Sickle Cell Disease Advisory Committee Minutes

Video conference


Dr. Julie Panepinto, 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. She 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 DBDR, welcomed everyone and thanked the new members for going through the on boarding process. After reading a disclosure in accordance with the legal requirements of FACA, she introduced the new committee chair Dr. Marsha Treadwell.

In the first part of the meeting, the NHLBI ex-officios presented an update on the major NHLBI funded programs in Sickle Celle Disease (SCD).

Dr. Nahed El Kassar presented an update on the REACH "Realizing Effectiveness Across Continents with Hydroxyurea" which is a phase 1/11 pilot study of Hydroxyurea (HU} for Children with SCD. The primary objective is to determine the feasibility, safety and benefits of HU to be measured by hematological cytopenic toxicities and serious bacterial and malarial infections. The secondary objectives are the long-term safety and benefits on organ function and growth measured by transcranial doppler (TCD} and growth rates respectively. Results were published in the NEJM in January 2019 showing a significant reduction of sickle cell event rates, vasoocclusive pain, a decrease in malaria cases, transfusion rates and death. Results on HU dosing and TCD were published at the American Society of Hematology in 2020 showing exciting results.

Patients have been followed for an average of 7 years. Clinical events continue to be observed (unpublished data). A lower malaria incidence in this cohort was recently published in Blood. Univariate and multivariate analysis of confirmed malaria infections identified ANC and splenomegaly as the two most important variables affecting malaria risk.

REACH grant funding has been renewed by the NIH. In the new cycle, another cohort of 240 SCD will be enrolled and will receive HU after detailed evaluation of their SCD in comparison with the current cohort.

Dr. Philip Tonkins presented the SPARCO (the Sickle Pan African Research Consortium) and SADaCC (the Sickle Africa Data Coordinating Center) in Sub Saharan Africa.

For the first period of funding (2017-2021), the aims of this program were to develop: a registry/database system; harmonized phenotype/definitions/ontologies; regionally appropriate clinical management guidelines; skills development for SCD management; planning for cohort studies, programs for newborn screening, infection prevention, wider HU use and database expansion. SPARCO was awarded to Dar es Salaam in Tanzania as a Hub, in addition to 3 clinical sites in Tanzania, Nigeria and Ghana. SADaCC was awarded to the University of Cape Town. The program exceeded their target enrollment (13500).

The program has been renewed to extend access to care and clinical management of patients with SCD enrolled in the registry. In this second funding period (2021-2025), 3 new sites have been awarded in Kampala, Uganda; Bamako, Mali and Harare, Zimbabwe as well as a biorepository.

Dr. Pankaj Qasba presented an update on Sickle Cell Disease Genomics Network of Africa: SicklegenAfrica.

The major goals of the project are to establish SickleGenAfrica: Sickle Cell Disease Genomics Network of Africa to build capacity to enable scientists in Africa to test overall hypothesis locally. SickleGenAfrica is comprised of investigators in nine institutions in five African countries and one institution in North America. The Center's goals align with the fundamental principle of H3Africa to building capacity for genomic research in Africa while fostering collaborations and synergy among African countries.

In brief- The studies focus on:
Project-1- Genetic determinants of hemolysis modifying defense in sickle cell disease
Project-2 - Genomics of severe malaria complications in sickle cell disease
Project-3 - Genomics of cardiovascular phenotypes in sickle cell disease

Three scientific cores, molecular hematology and sickle mouse, biorepository, and bioinformatics, support the projects.

Overall Concept and Organization: SickleGenAfrica is an international collaborative project operating in multiple institutions in Africa with a focus on the role and mechanism of hemolysis cytoprotective pathways on organ dysfunction in SCD.

The overall hypothesis is that genetic variation influences the body's defense against hemolysis and hemolysis-associated organ dysfunctions in sickle cell disease.

