Clancy, Marianne S.

Abstract Hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant vasculopathy affecting 1 in 5000 individuals, is the second most common inherited bleeding disorder worldwide. Despite this prevalence, comprehensive data on disease manifestations and complications remain limited. To address this gap, the US Congress allocated funding leading to the Comprehensive HHT Outcomes Registry of the United States (CHORUS), a prospective, 15-center longitudinal registry enrolling unselected patients with confirmed HHT. In this initial report, we describe findings from the first 600 participants, with a median age of 53 (range, 0-88) years and 60% female. Despite most participants developing typical HHT manifestations by age 13 years, the majority (63%) were not diagnosed until mid-to-late adulthood. Recurrent spontaneous epistaxis occurred in 95% of participants, chronic gastrointestinal bleeding in 30%, and heavy menstrual bleeding in 35% of postmenarche females, together resulting in moderate-to-severe mucosal bleeding in 76%. Iron deficiency and/or anemia were diagnosed in 68%, with 41% requiring IV iron and 25% requiring red cell transfusions. Serious complications of solid-organ arteriovenous malformations were frequent, including intracranial hemorrhage (3%), pulmonary hemorrhage (2%), venous thromboembolism (7%), arterial thromboembolism (11%), heart failure (7%), and pulmonary hypertension (7%). These data from CHORUS, the first national US registry of its kind, provide reliable, real-world estimates of the incidence, prevalence, and severity of numerous HHT manifestations and complications. HHT has a high burden of moderate-to-severe bleeding, anemia, thrombosis, and major neurologic and cardiopulmonary complications. There is a mean interval between first symptoms and diagnosis of >2 decades, during which substantial, serious, and preventable HHT morbidity, including early intracranial hemorrhage, may occur. This trial was registered at clinicaltrials.gov as NCT06259292.

Abstract Hereditary hemorrhagic telangiectasia (HHT) results in recurrent severe epistaxis, chronic gastrointestinal bleeding, and other morbid manifestations. Pomalidomide was recently demonstrated to be efficacious for bleeding in HHT in the landmark PATH-HHT trial. Given that the vascular remodeling that results in bleeding improvement may require several months, characteristics associated with treatment response would be invaluable to plan treatment. Using data from PATH-HHT (NCT03910244), we identified characteristics associated with change from baseline in Epistaxis Severity Score (ESS; a well-validated 10-point HHT bleeding scale and the trial’s primary end point) using multivariable-adjusted repeated-measures models. Characteristics associated with a better response to pomalidomide at weeks 16 to 24 of the trial included a higher (more severe) baseline ESS (change from baseline, −0.76 [95% confidence interval (CI), −0.99 to −0.54] points per 1-point higher baseline score, P< .001) and concomitant antifibrinolytic therapy (−0.73 [95% CI, −1.48 to 0.01] vs no therapy, P = .05). Characteristics associated with a less robust response were older age (0.29 [95% CI, 0.05-0.53] per 10 years older, P = .02) and underlying ACVRL1 germ line mutation (0.62 [95% CI, −0.04 to 1.27] vs ENG, SMAD4, or mutation not known, P = .06]. Characteristics notably associated with placebo response (placebo effect) were patient-reported outcome measures, such that those experiencing more severe disease at baseline had less placebo effect. In conclusion, several baseline patient and disease characteristics were associated with pomalidomide response, findings that may help guide patient selection for the use of pomalidomide in HHT. This trial was registered at www.Clinicaltrials.gov as NCT03910244.

ABSTRACT Hereditary hemorrhagic telangiectasia (HHT, Osler‐Weber‐Rendu disease) is the second most common inherited bleeding disorder worldwide, affecting approximately 1 in 5000 people. Development of disease‐modifying and efficacious hemostatic agents to treat HHT has finally begun after decades without such medical therapies. However, the lack of consensus on standardized severity definitions, outcome criteria, and terminology remains a major obstacle to clinical investigation and therapeutic development in HHT. Additionally, with the ongoing repurposing of antiangiogenic agents and emerging development of novel HHT‐specific therapies, comparative clinical trials are expected in the future. Therefore, to end the problematic heterogeneity hindering these efforts, the Global Research and Medical Advisory Board (GRMAB) of the Cure HHT Foundation, an international group of recognized HHT experts, convened a conference of expert HHT clinician‐investigators from within GRMAB as well as invited external experts in HHT and bleeding disorders generally, patients with HHT, and patient advocates to define standard terminology and definitions for outcomes and severity classification for bleeding and anemia in HHT. These criteria and definitions should be adopted by regulators, investigators, and the pharmaceutical industry in the development and performance of interventional clinical trials and cohort studies to allow improved comparability between clinical trials, facilitate communication between clinicians and investigators, improve therapeutic guideline development, and provide a standardized framework for regulatory agencies. Search Strategy and Selection Criteria Evidence for this report was systematically identified and evaluated utilizing two search strategies in Ovid MEDLINE, described in full detail in the Appendix, pp.4–13. The searches were conducted on January 7, 2025. The titles and abstracts of each record were reviewed, and the inclusion criteria were applied to all search results to identify full text articles to be retrieved for further review. All retrieved full texts were then reviewed to reach a final determination if a study met the inclusion criteria. Included references were then compiled into evidence tables, which were then utilized by the International Consensus Report Working Group throughout the development of report recommendations.

