NHLBI Sickle Cell Disease Advisory Committee |NHLBI

Attendees

NHLBI Staff: Dr. Julie Panepinto (Executive Secretary), Dr. Traci Mondoro, Juan Salomon Andonie, Dr. Idalia Yabe

Committee Members: Dr. Titilope Fasipe (Chair), Dr. Stella T. Chou, Dr. Nancy Green, Dr. Santosh Saraf, Dr. Yogen Saunthararajah, Dr. Vivien Sheehan, Dr. Eboni Lance

Ad hoc Subject Matter Experts: Dr. Sarah Reeves, Dr. Angela Rivers, Dr. Oyebimpe Adesina, Mr. Moses Akpan, Ms. Pamela White, Dr. Cece Calhoun

Guest Speakers: Dr. Lauren Klein (Vanderbilt), Dr. Ellen Fung (UCSF), Dr. Amanda Brandow (Medical College of Wisconsin)

Opening Remarks

Dr. Panepinto welcomed attendees and reiterated the committee's charge to advise NIH, NHLBI, and Blood Division Directors on SCD research priorities. The meeting theme — nutrition and SCD — was framed as critically relevant, understudied, and aligned with NIH's MAHA strategic framework. Dr. Fasipe highlighted holistic approaches to SCD care and the importance of lived-experience perspectives, nutrition, gut microbiome research, and food access.

Presentation Summaries

Dr. Lauren Klein – "Improving Nutrition and Growth in Children with SCD: Evidence Gaps and Lessons from Northern Nigeria" Dr. Klein presented evidence that children with SCD face elevated nutritional risk due to increased caloric and protein demands from chronic hemolysis, ongoing erythropoiesis, inflammation, and elevated cardiac energy expenditure — often compounded by reduced dietary intake — leading to growth faltering. Drawing on studies from Nigeria and high-income countries, she identified food insecurity, changing nutritional phenotypes, and the relationship between hydroxyurea and growth as key research priorities relevant to both low- and high-income settings.

Dr. Ellen Fung – "Micronutrients Matter: The Importance of Nutrition for Optimal Health in Patients with SCD" Dr. Fung reviewed micronutrient deficiencies in SCD, noting that poor diet, medication side effects, malabsorption, renal losses, and hypermetabolism all contribute. Deficiencies in vitamin D, folate, calcium, zinc, vitamin C, and protein are common. Vitamin D and zinc have the strongest evidence: vitamin D deficiency is linked to worse pain, inflammation, and emergency utilization, while zinc deficiency is associated with poor growth and increased complications. High-dose vitamins C and E showed no benefit and may worsen outcomes. Key gaps include the absence of standardized nutrition assessments, SCD-specific guidelines, and adequate trials across genotypes and age groups.

Dr. Amanda Brandow – "Investigating the Intestinal Microbiome in Individuals with SCD" Dr. Brandow presented findings showing that individuals with SCD have significantly lower gut microbial diversity and depletion of short-chain fatty acid (SCFA)-producing bacteria compared to controls. Lower heterogeneity was associated with higher acute pain frequency. Antibiotic exposure, opioid use, hydroxyurea, and disease-related gut barrier dysfunction were identified as likely contributors to dysbiosis. Proposed therapeutic approaches include SCFA supplementation, prebiotics, probiotics, and dietary interventions.

Discussion Highlights

The committee emphasized the dual burden of undernutrition and obesity, the limitations of BMI, and the value of DEXA for body composition assessment. Members advised against SCD-specific growth charts that could normalize poor growth, and called for longitudinal data on optimal growth trajectories. Food insecurity was identified as a major driver of outcomes. Additional priorities included inclusion of all SCD genotypes, effects of G6PD deficiency, organ dysfunction, and caregiver/maternal mental health. Longitudinal registries, "food as medicine" policy opportunities, and interdisciplinary collaboration were highlighted as key action areas.