The Summary of the major accomplishments is as follows:

  • Enrollment of the largest cohort of sickle cell patients in the world. The number of participants is currently around 6,812 (2,862 adults and 3950 children); target is 7,000. Surpasses the previous largest cohort study by over 3,000 patients.
  • Defined acquired hemopexin deficiency as a risk factor for acute kidney injury in sickle cell disease combining data from our Kumasi cohort, and experimental data from transgenic sickle cell mice in the mouse core in the University of Pittsburgh. The publication of this work was the first for the network (Ofori-Acquah et al., Blood. 2020;135:1044-1048)
  • Changed the focus of Project 2 from a human subject-based study in malaria to an ex vivo study examining the role and mechanism of hemoglobin S in malaria transmission.
  • Community engagement in Ghana, Nigeria and Tanzania -

Dr. Philip Tonkins presented the SCD Implementation consortium. The registry enrolled 2,441 patients. The needs assessment identified barriers for individuals living with sickle cell disease who transition care from pediatric to adult care and why they were not receiving care. As a result, multiple studies were initiated. One focused on increasing HU utilization through improved adherence and support of provider prescribing through mobile health (MESH study). It compares the days of HU covered by prescriptions at baseline and after 6 months of lnCharge Health; compares the change in provider prescribing of HU from baseline and 9 months; and evaluate the barriers and facilitators to the adoption of both mHealth interventions.

Another study focused on use of pain plans: Implementing an Individualized Pain Plan (IPP) with patient and provider electronic health record access, for adult emergency department treatment of vaso-occlusive episodes in SCD: A ·pre-post study design "ALIGN Study".

Finally, the consortium conducted research to understand how and why individuals with SCD become unaffiliated from SCD care through different studies.

Dr. Nancy DiFronzo presented "Advancing Curative Strategies for SCD through the Blood and Marrow Network". The network of 20 transplant centers or transplant-center consortia and Data Coordinating Center is funded by the NHLBI with co-funding by NCI. The goal of the network is to evaluate treatment strategies to improve outcomes for children and adults receiving Hematopoietic stem cell transplantation (HCT):
- Phase II and Phase Ill trials
- Malignant and non-malignant Blood diseases
- This includes patients with SCD: Allogeneic HCT (related or unrelated donors); or using genetically modified HCT (gene therapy).

STRIDE 2 (BMT CTN 1503) was a phase II trial in young adults (15-41) with SCD. The objective was to compare 2-year overall survival between 2 arms, based on the availability of an allogeneic-donor (design called biological assignment). The study opened in 2016 and was closed in 10/2020 due to lack of feasibility, with 96 enrolled in the no Donor arm and 28 in the Donor arm. The main lessons learned from this trial were that: patients come to transplant study expecting to receive a transplant; and that fewer SCD patients have available unrelated donors in the national registry than predicted (13% vs 25%). Results from this study will be reported late in 2023.

The second study is the haploidentical HCT-Cytoxan study (BMT CTN 1507) that uses Cytoxan in post-HCT to remove alloreactive T cells responsible for GVHD while sparing non-reactive T cells important for immune reconstitution. This is a phase II trial with 2 cohorts of patients with severe disease and without HLA-identical sibling donors: children 5-<15 years old and young adults <45 years. The study opened in 2017. The cohort for children closed for enrollment in 2023. The older age cohort completed enrollment in 2021. Results for both cohorts will be reported separately.

A third study for gene transfer for SCD (BMT CTN 2001) study: "A Multi-Cen~er, Phase 2 Gene Transfer Study Inducing Fetal Hemoglobin in SCD". This study is supported by the Cure for SCD initiative. This study is based on a pilot trial: single infusion of autologous blood stem cells treated using gene therapy (shmiR) to inhibit BCLllA, induced fetal hemoglobin (HbF) and led to clinically meaningful results (funded by NHLBI) and has been published in the NEJM 2021. Six of the 25 planned participants have been enrolled so far.

Drs. Traci Mondoro and Welniak presented the "The Cure for SCD initiative". Dr. Mondoro started by a reminder of the vision which is to accelerate the development of genetic therapies aimed at curing SCD. The goals are to create a collaborative, patient-focused research environment; engage academic researchers, the private sector, researchers, advocates, patients, and caregivers to develop strategies for cures; determine the safest, most effective, and most readily and widely adoptable genetic therapies; and move newly developed genetic therapies, including gene-editing approaches, into clinical trials within 5-10 years. Patients, families, providers and advocates are at the center of the discussion.

Different panels have been formed including a community input panel, a patient's readiness and resilience working work that includes include psychologists, and a research coordinators' committee that provides guidance directly from the SCD clinical researcher and provider community to the other groups. The Executive Community meets every 6 months and has 3 main priorities. Priority 1 is outreach to patients, providers and the SCD community. This work is done in collaboration with the American Society of Hematology. Priority 2 is developing and supporting clinical trials focused on genetic therapies. Priority 3 is developing data resources focused on facilitating the application of genetic therapies in clinical practice.

