Für Sie Recherchiert 2/2022
Evolution of haemophilia integrated care in the era of gene therapy: Treatment centre’s readiness in United States and EU
Miesbach W., Pasi K.J., Pipe S.W., Hermans C., O'Mahony B., Guelcher C., Steiner B., Skinner M.W.
Haemophilia 2021 27:4 (511-514)
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Comparative analysis of the pivotal studies of extended half-life recombinant FVIII products for treatment of haemophilia A
Mannucci P.M., Cortesi P.A., Di Minno M.N.D., Sanò M., Mantovani L.G., Di Minno G.
Haemophilia 2021 27:4 (e422-e433)
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Abstract
The need to reduce the burden of injections, and improve adherence and clinical outcomes in haemophilia A led to the development of recombinant FVIII products endowed with an extended plasma half-life (EHL-rFVIII) in comparison with standard half-life products (SHL-rFVIII). Lack of head-to-head studies makes difficult to grasp the relative value of each treatment option. We conducted a combined evaluation of the individual pivotal trials in order to assess between-product differences regarding the reported efficacy results and FVIII consumption. We evaluated 4 EHL-rFVIII products available to treat patients with haemophilia A without inhibitors and also a SHL-rFVIII as a comparator. In the frame of these clinical studies, all the EHL-rFVIII products showed a decrease in the injection burden coupled with good clinical efficacy, even though there were between-product differences in terms of reduction in injection frequencies. Further, between-product differences in terms of weekly/yearly consumption of rFVIII expressed in IU/Kg were identified, suggesting a different economic impact for the different EHL-rFVIII products in the context of comparable clinical efficacy. The present findings based upon the review of pivotal studies done in the frame of a highly selected clinical scenario should be integrated with real-life data.
The rising incidence of acquired haemophilia A in Germany
Tiede A., Wahler S.
Haemophilia 2021 27:4 (e466-e468)
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Reduced cardiovascular morbidity in patients with hemophilia: results of a 5-year multinational prospective study
Van Der Valk P., Makris M., Fischer K., Tait R.C., Chowdary P., Collins P.W., Meijer K., van Vulpen L.F.D., Mauser-Bunschoten E., Schutgens R.E.G.
Blood Adv (2022) 6 (3): 902–908
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Abstract
Hemophilia is a congenital bleeding disorder caused by low clotting factor VIII or IX levels. Life expectancy of people with hemophilia (PWH) has increased with the availability of clotting factor concentrates. At the same time, the incidence of cardiovascular disease (CVD) has increased. In retrospective studies there are conflicting data if, despite this increase, the incidence is still lower than in the general population. We prospectively compared the incidence of CVD in PWH with the predicted incidence. This prospective, multicenter, observational study included adult PWH (>30y) from the Netherlands and United Kingdom (UK). They were followed for a 5-year period and CVD incidence was compared with a predicted event rate based on the QRISK2-2011 CVD risk model. The primary endpoint was the observed fatal and nonfatal CVD incidence after 5 years compared to the estimated events and in relation to severity of hemophilia. The study included 709 patients, of whom 687 (96.9%) completed 5 years follow up or reached an endpoint. For 108 patients the QRISK score could not be calculated at inclusion. For the remaining 579 fewer CVD events were observed than predicted: 9 versus 24 (RR 0.38; 95% CI: 0.18 - 0.80 p=0.01), corresponding with an absolute risk reduction of 2.4%. Severe hemophilia treated on demand had the highest risk reduction. There was no statistical significant relation between severity of hemophilia and incidence of CVD. In hemophilia a lower than predicted CVD incidence was found, supporting the theory that hemophilia protects against CVD. The study is registered at www.clinicaltrials.gov (identification number NCT01303900).
Population pharmacokinetic modeling of factor concentrates in hemophilia: An overview and evaluation of best practice
Goedhart T.M.H.J., Bukkems L.H., Michel Zwaan C., Mathôt R.A.A., Cnossen M.H.
