Bleeds and resource use in hemophilia B: retrospective observational study.

OBJECTIVES: To describe people with hemophilia B (PWHB) in the US who experience bleeds despite factor replacement therapy and to quantify the associated burden from the third-party payer perspective. STUDY DESIGN: Observational study of adult male PWHB treated with factor IX replacement therapy identified from the PharMetrics Plus claims data from 2010 to 2019. METHODS: Patients with medically recorded bleeds (MRBs) were identified using diagnostic codes. Rates and rate ratios of inpatient admissions, emergency department (ED) visits, and outpatient visits among PWHB with and without MRBs were estimated. The presence of comorbidities was identified using diagnostic codes, and the analysis was stratified by age group. RESULTS: There were 345 PWHB with MRBs and 252 without MRBs. More than half of PWHB with MRBs (56.8%) had 1 or more comorbidity vs 39.3% of PWHB without MRBs. The prevalence of anxiety and depression was high in PWHB, regardless of bleed status and age group, whereas the prevalence of other comorbidities increased with age group. The rate of all-cause inpatient admissions for PWHB with MRBs was 14.8 per 100 person-years (95% CI, 12.8-17.1), 2.5 times higher than for PWHB without MRBs. The rate of all-cause ED visits for PWHB with MRBs was 67.6 per 100 person-years (95% CI, 63.2-72.3), 2.7 times higher than for those without MRBs. CONCLUSIONS: This study reports significant resource use and clinical burden among PWHB who seek medical care. PWHB with MRBs had considerable all-cause resource use compared with PWHB without MRBs. The prevalence of mental illness was consistently high across all age groups.

Romidepsin Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Versus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With Previously Untreated Peripheral T-Cell Lymphoma: Final Analysis of the Ro-CHOP Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The primary analysis of the Ro-CHOP phase III randomized controlled trial (ClinicalTrials.gov identifier: NCT01796002) established that romidepsin (Ro) plus cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) did not yield an increased efficacy compared with CHOP alone as first-line treatment of peripheral T-cell lymphoma. We report the planned final analysis 5 years after the last patient enrolled. With a median follow-up of 6 years, median progression-free survival (PFS) was 12.0 months compared with 10.2 months (hazard ratio [HR], 0.79 [95% CI, 0.62 to 1.005]; P = .054), while median overall survival was 62.2 months (35.7-86.6 months) and 43.8 months (30.1-70.2 months; HR, 0.88 [95% CI, 0.68 to 1.14]; P = .324) in the Ro-CHOP and CHOP arms, respectively. In an exploratory analysis, the median PFS in the centrally reviewed follicular helper T-cell lymphoma subgroup was significantly longer in the Ro-CHOP arm (19.5 v 10.6 months, HR, 0.703 [95% CI, 0.502 to 0.985]; P = .039). Second-line treatments were given to 251 patients with a median PFS2 and OS2 after relapse or progression of 3.3 months and 11.5 months, respectively. Within the limits of highly heterogeneous second-line treatments, no specific regimen seemed to provide superior disease control. However, a potential benefit was observed with brentuximab vedotin in association with chemotherapy even after excluding anaplastic large-cell lymphoma subtype or after adjusting for histology and international prognostic index in a multivariate model (HR for PFS, 0.431 [95% CI, 0.238 to 0.779]; P = .005).

Challenges for quality and utilization of real-world data for diffuse large B-cell lymphoma in REALYSA, a LYSA cohort.