Recommendations

1. Identified the need to develop multidisciplinary, evidence-informed clinical nutrition guidelines for SCD.
2. Support research focused on caloric, protein, and micronutrient needs in the context of current therapies (hydroxyurea, transfusion, biologics, and gene therapy) to inform nutritional requirements across the lifespan.
3. Support longitudinal studies of growth and nutrition — including pubertal development, body composition, bone mineral density, and long-term nutritional status — using registries and harmonized EMR data.
4. Expand intervention research beyond single nutrients to multi-nutrient and whole-diet trials reflecting real-world dietary patterns, with adequate duration, functional biomarkers, and statistical power.
5. Invest in mechanistic studies in human and animal models to clarify how nutrient deficiencies influence hemolysis, inflammation, pain, immune function, red cell stability, and organ damage.
6. Advance microbiome research to characterize the impact of dysbiosis and SCFA depletion on SCD pain and other complications, identify key drivers of dysbiosis, and evaluate interventions including prebiotics, probiotics, symbiotics, dietary fiber, and direct SCFA supplementation.
7. Distinguish nutritional deficiency replacement from pharmacologic micronutrient use, recognizing that each requires different clinical and research frameworks, endpoints, and trial designs.
8. Identified the need to integrate nutritional status, micronutrient monitoring considering compartmental studies, and DEXA-based body composition assessment into studies of disease-modifying and curative therapies.
9. Include all SCD genotypes and important co-occurring conditions (e.g., G6PD deficiency) in funded trials to better define genotype-specific nutritional phenotypes.
10. Identified the need to address food insecurity and social determinants of health through validated screening, outcomes research, and policy opportunities such as "food as medicine" programs.
11. Strengthen interdisciplinary and cross-sector collaboration by engaging experts across relevant fields and incorporating patient advocates and lived experience into research design and priority-setting.

Closing Remarks

Dr. Panepinto thanked all participants, noted that recommendations would be posted publicly with the meeting minutes per FACA requirements, and adjourned the meeting.

For those interested, the full meeting is available on NIH Videocast.

Agenda

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.

Welcome and General Introductions

Dr. Julie Panepinto, Director for the Division of Blood Diseases and Resources (DBDR), and Executive Secretary of the Sickle Cell Disease Advisory Committee (SCDAC), opened the meeting by introducing the new chair of the SCDAC, Dr. Titilope Fasipe.  Dr. Panepinto explained the reason for the meeting, which was to provide NHLBI Sickle Cell Disease (SCD) and Cystic Fibrosis (CF) portfolio updates in response to the request made by the SCDAC members to NHLBI.

Dr. Fasipe thanked the outgoing members whose term ended on June 30, 2024, and welcomed the candidates who are in process of becoming members. She provided time for SCDAC members to introduce themselves followed by Dr. Panepinto who introduced the NHLBI team from the Portfolio Analysis and Evaluation Branch (OPAE), who prepared the analysis on NHLBI SCD and CF portfolios to be presented and discussed.

NHLBI SCD and CF Portfolio Updates

Dr. Lindsay Scott from OPAE presented the analysis of the SCD portfolio, as well as a portfolio comparison between SCD and CF at NHLBI alone, and across ICs at the NIH. The interest for the analysis stemmed from two peer reviewed publications1,2 which argued that the NIH provided more research funds per affected individual with CF than for SCD. The analyses presented were structured in an additive way comparing the funding trends between the two over a sixteen year time frame from 2008 to 2023.  Among the findings, it was noted that the overall funding for both diseases is similar, and that the NHLBI has increased its investment in SCD since the beginning of the reported timeframe. However, the number of applications has remained flat for both diseases despite SCD having more than double the patients than CF. The analyses were made using the Centers for Disease Control (CDC) estimates of US population affected by CF (35,000) and by SCD (100,000).

General Discussion

Dr. Fasipe opened up the session for questions and comments where the SCDAC committee members took the opportunity to thank the NHLBI for putting together the rich data presentation. The conclusion from the analysis was that there is a robust and equivalent investment to SCD compared to CF.  Dr. Panepinto commented on the difficulty to measure and evaluate what the right value is to invest per affected individual on any particular disease, posing the question “how much is enough?” Instead, she challenged the members to encourage their peers to submit more grant proposals to NHLBI to help increase the number of awards toward SCD research.  The consensus was that the flat number of grant applications for SCD was likely due to the reduced number of investigators applying for NIH funding.  In contrast to SCD where most of the research funds are coming from the NIH, there are numerous funding opportunities and an enormous lobbying and investment for CF coming from the CF Foundation (non-NIH), especially in the clinical trials/drug development space. This emphasized the importance for SCD researchers to submit grant applications as they rely heavily on NIH funding support.

