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. Hoots also introduced the new Deputy Director, Dr. Julie Panepinto who joined the division recently.
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, she introduced the new committee chair Dr. Allison King. Dr. Allison King, the committee chair introduced herself and ask all the committee members (and ad hoc) to do the same. All members except Dr. Sophie Lanzkron were able to join.
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 I/II 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 second objective is 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, vaso- occlusive 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.
Dr. Pankaj Qasba presented Sickle Cell Disease Genomics Network of Africa: SicklegenAfrica. This is an international collaborative project focusing on the mechanism of hemolysis and cytoprotective pathways on organ dysfunction in SCD. The center’s goals align with the fundamental principal of H3Africa to build capacity for genomic research in Africa while fostering collaborations and synergy among African countries. SickleGen Africa is comprised of investigators in nine institutions in five African countries and one institution in North America (Pittsburgh). The main Hub is in Ghana-Accra (also project 1);
In brief, the studies focus on:
- Project 1: Genetic determinants of hemolysis modifying defense in SCD (Ghana)
- Project 2: Genomics of severe malaria complications in SCD (Tanzania)
- Project 3: Genomics of cardiovascular phenotypes in SCD (Nigeria)
Three scientific cores, 1) molecular hematology,2) sickle mouse biorepository, and 3) bioinformatics, support the projects. H3 Bionet is in Cape Town; the bioinformatics core is in Pittsburgh. The mouse colony is currently in Pittsburgh and will also soon be shared with Accra. Dr Qasba mentioned that SickleGenAfrica launched a series of focus group workshops held in each of the 6 clinical sites that included patient and family stakeholders. More than 6800 participants have been recruited to the research network and their clinical data and samples banked. The data include 2860 adults and 3650 children. The investigators also published a paper in Blood in 2020 describing “the role of hemopexin deficiency as a risk factor for acute kidney injury in SCD”.
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 Uganda, Mali and Zimbabwe. A Biorepository will be also added in the second funding period.
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 III 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)-protocol under review.
The first study SCURT (BMT CTN 601) evaluated (cord blood or BM) HLA-identical unrelated donors and reduced intensity regimen conditioning to cure SCD. The cord blood arm closed early for no engraftment (BBMT 2012) and the BM arm showed excessive chronic GVHD (Blood 2016).
The second study 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 the was closed in 10/2020 due to lack of feasibility. 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%).
The third study is the haploidentical HCT-Cytoxan study (BMT CTN 1507) that uses Cytoxan in post-HCT to kill alloreactive T cells that cause GVHD while sparing non-reactive T cells that are 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 is still open for enrollment. The older age cohort completed enrollment.
A fourth study pending DSMB review is a gene transfer for SCD (BMT CTN 2001) study: “A Multi-Center, 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 BCL11A, induced fetal hemoglobin (HbF) and led to clinically meaningful results (funded by NHLBI) and has been published in the NEJM 2021. If approved, the study will include 25 patients.
Dr. Philip Tonkins presented the SCD Implementation consortium. The registry enrolled 2,441 patients so far. 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: incharge health app for the patient and SCD HU Toolbox app for the provider. Preliminary results showed that Apps are used but implementation was low and that there was a need to make the Apps more relevant.
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”. The study is still ongoing.
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. The different components of a curative strategy include biomarkers, health economics, trials to test safety and efficacy of product including understanding long-term, and understanding trial readiness physically and psychologically. Different panels have been formed including a community input panel, a patient’s readiness and resilience working work that will 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.
Dr. Welniak presented the programs funded by the Cure and mentioned the completion of work to identify Common Data Elements (CDEs) for use in genetic therapies is available on the CureSCi website. Metadata catalog (MDC), is also a resource for curation of data elements for past and current studies of SCD populations, and information for patients and advocacy groups and the wider SCD community are also available on the CureSCi website.
Dr. Julie Panepinto presented her work performed on COVID-19 and SCD while she was at Medical College of Wisconsin.
She started by an introduction highlighting the severity of COVID-19 disease in SCD including SCD in hemoglobin SC disease.
