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Jan 07 / Springer Healthcare

ASH 2021 In-Depth Report: Haemophilia


This ASH 2021 in-depth report provides an overview of the classification and management of haemophilia.

American Society of Hematology

2021 ASH Annual Meeting

December 11th– 14th, 2021

In-Depth Report

Welcome to ASH 2021

The 63rd ASH Annual Meeting took place as a hybrid event on 11th–14th December 2021, with attendees able to either attend the event in person in Atlanta, Georgia, USA, or via a virtual congress platform. As the world’s most comprehensive malignant and non-malignant haematology event of the year, the meeting continued its tradition of providing an invaluable educational experience and the opportunity to access updates in the hottest topics in haematology. The mission of ASH is to further the understanding, diagnosis, treatment, and prevention of disorders affecting the blood, bone marrow, and the immunologic, haemostatic, and vascular systems, by promoting research, clinical care, education, training, and advocacy in haematology.

First hybrid ASH Annual Meeting accessed by more than 20,000 delegates
ASH 2021 at a glance


Prophylaxis factor replacement therapy is now considered standard of care in both paediatric and adult patients with haemophilia with a severe phenotype to protect musculoskeletal health and improve quality of life. Ming Yeong Lim, University of Utah, Salt Lake City, USA, discussed current practical points on choosing the type of factor concentrate, dose, and interval while considering the appropriate target trough factor levels and bleeding triggers such as level of physical activity and joint status.

Mild to severe haemophilia according to WFH
Classification of haemophilia according to WFH

Heterogeneity in bleeding presentation among patients with haemophilia due to genetic, environmental, and treatment-related factors has been well described. Accordingly, the WFH recommends an individualised prophylaxis regimen that considers the factors mentioned above to meet the clinical needs of the patient, which can vary over time. The two main types of standard half-life (SHL) clotting factor concentrates (CFC) are the virally inactivated plasmaderived lyophilised factor concentrates and the recombinant factor concentrates; both have demonstrated a positive efficacy/safety profile.

Factors that lead to optimal utilisation of CFCs include those that are genetic, environmental and treatment-related
Factors that lead to optimal utilisation of CFCs include those that are genetic, environmental and treatment-related

Updated WFH trough plasma factor clotting levels specify a sufficient level to prevent spontaneous bleeding, based on individual needs and lifestyles (>3–5% or higher). However, challenges with SHL CFCs include:

In the last decade, recombinant extended half-life CFCs have been engineered to reduce infusion frequency and to maintain a higher factor trough level for better protection against spontaneous bleeding. The WFH recommend pharmacokinetic (PK) assessment for individuals with haemophilia to support optimisation of prophylaxis. Traditionally, obtaining PK evaluation was a huge inconvenience due to the need for a washout period and frequent factor measurements for 48 to 72 hours after infusion of a prophylaxis dose. However, the availability of population-based PK models now enables estimation of individual PK from only two or three factor measurements without a washout period.

“The adoption of an individualised prophylaxis regimen leads to optimal utilisation of factor concentrates with maximum efficacy and minimum waste.”

- Ming Yeong Lim, University of Utah, Salt Lake City, USA

Alice Ma, The University of North Carolina, Chapel Hill, USA, discussed novel non-factor therapies in use and in development for the management of haemophilia A and B (caused by a deficiency of Factor VIII or Factor IX, respectively).

While current standard of care is the administration of recombinant or purified factor, this treatment strategy still results in a high economic and personal burden to patients, which can be further exacerbated by the development of inhibitors (alloantibodies to factor). Emicizumab, a bispecific antibody that mimics the function of Factor VIIIa, is the first such non-factor therapy to gain US Food and Drug Administration approval and is rapidly changing the treatment paradigm for haemophilia A. Emicizumab binds to activated Factor IX (Factor IXa) and Factor X, thereby performing the function of Factor VIII by bringing Factor IXa and Factor X into close enough proximity to facilitate Factor X activation. Given the positive data with emicizumab demonstrating reductions in annualised bleeding rates, it suggests a new era of treatment for haemophilia A. In clinical practice, emicizumab is being successfully used in infants and other previously untreated patients, with its use being supported by a low incidence of antidrug antibodies, simple administration, and long half-life. However, much still remains unanswered about emicizumab, with an experienced haematologist needed to enable optimal use. Other antibody Factor VIIIa mimetics with the same mechanism of action are in development, including Mim8 (NCT05053139), BS-027125, and NIBX-2101.

