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.).

Adeno-associated viruses for gene therapy - clinical implications and liver-related complications, a guide for hepatologists.

Gene therapy has garnered increasing interest over recent decades. Several therapies employing gene transfer mechanisms have been developed, and, of these, adeno-associated virus (AAV) vectors have demonstrated viability for use with in vivo gene therapy. Several AAV-based therapeutics have received regulatory approval in the last few years including those for retinal disease, spinal muscular atrophy or aromatic L-amino acid decarboxylase deficiency. Lately, with the introduction of novel liver-directed AAV vector-based therapeutics for the treatment of haemophilia A and B, gene therapy has attracted significant attention in the hepatology community, with the liver increasingly recognised as a target for gene therapy. However, the introduction of foreign DNA into hepatocytes is associated with a risk of hepatic reactions, with raised ALT (alanine aminotransferase) and AST (aspartate aminotransferase) being - so far - the most commonly reported side effects. The complete mechanisms underlying the ALT flairs remain to be determined and the long-term risks associated with these new treatments is not yet known. The liver community is increasingly being asked to support liver-directed gene therapy to mitigate potential liver associated harm. In this review, we focus on AAV vector-based gene therapy, shedding light on this promising technique and its remarkable success in haemophilia, with a special focus on hepatic complications and their management in daily clinical practice.

Gene Therapy for Hemophilia B: Achievements, Open Issues, and Perspectives.

Hemophilia B is the first bleeding disorder for which gene therapy clinical programs began. Presently, adenovirus-associated vectors represent the best means to deliver the transgene, and their administration by intravenous route has been used in recent clinical trials. The natural occurring factor IX (FIX) Padua variant, which allows for a 5- to 8-fold higher activity of FIX, while maintaining a normal protein concentration, was subsequently used to enhance the level of transgene expression. All the recent trials using this variant showed good results, and accumulating data suggest that long-term expression durability could be maintained at a significant hemostatic level. However, the risk of loss of transgene expression associated to immune response with liver enzymes elevation remains a concern, especially as to the efficacy and duration of immunosuppressive treatment. Notwithstanding this limitation, the results of clinical trials suggest that gene therapy in hemophilia B has the potential to provide long-term benefits with sustained factor activity levels predicted to last several years in many patients.

Which patients should be considered for gene therapy.

Gene therapy for haemophilia, utilizing adeno-associated viral vectors (AAVs) and coagulation factor genes, have demonstrated promising results, leading to recent approvals and introduction of the first gene therapy products into clinical practice. For successful and safe use, there are predefined inclusion and exclusion criteria, and the treatment process and associated risks should be thoroughly understood and long-term safety and efficacy carefully evaluated during follow up. As gene therapy becomes more accessible outside of clinical study centers, continuous evaluation of patient eligibility for subsequent AAV-based treatments becomes essential. Thorough evaluation of factors such as liver condition, anti-AAV status, and medical history ensures that gene therapy maximizing benefits while minimizing risks. Apart from fulfilling the established inclusion and exclusion criteria, the success of gene therapy is greatly influenced by the motivation and willingness of patients to accept temporary constraints, such as regular laboratory monitoring, potential use of immunosuppressants, and thorough documentation. Furthermore, various patient-related factors play a significant role in the management and outcomes of gene therapy, making a comprehensive evaluation essential. With the accumulation of more data, there is potential for the expansion of certain inclusion criteria, which may allow for a larger number of eligible patients to benefit from gene therapy. Empowering patients through shared decision-making enables them to thoroughly consider the therapy's potential benefits and risks.

Next-generation strategies to improve safety and efficacy of adeno-associated virus-based gene therapy for hemophilia: lessons from clinical trials in other gene therapies.