The topic on the type of applications most commonly received/awarded and the conformation of study sections and inclusion of hematology expertise on them was discussed. Dr. Traci Mondoro explained that although some awards such as the K and SBIR awards are reviewed by NHLBI study sections, other applications such as R01s and Fs are managed by the Center for Scientific Review (CSR) and do not belong to any one particular institute. As a result, Dr. Panepinto made a plea to the members to accept when they are asked to participate as a reviewer in study sections.  She also briefly touched on how study sections are assembled and warned that some requirements and rules when forming a study section could make some candidates ineligible to participate.  A study section requires a balance based on geography, gender, as well as other demographic factors, and rules to ensure a diverse and unbiased representation. The idea for a SCD study section was brought up, specifically for K awards and the need to resolve the fact that there are not enough SCD experts to evaluate them, as well as the need to address the recusal rules since there are many collaborations between SCD researchers due to the small research community, which further reduces the availability of investigators who can participate as reviewers.  Dr. Mondoro emphasized the importance for trainees who are thinking to apply for K awards to contact the corresponding Program Officer at DBDR to discuss their particular interests, and what kind of expertise would be valuable for their ideal review.

Members asked whether or not the comparative analysis between SCD and CF included training grants such as K awards. The OPAE team responded that they were included in all of the applications or award cohorts reviewed; however, the main analysis was focused on Research Program Grants (RPGs), which do not include K awards. This topic could be a follow-on upon request from the SCDAC and DBDR leadership.  Dr. Fasipe asked how NHLBI/DBDR staff reacted after seeing the data  presented in terms of the level of satisfaction in the results, and whether or not SCD will remain a priority.  Dr. Panepinto alluded to her previous response stating there is much more to be done to continue improving the lives of people with SCD, “we are not nearly where we should be in advancing the quality of life, there is a lot more to do and sickle cell disease will remain a priority.”

Topics for next SCDAC meeting

The goal moving forward is to have two meetings per year, one virtual and the other in person.  The next SCDAC meeting will be scheduled at the end of January 2025 and will be virtual. Members were asked to suggest topics to be discussed, and the following topics were recommended:

• Discuss the importance of funding clinical trials as it pertains to SCD as well as information on the proportion of funding clinical trials v. basic science
• Perform similar analysis to what was presented, but related to research topics of awarded grants.  For example, transfusion versus neurologic, pain, gene therapy, etc. to identify research gaps and be able to direct new investigators to fill those gaps
• Determine how to increase applications for minority supplements submitted for SCD grants
• Investigators and clinicians are going to industry, potentially due to the lack of funding, or burnout from clinical responsibilities. Need to identify ways to attract, develop and retain physician scientists and researchers with great potential in the academic space while at the same time encourage minorities in research
• Identify ways in which patient and advocacy can be integrated into the SCDAC. Dr. Mondoro and Dr. Panepinto addressed the question of how community members can contribute in the SCDAC meetings and made clear that the DBDR wants to balance the meeting by providing a space to the community. The importance of Community Based Participatory Research (CBPR) was discussed including community advocate and warriors. Research cannot be done without the community as the community helps guide researchers and keep them anchored in the reality they are trying to address. Ideas recommended to improve community involvement included the following:
  • Schedule time outside the SCDAC meeting to discuss ideas, identify priorities from the community and debrief with the community members on the topics to be discussed before the SCDAC meeting
  • Identify current progress and disparities within NHLBI, and how to disseminate that information to the community
  • Use other NHLBI sponsored venues like the Annual SCD Research meeting that takes place in August as a space where the community voice can be heard
  • The NHLBI has the Cure Sickle Cell Initiative, which has an integrated space for the community, and it’s important for this advisory board to be aware of and understand it’s mission
  • Awareness of research findings from the NHLBI funded research that are of interest to the community and how to disseminate research findings of interest to the community.

Understanding the various ways that NHLBI interacts within the SCD community may help create one vision.

The meeting was adjourned.

Titilope Fasipe, MD, PhD
Julie A. Panepinto, MD, MSPH

Agenda

Welcome and General Introductions

On behalf of Dr. Julie Panepinto, Director for the Division of Blood Diseases and Resources (DBDR), Dr. Traci Mondoro, Chief of the Translational Blood Diseases and Resources Branch, opened the meeting by introducing the Sickle Cell Diseases Advisory Committee (SCDAC) members and NHLBI speakers. Dr. Mondoro emphasized the need to change the structure of future SCDAC meeting by having more dialogue between members and engaging in a two-way conversation, rather than one-sided presentations for a more effective meeting. She also mentioned the possibility of returning to in-person meetings (possibly a hybrid model) to facilitate more engaging discussions, all of which was well received by committee members.