Blood Adv. 2021 5:20 (4314-4325)
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Abstract
The accuracy of pharmacokinetic (PK)-guided dosing depends on the clinical and laboratory data used to construct a population PK model, as well as the patient’s individual PK profile. This review provides a detailed overview of data used for published population PK models for factor VIII (FVIII) and factor IX (FIX) concentrates, to support physicians in their choices of which model best suits each patient. Furthermore, to enhance detailed data collection and documentation, we do suggestions for best practice. A literature search was performed; publications describing prophylactic population PK models for FVIII and FIX concentrates based on original patient data and constructed using nonlinear mixed-effect modeling were included. The following data were collected: detailed demographics, type of product, assessed and included covariates, laboratory specifications, and validation of models. Included models were scored according to our recommendations for best practice, specifically scoring the quality of data documentation as reported. Respectively, 20 models for FVIII and 7 for FIX concentrates were retrieved. Although most models (22/27) included pediatric patients, only 4 reported detailed demographics. The wide range of body weights suggested that overweight and obese adults were represented. Twenty-six models reported the assay applied to measure factor levels, whereas only 16 models named reagents used. Eight models were internally validated using a data subset. This overview presents detailed information on clinical and laboratory data used for published population PK models. We provide recommendations on data collection and documentation to increase the reliability of PK-guided prophylactic dosing of factor concentrates in hemophilia A and B.
Current and Emerging Approaches for Pain Management in Hemophilic Arthropathy
Gualtierotti R., Tafuri F., Arcudi S., Solimeno P.L., Acquati J., Landi L., Peyvandi F.
Pain Ther. (2022) 11:1–15
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Abstract
Introduction: Hemophilia is an inherited bleeding hematological disorder characterized by the partial or complete deficiency of clotting factor VIII or IX. Hemophilic arthropathy is the consequence of repeated joint bleeding (hemarthrosis) and its management is based on the prevention of acute bleeding through the administration of the deficient clotting factor concentrate or non-factor therapies. In addition, the management of acute and chronic pain is pivotal in hemophilic arthropathy in order to restore function and allow rehabilitation of the joint. Methods: We conducted a qualitative review of the literature regarding current and emerging strategies for pain treatment in hemophilic arthropathy. This review considers systemic and local pharmacological and non-pharmacological interventions for acute and chronic pain management. Results: In hemophilic arthropathy, pain management is based on analgesics such as paracetamol, which represents the first choice for acute and chronic pain in adults and children, in association with opioids for adults. Non-steroidal anti-inflammatory drugs inhibit platelet function, so that the currently preferred drugs are short courses of cyclooxygenase 2 inhibitors. Local treatment with intra-articular injections of corticosteroids is an option for refractory cases and physiotherapy has an important role after hemarthrosis and for the long-term management of chronic pain for both pediatric and adult patients. Conclusions: The management of pain in hemophilia requires more standardization. Meanwhile, the safest drugs should be used at the lowest effective dosage and for periods as short as possible. For the non-pharmacological management of pain in these patients, a multidisciplinary team including hematologists, orthopedic surgeons, rheumatologists, and physiotherapists is warranted.
Joint status of patients with non-severe hemophilia A
Zwagemaker A.-F., Kloosterman F.R., Hemke R., Gouw S.C., Coppens M., Romano L.G.R., Kruip M.J.H.A., Cnossen M.H., Leebeek F.W.G., Hutten B.A., Maas M., Fijnvandraat K.
J Thromb Haemost 2022:
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Abstract
BACKGROUND: Joint bleeding in hemophilia may eventually lead to joint damage. In non-severe hemophilia, joint bleeds occur infrequently. Currently, knowledge on the joint status of patients with non-severe hemophilia using objective imaging is limited. OBJECTIVE: To investigate the joint status in patients with non-severe hemophilia A. METHODS: This cross-sectional study included patients with non-severe hemophilia A aged 24-55 years. Joint status was assessed by magnetic resonance imaging (MRI) of the elbows, knees and ankles and IPSG (International Prophylaxis Study Group) scores were calculated. Lifetime joint bleeding history was collected from medical files. The contribution of factors to joint outcome was explored using multivariable linear regression analysis. RESULTS: In total, 51 patients were included of whom 19 (37%) had moderate and 32 (63%) had mild hemophilia. Patients had a median age of 43 years (IQR 32-50), a median FVIII activity of 10 IU/dL (IQR 4-16) and a median annual joint bleeding rate (AJBR) of 0.0 (IQR 0.0-0.2). Soft tissue changes (IPSG sub-score >0) in the elbows, knees and ankles were present in 19%, 71% and 71% of patients, respectively. Osteochondral changes (IPSG sub-score >0) in the elbows, knees and ankles were present in 0%, 20% and 35% of patients, respectively. In 14% of bleed-free joints, hemosiderin depositions were observed. Age and AJBRs were most strongly associated with the IPSG-score. CONCLUSION: This study demonstrates that a substantial proportion of adults with non-severe hemophilia has joint changes on MRI despite low joint bleeding rates.
