McCrae, Keith R.

Background: Since publication of the American Society of Hematology 2019 Guidelines for Immune Thrombocytopenia (ITP), new clinical trials have been completed and new treatments have become available. Objective: These evidence-based guidelines from the American Society of Hematology (ASH) are a focused update of the 2019 ASH ITP guidelines, centering on treatment of adults with primary ITP. Methods: ASH formed a multidisciplinary guideline panel including two patient representatives that was balanced to minimize potential bias from conflicts of interest. The University of Oklahoma supported the guideline development process, including updating or performing systematic evidence reviews (up to July 19, 2025). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients and identification of areas with new data or where application of new methods would be of benefit. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks and the GRADE framework for multiple comparisons, to assess evidence and make recommendations, which were subject to public comment. Results: The panel agreed on recommendations in adults with primary ITP regarding initial therapy and second-line treatment in patients who failed first-line corticosteroids. The panel also issued good practice statements on thrombopoietic agent switching and splenectomy. Conclusions: Novel recommendations of these guidelines include: (1) initial therapy with a combination of rituximab plus corticosteroids or a thrombopoietic agent plus corticosteroids rather than corticosteroids alone (conditional recommendation) and (2) a thrombopoietic agent (strong recommendation) or rituximab (conditional recommendation) for patients who failed first-line corticosteroids.

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) causes severe recurrent epistaxis, chronic gastrointestinal bleeding, solid organ arteriovenous malformations, and significant anemia. Although it is the second most common inherited bleeding disorder worldwide, no approved therapies exist. The multicenter, US randomized, controlled PATH-HHT trial demonstrated efficacy of short-term pomalidomide treatment of epistaxis in HHT. However, questions regarding long-term safety, effectiveness, and utility for HHT-associated gastrointestinal bleeding remain. The PATH-HHT ATLAS (after trial longitudinal assessment study) was a multicenter US longitudinal observational study evaluating patients enrolled in PATH-HHT who continued pomalidomide after PATH-HHT through a poststudy drug access program, with ongoing close monitoring per PATH-HHT protocol and as mandated by the US Food and Drug Administration. Sixty-two patients treated with pomalidomide for HHT for up to 4.4 years were included. Significant, durable improvements in mean epistaxis severity score (5.55 points [baseline] to 2.80 points [month 12]; P< .0001) and mean hematologic support score (9.11 red cell unit equivalents [RUEs] during 6 months pretreatment to 5.73 RUEs [months 7-12]; P = .0056) were observed. Pomalidomide was less effective for gastrointestinal bleeding than for epistaxis, particularly in patients with high red blood cell transfusion requirements. Thirty-one patients (50%) underwent dose reduction from 4 mg daily, primarily due to neutropenia, but most maintained effectiveness at 2 or 3 mg daily. Over 105.2 patient-years of pomalidomide treatment, 0 patients developed peripheral neuropathy, 1 developed venous thromboembolism, and 5 developed serious infections. In conclusion, pomalidomide was effective for HHT-associated epistaxis over extended durations, albeit with nontrivial potential toxicities, and may be considered for certain patients with HHT. This trial was registered at www.clinicaltrials.gov as NCT07018401.

