Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B.

BACKGROUND: Moderate-to-severe hemophilia B is treated with lifelong, continuous coagulation factor IX replacement to prevent bleeding. Gene therapy for hemophilia B aims to establish sustained factor IX activity, thereby protecting against bleeding without burdensome factor IX replacement. METHODS: In this open-label, phase 3 study, after a lead-in period (≥6 months) of factor IX prophylaxis, we administered one infusion of adeno-associated virus 5 (AAV5) vector expressing the Padua factor IX variant (etranacogene dezaparvovec; 2×1013 genome copies per kilogram of body weight) to 54 men with hemophilia B (factor IX activity ≤2% of the normal value) regardless of preexisting AAV5 neutralizing antibodies. The primary end point was the annualized bleeding rate, evaluated in a noninferiority analysis comparing the rate during months 7 through 18 after etranacogene dezaparvovec treatment with the rate during the lead-in period. Noninferiority of etranacogene dezaparvovec was defined as an upper limit of the two-sided 95% Wald confidence interval of the annualized bleeding rate ratio that was less than the noninferiority margin of 1.8. Superiority, additional efficacy measures, and safety were also assessed. RESULTS: The annualized bleeding rate decreased from 4.19 (95% confidence interval [CI], 3.22 to 5.45) during the lead-in period to 1.51 (95% CI, 0.81 to 2.82) during months 7 through 18 after treatment, for a rate ratio of 0.36 (95% Wald CI, 0.20 to 0.64; P<0.001), demonstrating noninferiority and superiority of etranacogene dezaparvovec as compared with factor IX prophylaxis. Factor IX activity had increased from baseline by a least-squares mean of 36.2 percentage points (95% CI, 31.4 to 41.0) at 6 months and 34.3 percentage points (95% CI, 29.5 to 39.1) at 18 months after treatment, and usage of factor IX concentrate decreased by a mean of 248,825 IU per year per participant in the post-treatment period (P<0.001 for all three comparisons). Benefits and safety were observed in participants with predose AAV5 neutralizing antibody titers of less than 700. No treatment-related serious adverse events occurred. CONCLUSIONS: Etranacogene dezaparvovec gene therapy was superior to prophylactic factor IX with respect to the annualized bleeding rate, and it had a favorable safety profile. (Funded by uniQure and CSL Behring; HOPE-B ClinicalTrials.gov number, NCT03569891.).

How I treat von Willebrand disorders in older adults.

ABSTRACT: von Willebrand disease (VWD) is the most common bleeding disorder and especially milder type 1 VWD might not be cared for in specialty clinics. VW factor levels rise with age, but the rise of these levels does not necessarily correlate with bleeding risk. A recent bleeding history combined with recent labs are important for hemostatic management decision during surgical interventions. Antifibrinolytics appear safe in the population of older adults, whereas desmopressin (DDAVP) should be used cautiously. Where needed, factor concentrates present a great treatment option. Acquired von Willebrand syndrome is vastly underrecognized, but likely to surface in the aging, especially in the setting of comorbidities, such as plasma-cell dyscrasias. Intravenous immunoglobulin can be an effective treatment in this scenario, but potentially increases thrombotic risk.

Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1-4 studies.

Prophylaxis with emicizumab, a subcutaneously administered bispecific humanized monoclonal antibody, promotes effective hemostasis in persons with hemophilia A (PwHAs). The primary efficacy, safety, and pharmacokinetics of emicizumab were reported previously, but long-term data were limited. Here, data from 401 pediatric and adult PwHAs with/without factor VIII (FVIII) inhibitors who were enrolled in the phase 3 HAVEN 1, HAVEN 2, HAVEN 3, and HAVEN 4 studies (NCT02622321, NCT02795767, NCT02847637, NCT03020160) have been pooled to establish a long-term efficacy, safety, and pharmacokinetics profile. Across a median efficacy period of 120.4 weeks (interquartile range, 89.0-164.4) (data cutoff 15 May 2020), the model-based treated annualized bleed rate (ABR) was 1.4 (95% confidence interval [CI], 1.1-1.7). ABRs declined and then stabilized at <1 in an analysis of 24-week treatment intervals; at weeks 121 to 144 (n = 170), the mean treated ABR was 0.7 (95% CI, 0-5.0). During weeks 121 to 144, 82.4% of participants had 0 treated bleeds, 97.6% had ≤3 treated bleeds, and 94.1% reported no treated target joint bleeds. Bleeding into target joints decreased substantially. Emicizumab was well tolerated, and no participant discontinued because of adverse events beyond the 5 previously described. This data cutoff includes the previously reported 3 thrombotic microangiopathies (one in the PwHA with fatal rectal hemorrhage) and 2 thromboembolic events, all associated with activated prothrombin complex concentrate use, as well as a myocardial infarction and a venous device occlusion. With 970.3 patient-years of exposure, emicizumab prophylaxis maintained low bleed rates in PwHAs of all ages with/without FVIII inhibitors and remains well tolerated, with no new safety concerns identified.

