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Curative Therapies for Sickle Cell Disease: Option for Some but Not Quite All

Despite substantial improvements in care, individuals with sickle cell disease continue to experience substantial morbidity and a shortened life expectancy. With recent advances in the development of curative therapies, including allogeneic stem cell transplantation and gene therapy, it is important to identify barriers to accessing these treatments and adequately define suitable candidates for curative therapies.

In this session, Dr. Santosh Saraf will review the current guidelines for curative therapies, discuss the potential benefits and risks of the different curative therapies, and provide insight on when to refer patients for curative therapy.

In the second presentation, Dr. Payal Desai will discuss the various barriers to accessing curative therapies as well as the need for development of an integrated care approach.

Chair:

Kenneth I. Ataga, MD
University of Tennessee Health Science Center
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Speakers:

Santosh L. Saraf, MD
University of Illinois Chicago
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Curative Therapies in Sickle Cell Disease: Which Patient, What Modality, and When to Refer

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Wake Forest University
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Systemic Barriers to Curative Therapy and Need for Integrated Care

Gene Therapy and Hemophilia A: What Is the Future of Curative Therapy in the Age of Emicizumab?

There have been marked advancements in the treatment of hemophilia A over the past decades.  Adoption of routine prophylaxis to prevent bleeding as the standard of care has led to many children growing into adulthood with normal joint function and adults with improved function and quality of life.  However, there remains a continued treatment burden and bleeding events, including spontaneous hemorrhage. Newer therapeutics with regulatory approval and in late phase clinical trial may further decrease the treatment burden and improve efficacy.  This session will provide an update on gene therapy for hemophilia and discuss gene therapy in the context of new and coming therapies. 

Frank W.G. Leebeek, MD, PhD
The Promise of Gene Therapy for Severe Hemophilia A

In the past decade enormous improvements have been made in delivering AAV-based gene therapy in patients with hemophilia A. In several phase 1 and 3 studies patients reached normal levels of FVIII after a single dose of AAV-delivered FVIII-gene construct, leading to reduced bleeding rates and patients could stop regular FVIII prophylaxis. During follow up of more than five years FVIII activity declined over time, however the majority of patients still have residual FVIII expression enabling them to refrain for prophylaxis. These promising results led to FDA and EMA approval of gene therapy for hemophilia A in 2022.  Longer term follow-up is needed to show us the duration of benefits and (potential) drawbacks of gene therapy compared to current and other novel treatments.

Christine L Kempton, MD, MSc
Unknowns of Gene Therapy and Successes of Medical Therapies for Hemophilia A

Although gene therapy has held the promise of a cure, a consistent cure has yet to be realized. Additionally, the beneficial results seen in hemophilia A gene therapy clinical trials have occurred with meaningful challenges. This talk will review the risks and benefits of gene therapy for hemophilia A and consider them within the context of therapies (emicizumab and Fc-VWF-XTEN fusion protein-eht) that have shown consistent benefit compared with previously available factor VIII products as well as other promising therapies (Mim8, fitusiran, concizumab, and marstacimab) in late-stage clinical trials.

Chair:

Barbara A. Konkle, MD
Bloodworks Northwest
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Speakers:

Frank W.G. W.G. Leebeek, MD, PhD
Erasmus university Medical Center
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The Promise of Gene Therapy for Severe Hemophilia A

Christine L Kempton, MD,MSc
Emory University
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Unknowns of Gene Therapy and Successes of Medical Therapies for Hemophilia A

Making a Match: Optimal Donor HLA and Beyond

Selection of the optimal donor for allogeneic hematopoietic cell transplantation (allo-HCT) involves a comprehensive evaluation of several critical factors. Human leukocyte antigen (HLA) matching has proved to be the most likely crucial parameter in this process. However, several additional criteria can significantly influence allo-HCT outcomes.

Dr. Heather Stefanski will discuss the patient’s likelihood and probability of having a fully HLA-matched donor and finding a suitable donor prior to allo-HCT. She will summarize the historical barriers to transplant, especially for racially and ethnically diverse patients. A special focus will be put on new strategies, including post-transplant cyclophosphamide and abatacept, which can allow for safe and effective use of HLA-mismatched donor sources such as haploidentical donors and mismatched unrelated donors.  Dr. Stefanski will highlight the research evidence that shows alternative donors are a viable and safe option for many allo-HCT recipients.

