Weeks, Lachelle Dawn

Objective Vacuoles, E1 enzyme, X‐linked, autoinflammatory, somatic syndrome (VEXAS) syndrome is characterized by a complex spectrum of inflammatory and hematologic manifestations. Clinical research to identify effective therapies is urgently needed but is hindered by the lack of validated outcome measures. A VEXAS‐specific disease activity index (DAI) is an essential tool for reliably capturing changes in disease activity over time, thereby supporting clinical research and informing patient care in this emerging disease. This study aimed to develop a comprehensive DAI to assess disease‐related inflammation across affected organ systems in patients with VEXAS syndrome. Methods Inflammatory manifestations of VEXAS were previously identified through a systematic literature review and expert input. A multinational expert advisory committee developed the VEXAS‐DAI using modified Delphi methodology until consensus (defined as ≥75% concurrence) was reached. Item grading was adapted from the Common Terminology Criteria for Adverse Events. Scoring criteria were developed based on 158 test cases using the Physician Global Assessment of Inflammation. Results Consensus on the VEXAS‐DAI was achieved after four Delphi rounds. The index assesses inflammatory activity at the time of evaluation across 12 domains: inflammatory rash, chondritis, periorbital, ophthalmologic, joint, pulmonary, cardiovascular, genitourinary, neurologic, oral and gastrointestinal, renal, and constitutional symptoms. The total score ranges from 0 to 40. Conclusion The VEXAS‐DAI is a novel instrument designed to quantify active inflammation over time in patients with VEXAS. Prospective validation within a clinical trial setting is ongoing. image

VEXAS (Vacuoles, E1 ubiquitin-activating enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a systemic disorder characterized by an overlap of hematologic and inflammatory features. Most patients require chronic use of moderate-to-high doses of glucocorticoids (GCs) to maintain disease control. Data on GC-sparing therapies is limited, and there have been no prospective pharmacotherapeutic trials in VEXAS syndrome published to date. Pacritinib, an oral inhibitor of IRAK1, JAK2, and ACVR1, has emerged as a promising therapeutic option for VEXAS syndrome. The PAXIS trial is the first prospective, randomized pharmacotherapeutic study conducted in this rare and severe disease. Utilizing a novel study design and disease-specific endpoints, the trial will evaluate the efficacy and safety of two dose levels of pacritinib compared with placebo in patients with VEXAS syndrome (NCT06782373, EUCTR: 2024-516347-41-00).

Abstract Objective VEXAS syndrome is a severe systemic haemato-inflammatory disease with heterogeneous clinical presentations. Most patients experience recurrent inflammatory flares despite anti-inflammatory therapy. The lack of accepted definitions of flare in these patients is preventing development of disease activity tools that are essential for conducting clinical trials. We aimed to develop a consensus definition of a VEXAS flare for use in clinical trials. Methods A nine-member international expert advisory committee established a consensus definition of VEXAS flare using modified Delphi methodology. Clinical inflammatory manifestations of VEXAS syndrome were identified through a systematic literature review. Committee members developed a conceptual framework for flare definition, proposed revisions and voted on changes until consensus (≥75% concurrence) was reached. Results Consensus defined VEXAS flare as active inflammatory manifestation(s) of VEXAS syndrome requiring escalation in glucocorticoid therapy. Three flare categories were established: (i) recurrence of a prior documented VEXAS manifestation; (ii) development of a new VEXAS-defining inflammatory manifestation; or (iii) emergence of a new inflammatory manifestation not meeting criteria for A or B. The panel endorsed an independent adjudication committee to assess Category C flares in clinical trials. Conclusions This study proposes a standardized definition of VEXAS flare, providing uniform criteria for identifying VEXAS disease activity. Future research will evaluate its performance in clinical trials.