NHLBI SCD program updates

Dr. Andrei Kindzelski presented NHLBI clinical trial mechanisms while Dr. Traci Mondoro presented an overview of SCD programs, including updates on the portfolio. During the discussion, members expressed appreciation for time added to the agenda to allow for discussion and feedback. Recommendations for next year’s SCDAC meeting included for NHLBI to discuss different funding opportunities, incorporate specific funding mechanisms, present data analyses on NIH funding in SCD, and discuss the imbalance in the field of hematology, the latter due in part to the limited number of experts in the field available to participate on review panels. NHLBI agreed with the recommendations and encouraged colleagues in hematology to mentor young investigators and urge them to serve on review panels. In terms of applying to the various grant mechanisms, NHLBI highly recommends to first speak with a program officer to learn more on the procedure and process of applying. Second, every institute and center (IC) has their own strategy to support a clinical trial and as a result there are a number of mechanisms available to choose from. It is important for investigators to carefully review the criteria and reach out to the different ICs to help strengthen and increase the chances for a more successful application.

The committee members had discussions that centered on several other key points that included: the importance of NHLBI leadership to support SCD research and portfolio analyses for examining SCD funding and investment over time, and how to best support the infrastructure needed to conduct clinical trials.

NHLBI staff presented NHLBI initiatives and collaborations such as the NHLBI SickleInAfrica program, BloodSafe program; the Recipient Epidemiology and Donor Evaluation Study (REDS) program, and the Cure Sickle Cell initiative (CureSCI), which includes two ongoing gene therapy clinical trials and is accruing successfully. CureSCI also includes the following: the Natural History Data Resource, the Clinical and Economic Impact (CEIA) analysis group, the Community Input Panel, and work with the California Institute for Regenerative Medicine (CIRM). Members of the committee recommend for the CureSCi to include work to better understand existing scientific gaps in SCD, how to address them and involve the community in this work.

Committee members recommended for NHLBI to build a stronger collaboration with the ASH Clinical Research Hub better understand community needs when prioritizing future work; collaboration with the Gates Foundation whose current emphasis is on HIV; and finally, a closer collaboration with other ICs. Such as the Center for Translation Research and implementation Science (CTRIS), as well as the National Institute of Child Health and Human Development (NICHD), for potential co-funding of clinical trials with the Blood Division.

Leveraging Networks to Conduct Successful Clinical Trials in Sickle Cell Disease 

Dr. Kindzelski presented on the Strategies to Innovate Emergency Care Clinical Network (SIREN) and on Pediatric Emergency Care Applied Research Network (PECARN). He explained that SIREN is dynamic and has well-developed clinical trial methodology center which offers regular webinars and courses for investigators both within and outside the network. An interesting aspect of SIREN is that its mission also includes SCD and is not limited to trauma. However, to be part of the SIREN umbrella, projects must undergo a specific evaluation involving the joint communication between SIREN and NHLBI. The second network Dr. Kindzelski discussed was PECARN, a federally funded network which features seven research node center centers across the country and serves approximately one million children per year. Although PECARN has a complex structure, it is easy to get in touch with them. However, in order to do clinical research using PECARN infrastructure or utilize PECARN resources such as their research data sets, the applicant must have funding for the research that is being proposed (for example federal funding).

Dr. Traci Mondoro presented on NICHD networks in the absence of the NICHD speaker, who was unable to join the meeting. Dr. Mondoro explained that although NICHD has a small budget, they fund infrastructure and have networks that support clinical trials that can be leveraged by investigators and consortia, so that NHLBI does not need to recreate clinical trial networks. The networks discussed were: the Neonatal Research Network, which is comprised of 18 centers, focuses on transfusion, but it is not necessarily related to SCD; the Maternal-Fetal Medicine Network, which consists of more than 10 centers and has an open Request for Information (RFI) for pregnant women with SCD; the Psychiatric Intensive Care Unit (PIC-U) Network, and the Collaborative Pediatric Critical Care Research Network (CPCCRN), which are other smaller, but significant networks that facilitate work with animal models and therapeutics. More information will be obtained from NICHD and shared with the SCDAC members. In addition, NINDS leads the Common Fund’s Helping to End Addiction Long-term (HEAL) initiative that has specific SCD funding opportunities and also multiple pain focused initiative that can leveraged for pain focused funding.