Three major directions for the global progress of adeno-associated virus (AAV) vectors for gene therapies (GT) are analyzed: a) engineering vectors to increase transgene expression; b) aligning interests of the health system with costs and challenges for pharmaceutical industry; c) refining patient eligibility criteria, and endpoints definition. Currently employed AAV vectors may cause toxicity and adverse events. Furthermore, studies in animals do not fully predict risks and clinical benefits of AAV-based GT, and animal models reflecting the heterogeneity of certain clinical settings (e.g., congestive heart failure) are poorly available for improving AAV-based GT. Finally, antisense and gene editing approaches will soon complement gene augmentation strategies for the stable solution of unsolved issues of AAV-based GT. While minimizing toxicity, next-generation AAV vectors should decrease the viral load needed to achieve therapeutic efficacy; be functional in a restricted cellular subset; avoid transgene expression in unwanted cells (e.g., hepatocytes), and escape immune oversight in AAV-based GT. The role of stress-induced apoptosis in the loss of transgene expression in GT should be also explored. Aligning interests and obligations of pharmaceutical industry with those of the health system is critical for AAV-based GT success. Costs and challenges for pharmaceutical industry include a) removing impurities from AAV; b) validating tests to measure treatment efficacy, c) promoting training programs to standardize vector genomes delivery, d) collecting long-term follow-up data, and e) maintaining sustainability and cost-effectiveness of AAV-based GT. In rare disorders with small patient numbers (e.g., hemophilia), clearcut outcomes are mandatory as endpoints of unequivocal efficacy data.

Current and emerging gene therapies for haemophilia A and B.

INTRODUCTION: After decades of stumbling clinical development, the first gene therapies for haemophilia A and B have been commercialized and have normalized factor (F)VIII and factor (F)IX levels in some individuals in the long term. Several other clinical programs testing adeno-associated viral (AAV) vector gene therapy are at various stages of clinical testing. DISCUSSION: Multiyear follow-up in phase 1/2 and 3 studies showed long-term and sometimes curative but widely variable and unpredictable efficacy. Liver toxicities, mostly low-grade, occur in the 1st year in at least some individuals in all haemophilia A and B trials and are poorly understood. Wide variability and unpredictability of outcome and slow decline of FVIII levels are a major disadvantage because immune responses to AAV vectors preclude repeat dosing, which otherwise could improve suboptimal or restore declining expression, while overexpression may predispose to thrombosis. Long-term safety outcomes will need lifelong monitoring because AAV vectors infused at high doses integrate into chromosomes at rates that raise questions about potential oncogenicity and necessitate vigilance. Alternative gene transfer systems employing gene editing and/or non-viral vectors are under development and promise to overcome some limitations of the current state of the art for both haemophilia A and B. CONCLUSIONS: AAV gene therapies for haemophilia have now become new treatment options but not universal cures. AAV is a powerful but imperfect gene transfer platform. Biobetter FVIII transgenes may help solve some problems plaguing gene therapy for haemophilia A. Addressing variability and unpredictability of efficacy, and delivery of gene therapy to ineligible patient subgroups may require different gene transfer systems, most of which are not ready for clinical translation yet but bring innovations needed to overcome the current limitations of gene therapy.

Eptacog beta for the management of patients with haemophilia A and B with inhibitors: A European perspective.

Eptacog beta (activated), a recombinant human factor VIIa (rFVIIa), was approved by the US Food and Drug Administration (FDA) in 2020 (SEVENFACT®, LFB & HEMA Biologics) and the European Medicines Agency (EMA) in 2022 (CEVENFACTA®, LFB). In Europe, eptacog beta is indicated for the treatment of bleeds and the prevention of bleeds during surgery or invasive procedures in adults and adolescents (≥12 years old) with congenital haemophilia A or B with high-titre inhibitors (≥5 BU) or with low-titre inhibitors who are expected to have a high anamnestic response to factor VIII or factor IX, or to be refractory to increased dosing of these factors. The efficacy and safety of eptacog beta were evaluated in three Phase III clinical studies, PERSEPT 1, 2 and 3. For the EMA filing dossier, the analysis of data from PERSEPT 1 and 2 differed from the analysis used to support the filing in the US. In this review, we summarise current data regarding the mode of action, clinical efficacy and safety of eptacog beta for the management of haemophilia A and B in patients with inhibitors from a European perspective. In addition to providing a valuable summary of the analyses of the clinical data for eptacog beta conducted for the EMA, our review summarises the potential differentiators for eptacog beta compared with other current bypassing agents.