Abstract Globally, an estimated 300 million individuals have sickle cell trait (SCT), the carrier state for sickle cell disease (SCD). Although SCD is associated with increased morbidity and shortened life span, SCT has a life span comparable with that of the general population. However, “sickle cell crisis” has been used as a cause of death for decedents with SCT in reports of exertion-related death in athletes, military personnel, and individuals in police custody. To appraise this practice, the American Society of Hematology convened an expert panel of hematologists and forensic pathologists to conduct a systematic review of the literature relating to the occurrence of sickle cell pain crises and exertion-related mortality in people with SCT. Multiple bibliographic databases were searched with controlled vocabulary and keywords related to “sickle cell trait,” “vaso-occlusive pain,” and “death,” yielding 18 of 1474 citations. Independent pairs of reviewers selected studies and extracted data. We found no studies comparing uncomplicated acute pain crises in individuals with SCT and SCD. Additionally, no study was identified to support the occurrence of acute vaso-occlusive pain crises in individuals with SCT. Furthermore, this systematic review did not identify any evidence to support an association between SCT and sudden unexplained death in the absence of exertion-related rhabdomyolysis. We conclude that there are no data to support the diagnosis of acute vaso-occlusive sickle cell crisis as a cause of death in SCT, nor does the available evidence support the use of SCT as a cause of exertion-related death without rhabdomyolysis.

PURPOSE: The COVID-19 pandemic led to unprecedented challenges in medical training, and we sought to assess the specific impact of COVID-19 on hematology-oncology (HO) fellowship programs. METHODS: We conducted a cross-sectional anonymous online survey of 103 HO program directors (PDs) in conjunction with the American Society of Hematology (ASH) and ASCO. We sought to assess the specific impact of COVID-19 on HO fellowship programs' clinical, educational, and research activities, evaluate perceptions regarding PD and trainee emotional and mental health, and identify ways to support programs. Data were analyzed using descriptive statistics, parametric and nonparametric tests, and multivariable logistic regression models. Responses to open-ended questions were analyzed with thematic analysis. RESULTS: Significant changes to fellowship activities included transitioning fellow training from outpatient clinics to telehealth (77.7%), shifting to virtual education (94.2%), and moving to remote research work (63.1%). A minority (21.4%) of PDs reported that their fellows were redeployed to cover non-HO services. Most PDs (54.4%) believed COVID-19 had a slight negative impact on fellowship training. PD self-reported burnout increased significantly from 15.5% prepandemic to 44.7% during the pandemic, and most PDs witnessed minor signs of fellow burnout (52.4%). Common PD concerns included inadequate supervision for telehealth activities, reduced opportunities for fellow advancement and promotion, lack of professional development activities, limited research operations and funding, program financial constraints, and virtual recruitment. CONCLUSION: We encourage institutions and national societies to allocate resources and develop programs that can support fellowships and mitigate the potential negative effects of COVID-19 on trainee and PD career development.

PURPOSE: Graduate medical and research training has drastically changed during the COVID-19 pandemic, with widespread implementation of virtual learning, redeployment from core rotations to the care of patients with COVID-19, and significant emotional and physical stressors. The specific experience of hematology-oncology (HO) fellows during the COVID-19 pandemic is not known. METHODS: We conducted a mixed-methods study using a survey of Likert-style and open-ended questions to assess the training experience and well-being of HO fellows, including both clinical and postdoctoral trainee members of the American Society of Hematology and ASCO. RESULTS: A total of 2,306 surveys were distributed by e-mail; 548 (23.8%) fellows completed the survey. Nearly 40% of fellows felt that they had not received adequate mental health support during the pandemic, and 22% reported new symptoms of burnout. Pre-existing burnout before the pandemic, COVID-19–related clinical work, and working in a primary research or nonclinical setting were associated with increased burnout on multivariable logistic regression. Qualitative thematic analysis of open-ended responses revealed significant concerns about employment after training completion, perceived variable quality of virtual education and board preparation, loss of clinical opportunities to prepare for independent clinical practice, inadequate grant funding opportunities in part because of shifting research priorities, variable productivity, and mental health or stress during the pandemic. CONCLUSION: HO fellows have been profoundly affected by the pandemic, and our data illustrate multiple avenues for fellowship programs and national organizations to support both clinical and postdoctoral trainees.