Dr. Nancy DiFronzo presented on the Bone Marrow Transplant Clinical Trials Network (BMT CTN) which was established in 2001 by NHLBI. It supports 20 transplant centers or consortia along with one data coordinating center (DCC). Dr. DiFronzo explained that the BMT CTN steering committee oversees governance, reviews every trial concept coming their way, deciding which ones to pursue. All their meetings are open, which means investigators from core of affiliate centers can participate. Also, the BMT CTN can explore partnerships with industry; however, these partnerships require interactions with NHLBI & the DCC, as well as budget development to provide necessary support for studies. This network uses the Center for International Blood and Marrow Transplantation Research (CIBMTR) for data collection and evolves over time based on requirements. All data from BMT CTN must be posted in the Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC).

General Discussion & Committee Recommendations 

The last segment of the meeting was open for a general discussion, and for additional committee recommendations, which are listed below:

1. Established infrastructure for clinical trial networks with more focus on classical hematology to elevate scientific impact and develop better and less expensive trials leading to more affordable therapies. The model of Pragmatic Clinical Trials can leverage Electronic Health Records (EHRs) for more efficient trial management.
2. Creation of a specialized sickle cell study section to boost funding opportunities specific to SCD, and a strategy to route grants through such study sections that have an understanding of SCD.
3. Establish and follow-up cohorts from pediatrics to adults to understand which patients will develop end-organ failure, late stroke, or other SCD complications.
4. Foster advocacy within the NIH for resources to target patients with SCD and advocate for research in the SCD field.
5. Foster community-based participatory research, which should include a Community Advisory Board for each clinical trial site, and a central version, bringing lived experiences to the table.
6. Support gene therapy research with an implementation focus to reduce the time window for the development of new interventions.
7. Invest in disparities and implementation research.
8. Include international representatives in the SCDAC to increase innovation in sickle cell research globally as well as to obtain current updates from global advances in SCD research. Response from NHLBI: Per the SCDAC Charter, members have to be US citizens or have green card/permanent resident card.
9. Develop notices of funding opportunities (NOFOs) to advance research related to pregnancy, and aging in SCD because those topics are currently understudied. 
10. Increase resources for mental health interventions for patients with SCD.

Marsha J. Treadwell, PHD
Julie A. Panepinto, MD, MSPH

Description

Description

Dr. Keith Hoots, the Division Director at the Division of Blood Diseases and Resources (DBDR) opened the meeting by greeting the Sickle Cell Disease Advisory committee (SCDAC) members. He reminded everyone in attendance that the committee follows the regulations set forth by the Federal Advisory Committee Act (FACA).

Dr. Nahed El Kassar, medical officer within the DBDR ,welcomed everyone and thanked the new members for going through the onboarding process. After reading a disclosure in accordance with the legal requirements of FACA, the committee chair Dr. Allison King took the lead.

After general introduction of each committee member, speaker and NHLBI member, Dr. Asif Rizwan from DBDR presented the HEAL initiative RFAs: HEAL Non-addictive Analgesic Therapeutics Development to Treat Pain (R61, U19, UG3/UH3) Secondary NHLBI sign-on.

The second presentation was by Dr. Courtney Fitzhugh, M.D, Lasker Clinical Research Scholar, Laboratory of Early Sickle Mortality Prevention on the NIH Experience in Nonmyeloablative Allogeneic Transplant for SCD.

SCD leads to debilitating painful episodes as well as subclinical and overt organ damage. In a publication on 225 patients, primarily with Hb SS disease, data shows that even though 60% of patients were taking hydroxyurea, the median survival age was only 48 years. Thus patients with SCD continue to experience early mortality (DeBaun M et al. Blood, 2019. 133(6): 615-617). In another paper, the cumulative survival in 150 adults was followed from 2003 to 2016 and patients were screened for heart, lung, and kidney disease. They found that survival was significantly higher in patients who had < 1 organ involved with a mean time to death of 14.0 years as compared to those who had more than 1 organ involved with a mean time to death of 7.8 years. (Chaturvedi S et al. American Journal of Hematology, 2018. 93(9): 1153-1160).