Consistency of serial ultrasonographic joint tissue measurements by the Joint tissueActivity and Damage Exam (JADE) protocol in relation to hemophilic joint health parameters.

OBJECTIVES: The Joint tissueActivity and Damage Exam (JADE) is a point-of-care (POC) musculoskeletal ultrasound (MSKUS) protocol for non-radiologists to evaluate hemophilic arthopathy. Our aim was to determine the consistency of cross-sectional analyses of direct tissue measurements (JADE protocol) and clinical Hemophilia Joint Health Score [HJHS] and functional joint assessments (arc) at three clinic visits. METHODS: We prospectively studied adults (n = 44) with hemophilia (A or B) of any severity and arthropathy at 3 North American sites. We assessed HJHS, total arc, and JADE parameters (bilateral elbows, ankles, and knees) at study entry, at ≈12-18 months, and at ≈24-36 months, and used MSKUS to evaluate painful episodes between study visits. JADE measurements included osteochondral alterations, cartilage thickness, and soft tissue expansion at sentinel positions. Associations between joint HJHS and total arc with each JADE variable were examined with random intercept models. RESULTS: At each visit increasing HJHS and decreasing total arc were associated in the expected direction with increasing length of OAs and soft tissue expansion in all joints, and decreasing cartilage thickness in the knee. However, HJHS associations with cartilage thickness were U-shaped for elbow and ankle (i.e. cartilage thinning and thickening). Associations between total arc and cartilage thickness followed a similar curve. (Near) normal levels of both joint parameters (HJHS and total arc) were associated with normal ranges of cartilage thickness. JADE views were also helpful to detect hemarthrosis in association with joint pains. CONCLUSIONS: POC MSKUS applying direct tissue measurements using the JADE protocol provided reproducible cross-sectional associations with joint health outcomes on three visits. These findings advance protocol validation and enable iterative adaptations resulting in JADE protocol version 2.

Diabetes, hepatitis C and human immunodeficiency virus influence hypertension risk differently in cohorts of haemophilia patients, veterans and the general population.

INTRODUCTION: The reasons for the high prevalence of hypertension in persons with haemophilia (PWH) are poorly understood. AIM: To examine the roles of diabetes, Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) in the etiology of hypertension for PWH. METHODS: Retrospective cross-sectional design. Adult PWH (n = 691) were divided into two groups: (A) free of diabetes, HCV and HIV; (B) with diabetes and/or HCV positivity and/or HIV positivity. Each group was matched by race and age with random samples from the general population of the US (National Health and Nutrition Examination Surveys, NHANES) and outpatients at the Veterans Affairs Medical Center (VAMC) in San Diego. Generalized additive models (GAMs) were fitted for graphical analysis of hypertension risk over the lifespan. RESULTS: In Group A, PWH had the highest prevalence of hypertension compared to NHANES and VAMC, especially in young adults. In Group B, diabetes increased the risk of hypertension for all three cohorts (PWH, NHANES and VAMC), especially for PWH. In PWH, hypertension risk was also increased by HIV, in NHANES by HCV, and in VAMC by HCV and HIV. CONCLUSION: Diabetes conferred the greatest risk of hypertension for all three cohorts. However, curves of hypertension in relation to age revealed that diabetes, HCV and HIV modulated hypertension risk differently in PWH. PWH experienced a disproportionally high risk increase with diabetes. Therefore, haemophilia care should include screening for hypertension and diabetes at a young age.