Abstract BACKGROUND Hereditary hemorrhagic telangiectasia (HHT) is the second most common inherited bleeding disorder (IBD) worldwide, afflicting 1 in 5,000 people. HHT is likely the most morbid IBD of women. Severe, recurrent epistaxis, gastrointestinal (GI) bleeding, and solid organ arteriovenous malformations (AVMs) cause major clinical and psychosocial morbidity and reduced survival. In recognition of the serious morbidity of HHT as an IBD, in 2022 the U.S. Congress allocated funding to create CHORUS, the Comprehensive HHT Outcomes Registry of the United States (NCT06259292). Herein, we present the initial report from CHORUS. METHODS CHORUS is a prospective, multicenter, U.S. longitudinal registry enrolling unselected patients with HHT, collecting over 2400 data elements. Data were collected by trained research coordinators at enrollment and follow-up visits via the medical record and direct participant interviews. RESULTS Patients. 600 patients with genetically- or Curacao criteria-confirmed HHT were enrolled from November 2023 to April 2025 at 15 U.S. HHT Centers of Excellence. Median (range) age was 53 (0-88) years, and the cohort was 60% female. Despite most patients developing typical HHT disease manifestations by age 13, most HHT diagnoses (63%) were made during mid-to-late adulthood. Mucosal Bleeding. 568 patients (95%) developed recurrent spontaneous epistaxis, with 339 (60%) developing recurrent epistaxis prior to age 13; 43% had at least one nasal surgery/procedure and 22% had at least one medical therapy (e.g., antifibrinolytic or antiangiogenic) for epistaxis. 180 (30%) had a known diagnosis of chronic GI bleeding. Among post-menarche females, 124 (34%) had been diagnosed with heavy menstrual bleeding. 247 (41%) reported other clinically significant mucocutaneous oral or skin bleeding. 454 (76%) had developed moderate-to-severe HHT-associated mucocutaneous bleeding, defined as an Epistaxis Severity Score >4, bleeding requiring targeted pharmaceutical or surgical intervention, IV iron, and/or red cell transfusion. This includes 334 (56%) with moderate-to-severe HHT-associated epistaxis. CNS and Pulmonary Hemorrhage. 16 patients (3%) suffered one or more intracranial hemorrhages (ICH), with 10 (63%) suffering a first ICH by age 25. 13 (2%) suffered one or more pulmonary hemorrhages. Iron Deficiency and Anemia. 408 patients (68%) had been diagnosed with anemia (351, 59%) or iron deficiency (381, 64%). Of those, 247 (61%) and 150 (37%) required IV iron and RBC transfusion, respectively. Solid Organ AVMs. Brain, pulmonary, and liver AVMs were diagnosed in 81 (15%), 268 (45%), and 128 patients (21%), respectively. Just 30 with brain AVMs (37%) had these diagnosed by age 25. 3 patients (2%) had undergone liver transplantation. Thrombosis. Venous and arterial thromboembolism occurred in 44 (7%) and 38 patients (6%), respectively, including 34 (6%) with ischemic stroke (94% of whom had pulmonary AVMs). Other Serious HHT Complications. These included heart failure in 41 patients (7%), pulmonary hypertension in 44 (7%), chronic liver disease in 17 (2.8%), epilepsy in 24 (4%), severe bacterial/deep-seated tissue infection in 35 (6%), and brain abscess in 15 (3%). 205 (34%) developed migraine. Notably, serious CNS manifestations of HHT (brain AVM, ischemic stroke, intracranial hemorrhage, and/or epilepsy) occurred in 128 (21%). 241 (40%) required emergency room visits and/or hospital admissions specifically to manage HHT complications. CONCLUSIONS This first-of-its-kind HHT registry reliably describes for the first time the incidence and severity of numerous HHT complications. Most patients develop moderate-to-severe recurrent epistaxis and/or chronic GI bleeding as well as iron deficiency anemia (usually requiring IV iron and/or RBC transfusion). Heavy menstrual bleeding, thromboembolism, severe cardiopulmonary complications, and serious CNS complications are all substantially more common in HHT than previously thought. Notably, ICH occurred in 3% of patients, which approximates the ICH incidence of hemophilia in the pre-factor prophylaxis era and is ~2-fold and ~9-fold higher than in hemophilia A treated with modern factor prophylaxis (1.6%) and modern non-factor prophylactic agents (0.3%), respectively, per the ATHN registry. This 3% number may be an underestimation given the known high ICH mortality rate, pervasive delay in HHT diagnosis, and the fact that survival post-ICH is necessary to enroll in CHORUS.

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.

Abstract Immune thrombotic thrombocytopenic purpura (iTTP) is a chronically relapsing disorder caused by autoantibody-mediated deficiency of ADAMTS13. Rituximab is frequently administered to prevent relapses, but whether the durability of rituximab effect is maintained with subsequent treatment courses has not been studied. Using the United States Thrombotic Microangiopathy Consortium (USTMA) retrospective iTTP registry, we evaluated clinical relapse-free survival (RFS) with subsequent courses of rituximab treatment in multiply relapsing patients. Separately, we evaluated overall RFS (composite of time to clinical relapse, ADAMTS13 relapse, or preemptive rituximab) in a prospective iTTP cohort from the Johns Hopkins University and the University of Minnesota. In the USTMA registry, median clinical RFS was shorter after the second or subsequent rituximab-treated episode than the first (2.1 vs 6.0 years; P = .04). White patients’ clinical relapse risk after the second and subsequent rituximab courses was not significantly different compared with the first (hazard ratio [HR], 1.86; 95% confidence interval [CI], 0.22-15.80; P = .57), whereas for Black patients, clinical relapse risk was significantly higher after the second or subsequent courses (HR, 2.82; 95% CI, 1.52-5.24; P = .001). In the prospective cohort, overall RFS progressively shortened after each episode of rituximab treatment with the first episode having the longest RFS (2.8 years; interquartile range, 2.0-6.0) and this loss of response durability was most pronounced in Black patients. The durability of rituximab’s effect declines with subsequent treatments, which is more pronounced in Black patients, who may benefit from closer monitoring and alternative immunomodulatory approaches such as maintenance rituximab and consideration of other agents.

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.

Abstract Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by recurring episodes of thrombotic microangiopathy, causing ischemic organ impairment. Black patients are overrepresented in iTTP cohorts in the United States, but racial disparities in iTTP outcome and response to therapy have not been studied. Using the United States Thrombotic Microangiopathies Consortium iTTP Registry, we evaluated the impact of race on mortality and relapse-free survival (RFS) in confirmed iTTP in the United States from 1995 to 2020. We separately examined the impact of rituximab therapy and presentation with newly diagnosed (de novo) or relapsed iTTP on RFS by race. A total of 645 participants with 1308 iTTP episodes were available for analysis. Acute iTTP mortality did not differ by race. When all episodes of iTTP were included, Black race was associated with shorter RFS (hazard ratio [HR], 1.60; 95% CI, 1.16-2.21); the addition of rituximab to corticosteroids improved RFS in White (HR, 0.37; 95% CI, 0.18-0.73) but not Black patients (HR, 0.96; 95% CI, 0.71-1.31). In de novo iTTP, rituximab delayed relapse, but Black patients had shorter RFS than White patients, regardless of treatment. In relapsed iTTP, rituximab significantly improved RFS in White but not Black patients. Race affects overall relapse risk and response to rituximab in iTTP. Black patients may require closer monitoring, earlier retreatment, and alternative immunosuppression after rituximab treatment. How race, racism, and social determinants of health contribute to the disparity in relapse risk in iTTP deserves further study.