Aflibercept for Gastrointestinal Bleeding in Hereditary Hemorrhagic Telangiectasia: A Case Report.

Herein, we present the first described hereditary hemorrhagic telangiectasia (HHT) patient treated with aflibercept for severe GI involvement after tachyphylaxis to bevacizumab, with promising results. HHT is a rare genetic disease characterized by systemic vascular malformations. Gastrointestinal telangiectasia is one of the major involvements that can produce chronic severe iron-deficiency anemia. Nowadays, support treatment with iron replacement therapy, red blood cell transfusions, and antiangiogenic drugs-mainly bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF)-are the main therapeutic options for this complication. The evidence of alternative drugs in patients with failure to this approach, such as tachyphylaxis to bevacizumab, is scarce. Aflibercept is a VEGF inhibitor with antiangiogenic properties approved for the treatment of different types of cancer and ocular neovascularization diseases.

Long-term use of somatostatin analogs for chronic gastrointestinal bleeding in hereditary hemorrhagic telangiectasia.

Background: Chronic bleeding due to gastrointestinal (GI) involvement in patients with hemorrhagic hereditary telangiectasia (HHT) can provoke severe anemia with high red blood cells (RBC) transfusion requirements. However, the evidence about how to deal with these patients is scarce. We aimed to assess the long-term efficacy and safety of somatostatin analogs (SA) for anemia management in HHT patients with GI involvement. Methods: This is a prospective observational study including patients with HHT and GI involvement attended at a referral center. SA were considered for those patients with chronic anemia. Anemia-related variables were compared in patients receiving SA before and during treatment. Patients receiving SA were divided into responders (patients with minimal hemoglobin levels improvement >10 g/L and maintaining hemoglobin levels ≥80 g/L during treatment), and non-responders. Adverse effects during follow-up were collected. Results: Among 119 HHT patients with GI involvement, 67 (56.3%) received SA. These patients showed lower minimal hemoglobin levels (73 [60-87] vs. 99 [70.2-122.5], p < 0.001), and more RBC transfusion requirements (61.2% vs. 38.5%, p = 0.014) than patients without SA therapy. Median treatment period was 20.9 ± 15.2 months. During treatment, there was a statistically significant improvement in minimum hemoglobin levels (94.7 ± 29.8 g/L vs. 74.7 ± 19.7, p < 0.001) and a reduction of patients with minimal hemoglobin levels <80 g/L (39 vs. 61%, p = 0.007) and RBC transfusions requirement (33.9% vs. 59.3%, p < 0.001). Sixteen (23.9%) patients showed mild adverse effects, mostly diarrhea or abdominal pain, leading to treatment discontinuation in 12 (17.9%) patients. Fifty-nine patients were eligible for efficacy assessment and 32 (54.2%) of them were considered responders. Age was associated with non-responder patients, OR 95% CI; 1.070 (1.014-1.130), p = 0.015. Conclusion: SA can be considered a long-term effective and safe option for anemia management in HHT patients with GI bleeding. Older age is associated with poorer response.

Improving Hereditary Hemorrhagic Telangiectasia Molecular Diagnosis: A Referral Center Experience.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular disease inherited in an autosomal dominant manner. Disease-causing variants in endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1) genes are detected in more than 90% of the patients undergoing molecular testing. The identification of variants of unknown significance is often seen as a challenge in clinical practice that makes family screening and genetic counseling difficult. Here, we show that the implementation of cDNA analysis to assess the effect of splice site variants on mRNA splicing is a powerful tool. METHODS: Gene panel sequencing of genes associated with HHT and other arteriovenous malformation-related syndromes was performed. To evaluate the effect of the splice site variants, cDNA analysis of ENG and ACVRL1 genes was carried out. RESULTS: three novel splice site variants were identified in ENG (c.68-2A > T and c.1311+4_1311+8del) and ACVLR1 (c.526-6C > G) genes correspondingly in three individuals with HHT that met ≥ 3 Curaçao criteria. All three variants led to an aberrant splicing inducing exon skipping (ENG:c.68-2A > T and ACVRL1:c.526-6C > G) or intron retention (ENG:c.1311+4_1311+8del) allowing the confirmation of the predicted effect on splicing and the reclassification from unknown significance to pathogenic/likely pathogenic of two of them. CONCLUSIONS: RNA analysis should be performed to assess and/or confirm the impact of variants on splicing. The molecular diagnosis of HHT patients is crucial to allow family screening and accurate genetic counseling. A multidisciplinary approach including clinicians and geneticists is crucial when dealing with patients with rare diseases.