Blood pressure in persons with haemophilia with a focus on haemophilia-specific risk factors.

INTRODUCTION: Persons with haemophilia (PWH) have a higher prevalence of hypertension compared to the general population, which cannot be explained entirely by the usual cardiovascular risk factors. Neutralizing antibodies (inhibitors) against clotting factors might have some relation to cardiovascular disease in PWH. However, whether inhibitors facilitate hypertension is unknown. AIM: We investigated the relationship between hypertension/blood pressure and inhibitors in PWH. Additional goals were to determine the relationships with haemophilia type, race, and viral status. METHODS: Records were extracted retrospectively for PWH (age ≥18 years) between 2003 and 2014 from four Hemophilia Treatment Centers in North America and included demographics, weight, height, haemophilia type/severity, HCV and HIV infection status, hypertension, use of anti-hypertensive medications, and inhibitor status. We fitted semiparametric generalized additive models (GAMs) to describe adjusted curves of blood pressure (BP) against age. RESULTS: Among 691 PWH, 534 had haemophilia A and 157 had haemophilia B, with a median age of 39 years (range 18 to 79). Forty-four PWH (6.5%) had a history of inhibitors, without evidence for a higher prevalence of hypertension or higher BP. A higher prevalence of hypertension and higher BP were noted for haemophilia A (vs. haemophilia B), coinfection with HCV/HIV (vs. uninfected), or moderate haemophilia (vs. severe haemophilia). CONCLUSION: While there was no signal to suggest that a history of inhibitors is associated with hypertension, differences based on haemophilia type, severity, and viral infection status were identified, encouraging prospective investigations to better delineate haemophilia-specific risk factors for hypertension.

Risk of diabetes in haemophilia patients compared to clinic and non-clinic control cohorts.

INTRODUCTION: Ageing patients with haemophilia (PWH) develop cardiovascular risk factors impacting care. Little is known about the prevalence of diabetes in PWH and its relation to other comorbidities. AIM: To examine the risk of diabetes for adult PWH compared to men from the general United States population (National Health and Nutrition Examination Surveys [NHANES]) and outpatients attending a Veterans Affairs Medical Center (VAMC) clinic. METHODS: Retrospective cross-sectional design. PWH from four haemophilia centres (n = 690) were matched with random samples from NHANES and VAMC. Diabetes (yes/no) was the outcome, while age, body mass index (BMI), race and Hepatitis C (HCV; by serology) and human immunodeficiency virus (HIV) positivity were covariates. We fitted semiparametric generalized additive models (GAMs) in order to compare diabetes risk between cohorts. RESULTS: Younger PWH were at lower risk of diabetes than NHANES or VAMC subjects irrespective of BMI. However, the risk of diabetes rose in older PWH and was closely associated with HCV. For HCV-negative subjects, the risk of diabetes was considerably lower for PWH than NHANES and VAMC subjects. The difference persisted after controlling for BMI and age, indicating that the low risk of diabetes in PWH cannot be explained by lean body mass alone. CONCLUSION: Since many ageing PWH are HCV positive and therefore at heightened risk for diabetes, it is important to incorporate diabetes screening into care algorithms in Haemophilia Treatment Centers, especially since PWH are not always followed in primary care clinics.

Emicizumab Prophylaxis in Patients Who Have Hemophilia A without Inhibitors.