ABSTRACT: Real-world data (RWD) are essential to complement clinical trial (CT) data, but major challenges remain, such as data quality. REal world dAta in LYmphoma and Survival in Adults (REALYSA) is a prospective noninterventional multicentric cohort started in 2018 that included patients newly diagnosed with lymphoma in France. Herein is a proof-of-concept analysis on patients with first-line diffuse large B-cell lymphoma (DLBCL) to (1) evaluate the capacity of the cohort to provide robust data through a multistep validation process; (2) assess the consistency of the results; and (3) conduct an exploratory transportability assessment of 2 recent phase 3 CTs (POLARIX and SENIOR). The analysis population comprised 645 patients with DLBCL included before 31 March 2021 who received immunochemotherapy and for whom 3589 queries were generated, resulting in high data completeness (<4% missing data). Median age was 66 years, with mostly advanced-stage disease and high international prognostic index (IPI) score. Treatments were mostly rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone (R-CHOP 75%) and reduced dose R-CHOP (13%). Estimated 1-year event-free survival (EFS) and overall survival rates were 77.9% and 90.0%, respectively (median follow-up, 9.9 months). Regarding transportability, when applying the CT's main inclusion criteria (age, performance status, and IPI), outcomes seemed comparable between patients in REALYSA and standard arms of POLARIX (1-year progression-free survival 79.8% vs 79.8%) and SENIOR (1-year EFS, 64.5% vs 60.0%). With its rigorous data validation process, REALYSA provides high-quality RWD, thus constituting a platform for numerous scientific purposes. The REALYSA study was registered at www.clinicaltrials.gov as #NCT03869619.

Delivery of gene therapy in haemophilia treatment centres in the United States: Practical aspects of preparedness and implementation.

INTRODUCTION: Haemophilia treatment centres (HTCs) and healthcare providers (HCPs) will need to adapt to a new treatment paradigm with the emergence of adeno-associated virus (AAV)-based gene therapy for the treatment of haemophilia in adults. AIM: This review examines the upcoming patient and institutional journeys, along with practical aspects of preparedness for clinical delivery of gene therapy by HTCs. METHODS: Based on our clinical experience and examination of published literature, we explored the parallel journeys for patients and treatment centres to navigate before, during, and after administration of gene therapy. RESULTS: The patient journey includes: information gathering; decision making; comprehensive patient assessment; preparation for the infusion itself; short- and long-term monitoring; lifestyle modifications; and the possible need for immunosuppressive treatment. Informed decision-making may require patient education with extensive discussions and an understanding that not all people with haemophilia will choose or be eligible for gene therapy, although eligibility criteria continue to evolve. The institutional journey includes: consideration of biosafety procedures; planning for product procurement, handling, storage, and administration; development of detailed protocols and guidance documents; contingency planning for immunosuppressive and haemostatic management; consideration of clinical capabilities and staff training needs; coordination of efforts by the full multidisciplinary team; and collaboration between referring, dosing, and follow-up treatment centres. Documented protocols and guidance documents are pivotal for this complex therapy to ensure safe handling, optimal delivery, and post-infusion management and follow-up. CONCLUSION: Successful implementation of this new treatment modality will require communication and collaboration among multiple stakeholders.

Bendamustine-EAM versus R-BEAM after high-dose cytarabine-based induction in newly diagnosed patients with mantle cell lymphoma, a LYSA retrospective study.

Cytarabine-based immuno-chemotherapy followed by autologous stem cell transplantation (ASCT) consolidation is standard of care for fit patients with Mantle Cell Lymphoma (MCL). BEAM (Carmustine, Etoposide, Aracytine, Melphalan) is among the most frequently used conditioning regimen. Studies comparing BEAM with Bendamustine-EAM (BeEAM) have suggested that patients treated with BeEAM have a better progression-free survival (PFS). We performed a cross-study analysis to better evaluate BeEAM. Thirty-five patients from a retrospective study who received R-DHAP/BeEAM were compared to 245 patients from the LyMa trial (NCT00921414) who all received R-DHAP followed by R-BEAM. PFS and Overall Survival (OS) were estimated using Kaplan-Meier methods. At 2 years there was no difference between R-BEAM and BeEAM in either PFS (84.9% versus 87.9%; p = 0.95) or OS (91.8% versus 94.2%; p = 0.30). Analyses were repeated on a propensity score to reduce biases. Each patient from the BeEAM cohort (n = 30) was matched to three patients from the R-BEAM cohort (n = 90) for age, sex, MIPI score, pre-transplant status disease and rituximab maintenance (RM). PFS and OS at 2 years remained similar between R-BEAM and BeEAM with more renal toxicity in BeEAM group. MCL patients who received R-DHAP induction before ASCT have similar outcome after R-BEAM or BeEAM conditioning regimen.