Dr. Mohamad Mohty will discuss the non-HLA factors which can contribute to further optimizing the selection of a donor prior to allo-HCT. These factors include the age of the donor (especially data favoring younger donors), recipient-donor gender mismatch and its impact on graft-versus-host disease, cytomegalovirus serostatus, and blood type compatibility. Dr Mohty will also briefly discuss the potential role of killer immunoglobulin-like receptor (KIR) matching, and donor-recipient kinship.

By integrating HLA and non-HLA variables into the donor selection process, one can significantly enhance the outcome of patients who are candidates for allo-HCT.

Chair:

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Saint-Antoine Hospital
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Speakers:

Heather E. Stefanski, MD,PhD
CIBMTR® (Center for International Blood and Marrow Transplant Research), NMDP
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HLA: Optimizing the ’Full HLA Match’

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Saint-Antoine Hospital
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Beyond HLA: Optimizing Non-HLA Variables

Smoldering Myeloma: A Case for Early Intervention?

Smoldering Multiple Myeloma (SMM) is a precursor plasma cell disorder characterized by the presence of an M-component concentration equal to or greater than 3 g/dL and/or bone marrow plasma cell infiltration of 10-59%, without any myeloma-defining events. The outcome is heterogeneous, especially regarding progression to active disease such as Multiple Myeloma or other plasma-cell related disorders. The current standard of care is observation, but ongoing and completed research suggests it is possible and straightforward to identify SMM patients at high risk of progression to Multiple Myeloma (50% at 2 years).

This session will feature two clinical cases that highlight the issues involved in determining whether early treatment is the optimal approach for managing this precursor plasma cell disorder and if early treatment is the only way to potentially cure Multiple Myeloma.

Dr. Mateos will discuss the role of early treatment in Smoldering Myeloma as a strategy to cure the disease. She will present evidence supporting the benefits of early intervention and its impact on long-term outcomes.

Dr. Ramasamy will provide a counterpoint to this approach, addressing the costs and toxicities associated with early treatment. He will discuss the potential downsides and argue for a more conservative management approach based on observation.

We look forward to a dynamic and educational session that will provide valuable insights into the management of Smoldering Multiple Myeloma

Chair:

Maria-Victoria Mateos, MD, PhD
University Hospital of Salamanca/IBSAL/Cancer Research Center-IBMCC (USAL-CSIC)
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Speakers:

Maria-Victoria Mateos, MD, PhD
University Hospital of Salamanca
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Point: Yes, That is the Only Way We Can Cure Myeloma?

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University of Oxford
Oxford, United Kingdom
Counterpoint: No, It Just Adds Cost and Toxicity?

The Clone Wars: Myeloid Neoplasia Risk in Clonal Hematopoiesis

Clonal expansions in the hematopoietic system, referred to as clonal hematopoiesis (CH), is common throughout life and associated with significant clinical outcomes, including increased risk of hematologic cancers, all-cause mortality and nonmalignant conditions. Recently, clinical definitions of disorders within the spectrum of CH have been introduced, including clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS), providing the framework for harmonized classification and registration. However, while clone features and dynamics have been well described, relevant key issues remain to be clarified.

In the first presentation, Dr. Malcovati will provide an overview of biological underpinnings and clinical implications of CH. In addition, the spectrum of clonal cytopenias, as well as current classification framework and its pitfalls, will be critically discussed. Finally, the contribution of intra- and extra-clonal factors to clonal evolution, and the models developed for predicting the risk of developing myeloid neoplasms and the trajectory of evolution will be reviewed, as a basis for informing early-detection and prevention strategies.

In the second presentation, Dr Grønbæk will discuss the clinical management of CH in everyday clinical practice, focusing on how individual/patients with CH are identified, including the incidental finding, which emphasizes the need for informed consent before sequencing. She will elaborate on the importance of identifying and following high-risk individuals/patients while sparing low risk individuals unnecessary worries. The importance of enrolling these individuals/patients in clinical trials will be discussed including the optimal trials designs. Examples of ongoing trials will be presented and critically appraised.

Chair:

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University of Pavia and S. Matteo Hospital
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Speakers:

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University of Pavia
Piazzale Golgi 2, Italy
Predicting Risk of MN in CH

Kirsten Gronbaek, Professor, MD, DMSc
Kirsten Grønbæk
Copenhagen N, Denmark
How to Follow CH Patients