BACKGROUND: Emicizumab is a bispecific monoclonal antibody that bridges activated factor IX and factor X to replace the function of missing activated factor VIII, thereby restoring hemostasis. In a phase 3, multicenter trial, we investigated its use as prophylaxis in persons who have hemophilia A without factor VIII inhibitors. METHODS: We randomly assigned, in a 2:2:1 ratio, participants 12 years of age or older who had been receiving episodic treatment with factor VIII to receive a subcutaneous maintenance dose of emicizumab of 1.5 mg per kilogram of body weight per week (group A) or 3.0 mg per kilogram every 2 weeks (group B) or no prophylaxis (group C). The primary end point was the difference in rates of treated bleeding (group A vs. group C and group B vs. group C). Participants who had been receiving factor VIII prophylaxis received emicizumab at a maintenance dose of 1.5 mg per kilogram per week (group D); intraindividual comparisons were performed in those who had participated in a noninterventional study. RESULTS: A total of 152 participants were enrolled. The annualized bleeding rate was 1.5 events (95% confidence interval [CI], 0.9 to 2.5) in group A and 1.3 events (95% CI, 0.8 to 2.3) in group B, as compared with 38.2 events (95% CI, 22.9 to 63.8) in group C; thus, the rate was 96% lower in group A and 97% lower in group B (P<0.001 for both comparisons). A total of 56% of the participants in group A and 60% of those in group B had no treated bleeding events, as compared with those in group C, who all had treated bleeding events. In the intraindividual comparison involving 48 participants, emicizumab prophylaxis resulted in an annualized bleeding rate that was 68% lower than the rate with previous factor VIII prophylaxis (P<0.001). The most frequent adverse event was low-grade injection-site reaction. There were no thrombotic or thrombotic microangiopathy events, development of antidrug antibodies, or new development of factor VIII inhibitors. CONCLUSIONS: Emicizumab prophylaxis administered subcutaneously once weekly or every 2 weeks led to a significantly lower bleeding rate than no prophylaxis among persons with hemophilia A without inhibitors; more than half the participants who received prophylaxis had no treated bleeding events. In an intraindividual comparison, emicizumab therapy led to a significantly lower bleeding rate than previous factor VIII prophylaxis. (Funded by F. Hoffmann-La Roche and Chugai Pharmaceutical; HAVEN 3 ClinicalTrials.gov number, NCT02847637 .).

A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors.

Emicizumab, a bispecific humanized monoclonal antibody, bridges activated factor IX (FIX) and FX to restore the function of missing activated FVIII in hemophilia A. Emicizumab prophylaxis in children with hemophilia A and FVIII inhibitors was investigated in a phase 3 trial (HAVEN 2). Participants, previously receiving episodic/prophylactic bypassing agents (BPAs), were treated with subcutaneous emicizumab: 1.5 mg/kg weekly (group A), 3 mg/kg every 2 weeks (group B), or 6 mg/kg every 4 weeks (group C). Pharmacokinetics, safety, and efficacy (including an intraindividual comparison of participants from a noninterventional study) were evaluated. Eighty-five participants aged <12 years were enrolled. In group A (n = 65), the annualized rate of treated bleeding events (ABRs) was 0.3 (95% confidence interval [CI], 0.17-0.50), and 77% had no treated bleeding events. Intraindividual comparison of 15 participants who previously took BPA prophylaxis showed that emicizumab prophylaxis reduced the ABR by 99% (95% CI, 97.4-99.4). In groups B (n = 10) and C (n = 10), ABRs were 0.2 (95% CI, 0.03-1.72) and 2.2 (95% CI, 0.69-6.81), respectively. The most frequent adverse events were nasopharyngitis and injection-site reactions; no thrombotic events occurred. Two of 88 participants developed antidrug antibodies (ADAs) with neutralizing potential, that is, associated with decreased emicizumab plasma concentrations: 1 experienced loss of efficacy, and, in the other, ADAs disappeared over time without intervention or breakthrough bleeding. All other participants achieved effective emicizumab plasma concentrations, regardless of the treatment regimen. Emicizumab prophylaxis has been shown to be a highly effective novel medication for children with hemophilia A and inhibitors. This trial was registered at www.clinicaltrials.gov as #NCT02795767.

Quantitative measurements of haemophilic joint tissues by point-of-care musculoskeletal ultrasound: Associations with clinical and functional joint outcome parameters.