Global Seroprevalence of Pre-existing Immunity Against AAV5 and Other AAV Serotypes in People with Hemophilia A
Klamroth R., Hayes G., Andreeva T., Gregg K., Suzuki T., Mitha I.H., Hardesty B., Shima M., Pollock T., Slev P., Oldenburg J., Ozelo M.C., Stieltjes N., Castet S.-M., Mahlangu J., Peyvandi F., Kazmi R., Schved J.-F., Leavitt A.D., Callaghan M., Pan-Petesch B., Quon D.V., Andrews J., Trinh A., Li M., Wong W.Y.
Hum Gene Ther 2022:
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Abstract
Adeno-associated virus (AAV)-mediated gene therapy may provide durable protection from bleeding events and reduce treatment burden for people with hemophilia A (HA). However, pre-existing immunity against AAV may limit transduction efficiency and hence treatment success. Global data on the prevalence of AAV serotypes are limited. In this global, prospective, noninterventional study, we determined the prevalence of pre-existing immunity against AAV2, AAV5, AAV6, AAV8, and AAVrh10 among people ≥12 years of age with HA and residual FVIII levels ≤2 IU/dL. Antibodies against each serotype were detected using validated, electrochemiluminescent-based enzyme-linked immunosorbent assays. To evaluate changes in antibody titers over time, 20% of participants were retested at 3 and 6 months. In total, 546 participants with HA were enrolled at 19 sites in 9 countries. Mean (standard deviation) age at enrollment was 36.0 (14.87) years, including 12.5% under age 18 and 20.0% aged 50 and older. On Day 1, global seroprevalence was 58.5% for AAV2, 34.8% for AAV5, 48.7% for AAV6, 45.6% for AAV8, and 46.0% for AAVrh10. Considerable geographic variability was observed in the prevalence of pre-existing antibodies against each serotype, but AAV5 consistently had the lowest seroprevalence across the countries studied. AAV5 seropositivity rates were 51.8% in South Africa (n = 56), 46.2% in Russia (n = 91), 40% in Italy (n = 20), 37.2% in France (n = 86), 26.8% in the USA (n = 71), 26.9% in Brazil (n = 26), 28.1% in Germany (n = 89), 29.8% in Japan (n = 84), and 5.9% in the UK (n = 17). For all serotypes, seropositivity tended to increase with age. Serostatus and antibody titer were generally stable over the 6-month sampling period. As clinical trials of AAV-mediated gene therapies progress, data on the natural prevalence of antibodies against various AAV serotypes may become increasingly important.
Current Choices and Management of Treatment in Persons with Severe Hemophilia A without Inhibitors: A Mini‐Delphi Consensus
Coppola A., Franchini M., Pappagallo G., Borchiellini A., De Cristofaro R., Molinari A.C., Santoro R.C., Santoro C., Tagliaferri A.