The conditional survival analysis of relapsed DLBCL after autologous transplant: a subgroup analysis of LY.12 and CORAL.

The conditional survival of patients after frontline therapy for diffuse large B-cell lymphoma (DLBCL) approaches that of the general population once patients have survived disease free for 2 years. We sought to determine the conditional survival of patients among patients with relapsed de novo DLBCL successfully undergoing an autologous stem-cell transplant (ASCT) after first relapse. A total of 478 patients with de novo DLBCL, relapsed after 1 treatment from the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) and LY.12, were included. Patients were followed prospectively after ASCT for a median of 5.3 and 8.2 years, respectively. Individual patient data were analyzed for event-free survival (EFS) and overall survival. Standardized mortality ratios (SMRs) were estimated using French and Canadian life tables. The EFS estimates declined with each year of follow-up after ASCT and were 50.1% (95% confidence interval [CI]: 43.7% to 56.3%) and 43.4% (95% CI: 36.7% to 49.9%) at 5 years in CORAL and LY.12, respectively. The rate of death stabilized once patients achieved at least 4 years of EFS. Compared with the age- and sex-matched population, the SMR was significantly higher until 5 years after ASCT, when values were no longer statistically significant. Patients undergoing ASCT for relapsed DLBCL continue to have a higher rate of death at least until they have survived event free for 5 years. These observations can help to determine endpoints for future clinical trials in this population and for patient counseling. This trial was registered at www.clinicaltrials.gov as #NCT00078949.

Real-world outcomes associated with standard half-life and extended half-life factor replacement products for treatment of haemophilia A and B.

: Standard-of-care treatment for haemophilia A or B is to maintain adequate coagulation factor levels through clotting factor administration. The current study aimed to evaluate annualised bleeding rates (ABR) and treatment adherence for haemophilia A or B patients receiving standard half-life (SHL) vs. extended half-life (EHL) factor replacement products. We analysed data from the Adelphi Disease-Specific Programmes, a health record-based survey of United States and European haematologists. Analysis included 651 males with moderate-to-severe haemophilia A or B (the United States, n = 132; Europe, n = 519). The haemophilia A analysis included 501 patients (SHL, n = 435; EHL, n = 66). In the combined United States/European population, mean (SD) ABR was 1.7 (1.69) for the SHL group and 1.8 (2.00) for the EHL group. A total of 72% of patients receiving SHL factor VIII and 75% of patients receiving EHL factor VIII in the combined population were fully adherent (no doses missed of the last 10 doses), as reported by physicians. The haemophilia B analysis included 150 patients (SHL, n = 114; EHL, n = 36). The mean (SD) ABR in the combined population was 2.1 (2.16) for patients receiving SHL factor IX (FIX) and 1.4 (1.48) for patients receiving EHL FIX. The percentage of fully adherent patients (physician-reported) was similar in both treatment groups (SHL FIX, 68%; EHL FIX, 73%). In this preliminary real-world survey in a relatively small sample of patients, measures of ABR and adherence between SHL and EHL products were evaluated. Additional real-world research on prescribing patterns, SHL vs. EHL effectiveness, and adherence is warranted.

Real-World Analysis of Dispensed International Units of Coagulation Factor VIII and Resultant Expenditures for Hemophilia A Patients: A Comparison Between Standard Half-Life and Extended Half-Life Products.