BACKGROUND: Painful arthropathy is a long-term complication in patients with hemophilia (PWH), affecting mobility and quality of life. A major barrier for the appraisal of joint health is the absence of point-of-care (POC) imaging modalities to promptly identify and manage arthropathic changes. Accordingly, we developed the Joint tissue Activity and Damage Exam (JADE) POC musculoskeletal ultrasound (MSKUS) protocol. JADE is validated for haemophilic joint tissue recognition with high intra/inter-rater and inter-operator reliability. AIMS: Evaluate associations of JADE with clinical (Hemophilia Joint Health Score, [HJHS]) and functional (total arc [combined flexion and extension range of motion [ROM]]) parameters. METHODOLOGY: In this multi-centre prospective study, we recruited PWH A or B with at least one arthropathic joint. We evaluated joint health (both elbows, knees, and ankles) by comparing JADE measurements (soft tissue and cartilage thickness, and osteochondral alterations) with HJHS and total arc. RESULTS: Of 44 PWH, most had hemophilia A (35/44), were severe (36/44) and had a median age of 36 years. Increasing HJHSs and declining total arc, indicating worsening arthropathy, were associated with JADE measurements in the expected direction, including (1) increasing length of osteochondral alterations, (2) diminished cartilage thickness, and (3) greater soft tissue expansion. The ankles had the highest proportion of joints without measurable (missing) cartilage. In multivariable models MSKUS measurements explained 68% and 71% of the variation in HJHS and total arc respectively for the elbow, 55% and 29% respectively for the knee, and 50% and 73% for the ankle. CONCLUSIONS: This study highlights the associations of direct intra-articular ultrasonography measurements using the JADE protocol with clinical and functional parameters. Our findings underscore the clinical value of POC MSKUS using the JADE protocol as a complementary instrument for the diagnosis and management of haemophilic arthropathy.

Emicizumab Prophylaxis in Hemophilia A with Inhibitors.

BACKGROUND: Emicizumab (ACE910) bridges activated factor IX and factor X to restore the function of activated factor VIII, which is deficient in persons with hemophilia A. This phase 3, multicenter trial assessed once-weekly subcutaneous emicizumab prophylaxis in persons with hemophilia A with factor VIII inhibitors. METHODS: We enrolled participants who were 12 years of age or older. Those who had previously received episodic treatment with bypassing agents were randomly assigned in a 2:1 ratio to emicizumab prophylaxis (group A) or no prophylaxis (group B). The primary end point was the difference in bleeding rates between group A and group B. Participants who had previously received prophylactic treatment with bypassing agents received emicizumab prophylaxis in group C. RESULTS: A total of 109 male participants with hemophilia A with inhibitors were enrolled. The annualized bleeding rate was 2.9 events (95% confidence interval [CI], 1.7 to 5.0) among participants who were randomly assigned to emicizumab prophylaxis (group A, 35 participants) versus 23.3 events (95% CI, 12.3 to 43.9) among those assigned to no prophylaxis (group B, 18 participants), representing a significant difference of 87% in favor of emicizumab prophylaxis (P<0.001). A total of 22 participants in group A (63%) had zero bleeding events, as compared with 1 participant (6%) in group B. Among 24 participants in group C who had participated in a noninterventional study, emicizumab prophylaxis resulted in a bleeding rate that was significantly lower by 79% than the rate with previous bypassing-agent prophylaxis (P<0.001). Overall, 198 adverse events were reported in 103 participants receiving emicizumab prophylaxis; the most frequent events were injection-site reactions (in 15% of participants). Thrombotic microangiopathy and thrombosis were reported in 2 participants each (in the primary analysis) who had received multiple infusions of activated prothrombin complex concentrate for breakthrough bleeding. No antidrug antibodies were detected. CONCLUSIONS: Emicizumab prophylaxis was associated with a significantly lower rate of bleeding events than no prophylaxis among participants with hemophilia A with inhibitors. (Funded by F. Hoffmann-La Roche and Chugai Pharmaceutical; HAVEN 1 ClinicalTrials.gov number, NCT02622321 .).

Urinary cross-linked carboxyterminal telopeptide, a bone resorption marker, decreases after vaso-occlusive crises in adults with sickle cell disease.