Transitioning from emicizumab prophylaxis to valoctocogene roxaparvovec gene therapy: A simulation study for individuals with severe haemophilia A.

INTRODUCTION: Valoctocogene roxaparvovec, a gene therapy evaluated in the phase 3 GENEr8-1 trial, supports endogenous factor VIII (FVIII) production to prevent bleeding in people with severe haemophilia A. Individuals receiving emicizumab, an antibody mimicking the function of activated FVIII, were excluded from GENEr8-1 enrolment since emicizumab was an investigational therapy at the time of trial initiation. AIM: Utilize pharmacokinetic simulations to provide guidance on best practices for maintaining haemostatic control while transitioning from emicizumab prophylaxis to valoctocogene roxaparvovec. METHODS: To estimate bleeding risk at weekly intervals following valoctocogene roxaparvovec infusion, a published emicizumab pharmacokinetic model was used to simulate emicizumab concentrations and merged with FVIII activity time-course data for participants in GENEr8-1. The analysis investigated three approved emicizumab dosing regimens for two transition scenarios that varied whether the last dose of emicizumab was administered on the same day or 4 weeks after valoctocogene roxaparvovec infusion. RESULTS: Simulations demonstrated administering the last emicizumab dose the day of valoctocogene roxaparvovec infusion and 4 weeks after offered similar levels of haemostatic control, and bleeding risk was similar for all emicizumab dosing regimens. An algorithm was developed to provide guidance for discontinuation of emicizumab. Theoretical cases based on GENEr8-1 participants are presented to illustrate how decisions may vary among individuals. CONCLUSION: Pharmacokinetic simulations demonstrated no clinically meaningful difference in bleeding risk caused by decaying emicizumab levels and rising gene therapy-derived endogenous FVIII for all examined emicizumab doses and dosing regimens. Therefore, multiple approaches can safely transition individuals from emicizumab prophylaxis to valoctocogene roxaparvovec.

The current challenges faced by people with hemophilia B.

Hemophilia B (HB) is a rare, hereditary disease caused by a defect in the gene encoding factor IX (FIX) and leads to varying degrees of coagulation deficiency. The prevailing treatment for people with HB (PWHB) is FIX replacement product. The advent of recombinant coagulation products ushered in a new era of safety, efficacy, and improved availability compared with plasma-derived products. For people with severe HB, lifelong prophylaxis with a FIX replacement product is standard of care. Development of extended half-life FIX replacement products has allowed for advancements in the care of these PWHB. Nonetheless, lifelong need for periodic dosing and complex surveillance protocols pose substantive challenges in terms of access, adherence, and healthcare resource utilization. Further, some PWHB on prophylactic regimens continue to experience breakthrough bleeds and joint damage, and subpopulations of PWHB, including women, those with mild-to-moderate HB, and those with inhibitors to FIX, experience additional unique difficulties. This review summarizes the current challenges faced by PWHB, including the unique subpopulations; identifying the need for improved awareness, personalized care strategies, and new therapeutic options for severe HB, which may provide future solutions for some of the remaining unmet needs of PWHB.

Gene therapy for hemophilia: a review on clinical benefit, limitations, and remaining issues.