The journeys in mental health: webinar on September 27th 2022, Hosted by the Cure Sickle Cell Initiative, in collaboration with the Sickle Cell Disease Association of America (SCDAA) and the Sickle Cell Community Consortium (SCCC). The roundtable discussion was chaired by Dr. Wanda Whitten-Shurney with patients, caregivers, and providers on the importance of mental health when considering curative therapies. Recording is available on the CureSCi website and YouTube. The patient's readiness and resilience working work developed the document "Pre-Genetic Therapy Assessments of Patient Readiness and Resilience: Best Practices and recommendations for Implementation in Sickle Cell Disease." Public comment was solicited in Spring 2022. Recommendations were developed based on scientific evidence, expert clinical guidance, review of strategic planning documents, and consultation with CureSCi subcommittees and working groups representative of patient, advocate, clinician, and researcher perspectives.

Data Resources:
Natural History Data Resource (NHDR) is focusing on what is needed to provide adequate comparison for the gene therapy trials. There are two tracks; non-transplanted controls come from SCDIC and GRNDaD; allogeneic transplanted controls will come from CIBMTR-led partnerships. The study team have closely compared the CRFs in the CureSC supported trials to the core elements selected for the work with registry partners. The NHDR provides support for collection of additional data elements needed for this resource.

Each Registry will collect a "core" dataset based on the CureSCi Working Group and ASH/FDA recommendations. Automated data extraction will be used to the extent possible. RTI will coordinate, QC and combine the registry data into a natural history resource. BioData Catalyst will provide storage, access and investigator support.

PIC-SURE and the CureSCi Meta Data Catalogue (MDC) will enable investigators to find data and build control cohorts.

Assessing and Mitigating Risks
1-Developing a deep sequencing protocol:
Goal is to evaluate risk of developing clonal hematopoiesis and myelodysplasia.
This is a research project in an early stage, and results will not be clinically reportable.
Working with our Community Input Panel and other partners to determine how to talk about unknown and unmeasurable risks.
2-Identify partnerships to develop educational materials on fertility and fertility preservation associated with clinical trial involvement.

Hosting speakers on these topics at our Executive Committee Retreat in April.

Dr. Lanzkron, MD., Professor of Medicine at JHU, presented on "Engaging the sickle cell community in clinical research".

From a study of 291 people with SCD in IMPORT Cohort (Clin Trials. 2014 Jun;11(3):275-283), aged 15 years and older getting care at Howard U or JHH; used subscale of perceptions of participating in clinical research tool, there were agreements with:
-Clinical trials are a necessary way to learn about treatments
-It is important for people to take part in clinical trials
-Participation in a clinical trial can help me and my family
-Participation in a clinical trial can help future generations

From the CureSCi patient engagement experience, (Journal of the National Medical Association, 2022-04-01, Volume 114, Issue 2, Pages 211-217), with 17 people living with SCD in focus group setting, about 50% had participated in a clinical trial, the majority would consider participating if approached and most patients cite their provider as the best source of information. The aspects that affect their decision to participate are: 1-severity of disease; 2-knowing the expected side effects/risks and the likelihood of the new treatment being better than their current treatment; 3-would like to see a "noticeable" impact on health; 5-they want to be advised of the results of the trial when complete; 6-Some patients are seeking a more Holistic approach to their treatment, which may result in them declining to participate in clinical trials.

Dr. Lanzkron completed a community engagement exercise within the American Society of Hematology (Blood Adv. 2021 Dec 14;5(23):5323-5331). Eight Community based workshops across the US with 472 attendees and four distinct groups:
1-Parents of children living with SCD;
2-Adolescents and teens with SCD (aged 13-17 years)
3-Young adults living with SCD (aged 18-39 years);
4-Older adults with SCD (aged 40+ years).

Few workshop attendees were familiar with what is involved with clinical trial participation; priorities for patients were to address by order of priorities: VOC crisis, chronic pain, fatigue, organ damage, acute chest syndrome, mental health issues, then other issues.