People with sickle cell disease often report severe bone pain with repeated bouts of vaso-occlusive crises, but the extent of skeletal injury incurred during these painful episodes remain unclear. We sought to quantify bone degradation by comparing urinary concentrations of carboxyterminal cross-linked telopeptide of type I collagen (CTX-1), a well-described marker of bone resorption, in a prospective cohort of 52 adults with sickle cell disease enrolled in the Sickle Cell Pain Markers Study. We also questioned if changes in urinary CTX-1 concentrations correlated with changes in hemolysis and inflammatory markers measured both during and after resolution of a painful vaso-occlusive episode. Thirty-one of the 52 adults enrolled in the study had paired urine samples for CTX-1 analysis. Urinary CTX-1, corrected for urine creatinine, significantly decreased from a mean of 3.45 µg/mmol during vaso-occlusive crises to 2.62 µg/mmol at recovery (p = 0.01). Thus, increased bone loss appears to correlate with acute vaso-occlusive crises in sickle cell disease. Our finding that urinary CTX-1 can be used to probe bone degradation in sickle cell disease provides an important new tool for diagnosing and monitoring response to therapy for people with sickle cell-related bone loss.

How I treat type 2B von Willebrand disease.

Type 2B von Willebrand disease (VWD) is an inherited bleeding disorder caused by changes in von Willebrand factor (VWF) that enhance binding of VWF to GPIb on platelets. Although this disorder is seemingly well defined because of this single molecular defect, in reality type 2B VWD is a clinically heterogeneous disorder that can be difficult to identify and manage. Diagnostic criteria include a history of mucocutaneous bleeding, laboratory studies showing enhanced VWF binding of platelets and/or a 2B VWD genetic variant, and a family history consistent with autosomal dominant inheritance. Thrombocytopenia, although not always present, is common and can be exacerbated by physiologic stressors such as pregnancy. The mainstay of therapy for type 2B VWD is VWF replacement therapy. Adjunct therapies useful in other types of VWD, such as antifibrinolytics, are also used in type 2B VWD. 1-Desamino-8-d-arginine vasopressin (DDAVP) is controversial because of exacerbation of thrombocytopenia, but is, in practice, sometimes used for minor bleeding. Here we review the available evidence and provide 3 clinical cases to illustrate the intricacies of diagnosing type 2B VWD to describe the response to DDAVP and to review complexities and management during pregnancy.

Outcomes in children with hemophilia A with inhibitors: Results from a noninterventional study.

BACKGROUND: Data regarding management of pediatric persons with hemophilia A (PwHA) with factor VIII (FVIII) inhibitors are limited. This prospective noninterventional study (NCT02476942) evaluated annualized bleeding rates (ABRs), safety, and health-related quality of life (HRQoL) in pediatric PwHA with FVIII inhibitors. PROCEDURE: PwHA aged <12 years with current FVIII inhibitors and high-titer inhibitor history were enrolled. Participants remained on usual treatment; no interventions were applied. Outcomes included ABR, safety, and HRQoL. RESULTS: Twenty-four PwHA aged 2-11 years (median 7.5) were enrolled and monitored for 8.7-44.1 weeks (median 23.4). In the episodic (n = 10) and prophylactic (n = 14) groups, respectively, 121 of 185 (65.4%) and 101 of 186 (54.3%) bleeds were treated using activated prothrombin complex concentrate (aPCC) and/or recombinant activated FVII (rFVIIa). ABRs (95% confidence interval) were 19.4 (13.2-28.4) and 18.5 (14.2-24.0) for treated bleeds, and 32.7 (20.5-52.2) and 33.1 (22.4-48.9) for all bleeds, respectively. Most prophylactic group participants (92.9%) were prescribed aPCC; 50% adhered to their prescribed treatment regimen. Adherence to prophylactic rFVIIa was not assessed. Serious adverse events included hemarthrosis (12.5%) and mouth hemorrhage (12.5%); the most common nonserious adverse event was viral upper respiratory tract infection (12.5%). HRQoL showed functional impairment at baseline; scores remained stable throughout, with little intergroup variation. CONCLUSIONS: ABRs remained high in pediatric PwHA with inhibitors receiving standard treatment. This study demonstrates the need for more effective treatments, with reduced treatment burden, to prevent bleeds, increase prophylaxis adherence, and improve patient outcomes.

Bleeding and safety outcomes in persons with haemophilia A without inhibitors: Results from a prospective non-interventional study in a real-world setting.