In the last decade, enormous progress has been made in the development of gene therapy for hemophilia A and B. After the first encouraging results of intravenously administered adeno-associated virus (AAV)-based liver-directed gene therapy in patients with severe hemophilia B were reported in 2011, many gene therapy studies have been initiated. Most of these studies, using AAV vectors with various gene constructs, showed sufficient factor VIII and IX expression in patients to significantly reduce the number of bleeds and the need for prophylaxis in most patients with severe hemophilia. This resulted in great clinical benefit for nearly all patients. In this review, we will summarize the most recent findings of reported and ongoing gene therapy trials. We will highlight the successful outcome of trials with focus on the results of recently reported phase 1 trials and preliminary results of phase 2b/3 trials for hemophilia A and B. These new reports also reveal the impact of side effects and drawbacks associated with gene therapy. We will therefore also discuss the limitations and remaining issues of the current gene therapy approaches. These issues must be resolved before gene therapy will be widely available for the hemophilia patient population.

Endothelial dysfunction and atherosclerosis related miRNA-expression in patients with haemophilia.

INTRODUCTION: Elevated markers of endothelial dysfunction and inflammation indicate worse endothelial function in the aging haemophilia population. MicroRNAs (miRNAs) regulate gene expression post-transcriptionally. Several miRNAs have been shown to be involved in the process of endothelial dysfunction and atherosclerosis. AIM: The aim of this study was to determine the underlying molecular pathways of endothelial dysfunction and inflammation in haemophilia patients. METHODS: A total of 25 patients with severe or moderate haemophilia A (20 patients) or B (5 patients), 14 controls and 18 patients with coronary artery disease (CAD) after myocardial infarction were included in this study. Expression of miRNA-126, -155, -222, -1, -let7a, -21 and -197 were analysed using a real time polymerase chain reaction. Network-based visualisation and analysis of the miRNA-target interactions were performed using the MicroRNA ENrichment TURned NETwork (MIENTURNET). RESULTS: Expression of miRNA-126 (p < .05) and miRNA-let7a (p < .05) were significantly higher in CAD patients compared to haemophilia patients and controls. MiRNA-21 (p < .05) was significantly elevated in CAD patients compared to controls. MiRNA-155 (p < .05), miRNA-1 (p < .05) and miRNA-197 (p < .05) were significantly higher expressed in CAD and haemophilia patients compared to controls and showed a strong correlation with increased levels of interleukin-6 (IL-6) and soluble intercellular adhesion molecule-1 (sICAM-1). The network analysis revealed interactions in the cytokine signalling, focal adhesion and VEGFA-VEGFR2 pathway (Vascular endothelial growth factor, -receptor). CONCLUSION: This study characterises miRNA expression in haemophilia patients in comparison to CAD patients and healthy controls. The results imply comparable biological processes in CAD and haemophilia patients.

Accreditation model of European Haemophilia Centres in the era of novel treatments and gene therapy.

INTRODUCTION: The international certification of haemophilia centres in Europe is run by the European Association of Haemophilia and Allied Disorders (EAHAD) and European Haemophilia Consortium (EHC) since 2013. The centres are designated as European Haemophilia Comprehensive Care Centres (EHCCC) or European Haemophilia Treatment Centres (EHTC), based on the specific requirements which evaluate centres' ability to provide care for patients with haemophilia and allied disorders. AIM: To establish the new protocol for accreditation of European Haemophilia Centres. METHODS: EAHAD, in collaboration with EHC, established Accreditation Working Group with the aim to define necessary measures to safeguard quality and improvement of bleeding disorders care throughout Europe and to build a novel model for accreditation of European Haemophilia Centres. RESULTS: The European guidelines for certification of haemophilia centres have been updated to guidelines for the accreditation and include all the requirements regarding facilities, laboratory and personnel needed for optimal management of novel treatment options, including the introduction of the hub-and-spoke model for delivery of gene therapy. A pilot project for the accreditation of haemophilia centres including on-site audit has been designed. CONCLUSION: Implementation of the novel accreditation protocol of the haemophilia treatment and haemophilia gene therapy centres has been made to further improve the quality of care for patients with haemophilia and other inherited bleeding disorders.