In 1999 there were 2 major obstacles for curing adults with sickle cell disease. The first step was to provide a curative option for the majority of adults with SCD that are not eligible for the standard transplant because of age and co-morbidities including heart, lung, and kidney disease. Dr. Fitzhugh and her colleagues therefore sought to develop a less toxic (or nonmyeloablative) regimen which focused on drugs not only to suppress the immune system but also to re-educate the immune system, leading to immunologic tolerance, so that donor and recipient cells would no longer recognize each other as foreign, therefore decreasing the incidence of graft rejection and graft versus host disease (Hsieh MM, Kang E, Fitzhugh CD, et al. NEJM, 2009. 361(24): 2309-2317). The second obstacle was the availability of transplant donors. While the HLA-matched sibling protocol was very successful, <15% of patients with SCD have an HLA-matched sibling donor. Therefore, the goal was to develop a nonmyeloablative haploidentical (or half-matched) protocol for adults with severe SCD. Using mice models, Dr. Fitzhugh et al showed for the first time that sirolimus and post-transplant cyclophosphamide work synergistically to induce tolerance (Fitzhugh CD et al. Bone Marrow Transplantation, 2013. 48(10): 1335-1341).

Between 2009 and 2017, results translated into a phase I-II trial for adults with severe SCD not eligible for other curative therapies and with severe organ damage. The study contained 3 cohorts. Patients in the first cohort did not receive post-transplant (PT)-cyclophosphamide (Cy) and 3 patients were transplanted. One of the 3 patients engrafted but lost the graft at 7 months post-transplant. Stopping rules were built into the study so that if too many patients either rejected their grafts or developed moderate to severe GVHD, the study would move to the 2nd cohort. Based on the three patients losing their grafts, stopping rules were met and the study moved to the 2nd cohort where 1 dose of Cy was given at 50mg/kg on day 3 post-transplant. Eight patients were transplanted in the 2nd cohort. Five of eight patients engrafted and only two remain free of SCD. When stopping rules were again met, the study advanced to the third cohort which included 100mg/kg Cy in divided doses on days 3 and 4 post-transplant. Ten of twelve patients engrafted, but only six remain free of SCD. The study met stopping rules and closed to accrual. Despite enrolling such sick patients, none died before 100 days post-transplant. One patient in the third cohort died as a result of the transplant at 6 months post-transplant. Four other patients died after rejecting their grafts between 3 and 8 years post-transplant. The major problem was that either patients failed to engraft, or they engrafted and then subsequently acutely rejected their graft between days 60 and 100 post-transplant. Because no significant GVHD developed, the investigators concluded that additional upfront immunosuppression would decrease the graft rejection rate while avoiding unacceptable GVHD or viral disease.

Pentostatin and cyclophosphamide were shown in a mismatched murine model and in humans to deplete lymphocytes and promote stable mixed chimerism. In 2017, the same group designed a phase I-II nonmyeloablative haploidentical trial which included pentostatin and Cy preconditioning starting at -21 days before transplant with the goal of decreasing the incidence of graft rejection. Alemtuzumab starts at -7 days before transplant followed by 400cGy TBI in divided doses. Patients also receive sirolimus starting at 4 days post-transplant. The study is currently ongoing.

From previously reported 67 patients with SCD who underwent nonmyeloablative transplant at the NIH and were prospectively followed, Dr. Fitzhugh et al. evaluated the percentage of donor myeloid chimerism (DMC) sufficient to reverse sickle cell disease. They were most interested in donor myeloid chimerism because it tracks the percentage of donor erythroid chimerism in the bone marrow. Three patients whose donors had sickle cell trait initially achieved high donor myeloid chimerism levels, but they slowly fell over time. As long as the DMC was at least 20%, the patients HbS was close to their donors’ HbS at <50%. As the DMC decreased below 20%, HbS rose above 50%, and all three patients had return of their SCD. A mathematical model was developed which showed the reason only 20% DMC is necessary is due to the vast differences in RBC survival of 3 months for donor RBCs and only 5 to 20 days for RBCs in patients with SCD.

In conclusion, in the HLA-matched sibling setting, myeloablative conditioning has high efficacy in children. Non-myeloablative conditioning aimed at tolerance induction has a lower rate of GVHD despite the use of PBSCs, but appears to have a higher rate of graft rejection. Newer studies are being developed in an attempt to decrease the graft rejection rate. With haploidentical HSCT, recent published studies including PT-Cy have event free survival (EFS), GVHD, and mortality rates similar to the HLA-matched sibling setting. As tricuspid regurgitation velocity (TRV), (a biomarker that when elevated is associated with early mortality), decreases after non-myeloablative allo-HSCT (results presented by Dr. Fitzhugh at ASH in Dec 2021), this approach may positively impact survival. And finally, long-term follow-up is critical to assess late effects of curative therapies for patients with SCD.