INTRODUCTION: Prospectively collected real-world data on bleeds, haemophilia treatment and safety in persons with haemophilia A (PwHA) without factor VIII (FVIII) inhibitors are limited. A global, non-interventional study (NIS; NCT02476942) prospectively collected real-world data in PwHA who were treated per local routine clinical practice. AIM: Assess annualized bleeding rate (ABR), haemophilia treatment practices and adverse events (AEs) in adult/adolescent PwHA without inhibitors. METHODS: Eligible participants aged ≥12 years with severe HA without history of inhibitors prospectively collected bleeding and treatment information. RESULTS: Ninety-four participants were enrolled (median [range] age, 34 [12-76] years) and monitored for a median (range) of 29.8 (12.4-47.7) weeks. In the episodic (n = 45) and prophylactic (n = 49) treatment groups, respectively, 872/1066 (81.8%) and 151/189 (79.9%), bleeds were treated; ABRs (95% confidence interval) were 36.1 (30.8-42.3) and 5.0 (3.3-7.5), respectively, for treated bleeds and 43.1 (36.5-50.9) and 6.2 (4.2-9.2), respectively, for all bleeds, and median (interquartile range) ABRs were 31.1 (19.8-51.6) and 1.9 (0.0-8.2), respectively, for treated bleeds and 35.3 (21.7-62.9) and 2.7 (0.0-9.4), respectively, for all bleeds. Half of the participants on FVIII prophylaxis had relatively high adherence to treatment, using 2.9 and 2.1 median doses/wk of standard and extended half-life FVIII, respectively. Serious AEs included gastrointestinal polyp haemorrhage and haemarthrosis; the most common AE was viral upper respiratory tract infection. CONCLUSION: PwHA without inhibitors continue to bleed on prophylaxis, consistent with the literature, and require treatment for breakthrough bleeds. This prospective NIS demonstrates the need for more efficacious haemostatic approaches.

Health-related quality of life and health status in persons with haemophilia A with inhibitors: A prospective, multicentre, non-interventional study (NIS).

INTRODUCTION: Real-world data (RWD) on health-related outcomes in persons with haemophilia A (PwHA) provide insights into patient needs and can guide clinical study design. A global, prospective, non-interventional study (NIS; NCT02476942) collected detailed RWD on bleeding outcomes, health-related quality of life (HRQoL) and health status in PwHA treated per local routine clinical practice. AIM: To report HRQoL and health status in the adult/adolescent PwHA with inhibitors cohort in the NIS. METHODS: This cohort enrolled PwHA aged ≥12 years with high-titre factor VIII inhibitor history. Participants remained on their usual treatment (no protocol-specified interventions). Health-related outcomes: Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL), Haemophilia-specific Quality of Life Questionnaire for Children Short Form (Haemo-QoL SF), EuroQol 5-Dimensions 5-Levels (EQ-5D-5L) index utility score (IUS) and visual analogue scale (EQ-VAS). RESULTS: One hundred three participants were enrolled on episodic (n = 75) or prophylactic treatment (n = 28); median (range) age, 31 (12-75) years; median (range) observation time, 26 (4-70) weeks. Haem-A-QoL scores indicated impairments in HRQoL aspects; comparable between episodic/prophylactic regimens and relatively consistent over time. Haemo-QoL SF scores with both regimens varied over time, and appeared poorer with episodic than prophylactic treatment. IUS and EQ-VAS were comparable between regimens, stable over time and lower on bleeding days. Mean proportions of missed work and school days were 16% and 23%, respectively; mean (standard deviation) number of days hospitalized was 3.2 (8.8) (comparable between groups). CONCLUSIONS: These RWD demonstrate that PwHA with inhibitors have impaired HRQoL, despite standard treatment, and that more effective treatment options are needed.

The effect of emicizumab prophylaxis on health-related outcomes in persons with haemophilia A with inhibitors: HAVEN 1 Study.