Early-onset venous thromboembolisms in newly diagnosed non-promyelocytic acute myeloid leukemia patients undergoing intensive induction chemotherapy.

OBJECTIVES AND METHODS: Venous thromboembolic (VTE) events are emerging as frequent complications in acute myeloid leukemia (AML); however, there is insufficient data regarding epidemiology, risk factors, and impact on outcomes. The optimal approach to balance risks of thrombosis and hemorrhage remains unclear. This retrospective single-center study in AML patients undergoing induction chemotherapy between 2007 and 2018 assessed incidence, risk factors, features, and outcomes of early-onset VTE. RESULTS: 423 patients (median age 59 years) were enrolled. VTE was diagnosed in 31 patients (7.3%) within 3 months of admission. The median time to VTE was 3 days. Non-central venous catheter (CVC)-related VTE occurred in 19 patients (61%). Main risk factor for VTE was leukocytosis at admission, independent of platelet counts/INR. Four patients (13%) exhibited VTE recurrence. No deaths directly related to VTE or major bleeding events associated with platelet-adjusted anticoagulation in patients with VTE were recorded. There was no clear impact of VTE on 1-year overall survival; however, non-CVC-related VTE may be associated with adverse outcomes. CONCLUSIONS: Early-onset VTE is a common complication in newly diagnosed AML patients admitted for induction chemotherapy. Leukocytosis is an independent VTE risk factor. The potentially adverse impact of non-CVC-related VTE merits further study.

Prophylaxis with recombinant von Willebrand factor in patients with type 3 von Willebrand disease: Results of a post hoc analysis from a phase 3 trial.

OBJECTIVES: To describe efficacy/safety of recombinant von Willebrand factor (rVWF) prophylaxis in patients with type 3 von Willebrand disease (VWD). METHODS: This post hoc analysis of a phase 3 open-label trial provides a more detailed analysis of adults with type 3 VWD, categorized based on prior treatment at screening: "Prior On-Demand (OD)" (OD VWF; ≥3 documented spontaneous bleeding events [BEs] requiring VWF in previous 12 months) or "Switch" (plasma-derived [pd] VWF prophylaxis for ≥12 months). Annualized bleeding rates (ABRs) were evaluated during 12 months of rVWF prophylaxis versus historical data from medical records. RESULTS: In the Prior OD group (n = 10), mean spontaneous ABR (sABR) for treated BEs was reduced by 91.6% (ratio, 0.08; 95% CI, 0.02-0.45) versus mean historical sABR. In the Switch group (n = 8), mean sABR for treated BEs was reduced by 47% (ratio, 0.53; 95% CI, 0.08-3.62). One non-serious adverse event (AE) was considered possibly related to rVWF. No treatment-related, fatal, or life-threatening serious AEs were reported, and no patient developed VWF inhibitors. CONCLUSIONS: rVWF prophylaxis reduced sABR in type 3 VWD patients previously treated with OD VWF therapy, and maintained a similar level of hemostatic control in those switching from pdVWF prophylaxis to rVWF prophylaxis.

Bleeding and response to hemostatic therapy in acquired hemophilia A: results from the GTH-AH 01/2010 study.

Acquired hemophilia A (AHA) is due to autoantibodies against coagulation factor VIII (FVIII) and most often presents with unexpected bleeding. In contrast to congenital hemophilia, the patient's residual FVIII activity does not seem to correlate with the risk of bleeding as suggested from previous studies. Risk factors for bleeding have not been described. We used data from the prospective GTH-AH 01/2010 study to assess the risk of bleeding and the efficacy of hemostatic therapy. FVIII activity was measured at baseline and weekly thereafter. Bleeding events were assessed by treating physicians. A total of 289 bleeds were recorded in 102 patients. There were 141 new bleeds observed starting after day 1 in 59% of the patients, with a mean rate of 0.13 bleed per patient-week in weeks 1 to 12, or 0.27 bleed per patient-week before achieving partial remission. Weekly measured FVIII activity was significantly associated with the bleeding rate, but only achieving FVIII activity ≥50% abolished the risk of bleeding. A good World Health Organization performance status assessed at baseline (score 0 vs higher) was associated with a lower bleeding rate. Hemostatic treatment was reportedly effective in 96% of bleeds. Thus, the risk of new bleeds after a first diagnosis of AHA remains high until partial remission is achieved, and weekly measured FVIII activity may aid in assessing the individual risk of bleeding. These results will help to define future strategies for prophylaxis of bleeding in AHA.