J. Clin. Med. 2022 11:3
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Abstract
Background. Regular treatment to prevent bleeding and consequent joint deterioration (prophylaxis) is the standard of care for persons with severe hemophilia A, traditionally based on intravenous infusions of the deficient clotting FVIII concentrates (CFCs). In recent years, extended half‐life (EHL) CFCs and the non‐replacement agent emicizumab, subcutaneously administered, have reduced the treatment burden. Methods. To compare and integrate the opinions on the different therapies available, eight hemophilia specialists were involved in drafting items of interest and relative statements through the Estimate‐Talk‐Estimate (ETE) method (“mini‐Delphi”), in this way reaching consensus. Results. Eighteen items were identified, then harmonized to 10, and a statement was generated for each. These statements highlight the importance of personalized prophylaxis regimens. CFCs, particularly EHL products, seem more suitable for this, despite the challenging intravenous (i.v.) administration. Limited real‐world experience, particularly in some clinical settings, and the lack of evidence on long‐term safety and efficacy of non‐replacement agents, require careful individual risk/benefit assessment and multidisciplinary data collection. Conclusions. The increased treatment options extend the opportunities of personalized prophylaxis, the mainstay of modern management of hemophilia. Close, long‐term clinical and laboratory follow‐up of patients using newer therapeutic approaches by specialized hemophilia treatment centers is needed.
Postoperative bleeding complications in patients with hemophilia undergoing major orthopedic surgery: A prospective multicenter observational study
Kleiboer B., Layer M.A., Cafuir L.A., Cuker A., Escobar M., Eyster M.E., Kraut E., Leavitt A.D., Lentz S., Quon D., Ragni M.V., Thornhill D., Wang M., Key N.S., Buckner T.W.
J. Thromb. Haemost. 2022:
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Abstract
Background: Persons with hemophilia (PWH) are at risk for chronic hemophilic arthropathy (HA). Joint replacement surgery may be used to relieve intractable pain and/or restore joint function. Objectives: This multicenter, prospective, observational cohort study evaluated the rate of bleeding during the postoperative period after total hip (THA) or knee arthroplasty (TKA). Patients/Methods: We included PWH of any severity ≥18 years of age who were undergoing THA or TKA. Clinical decisions were made at the discretion of the treating physician according to local standards of care. Clinical data were prospectively recorded. Major bleeding was defined as bleeding in a critical site, bleeding that resulted in either a 2 g/dl or greater decrease in hemoglobin during any 24-h period, or transfusion of two or more units of packed red blood cells. Results: One hundred thirty-one procedures (98 TKA and 33 THA) were performed, 39 (29.8%) of which were complicated by major bleeding, including 46% of THA and 25% of TKA. The risk of major bleeding was increased in THA compared to TKA (OR 2.50, p =.05), and by the presence of an inhibitor (OR 4.29, p =.04), increased BMI (OR 4.49 and 6.09 for overweight and obese, respectively, compared to normal BMI, each p <.01), and non-use of an antifibrinolytic medication (OR 3.00, p =.03). Neither continuous clotting factor infusion (versus bolus infusion) nor pharmacologic thromboprophylaxis were associated with bleeding risk. Conclusions: The bleeding risk remains substantial after THA and TKA in PWH, despite factor replacement. Use of antifibrinolytic medications is associated with decreased risk.
Digital haemophilia: Insights into the use of social media for haemophilia care, research and advocacy
Chen R., Muralidharan K., Samelson-Jones B.J.
Haemophilia 2022:
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Abstract
Introduction: The haemophilia community on Twitter is diverse, consisting of advocacy groups, patients, physicians, researchers and other users. However, the scope of this community is uncharacterized, and limited data is available regarding effective participation in this community. Aim: To assess the types of users active in the haemophilia community on Twitter, as well as major themes present in haemophilia-related tweets. Methods: Forty-nine thousand five hundred and twelve tweets between September 2019 and September 2021 were classified using regular expressions. A subset of the classified tweets was manually analysed to identify prevalent discussion themes. Results: Among the top 250 users by post count, the largest categories of users were support and advocacy groups, people with bleeding disorders and healthcare providers. The largest thematic categories of tweets were gene therapy, contaminated haemophilia blood products, haemophilia research, clinical management of haemophilia and COVID-19. While misinformation was rare, negative and incorrect perceptions of haemophilia were present among the general public. Conclusion: Our results demonstrate patterns of effective Twitter usage for patient care, research and advocacy purposes among the haemophilia community.
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)
Miesbach W., Eichler H., Holstein K., Holzhauer S., Klamroth R., Knöfler R., Male C., Olivieri M., Oldenburg J., Tiede A.
Haemophilia 2022:
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Abstract
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.