INTRODUCTION: Persons with haemophilia A (PwHA) with inhibitors to factor VIII often experience decreased health-related outcomes. In HAVEN 1 (NCT02622321), there was a statistically significant reduction in bleeding with emicizumab prophylaxis versus no prophylaxis. AIM: Describe health-related outcomes in PwHA with inhibitors in HAVEN 1. METHODS: PwHA with inhibitors aged ≥12 years previously on episodic bypassing agents (BPAs) were randomized to emicizumab prophylaxis (Arm A; n = 35) or no prophylaxis (Arm B; n = 18); participants previously on BPA prophylaxis received emicizumab prophylaxis (Arm C; n = 49). Health-related outcomes assessed at baseline and monthly thereafter: Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL), Haemophilia-specific Quality of Life Questionnaire for Children Short Form (Haemo-QoL SF), EuroQol 5-Dimensions 5-Levels (EQ-5D-5L) index utility score (IUS) and visual analogue scale (EQ-VAS) and work/school days. Days hospitalized also recorded. RESULTS: At week 25, differences (ANCOVA) in adjusted mean scores (95% confidence interval) favoured Arm A versus B for Haem-A-QoL "Total" score (14.0 [5.6, 22.5]; P = 0.002) and "Physical Health" (21.6 [7.9, 35.2]; P = 0.003); EQ-VAS (-9.7 [-17.6, -1.82]; P = 0.017); and IUS (-0.16 [-0.25, -0.07]; P = 0.001); mean scores are comparable in Arms A and C. Throughout the study, a greater proportion of participants on emicizumab prophylaxis than no prophylaxis exceeded questionnaire-specific responder thresholds. Mean proportion of missed work days and number of days hospitalized were lower with emicizumab prophylaxis than no prophylaxis. CONCLUSIONS: In PwHA with inhibitors, emicizumab prophylaxis was associated with substantial and meaningful improvements in health-related outcomes.

Development and Reliability of the Joint Tissue Activity and Damage Examination for Quantitation of Structural Abnormalities by Musculoskeletal Ultrasound in Hemophilic Joints.

OBJECTIVES: Musculoskeletal ultrasound (US) is used increasingly to examine hemophilic arthropathy. However, quantitative algorithms to document findings are lacking. We developed and sought to validate a protocol quantifying hemophilic joint abnormalities. METHODS: Thirty-one patients with hemophilia were examined serially for 2 years with musculoskeletal US (≈600 joint examinations and ≈6000 images). Based on the spectrum of pathologies, a quantitative algorithm, named Joint Tissue Activity and Damage Examination (JADE), was developed for soft tissue and osteochondral measurements, including power Doppler, using nominal group techniques. To study intra- and inter-rater reliability, 8 musculoskeletal US-experienced hemophilia providers performed anatomic landmark recognition and tissue measurements on 86 images with arthropathic changes, with repetition 1 month later. Twenty-three musculoskeletal US-inexperienced providers performed similar assessments. Inter-operator reliability was established by 6 musculoskeletal US-experienced hemophilia providers, each acquiring images and JADE assessments of 3 hemophilic arthropathic joints. A radiologist and musculoskeletal sonographer functioned as adjudicators. The statistical analysis was performed with the intraclass correlation coefficient (ICC), Fleiss κ, and Cohen κ where appropriate. RESULTS: The musculoskeletal US-experienced providers showed excellent intra-and inter-rater reliability for tissue measurements (ICCs, 0.94-0.96). Agreement was good to excellent for landmark recognition (Fleiss κ, 0.87-0.94). Inter-operator reliability was excellent for measurements and landmark recognition (ICC, 0.90; Fleiss κ, 1.0). Agreement with adjudicators was mostly good to excellent. Musculoskeletal US-inexperienced providers showed excellent inter-rater reliability for measurements (ICC, 0.96) and moderate agreement for landmark recognition (Fleiss κ, 0.58). CONCLUSIONS: The JADE protocol appears feasible for quantifying hemophilic intra-articular abnormalities. Musculoskeletal US-trained hemophilia providers showed high intra-rater, inter-rater, and inter-operator reliability, supporting JADE as a protocol for clinical management and research.

A new era for hemophilia B treatment.

In this issue of Blood, Santagostino et al, in their phase 3 study, demonstrate efficacy and safety of recombinant fusion protein linking coagulation factor IX (FIX) with albumin (rIX-FP) which, along with the other 2 extended half-life FIX products, heralds a new era for the treatment of hemophilia B.