Electronic diaries in the management of haemophilia gene therapy: Perspective of an expert group from the German, Austrian and Swiss Society on Thrombosis and Haemostasis (GTH).

INTRODUCTION: Gene therapy (GT) is becoming a realistic treatment option for patients with haemophilia. Outside clinical trials, the complexity and potential complications of GT will pose unprecedented challenges to haemophilia care centres. AIM: To explore the potential use of electronic tools to improve the delivery of GT under real-world conditions. METHODS: Considering the hub-and-spoke model, the GTH working group on GT considered the entire patient pathway and reached consensus on requirements for an integrative software tool to secure documenting and sharing information between treaters, pharmacies and patients. RESULTS: Six steps of the gene therapy process were identified, each requiring completion of the previous step as a prerequisite for entry. The responsibilities of GT dosing and follow-up treatment centres, read/write access rules, and the minimum data set were outlined. Data contributed by patients through mobile devices was also considered. CONCLUSION: Important information needs to be shared between patients and treatment centres in a real-world GT hub-and-spoke model. Collecting and sharing this information in well-organised electronic applications will not only improve patient care but also enable national and international data collection in clinical registries.

Intracranial hemorrhage in newly diagnosed non-promyelocytic acute myeloid leukemia patients admitted for intensive induction chemotherapy.

OBJECTIVES AND METHODS: Intracranial hemorrhage (ICH) in acute myeloid leukemia (AML) patients is a major concern due to the increased risk of mortality. Few studies have examined ICH specifically in newly diagnosed AML patients receiving intensive induction chemotherapy (IC) and prophylactic platelet transfusions during thrombocytopenia <10/nL. This retrospective cohort study included 423 newly diagnosed AML patients without acute promyelocytic leukemia who underwent IC between 2007 and 2019. We assessed risk factors, clinical features, and outcomes of ICH. RESULTS: 17 of 423 patients (4%) suffered ICH during hospital stay, and 4 patients (24%) died directly because of ICH despite routine prophylactic platelet transfusions. Patients with ICH had a negatively impacted overall survival (median OS, 20.1 vs. 104.8 months) and were more likely not to continue with curative treatment. Main risk factors were female gender, severe thrombocytopenia, and decreased fibrinogen. Patients with subsequent ICH also had laboratory signs of liver dysfunction. CONCLUSIONS: Intracranial hemorrhage remains a potentially deadly complication with notable incidence despite prophylactic platelet substitution, suggesting that additional prophylactic interventions may be required to further reduce the frequency of ICH in high-risk patients. Unrecognized genetic factors may simultaneously predispose to AML and platelet dysfunction with ICH.

Direct oral anticoagulants vs. low-molecular-weight heparin for pulmonary embolism in patients with glioblastoma.