PURPOSE: To identify international units (IUs) dispensed and consequent expenditures for standard half-life (SHL) versus extended half-life (EHL) recombinant factor VIII (rFVIII) replacement products in hemophilia A patients in a real-world setting. DESIGN: Two U.S. claims databases were analyzed. METHODOLOGY: Number of IUs dispensed and quarterly expenditures for rFVIII products were collected from the Optum Clinformatics Data Mart and Truven Health MarketScan Databases. Truven claims were also analyzed for factor IUs dispensed and expenditures for patients with data for ≥3 months before and after switching to an EHL product. RESULTS: The Optum and Truven databases, respectively, included 276 (SHL, n=243; EHL, n=33) and 500 (SHL, n=409; EHL, n=91) hemophilia A patients. Median quarterly factor IUs dispensed in Optum were 10% higher with EHL versus SHL products over nine quarters, and 45% higher with EHL versus SHL products in Truven over 10 quarters. Median quarterly expenditures in the EHL cohort were 51% (individual quarterly medians range, 1%-101%) higher than in the SHL cohort in Optum and 122% higher (individual quarterly medians range, 1%-189%) in Truven. Twenty-nine Truven patients switched to an EHL product; median factor IUs dispensed varied quarterly. The lowest SHL and highest EHL values occurred in the quarter immediately before switching and the first quarter post-switch, respectively. Overall median quarterly expenditures were higher post-switch; this was consistent over seven quarters. CONCLUSION: We found higher expenditures over two years for hemophilia A patients using EHL versus SHL products. Switching to an EHL rFVIII product was associated with variable factor IUs dispensed and consistently higher expenditures.

Real-World Analysis of Dispensed IUs of Coagulation Factor IX and Resultant Expenditures in Hemophilia B Patients Receiving Standard Half-Life Versus Extended Half-Life Products and Those Switching from Standard Half-Life to Extended Half-Life Products.

BACKGROUND: Hemophilia B requires replacement therapy with factor IX (FIX) coagulation products to treat and prevent bleeding episodes. A recently introduced extended half-life (EHL) recombinant FIX replacement product provided the opportunity to compare the amount of dispensed factor and expenditures for EHL treatment compared with a standard half-life (SHL) product. OBJECTIVE: To determine factor international units (IUs) dispensed and expenditures associated with switching from nonacog alfa, the most commonly used SHL replacement product, to eftrenonacog alfa, an EHL FIX replacement product. METHODS: Two U.S. claims databases were analyzed. A large national specialty pharmacy dispensation claims database was used to identify the number of IUs dispensed and monthly charges for all patients with hemophilia B from April 2015 to June 2016. Truven Health MarketScan Research Databases (January 2010-July 2016) were used to identify IUs and expenditures for patients with claims data for at least 3 months before and after switching from the SHL to the EHL product. Medians for IUs and expenditures are presented to accommodate for skewness of data distribution. RESULTS: The national specialty pharmacy database analysis included 296 patients with moderate or severe hemophilia B (233 on SHL; 94 on EHL). Median monthly factor dispensed was 11% lower (2,142 IU) in the EHL versus SHL cohort over the study period, while individual monthly reductions ranged from 32% to 47% (9,838 IU to 16,514 IU). Using the wholesale acquisition cost, the median per-patient monthly factor expenditures over the 15-month study period were 94% higher ($23,005) for the EHL than for the SHL product. Individual median monthly expenditure differences ranged from 15% ($6,562) to 49% ($19,624). In the Truven database, 14 patients switched from the SHL to the EHL product. The amount of factor dispensed was variable; in the 1-year period before and after the switch from the SHL to the EHL product, mean IUs dispensed decreased by 3,005 IU, while median IUs dispensed increased by 4,775 IU. Factor replacement expenditures were higher after switching from the SHL to the EHL product in each of the 3-month periods examined before versus after the switch. CONCLUSIONS: This analysis of real-world data showed that switching from the SHL to the EHL product was associated with higher expenditures. Increased expenditures noted in the first 3 months after switching may be related to initial stocking up of the EHL product, but expenditures were sustained throughout the 1-year period of data analysis. Further analysis of these findings with larger numbers of patients should be explored. DISCLOSURES: This study was sponsored by Pfizer. Pfizer employees were involved in the study design; the collection, analysis, and interpretation of data; the review of the manuscript; and the decision to submit for publication. All authors are employees of Pfizer. No author received an honorarium or other form of payment related to the development of this manuscript. All authors participated in the study design, data interpretation, and manuscript review and revisions and granted approval for the submission of the manuscript. Alvir, McDonald, and Tortella also participated in data analysis. Data from this paper were presented in part at the European Association for Haemophilia and Allied Disorders Annual Meeting, February 1-3, 2017, Paris, France; at the International Society for Pharmacoeconomics and Outcomes Research Annual Meeting, May 20-24, 2017, Boston, MA; and at the International Society on Thrombosis and Haemostasis Congress, July 8-13, 2017, Berlin, Germany.