Other therapies on the horizon aim to target anticoagulant proteins in the coagulation cascade, thus ‘rebalancing’ a haemorrhagic tendency by introducing a thrombotic tendency. This intricate haemostatic balancing act offers some promise for patients in need of more treatment options. Fitusiran is a small-molecule RNA interference therapeutic that acts by binding and degrading the mRNA encoding antithrombin, leading to increased total thrombin generated with a haemostatic challenge. Selected doses lead to antithrombin activity levels of 20%, normalising thrombin generation in individuals with haemophilia, although some thrombosis issues have been reported. Tissue factor (TF) pathway inhibitors, such as concizumab and befovacimab, are also in development to prevent the activation of Factor X by the TF-Factor VIIa complex, thus limiting the degree of thrombin generation via the contact pathway.

“The treatment landscape is changing, with nonfactor therapeutics playing an increasing role in what we consider to be the standard of care.”

- Alice Ma, The University of North Carolina, Chapel Hill, USA

Lindsey A. George, University of Pennsylvania, Philadelphia, USA, discussed the current status of haemophilia gene therapy. Current research efforts are largely focused on the use of systemically administered recombinant adeno-associated viral (rAAV) vectors for F8 or F9 gene addition. While hepatocytes are the natural site of Factor IX synthesis, liver sinusoidal endothelial cells are the predominant site of Factor VIII synthesis. Most haemophilia A rAAV vectors contain a B-domain deleted Factor VIII, Factor VIII-SQ transgene that retains full procoagulant function and accommodates AAV vector packaging constraints. Because AAV efficiently targets the liver, the bulk of safety considerations of systemic rAAV delivery have focused on hepatotoxicity. Most transaminase elevations observed in haemophilia trials occurred in the setting of an immune response to the rAAV capsid, highlighting the need for close patient monitoring, particularly within the first few months of treatment. This immune response is thought to occur when CD8+ T cells recognise capsid peptides on the surface of transduced hepatocytes, triggering a cellular immune response that results in clearance of the transduced cells.

Known and unknown considerations for gene therapy in haemophilia
Known and unknown considerations for gene therapy in haemophilia

Immune-modulating therapies can be used to support transgene expression and maintain efficacy, although additional studies are needed to fully understand which regimens are most effective. Nearly all patients aged >40 years with severe haemophilia contracted iatrogenic hepatitis B virus and/or hepatitis C virus, which are known risk factors for hepatocellular carcinoma (HCC) such that the haemophilia population has an increased risk of HCC relative to the general population.

Currently available efficacy data with rAAV vectors are consistent with haemophilia natural history studies that suggest factor activity >10% ameliorates spontaneous bleeding; however, higher factor activity will likely be required in some patients (e.g. those with pre-existing joint disease), highlighting the need for accurate measurement of in vivo activity of transgene haemostatic function. Durability of response to systemic AAV appears to vary, although some data suggest generally stable Factor VIII expression after 1 year post vector.

“Repeated proof of concept success for haemophilia A and B gene therapy warrants considerable optimism.”

- Lindsey A. George, University of Pennsylvania, Philadelphia, USA

Closing remarks

ASH 2021 provided an invaluable educational experience, with attendees able to access new haematology data and insights, both virtually and in person, which will hopefully stimulate new ways of thinking to support optimal patient care. The revised hybrid format for 2021 continued to provide the opportunity for participants, particularly those outside the US, to attend ASH perhaps for the first time, enabling more institutions around the world to gain access to the meeting content. The meeting in Atlanta, Georgia, USA, also allowed peer-to-peer interaction and the chance to interact face-to-face with top minds in the field.

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