with dose reduction suggested that lower treatment doses may also be effective in HHT patients’ symptom management.
The patients with mucosal lesions with a history of bleeding from the tongue and fingertips for many years that were resistant to local and systemic treatments showed a decrease in bleeding from the first application of bevacizumab treatment. In the 3rd month, bleeding from the tongue and fingertips was almost completely controlled. The patients did not need iron and blood transfusions during the treatment. This suggests that bevacizumab may be more effective in skin and oral mucosa involvement.
All antiangiogenic therapies carry a theoretical risk of thrombosis that should be discussed with patients during the process of obtaining approval for treatment. However, published literature suggests that thromboembolic rates in HHT patients are significantly lower compared to rates in cancer patients, even among individuals treated with these agents for several years [21]. We did not observe any side effects of neuropathy or thrombosis in our patients treated with bevacizumab. This finding supports the routine and long-term use of bevacizumab in patients with HHT.

Limitations

The most important limitation of our study was the small number of patients, but each patient was followed up closely and for a considerably longer time than in the literature, and important details were able to be observed. The lack of a control arm in the study was another limitation. Both of these limitations were related to the small number of HHT patients in daily practice. Another limitation of our study was that it was not prospective and randomized, but it should be taken into account that in randomized clinical trials, even if the data quality is at the highest levels, patients who are not fit enough are not included, and thus, real life is not adequately represented.

Conclusion

HHT is a little-recognized inherited bleeding disorder for which standard treatment approaches have not yet been developed. We found that bevacizumab was an effective and safe treatment method in patients with HHT. In our long-term follow-up, efficacy was sustained, and no additional toxicity was observed. Bevacizumab treatment positively affected the psychological and social lives of the patients. However, prospectively designed studies with a larger number of patients are needed to reach more precise information.

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