Attendance

Titilope Fasipe (Chair)
Julie Panepinto (Exec. Secretary, NHLBI)
Santosh Saraf
Traci Mondoro (NHLBI)
Vivien Sheehan
Idalia Yabe (NHLBI)
Nancy Green
Juan Salomon (NHLBI)
Stella Chou
Akary Nyan Win (NHLBI)
Lakshmanan Krishnamurti
Yogen Saunthararajah

Speakers

Charles Jonassaint
Elizabeth Klings
Ankit Desai
Allison King
Jeffrey Lebensburger
Teonna Woolford
Eboni Lance

Meeting Minutes

Welcome and General Introductions

On January 14th, 2025, the Division of Blood Diseases and Disorders (DBDR) from the National Heart, Lung, and Blood Institute (NHLBI) convened a virtual meeting with the Sickle Cell Disease Advisory Committee (SCDAC). The agenda for this SCDAC meeting was long-term follow-up (LTFU) for individuals with sickle cell disease (SCD) who have undergone transformative therapies. The meeting commenced with opening remarks from Dr. Julie Panepinto, the Division Director, who welcomed NHLBI staff, committee members, and guest speakers, and emphasized the importance of the committee’s input in advising the NHLBI director and shaping future directions in SCD management.

The primary objective of this meeting was to address the long term impact of transformative therapies, such as gene therapy and hematopoietic stem cell transplantation, on four critical end organs affected by SCD: the heart, lungs, kidneys, and brain. Dr. Panepinto underscored the need to understand whether these therapies stabilize, improve, or exacerbate end organ damage, thus better informing the SCD community about the long-term effects of these treatments.

Dr. Titilope Fasipe, Chair of the SCDAC, facilitated introductions, inviting members to share their names, affiliations, and perspectives. The participants represented an array of experts in the fields of hematology, cardiology, pulmonology, and neurology, as well as individuals living with sickle cell disease. The collaborative environment underscored the importance of integrating patient experiences with clinical expertise.

Overview of the Cure Sickle Cell Initiative (CureSCi), Natural History Data Resource (NHDR), and the FDA LTFU Guidance

Dr. Traci Mondoro delivered a comprehensive overview of the CureSCi, that included the gene therapy clinical trials and NHDR funded by the initiative. The NHDR provides phenotypic data from SCD participants that will be used as contemporaneous controls for gene therapy clinical trials. Dr. Mondoro also discussed the FDA’s guidance on LTFU for gene therapy recipients, highlighting the need of 15-year monitoring to assess delayed adverse events and evaluate therapy efficacy. She highlighted the critical need for collaboration with industry partners to develop a standardized follow-up protocol that benefits both patients and healthcare providers.

The meeting featured several expert presentations, each focusing on a specific end organ affected in SCD:

Pulmonary Considerations: Dr. Elizabeth Klings discussed the significant cardiopulmonary complications in SCD, including acute chest syndrome and pulmonary hypertension. She advocated for thorough pulmonary evaluations, including pulmonary function tests and six-minute walk tests, to effectively monitor lung function post-therapy. Dr. Klings emphasized the impact of myeloablative conditioning regimens, such as busulfan, on lung health and the necessity of monitoring for potential pulmonary toxicities.

Cardiac Health: Dr. Ankit Desai highlighted the prevalence of heart failure and arrhythmias in individuals with SCD, noting the potential risks for cardiac remodeling and fibrosis. He discussed the utility of echocardiography and cardiac MRI in assessing cardiac function and structure. Dr. Desai also discussed the potential predictive role of biomarkers like interleukin-18 for predicting cardiac outcomes, advocating for a nuanced approach to cardiac monitoring.

Central Nervous System Impact: Dr. Allison King addressed the cognitive and cerebrovascular consequences of SCD, particularly the high incidence of silent cerebral infarcts and overt strokes. She outlined the importance of conducting neurocognitive assessments and utilizing brain imaging to monitor cognitive function post-therapy. Dr. King also emphasized the need for educational interventions and accommodations to support individuals experiencing cognitive deficits.

Renal Function: Dr. Jeffrey Lebensburger focused on the prevalence of chronic kidney disease (CKD) among individuals with SCD, stressing the importance of early detection and intervention. He recommended regular monitoring of estimated glomerular filtration rate (eGFR) and albumin-creatinine ratio to assess kidney function and track any changes over time. Dr. Lebensburger highlighted the potential for transformative therapies to improve or stabilize renal function, providing a more optimistic outlook for patients.

Community and Ethical Considerations

The SCDAC members addressed important community concerns, such as the differentiation between the types of gene therapy and the challenges patients face in accessing post-transplant care. There was a robust discussion on the ethics of clinical trials and patient follow-up after transformative therapies. Participants acknowledged the need for clear communication and collaborative decision-making with patients, particularly concerning the risks and benefits of different therapeutic options.

Long-Term Care Models

A key theme of the meeting was the development of long-term care models for SCD patients. Dr. Panepinto and other participants discussed the potential of multidisciplinary care models, similar to those used in oncology survivorship clinics, to provide comprehensive LTFU care. The importance of creating sustainable and accessible care models that can be adapted to various clinical settings was emphasized, ensuring that all patients receive the support they need post-therapy.

Discussions throughout the meeting centered on the challenges of implementing LTFU protocols, including logistical considerations, patient engagement, and the integration of patient-reported outcomes. Attendees recognized the importance and the need of standardized protocols that are adaptable to various clinical settings and accessible to all patients, regardless of geographic or economic barriers.

Future Directions

Looking ahead, the NHLBI plans to further develop a LTFU protocol, engaging with stakeholders and exploring collaborative opportunities with industry partners. The meeting underscored the importance of ongoing research and the need for a patient-centered approach in developing and implementing this protocol. Through collaboration and open dialogue with the SCD community, the NHLBI aims to advance the understanding of transformative therapies and their long-term impact on individuals with SCD.

Dr. Fasipe concluded the meeting by calling for continued collaboration among researchers, clinicians, and the SCD community. Participants acknowledged the need for comprehensive data collection and analysis to inform future therapeutic developments and improve patient outcomes. By fostering a collaborative and patient-centered approach, the NHLBI aims to advance the understanding of transformative therapies and their long-term impact on individuals with SCD.

In summary, this SCDAC meeting served as a crucial platform for discussing the complexities of LTFU after transformative gene therapies for SCD and provided valuable insights into the challenges and opportunities in this rapidly evolving field. By addressing these multifaceted challenges, the NHLBI and its partners are working towards a future where individuals with SCD can experience improved health and quality of life.