Race and ethnicity reporting and representation in hemophilia clinical trials.

ABSTRACT: Racial and ethnic representativeness in clinical trials is crucial to mitigate disparities in outcomes; however, diversity among hemophilia trials is unknown. The aim of this study is to examine the reporting and representation of race and ethnicity in trials of people with hemophilia (PwH). In this cross-sectional study, the ClinicalTrials.gov database was queried in April 2023 for interventional clinical trials involving PwH between 2007 and 2022. The distribution of participants (observed) was compared with expected proportions based on US Hemophilia Treatment Center (HTC) and country-specific census data with observed-to-expected ratios (OERs). Of 129 trials included, 94.6% were industry sponsored, with a mean of 62 participants and mean age of 26.8 years. Overall, 52.0% (n = 66) of trials reported data on race and ethnicity, increasing from 13.9% in 2007-2012 to 22.5% in 2013-2016 to 100% in 2017-2022 (P = .001). Among these 66 trials, 65.8%, 22.8%, 5.1%, 3.9% of participants were White, Asian, Hispanic, and Black, respectively. OERs were 10% to 20% lower for White participants vs US HTC, and US, UK, and Canadian census populations and ∼75% lower for Black or Hispanic participants when compared with US HTC and US census population. OERs for Asian participants were 1.6 to 3 times higher than Canada, US, and UK census populations. The reporting of race and ethnicity in hemophilia trials has drastically improved; however, Black and Hispanic PwH remain especially underrepresented. To address these disparities, stakeholders across the clinical trial enterprise need to implement strategies to ensure equitable participation.

Racial and ethnic differences in reported haemophilia death rates in the United States.

INTRODUCTION: People with haemophilia's life expectancies have improved over time. Whether progress has been experienced equitably is unknown. AIM: To examine recorded haemophilia death (rHD) rates according to race and ethnicity in the United States (US). METHODS: In this cohort study, rHDs were examined with US National Vital Statistics' 1999-2020 Multiple Cause-of-Death data. rHD was defined as having a haemophilia A (D66) or B (D67) ICD-10 code in the death certificate (underlying or multiple causes of death). Age-adjusted rHD rates were compared with age-adjusted rate ratios (aRR) and 95% Confidence Intervals (CI). RESULTS: There were 3115 rHDs in males with an rHD rate of 0.98 per 1 million males. Between 1999 and 2020, rHD rates declined by 46% in NH (Non-Hispanic) White, 44% in NH Black (aRR = 0.56, 95%CI 0.43, 0.74), and 42% in Hispanic (aRR = 0.58, 95%CI 0.39, 0.88) males. However, rHD rates remained higher and were on average 30% greater in NH Black versus NH White males (aRR = 1.30 95% CI 1.16, 1.46). Among males with rHD, the median age at death rose from 54.5 to 65.5 years between 1999 and 2020 and was 12 years lower in NH Black (56 years) versus NH White (68 years) males in 2010-2020. There were 930 females with rHD, with an age-adjusted rate of 0.22 per 1 million females, which was consistent between 1999 and 2020. CONCLUSION: Reported haemophilia-death rates improved in males across all race/ethnicities, but rates were higher Black versus White males. Given the inherent limitations of the current study's data source, further investigation of survival rates and disparities in haemophilia are needed.

Racial and Ethnic Differences in Distress, Depression, and Quality of Life in people with hemophilia.

Hemophilia-related distress (HRD) has been shown to be higher among those with lower educational attainment, but potential racial/ethnic differences have not been previously described. Thus, we examined HRD according to race/ethnicity. This cross-sectional study was a planned secondary analysis of the hemophilia-related distress questionnaire (HRDq) validation study data. Adults aged ≥ 18 years with Hemophilia A or B were recruited from one of two hemophilia treatment centers between July 2017-December 2019. HRDq scores can range from 0-120, and higher scores indicate higher distress. Self-reported race/ethnicity was grouped as Hispanic, non-Hispanic White (NHW) and non-Hispanic Black (NHB). Unadjusted and multivariable linear regression models were used to examine mediators of race/ethnicity and HRDq scores. Among 149 participants enrolled, 143 completed the HRDq and were included in analyses. Approximately 17.5% of participants were NHB, 9.1% were Hispanic and 72.0% were NHW. HRDq scores ranged from 2 to 83, with a mean of 35.1 [standard deviation (SD) = 16.5]. Average HRDq scores were significantly higher among NHB participants (mean = 42.6,SD = 20.6; p-value = .038) and similar in Hispanic participants (mean = 33.8,SD = 16.7, p-value = .89) compared to NHW (mean = 33.2,SD = 14.9) participants. In multivariable models, differences between NHB vs NHW participants persisted when adjusting for inhibitor status, severity, and target joint. However, after household income was adjusted for, differences in HRDq scores were no longer statistically significant (ß = 6.0 SD = 3.7; p-value = .10). NHB participants reported higher HRD than NHW participants. Household income mediated higher distress scores in NHB compared to NHW participants, highlighting the urgent need to understand social determinants of health and financial hardship in persons with hemophilia.