Glioblastoma (GBM) is a cancer type with high thrombogenic potential and GBM patients are therefore at a particularly high risk for thrombotic events. To date, only limited data on anticoagulation management after pulmonary embolism (PE) in GBM is available and the sporadic use of DOACs remains off-label. A retrospective cohort analysis of patients with GBM and postoperative, thoracic CT scan confirmed PE was performed. Clinical course, follow-up at 6 and 12 months and the overall survival (OS) were evaluated using medical charts and neuroradiological data. Out of 584 GBM patients, 8% suffered from postoperative PE. Out of these, 30% received direct oral anticoagulants (DOACs) and 70% low-molecular-weight heparin (LMWH) for therapeutic anticoagulation. There was no significant difference in major intracranial hemorrhage (ICH), re-thrombosis, or re-embolism between the two cohorts. Although statistically non-significant, a tendency to reduced mRS at 6 and 12 months was observed in the LMWH cohort. Furthermore, patients receiving DOACs had a statistical benefit in OS. In our analysis, DOACs showed a satisfactory safety profile in terms of major ICH, re-thrombosis, and re-embolism compared to LMWH in GBM patients with postoperative PE. Prospective, randomized trials are urgent to evaluate DOACs for therapeutic anticoagulation in GBM patients with PE.

Biomarkers and immunological parameters in haemophilia and rheumatoid arthritis patients: a comparative multiplexing laboratory study.

INTRODUCTION: Haemophilia (HA) and rheumatoid arthritis (RA) patients may develop joint damage caused by recurrent joint bleedings in HA or by chronic inflammation in RA. Only few data exist for biomarker studies in these patients. AIM: The objective of the present study is to assess a large array of biomarkers in peripheral blood samples obtained from HA patients without or with arthropathy and to compare pattern to RA patients and healthy controls. METHODS: A panel of biomarkers was assessed in 129 men (40 HA patients without arthropathy, 23 HA patients with arthropathy, 23 RA patients and 43 control subjects). 37 different biomarkers (cytokines, angiogenesis-related proteins) were analysed using a multiple analyte profiling technology and supplemented by acute phase proteins, coagulation and immunological parameters. RESULTS: Evidence for systemic inflammation was obtained by increased acute phase reactants in all patient groups. 13 or 14 from 42 soluble parameters demonstrated significant differences (p < .05) between HA patients without arthropathy and healthy controls, or between HA patients with arthropathy and healthy controls, respectively. Largely overlapping patterns were obtained except for interleukin-7 being increased in HA patients without arthropathy and being decreased in HA in the presence of arthropathy. CONCLUSIONS: In addition to data supporting systemic inflammation, we provide evidence for a common biomarker profile in HA patients and RA patients compared to healthy controls. A distinctive biomarker profile for HA patients with arthropathy did not appear except for interleukin-7 demonstrating specific changes depending on the absence or presence of arthropathy in HA patients.

Delivery of AAV-based gene therapy through haemophilia centres-A need for re-evaluation of infrastructure and comprehensive care: A Joint publication of EAHAD and EHC.

INTRODUCTION: Adeno-associated virus (AAV)-based gene therapy for haemophilia presents a challenge to the existing structure of haemophilia centres and requires a rethink of current collaboration and information exchange with the aim of ensuring a system that is fit-for-purpose for advanced therapies to maximise benefits and minimise risks. In Europe, a certification process based on the number of patients and facilities is offered to the haemophilia centres by European Haemophilia Network (EUHANET). AIM AND METHODS: This joint European Association for Haemophilia and Allied Disorders (EAHAD) and European Haemophilia Consortium (EHC) publication describes criteria for centres participating in gene therapy care that require a reassessment of the infrastructure of comprehensive care and provides an outlook on how these criteria can be implemented in the future work of haemophilia centres. RESULTS: The core definition of a haemophilia treatment centre remains, but additional roles could be implemented. A modifiable 'hub-and-spoke' model addresses all aspects associated with gene therapy, including preparation and administration of the gene therapy product, determination of coagulation and immunological parameters, joint score and function, and liver health. This will also include the strategy on how to follow-up patients for a long-term safety and efficacy surveillance. CONCLUSION: We propose a modifiable, networked 'hub and spoke' model with a long term safety and efficacy surveillance system. This approach will be progressively developed with the goal of making haemophilia centres better qualified to deliver gene therapy and to make gene therapy accessible to all persons with haemophilia, irrespective of their country or centre of origin.