They expressed their ideal experience before participation as follow:
1-Learn about the trial from trusted source (e.g., physician);
2-Personal physician supports participation;
3-All study information accessible and in plain language;
4-Less strict eligibility criteria to allow more to participate (especially age);
5-Time to consider participation;
6-Trial is sponsored or conducted by a trusted organization

Their Ideal experience during the trial would be:
1-To be treated as a partner by study personnel
2-Lodging and travel expenses covered
3-Study personnel keep their regular physician informed
4-Participation has little to no impact on personal/day-to-day life
5-Study clinic environments are welcoming
6-Those enrolled can stay on their existing medication
7-Compensation provided throughout the study as opposed to just at the end
8-Only minimally invasive procedures are required;
9-Access to mental health support, support groups, and other resources

And finally, the ideal experience after the trial would be:
1-Free access to the drug (if study is a success);
2-Access to long-term care and follow-up
3-Trial sponsor re-invests in the SCD community by sponsoring events or offering scholarships
4-Receive support during the transition to regular standard clinical care
5-Access to counseling sessions
6-Receive recognition for participation
7-Results of the study are communicated to personal physician

At the end, Dr. Lanzkron emphasized the role of the sponsor in:
1-Pressure to enroll doesn't lead to the wrong subjects being enrolled in a trial, especially in pharma sponsored trials- where financial incentives are offered.
2-Ethical responsibility to assess accrual but also to understand difficulties of enrollment before closing a trial early; In study with significant enrollment closing study prior to full accrual risks having all subjects exposed to risk without any potential benefit.
3-There is a need to use implementation science to improve success of clinical trials.
Implementation science helps identifying barriers and facilitators to enrollment facilitated with the Consolidated Framework for Implementation Research; Assess context including provider, clinic, and organizational factors; Identified barriers can be linked to targeted, evidence-based implementation strategies through the Expert Recommendations for Implementing Change project (compilation of 73 improvement strategies); Success of the selected strategy could be evaluated using Proctor's Implementation Outcomes Framework.

Dr. Titilope Fasipe, a sickle cell disease warrior and MD., Ph.D at the Department of Pediatrics, section of Hematology-Oncology, Baylor College of Medicine in Houston, TX gave a background review on the history and challenges of SCD.

Dr. Fasipe mentioned that SCD is an ancient disease, an invisible disease, steeped in stigma, a scientific double edged sword, a worldwide disparity. In Africa, SCD had another name, that described pain and suffering, such as "body chewing" or "body biting". That's how the advocacy started.

In 1972, there was the "National Sickle Cell Anemia Control Act"; In 2003, the "Sickle Cell Treatment Act"; In 2018, the "Sickle Cell Disease and Other Heritable Blood Disorders Research, Surveillance, Prevention, and Treatment Act".

Dr. Fasipe thinks that now there is a need to redefine the problem. She mentioned the importance of the "NIH Cure initiative", with interventions of patients, families and advocates. She also mentioned that with all the cures and drugs for SCD, it is "complicated". Despite that, she feels that stigma continues; there are unmet expectations; a mix of hope and anxiety. Dr. Fasipe recognizes that experts listen more to patient's voices, and that they are engaging more communities but we still need to listen to their queries. Also there is a need to disseminate more SCD research on the NIH website.

Therefore, as reflection points: sickle cell is an ancient disease; sickle cell is synonymous with disparity and stigma; outcomes continue to reflect ongoing structural disparities; optimizing evidence-based guidelines and innovation is key; emerging therapies offer hope, but acknowledge the double edged sword reflection points.

Ms. Heather Avent, SCD warrior and advocate presented "forwarding the message". Ms. Avent is the chair of the "NIH Cure initiative's Community lnputPanel".

Ms. Avent started by emphasizing the importance of building trust as a solid foundation for all SCD patients; "patient needs trust; needs to feel others like family" she said. She explained important elements of trust such as: listening, expressing empathy and providing support. Elements that influence are education and costs. They are important in order to live better with SCD.

There are 20 conferences on SCD. Ms. Avent tries to go as often as she can knowing she is also a mother to a 5 year old boy.

Ms. Avent mentioned the importance of listening, welcoming new opinion, building bridges and infrastructures. She is satisfied to see investment into mental health and SCD, including the joint webinar organized by the Cure and SCDAA.

The speaker also reiterated that dissemination and evidence based information coming from the NHLBI is much more trusted source than from other sources.

Ms. Avent suggested that another way to disseminate new evidence and new trials would be on "Mychart" that the patient can access when going to the doctor.

Finally she suggested that it is important for a provider to know when to approach a patient when considering a discussion on enrolling him/her in a CT.

After a short Q&A session, the meeting adjourned.

Nahed El Kassar
Marsha Treadwell