The third presentation was by Dr. Phuong Vo, Assistant Professor of Medicine University of Washington, Clinical Research Division, Fred Hutch presented Radioimmunotherapy (RIT)-based conditioning regimen to reduce toxicity post-transplant for nonmalignant hematologic disorders, research funded by NHLBI and NCI. She presented on behalf of Dr. Sandmaier.

Dr. Vo started with a background explaining that the ideal conditioning regimen enables engraftment with limited early toxicity and decreased late effects. The basic elements of RIT are 1-the use of a specific antigen: expressed on the target cell surface and not expressed on non-hematopoietic normal tissues; 2-the radioisotope selection and its interaction with tumor cells. The main advantage of RIT is reduction of late toxicity. It is selected based on different properties including its half life and its interaction with specific tumor cells. Radioisotopes used are: Iodine 131 with 8.07 days half-life; Yttrium-90 β with 2.7 days half-life and Astatine-211 α with7.2 hours half-life. The antigen used by Fred Hutch team is CD45, a tyrosine phosphatase expressed on virtually all leukocytes. Targeting CD45 contributes significant lympho-myelosuppression that necessitates HCT to reconstitute hematopoiesis.

Dr. Vo presented Phase 1 trial of 131I-anti-CD45 Ab for older AML and MDS patients results published in Blood 2009; 58 patients- Median age 63, range (50-74 years) 86% with refractory/active disease. Results were encouraging with 38% 3-year DFS. Dr. Vo et al also published in Haematologica, 2019 the results of their CT 90Y-anti-CD45 Ab followed by RIC-HCT for high risk MDS/AML patients (NCT01300572) . The 1-year estimate of relapse was 41% in 15 patients treated in this protocol.

Alpha-emitters have favorable qualities compared to β particles: Short path length, high linear energy transfer (LET) and short half-life. This was the reason for switching the Astatin 211At, conjugated to anti-CD45 to induce myelosuppression at Fred Hutch; results in mouse models were published in Cancer Res 2009, then in Canine models in Blood 2012 where in these models there was achievement of rapid and stable donor engrafment. Eight dogs conditioned with a dose range 155-625 uCi/kg achieved rapid and stable donor engraftment. In research published by Aya Nakaya et al.,Transplantation and Cellular Therapy 2021, authors found that 211At-Anti-CD45 RIT conditioning overcomes graft rejection pre-sensitization model in a canine model.

Finally, Dr. Vo presented protocol 9595 (NCT 03128034) funded by NCI and published in Sandmaier, et al. TCT 2021: Phase I/II 211At-BC8-B10 Before Donor Stem Cell Transplant in Treating Patients With High-Risk Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Myelodysplastic Syndrome, or Mixed-Phenotype Acute Leukemia. Patients received 211At-BC8-B10 intravenously (IV) over 6-8 hours on day -7 and fludarabine phosphate IV over 30 minutes on days -4, -3 and -2; then they underwent TBI and peripheral blood stem cell transplant (PBSC) on day 0; received cyclosporine orally or IV every 12 hours on days -3 to 56 and then tapered to day 180, or continuing to day 96 and then tapered to day 150; patients also received mycophenolate mofetil PO or IV (first dose to occur 4-6 hours after PBSC infusion) every 12 hours on days 0-27, or every 8 hours on day 0 and then reduced to every 12 hours on days 30-40. Patients with HLA-matched unrelated donors received sirolimus PO once daily (QD) on days -3 to 150 and then tapered to day 180. After completion of study treatment, patients were followed up at 100 days and then at 6, 9, 12, 18 and 24 months. With a median follow-up of one year, 35% of these high risk patients remain in relapse free survival.

This protocol has inspired protocol FH 9524 211At-Anti-CD45 for nonmalignant hematologic disorders (NCT 04083183), funded by the NHLBI, with the goal of developing a safe and effective regimen that enables stable engraftment without increasing the risk for early toxicities, such as GVHD and late effects secondary to TBI. Arm A (HLA-MRD, -MURD, or an URD with a single HLA-class-1 allele MM or DQB1 antigen or allele MM) endpoint will be graft rejection, defined as the establishment of <5% donor CD3 and CD33 chimerism at day 80-100. Arm B (HLA-haploidentical or an URD MM for a single HLA-class 1 antigen or a single HLA-DRB1 allele MM) endpoint will be Graft rejection, defined as the establishment of <5% donor CD3 and CD33 chimerism at day 80-100. This protocol is open for enrollment.