Comparing direct oral anticoagulants and vitamin K antagonist use in morbidly obese patients with venous thromboembolism: A single center retrospective cohort study.

Introduction: Limited data exists on the safety and efficacy of direct-acting oral anticoagulants (DOAC) use in morbidly obese patients with venous thromboembolism (VTE). Given the benefits of DOAC use over vitamin K antagonists (VKAs), in terms of monitoring requirements, and dietary and drug interactions, it is important to evaluate whether this is consistent in the higher risk for VTE recurrence morbidly obese group body mass index (BMI ≥ 40 kg/m2). Materials and methods: This retrospective, single-center cohort study included patients with a BMI of at least 40 kg/m2 who were admitted to Emory University Hospital from 1st January 2012 to 31st May 2020 with acute VTE, and subsequently initiated on anticoagulation treatment with either DOAC or VKA (warfarin). Univariate and bivariate analyses were used to evaluate differences in demographics by treatment type and BMI. Multivariate Cox proportional hazard regression was used to assess the risk of VTE recurrence by type of treatment among morbidly obese patient subgroup. Results: There were 247 (11.8%) morbidly obese (≥ 40 kg/m2) patients who were more likely than non-obese patients to be younger, female, and of non-white race. Thirty percent of the study population (n=74) had a BMI >50 kg/m2. T ime-to-event analysis confirmed that the hazard of experiencing a recurrent thrombosis was not statistically significantly different among morbidly obese patients treated with a DOAC compared with VKA (hazard ratio [HR]: 0.28, confidence interval [CI] 0.07-1.11, p = 0.07). Conclusions: This study aligns with previous literature and confirms that morbidly obese patients receiving DOAC or VKA have similar risks of recurrent VTE.

Early real-world experience with emicizumab and concomitant factor VIII replacement products in adult males with Hemophilia A without inhibitors.

AIMS: To assess real-world use of emicizumab in adult people with hemophilia A (PwHA) without inhibitors including healthcare resource utilization (HCRU) and costs. MATERIALS AND METHODS: Adult, male PwHA without inhibitors initiating emicizumab (index date) were identified using IBM MarketScan after 4 October 2016. Patients were required to have continuous health insurance coverage for ≥180 days prior to and ≥90 days after index date and have ≥90 days of continuous use of emicizumab. Patients were followed until treatment gap, disenrollment, or end of data. Results were reported overall and among a subgroup with prior factor VIII (FVIII) prophylaxis. Emicizumab use, concomitant FVIII treatment use, HCRU, and costs were assessed separately over baseline, the emicizumab induction period, emicizumab maintenance period, and annualized. RESULTS: Among the 71 emicizumab patients (FVIII prophylaxis subgroup: 52) included in the study, the mean age was 35 (subgroup: 34) years and mean follow-up was 12 (subgroup: 11.1) months. At baseline, the annualized mean total healthcare cost was $532,948 (subgroup: $645,727). After emicizumab initiation, per-patient-per-month (PPPM) HCRU was higher in the emicizumab induction period compared to the maintenance period with higher monthly FVIII fills/in-office administrations (0.37 vs 0.17), non-FVIII outpatient visits (2.23 vs 1.55), and emergency department visits (0.06 vs 0.03). The FVIII prophylaxis subgroup yielded similar HCRU trends. Hemophilia treatment costs accounted for over 95% of total healthcare costs. The annualized mean cost was $50,491 (subgroup: $61,512) for concomitant FVIII treatment and $777,171 (subgroup: $793,168) for emicizumab and concomitant FVIII treatment for the first year of emicizumab treatment. CONCLUSION: This study represented experience with emicizumab after the approval for PwHA without inhibitors. The study cohort may not be representative of all PwHA taking emicizumab. The findings highlight the continued burden of treatment and healthcare cost for PwHA without inhibitors despite advances in treatment options.

Postoperative bleeding complications in patients with hemophilia undergoing major orthopedic surgery: A prospective multicenter observational study.

BACKGROUND: Persons with hemophilia (PWH) are at risk for chronic hemophilic arthropathy (HA). Joint replacement surgery may be used to relieve intractable pain and/or restore joint function. OBJECTIVES: This multicenter, prospective, observational cohort study evaluated the rate of bleeding during the postoperative period after total hip (THA) or knee arthroplasty (TKA). PATIENTS/METHODS: We included PWH of any severity ≥18 years of age who were undergoing THA or TKA. Clinical decisions were made at the discretion of the treating physician according to local standards of care. Clinical data were prospectively recorded. Major bleeding was defined as bleeding in a critical site, bleeding that resulted in either a 2 g/dl or greater decrease in hemoglobin during any 24-h period, or transfusion of two or more units of packed red blood cells. RESULTS: One hundred thirty-one procedures (98 TKA and 33 THA) were performed, 39 (29.8%) of which were complicated by major bleeding, including 46% of THA and 25% of TKA. The risk of major bleeding was increased in THA compared to TKA (OR 2.50, p = .05), and by the presence of an inhibitor (OR 4.29, p = .04), increased BMI (OR 4.49 and 6.09 for overweight and obese, respectively, compared to normal BMI, each p < .01), and non-use of an antifibrinolytic medication (OR 3.00, p = .03). Neither continuous clotting factor infusion (versus bolus infusion) nor pharmacologic thromboprophylaxis were associated with bleeding risk. CONCLUSIONS: The bleeding risk remains substantial after THA and TKA in PWH, despite factor replacement. Use of antifibrinolytic medications is associated with decreased risk.