An Update on Laboratory Diagnostics in Haemophilia A and B
Müller J., Miesbach W., Prüller F., Siegemund T., Scholz U., Sachs U.J..
Hamostaseologie 2022:
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Abstract
Haemophilia A (HA) and B (HB) are X-linked hereditary bleeding disorders caused by lack of activity of coagulation factors VIII (FVIII) or IX (FIX), respectively. Besides conventional products, modern replacement therapies include FVIII or FIX concentrates with an extended half-life (EHL-FVIII/FIX). Two main strategies for measuring plasma FVIII or FIX activity are applied: the one-stage clotting assay (OSCA) and the chromogenic substrate assay (CSA), both calibrated against plasma (FVIII/FIX) standards. Due to the structural modifications of EHL-FVIII/FIX, reagent-dependent assay discrepancies have been described when measuring the activity of these molecules. Assay discrepancies have also been observed in FVIII/FIX gene therapy approaches. On the other hand, nonfactor replacement by the bispecific antibody emicizumab, a FVIIIa-mimicking molecule, artificially shortens activated partial thromboplastin time-based clotting times, making standard OSCAs inapplicable for analysis of samples from patients treated with this drug. In this review, we aim to give an overview on both, the currently applied and future therapies in HA and HB with or without inhibitors and corresponding test systems suitable for accompanying diagnostics
Regulation of coagulation by tissue factor pathway inhibitor: Implications for hemophilia therapy
Mast A.E., Ruf W.
J Thromb Haemost 2022:
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Abstract
Tissue factor pathway inhibitor (TFPI) is an alternatively spliced anticoagulant protein that primarily dampens the initiation phase of coagulation before thrombin is generated. As such, TFPI's actions are localized to cells expressing TF and to sites of injury, where it is an important regulator of bleeding in hemophilia. The major splice isoforms TFPIα and TFPIβ localize to different sites within and surrounding the vasculature. Both forms directly inhibit FXa via their Kunitz 2 domain and inhibit TF-FVIIa via their Kunitz 1 domain in a tight complex primarily localized to cells. By forming complexes localized to distinct cellular microenvironments and engaging additional cell surface receptors, TFPI alters cellular trafficking and signaling pathways driven by coagulation proteases of the TF pathway. TFPIα, which circulates in complex with FV and Protein S, also serves an inhibitor of FXa independent of the TF initiation complex and prevents the formation of an active prothrombinase. This regulation of thrombin generation in the context of vessel injury is effectively blocked by antibodies to Kunitz 2 domain of TFPI and exploited as a therapy to restore efficient hemostasis in hemophilia.
Preparing for tomorrow: Defining a future agenda
O'Mahony B., Wong O., Eichler H., Neumann P., Carlsson K.S., Noone D.
Haemophilia 2022 28:S2 (35-41)
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Abstract
Gene therapy will be the first long-term therapy with potential to produce a functional cure for haemophilia. As a single dose (‘once-and-done’) therapy with significant uncertainties regarding impact and duration of factor expression, flexibility and adaptability of (1) value framework, (2) health technology assessment (HTA) methodology, and (3) development of alternative payment models will be needed for adoption of this new technology and to facilitate transparent decision-making to support its implementation. The responsibility for each of these currently lies with distinct entities, underscoring a need for enhanced collaboration between all stakeholders, as expanded engagement by key stakeholders will be critical to optimizing the assessment of value, enabling an optimised approach to HTA, and opening receptivity to new and innovative payment models. This supplement issue describes important considerations for a gene therapy ‘toolkit’, highlighting key considerations for each of the aforementioned tools, which will be useful for guiding decision-making regarding gene therapy as a novel treatment modality. In this article, we outline how the tools presented in this supplement can be applied as part of a framework to address the requirements of the relevant stakeholders, including payers, manufacturers, treaters, and patients. The paper also provides an illustrative example of how to understand the features of alternative payment models depending on the organization of and payment for healthcare.
Risk of diabetes in haemophilia patients compared to clinic and non-clinic control cohorts
Pandey B., Barnes R.F.W., Sun H., Jackson S., Kruse-Jarres R., Quon D.V., von Drygalski A.
Haemophilia 2022:
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Abstract
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.