Revascularization strategies and in-hospital management in acute coronary syndromes complicated by hemophilia A or hemophilia B.

: Among adult patients with hemophilia A and hemophilia B the emergent management of acute coronary syndromes (ACSs) is challenging, and exposure to antithrombotic agents and/or revascularization procedures may confer an enhanced risk of bleeding. We sought to identify clinical characteristics and in-hospital outcomes among ACS patients with hemophilia A/hemophilia B, compared with matched noncoagulopathic ACS controls. Case discharges from the Nationwide Inpatient Sample, Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality (1998-2011) had International Classification of Diseases, 9th Revision codes for hemophilia A/hemophilia B and ACS. Control discharges were matched to cases by year of discharge and hospital. Discharges in both groups were assessed for cardiovascular risk factors, type of ACS, use of coronary artery bypass grafting, percutaneous coronary intervention (PCI), bare-metal stent and/or drug-eluting stent, bleeding, and death. In total, 237 cases and 148 848 matched controls were identified. Among cases, HIV/Hepatitis C positivity was more common and obesity/hyperlipidemia less common. ST-elevation myocardial infarction (STEMI) occurred less frequently among hemophilia A cases than controls. hemophilia A and hemophilia B cases were more likely to be managed medically. Cases treated with coronary stent placement were more likely to receive a bare-metal stent than controls. Among PCI, bleeding was more common among hemophilia A cases. The death rates were comparable between groups. ACS-hemophilia A/hemophilia B cases were more often treated noninvasively compared with controls, suggesting an avoidance of PCI/coronary artery bypass grafting in this population, and bleeding (among hemophilia A) was more common. These findings support further study of the management of ACS and in-hospital outcomes among individuals with hemophilia.

Gene therapy for hemophilia: past, present and future.

After numerous preclinical studies demonstrated consistent success in large and small animal models, gene therapy has finally seen initial signs of clinically meaningful success. In a landmark study, Nathwani and colleagues reported sustained factor (F)IX expression in individuals with severe hemophilia B following adeno-associated virus (AAV)-mediated in vivo FIX gene transfer. As the next possible treatment-changing paradigm in hemophilia care, gene therapy may provide patients with sufficient hemostatic improvement to achieve the World Federation of Hemophilia's aspirational goal of "integration of opportunities in all aspects of life… equivalent to someone without a bleeding disorder." Although promising momentum supports the potential of gene therapy to replace protein-based therapeutics for hemophilia, several obstacles remain. The largest challenges appear to be overcoming the cellular immune responses to the AAV capsid; preexisting AAV neutralizing antibodies, which immediately exclude approximately 50% of the target population; and the ability to scale-up vector manufacturing for widespread applicability. Additional obstacles specific to hemophilia A (HA) include designing a vector cassette to accommodate a larger cDNA; avoiding development of inhibitory antibodies; and, perhaps the greatest difficulty to overcome, ensuring adequate expression efficiency. This review discusses the relevance of gene therapy to the hemophilia disease state, previous research progress, the current landscape of clinical trials, and considerations for promoting the future availability of gene therapy for hemophilia.

Dental procedures in 24 patients with chronic immune thrombocytopenia in prospective clinical studies of eltrombopag.