Emicizumab for hemophilia A without inhibitors.

Introduction: Hemophilia A (HA) is an inherited bleeding disorder that, if not properly treated, is associated with debilitating joint damage due to recurrent hemarthroses as well as life-threatening bleeds including intracranial hemorrhage. For decades, the only method to prevent bleeding events was to infuse factor (F) VIII concentrates intravenously two to three times weekly. Although successful in reducing bleeding frequency, preventing a high proportion of joint disease, and extending life expectancy, standard continuous prophylaxis with FVIII is burdensome and insufficiently effective at preventing long-term joint dysfunction in some patients. In October 2018, the Federal Drug Administration approved a novel agent, emicizumab-kxwh, for the treatment of patients with HA without inhibitors. Areas covered: In this article, the preclinical and clinical development of emicizumab-kxwh will be reviewed. Data from licensure phase 3 clinical trials will be reviewed in detail discussing issues of both safety and efficacy. Expert opinion: As emicizumab-kxwh leads the way of a shift in treatment paradigm for patients with HA without inhibitors, a number of questions remain, including the impact of emicizumab-kxwh on joint and bone health, inhibitor development, and thrombotic risk. Ultimately, time and clinical investigation will be able to elucidate the influence of emicizumab-kxwh in these areas.

Inflammatory demyelinating polyneuropathy versus leptomeningeal disease following Ipilimumab.

BACKGROUND: Ipilimumab is an FDA-approved anti-CTLA-4 monoclonal antibody used in treatment of metastatic melanoma. We present an unusual neurological complication of Ipilimumab therapy and the diagnostic dilemma it caused. CASE PRESENTATION: A 42 year old male with Stage IV metastatic melanoma developed lower extremity weakness and sensory neuropathy following three doses of Ipilimumab. MRI of the lumbar spine was initially interpreted as diffuse leptomeningeal disease, and patient began Dexamethasone and radiation with improvement in symptoms. However, subsequent completion imaging revealed smooth nerve root involvement with sparing of the spinal cord, findings more compatible with inflammatory demyelinating polyneuropathy. The absence of malignant cells in the cerebrospinal fluid (CSF) and nerve conduction study (NCS) showing lumbar polyradiculoneuropathy with axonal involvement and demyelinating features supported the diagnosis of inflammatory demyelinating polyneuropathy. Later in the course of his disease, the patient developed frank leptomeningeal melanoma. CONCLUSION: Ipilimumab immune-related toxicity presented as inflammatory demyelinating polyneuropathy, which was difficult to distinguish from leptomeningeal disease, a common complication of melanoma.

Current and emerging factor VIII replacement products for hemophilia A.

Hemophilia A is a congenital X-linked bleeding disorder caused by coagulation factor VIII (FVIII) deficiency. Routine infusion of factor replacement products is the current standard of care; however, the development of alloantibodies against FVIII remains a challenge. The treatment of hemophilia has undergone major advances over the past century to improve safety, effectiveness, manufacturing, and convenience of factor products. Major recent advances in the treatment of hemophilia A include the emergence of extended half-life products, factor VIII orthologs, and gene therapy products. Extended half-life products were designed to decrease the frequency of infusions, but only modest half-life extension is achieved. Factor VIII orthologs featuring lower cross-reactivity with anti-FVIII antibodies may be less susceptible to inactivation by inhibitors. Meanwhile, gene therapy may potentially provide a cure for hemophilia A, thus abrogating the need for protein-based factor replacement. This review aims to discuss current and emerging FVIII replacement products for hemophilia A.

The Runx3 distal transcript encodes an additional transcriptional activation domain.

The runt family transcriptional regulator, Runx3, is upregulated during the differentiation of CD8 single-positive thymocytes and is expressed in peripheral CD8(+) T cells. Mice carrying targeted deletions in Runx3 have severe defects in the development and activation of CD8(+) T cells, resulting in decreased CD8(+) T-cell numbers, aberrant coexpression of CD4, and failure to expand CD8(+) effector cells after activation in vivo or in vitro. Expression of each of the three vertebrate runt family members, including Runx3, is controlled by two promoters that generate proteins with alternative N-terminal sequences. The longer N-terminal region of Runx3, expressed from the distal promoter, is highly conserved among family members and across species. We show that transcripts from the distal Runx3 promoter are selectively expressed in mature CD8(+) T cells and are upregulated upon activation. We show that the N-terminal region encoded by these transcripts carries an independent transcriptional activation domain. This domain can activate transcription in isolation, and contributes to the increased transcriptional activity observed with this isoform as compared to those expressed from the ancestral, proximal promoter. Together, these data suggest an important role for the additional N-terminal Runx3 activation domain in CD8(+) T-cell function.