Introduction Hereditary hemorrhagic telangiectasia (HHT), the second most common bleeding disorder worldwide, affects 1 in 5000 people and is characterized by extensive formation of telangiectasia and arteriovenous malformations (AVM) in mucosa, lung, brain, and liver. The primary clinical manifestation is recurrent, often severe epistaxis which commonly results in iron deficiency anemia, emergency room visits, hospitalizations, and reduced quality of life (QOL). Though non-randomized and/or underpowered studies have suggested that systemic bevacizumab or thalidomide may be effective in treating HHT, there have been no pivotal studies and therefore no FDA or EMA approved therapies. Methods PATH-HHT was an NHLBI-funded, randomized, placebo-controlled clinical trial conducted at 13 centers in the US to determine the safety and efficacy of pomalidomide for bleeding in HHT. Pomalidomide was supplied by Celgene and Bristol Myers Squibb. Patients were randomized in a 2:1 ratio to receive pomalidomide 4 mg daily or matching placebo for 6 months. Dose reductions were allowed for toxicity. The primary endpoint was the change in the Epistaxis Severity Score (ESS), a well-validated bleeding score in HHT, from baseline (randomization) to the end of the six-month treatment period, analyzed using a mixed model for repeated measures with adjustment for baseline value, center, treatment, visit, and treatment by visit interaction. Key secondary endpoints included 1) change in the average daily self-reported epistaxis duration from the four weeks preceding the baseline visit to weeks 20-24 of treatment, 2) amount of parenteral iron infused or blood transfused, and 3) change in QOL measurements, including an HHT-specific QOL score. Results PATH-HHT opened in November 2019 and was closed to enrollment by the NHLBI in June 2023 after a planned 75% interim analysis met a prespecified threshold for efficacy. A total of 144 patients were randomized and treated (95 pomalidomide, 49 placebo). Early study discontinuation was 25% in pomalidomide: 14% AE, 11% withdrawn, 1 unrelated death, compared with placebo (4% withdrawn). Across groups, 8% were terminated after 12 weeks for early study closure. Participants included 48% females, 11% non-white race; mean (± SD) age was 58.8±12.2 years. The mean ESS at baseline was 5.0±1.5 (4.9 pomalidomide, 5.2 placebo), consistent with moderate to severe epistaxis. At 24 weeks, the ESS in patients treated with pomalidomide decreased by a mean [95% CI] of -1.84 [-2.24, -1.44] and in the placebo group decreased by -0.89 [-1.39, -0.39] (mean difference -0.95 [-1.58, -0.32], p = 0.003) (Figure, Panel A). Difference between groups was apparent by 12 weeks (mean difference -0.52, 95% CI [-1.04, -0.01], p = 0.045). The HHT-specific QOL score, which ranges from 0 to 16 with higher scores indicating more limitations, also decreased more in the pomalidomide (mean -2.6, 95% CI [-3.3, -1.9]) vs the placebo group at 24 weeks (mean -1.2, 95% CI [-2.1, -0.3], p = 0.015) (Figure, Panel B). Adverse events that occurred more in the pomalidomide group included mild to moderate neutropenia (45% vs. 10%), constipation/diarrhea (60% vs. 37%), and rash (36% vs. 10%). Venous thrombosis occurred in 2% of patients in each group. Conclusion PATH-HHT is the largest and the first adequately powered, randomized trial of systemic therapy in HHT. The study demonstrated a significant and highly clinically relevant reduction in epistaxis in pomalidomide-treated patients as well as an improvement in the HHT-specific QOL score. Pomalidomide may offer a novel approach to management of HHT. Since plasma was collected from patients in this study before and at the end of treatment, additional studies may identify biomarkers predicting pomalidomide responses.

AbstractIntroductionSystemic bevacizumab is a novel targeted therapy for severe epistaxis and chronic gastrointestinal bleeding in hereditary haemorrhagic telangiectasia (HHT), but published data are very limited.AimWe conducted a survey‐based study to characterize current treatment practices and physician‐reported safety and effectiveness of systemic bevacizumab for bleeding in (HHT).MethodsA 27‐item survey was sent to physician centre directors of 31 International HHT Centers of Excellence.ResultsResponse rate was 84%. Approximately half of centres had treated >10 HHT patients with systemic bevacizumab for chronic bleeding for a total of 291 patients treated. All centres utilize a 5 mg/kg dose for induction treatment and most administer six doses (range, 4‐8) every 2 weeks. However, maintenance regimens varied considerably between centres. Bevacizumab was highly effective, with 86% reporting significant (>50%) improvement in GI bleeding and/or epistaxis and haemoglobin rise in most patients treated with bevacizumab; 52% reported haemoglobin normalization in most patients. All centres reported adverse event rates <30% and two‐thirds of centres reported adverse event rates <10%. Discontinuation for adverse events or inefficacy was rare. Bleeding severity thresholds for initiation of bevacizumab were highly variable, and it is typically administered by haematologists (76% of centres). Two‐thirds of centres reported obtaining insurance approval for bevacizumab for most or all patients but 48% reported difficulty in obtaining coverage.ConclusionSystemic bevacizumab is widely used to treat bleeding in HHT with excellent physician‐reported effectiveness and safety. There is considerable variation in maintenance treatment practices and thresholds for initiation of bevacizumab among HHT centres.