Primary immune thrombocytopenia (ITP) is an autoimmune disease characterized by chronically low peripheral blood platelet counts. Eltrombopag is an oral, non-peptide, thrombopoietin-receptor agonist that increases platelet production. This report examines peri-procedural platelet counts and bleeding complications among chronic ITP patients requiring dental procedures while participating in clinical studies with eltrombopag. A total of 494 patients participated in five clinical studies of eltrombopag in chronic ITP. Information about dental procedures was collected prospectively in four studies and retrospectively in one study. Twenty-four patients (22 eltrombopag, 2 placebo) underwent 32 dental procedures (dental cleaning, tooth repair, artificial crown, dental prosthesis, tooth extraction, dental or wisdom teeth extraction, dental root extraction, and endodontic procedures, among others) during study treatment or up to 10 days later. Supplemental ITP therapy (e.g., corticosteroids, platelet transfusions) was given before the dental procedure to increase platelet counts in three eltrombopag-treated patients and both placebo-treated patients. The mean pre-procedure platelet count ± standard deviation for all procedures in the overall population of patients, eltrombopag group, and placebo group prior to undergoing dental procedures was 96 000 ± 81 069/µl,103 517 ± 81 522/µl, and 23 333 ± 9291/µl, respectively. Two patients in each group had platelet counts below 30 000/µl before the procedure. No patient who had a dental procedure experienced a bleeding adverse event. Among patients with chronic ITP who required a dental procedure during clinical studies of eltrombopag, supplemental ITP treatment was required for both patients who received placebo but was not required for most patients who received eltrombopag. No bleeding complications were reported. These data imply that patients with chronic ITP who receive eltrombopag and experience increases in platelet counts fulfill current pre-procedural platelet count recommendations to undergo invasive dental procedures, and may have a lower risk of bleeding complications and a reduced need for supplemental ITP treatment.

Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A.

This phase 3 pivotal study evaluated the safety, efficacy, and pharmacokinetics of a recombinant FVIII Fc fusion protein (rFVIIIFc) for prophylaxis, treatment of acute bleeding, and perioperative hemostatic control in 165 previously treated males aged ≥12 years with severe hemophilia A. The study had 3 treatment arms: arm 1, individualized prophylaxis (25-65 IU/kg every 3-5 days, n = 118); arm 2, weekly prophylaxis (65 IU/kg, n = 24); and arm 3, episodic treatment (10-50 IU/kg, n = 23). A subgroup compared recombinant FVIII (rFVIII) and rFVIIIFc pharmacokinetics. End points included annualized bleeding rate (ABR), inhibitor development, and adverse events. The terminal half-life of rFVIIIFc (19.0 hours) was extended 1.5-fold vs rFVIII (12.4 hours; P < .001). Median ABRs observed in arms 1, 2, and 3 were 1.6, 3.6, and 33.6, respectively. In arm 1, the median weekly dose was 77.9 IU/kg; approximately 30% of subjects achieved a 5-day dosing interval (last 3 months on study). Across arms, 87.3% of bleeding episodes resolved with 1 injection. Adverse events were consistent with those expected in this population; no subjects developed inhibitors. rFVIIIFc was well-tolerated, had a prolonged half-life compared with rFVIII, and resulted in low ABRs when dosed prophylactically 1 to 2 times per week.

Global Emerging HEmophilia Panel (GEHEP): A Multinational Collaboration for Advancing Hemophilia Research and Treatment.

GEHEP, established in 2009, is an independent, multi-institutional, international consortium of early career hematology specialists in the field of hemophilia and other inherited bleeding disorders. The main objective of the group, whose members practice at institutions in North America, Europe, and South Africa, is to advance hemophilia care by providing a forum for mentored collaborative research, developing programs for improving clinical care, and promoting academic career development of junior faculty. GEHEP members collect and document anonymized data on intra- and interinstitutional differences in patient populations, diagnosis, and treatment in the field of hemophilia and other bleeding disorders. To facilitate sharing of aggregated data among GEHEP members, a global protocol was developed and approved by most members' local institutional review board. Current GEHEP research initiatives are varied, encompassing work in pediatric and adult patients. GEHEP members have presented research at international meetings on the initiation of prophylaxis in children, use of immune tolerance induction in adults, and prevalence of acute coronary syndromes in older patients with hemophilia. The main goal of the continuing work of GEHEP is to advance the care of patients with hemophilia worldwide.