The last talk was by Lydia Pecker, MD., Director, Young Adult Clinic, Johns Hopkins Sickle Cell Center for Adults and Assistant Professor of Medicine. Dr. Pecker presented a thorough talk on reproductive health in SCD women. She started by reminding stigma on black women being described as hyper-fertile. She also mentioned that several fertility problems are also encountered by boys and men with SCD; those include vaso-occlusive complications such as priapism, but also fertility problems secondary to blood and marrow transplant (BMT).

She focused on reproductive health problems in girls and women with SCD.

- Delayed menstruation, also pain during menstruation that ends by missing school due to hospitalization. In addition, two major complications can be encountered: opioid addiction and treatment by contraceptives that can increase the pre-existing risk of thrombo-embolism.

- Later on, there is lack of family planning and genetic counseling or even sometimes a wrong interpretation of the partner genetic testing (with a HbC considered as normal) could lead to having kids with SCD. Genetic counseling and considering IVF is the solution of choice for most of couples when the right testing and counseling are done.

-Another major reproductive problem is the acceleration in decline of ovarian reserve. It seems that this is the reason for the high risk of miscarriage in SCD women. Of course, the major complications are decreased fertility and early menopause. This latter complication is a major problem especially because it causes early osteoporosis which will add to the risk of hip fracture in SCD patients (due to avascular osteonecrosis). The pathophysiology for the early decline in ovarian reserve in unclear and one publication suggested that HU could add to this risk. It is also unclear if there is a pituitary-hypothalamic component.

-BMT is indicated when there is a matched related sibling and age is <13 years which is the case in 10% of cases. Transplant represents a threat for gonadal fertility. Cryo-tissue preservation is only offered at the NIH and covered by insurance only in Illinois. This represents an important gap in reproductive treatment of women with SCD.

-Maternal morbidity and mortality of SCD patients is high and 70% is attributable to SCD complications.

-Those complications are preventable.

- Four drugs are approved for SCD but none during pregnancy. Transfusion is safe for the mother, but safety is unclear for the baby.

- Thinking beyond survival: Could reducing anemia and opioid exposure (with chronic transfusion) affect neurodevelopmental outcomes in children born to women with SCD.

There is high disparity in parents whose life is affected by having kids with SCD that Dr. Pecker mentioned at the beginning of her talk.

Finally, Dr. Pecker underlined the low funding rate for key words with ovary, fertility and reproductive health. She also emphasized that it is time to move the mean age of lifespan of SCD patients above the age of 40 y at which we have been immobilized. This requires a multi-disciplinary effort of hematologists, Ob/Gyn specialists, reproductive endocrinologists, neonatologists, maternal fetal medicine doctors and funding agencies.

Questions and answers followed each presentation. In addition, a general discussion took place at the end of all presentations.

The HEAL initiative was very well received by outside investigators since addiction was unfortunately often associated with pain in SCD.

Studies focused on chimerism are important for gene therapy, thalassemia, in addition to SCD transplant to study late effects and cure therapies.

In terms of SCD, creating silos of funding are not necessarily good solutions and opening doors of funding such as having “pain” as focus, or “cure for SCD”, or “behavioral science”, or “implementation science”.

A question might be “can the clinical trial for transplant cover for the basics such as pain and other problems in the patient?” Dr. Hoots answered that there are ongoing discussions with CMS based on data that are currently gathered for our CTs (evidence generation) to answer these kind of questions; the objective is to have the basic care covered by CMS while the research part covered by the NIH or Pharma.

Regarding fertility, we need basic science and clinical science to stratify the risk for SCD (males and females) because we don’t really have data. There is iron overload in the pituitary gland in half of chronically transfused patients. In a patient with a detectable cardiac iron overload, we should assume that there is a central component. Otherwise, the fertility problem is primarily due to ovarian failure.

Messaging to the communities was a recurrent theme; in addition to the need for the knowledge-base how to package and deliver the message are of equal importance in order to not to add/create inequities; how to engage stakeholders through implementation science, creating consortia, engaging patients families and different providers in important topics such as fertility were discussed.

At the end of the meeting, Dr Hoots announced that he was retiring from his position as DBDR director. He thanked the SCDAC for their continuous commitment and he was thanked in return for his outstanding dedication to the SCD mission as the DBDR direction.

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