Efficacy of eltrombopag in management of bleeding symptoms associated with chronic immune thrombocytopenia.

Bleeding is of particular clinical importance in the management of chronic immune thrombocytopenia (ITP), which involves impaired platelet production and accelerated destruction. We report the first comprehensive analysis of the impact of eltrombopag on bleeding in five clinical studies of adult chronic ITP: two 6-week phase 2 (TRA100773A) and phase 3 (TRA100773B) studies; a 6-month phase 3 study (RAISE); a phase 2 repeat-dose study (REPEAT); and a phase 3 extension study (EXTEND). Bleeding was assessed using the World Health Organization Bleeding Scale and categorized as no bleeding (grade 0), any bleeding (grades 1-4), and clinically significant bleeding (grades 2-4). Bleeding was also assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. Across all studies, bleeding at baseline ranged from 50 to 73% for eltrombopag-treated patients; by week 2, bleeding had decreased, ranging from 26 to 39%. This trend was maintained throughout treatment. Similar results were observed for clinically significant bleeding. No such trend was seen in placebo-treated patients for any bleeding or clinically significant bleeding. For TRA100773B and RAISE, the odds of any bleeding across the entire treatment period were 51 and 76% lower for eltrombopag-treated versus placebo-treated patients (P=0.021, P<0.001). The odds of clinically significant bleeding in RAISE were 65% lower (P<0.001). In conclusion, analysis of prospective data from five clinical studies demonstrates that eltrombopag significantly reduces bleeding in adult patients with chronic ITP.

A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A.

Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979-1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this population.

Selective validation of the WHO Bleeding Scale in patients with chronic immune thrombocytopenia.

OBJECTIVE: To evaluate the World Health Organization's (WHO) Bleeding Scale in two studies of eltrombopag in adults with chronic immune thrombocytopenia (ITP). RESEARCH DESIGN AND METHODS: Validated scales assessing bleeding in adults with ITP are lacking. Data from two long-term, phase 3 clinical trials (RAISE: NCT00370331; EXTEND: NCT00351468) that assessed eltrombopag in adults with chronic ITP were analyzed to evaluate the performance of the WHO Bleeding Scale. RESULTS: In RAISE, effect size (0.71), standardized response (0.75), and responsiveness statistics (0.57) were moderate for bleeding and bruising assessments. In EXTEND, effect size (0.62) and responsiveness statistics (0.59) were moderate; the standardized response statistic was 0.487. Intraclass correlation for test-retest reliability was 0.75 in RAISE and 0.71 in EXTEND. A positive correlation was observed between the WHO Bleeding Scale and the ITP Bleeding Scale. Bleeding scores and quality-of-life measures were inversely correlated (p < 0.05 for all). Minimal important differences for the WHO Bleeding Scale were 0.33-0.40 at baseline and last on-treatment assessment in both studies. LIMITATIONS: The majority of bleeding in these studies was mild to moderate, so this analysis cannot provide strong evidence of the validity of the WHO Bleeding Scale in patients with more severe bleeding. Potential limitations to the WHO Bleeding Scale itself include dependence on clinician interpretation of patient recall, inability to distinguish among bleeding events occurring at different anatomical sites, and an inherent assumption of linear increases in severity of bleeding across the response categories. CONCLUSIONS: These findings suggest potential usefulness of the WHO Bleeding Scale in adult patients with chronic ITP for standardizing grading of bleeding across research studies and in clinical practice.

An algorithmic approach to peripheral artery disease in hemophilia: extrapolation of management principles from noncoagulopathic patients.

The development of peripheral artery disease (PAD), a marker for systemic atherosclerosis and ischemic risk, is an increasingly important concern in the aging hemophilia population. A growing body of data suggests that an absence or deficiency of factor VIII or factor IX may not protect against atherogenesis, implying that the prevalence of PAD in men with hemophilia (MWH) may be higher than previously believed. This article describes special considerations in PAD screening, risk-factor modification, and management in older MWH.