There were two parts to her presentation:
The first part focused on factors associated with COVID-19 hospitalizations and illness severity using the SCD COVID-19 registry.
The origin of the registry was modeled after a similar registry in inflammatory bowel disease. It was an international effort; reporting on COVID-19 cases in SCD patients was voluntary; data were de-identified. As of May 1, 2021, 784 cases were reported, with average age of 22 years. The first objective was to identify the factors associated with hospitalization and serious COVID- 19 illness with the hypothesis that SCD-related comorbidities are associated with hospitalization and severe COVID-19 illness and that patients taking HU are less likely to be hospitalized and/or experience serious COVID-19 illness. The second objective was to examine the relationship between COVID-19 illness and pain.
48.5% of the individuals in the registry were children of which 40% were hospitalized and 0.7% (n=1) patients died; 52.5% were adults of which 60% were hospitalized and 4.7% (n=18) died. Variables associated with hospitalization were the association with previous acute care visits for pain (>2 vs 0) in the last 3 years for both children and adults, and the pre-existing SCD heart or lung co-morbidities only in children. HU use wasn’t associated with hospitalization. For serious COVID-19 illness (according to an early publication from China) in children, prior acute visits for pain (> 2 vs 0), SCD renal disease, SCD heart/lung co-morbidities were associated factors; in adults, age and prior acute care visits for pain were the associated factors. Looking at pain as an outcome, prior acute visits for pain and SCD renal co-morbidities were associated factors in children; in adults, prior acute visits for pain and SCD heart/lung co-morbidities were associated factors as well as the non-HU use and the male gender. This raises the question about the ACE receptor in the physiopathology of COVID-19 complications, knowing that there was an overrepresentation of more severe patients with a prior history of frequent pain events.
In the second part, the objective was to compare COVID-19 outcomes among individuals with SCD and trait to blacks who do not have SCD/trait.
The hypotheses were that individuals with SCD were at higher risk of severe COVID-19 illness compared to blacks who don’t have SCD/trait; and that individuals with sickle cell trait don’t have significantly different COVID-19 outcomes compared to blacks who don’t have the disease nor the trait.
This was a retrospective cohort study that used TriNetX as a data source. TriNetX is a research network that includes de-identified electronic record data from > 30 US sites.
Data were collected on 312 patients with SCD, 449 individuals with sickle cell trait, and 45,517 black individuals without SCD or trait. All had an ICD code for COVID-19 infection.
The results showed that:
- There was no significant difference in COVID-19 manifestations for those with sickle cell trait compared to controls: In a matched cohort (age, sex, clinical co-morbidities) COVID-19 and sickle cell trait (n=449) and without trait (n=449), for hospitalizations or mortality.
- Individuals with SCD compared to blacks without disease/trait are 2x more likely to be hospitalized, develop pneumonia; and are 3x more likely to have pain due to COVID-19.
- Mortality in SCD patients is similar to blacks without SCD/trait in the US
- COVID-19 is more severe in individuals with SCD: more likely to be hospitalized and have more severe course of COVID compared to blacks without SCD.
- Prior pain risk factor: more severe COVID-19 infection; hospitalization due to COVID-19
- HU wasn’t associated with COVID severity or hospitalization.
The panel discussion was led by Dr. Hoots, Dr. Coleman Lindsley and coordinated by Dr. Lis Welniak.
As an introduction for the topic, Dr. Hoots explained that the Bluebird Bio gene therapy trial for SCD was put on hold by the FDA because one patient developed an acute myeloid leukemia (AML) and another patient developed what was initially thought to be myelodysplastic syndrome (MDS) but later termed transfusion dependent anemia. The DBDR decided to hold the round table topic around the theme of clonal hematopoiesis. The goal was to facilitate discussion and develop questions regarding the risk factors that may contribute to the development of this outcome in genetic therapies such as conditioning regimen, the dose of vector transduction, or related to SCD.
Dr. Coleman Lindsley is a Physician Scientist at Dana Farber Institute in Boston and his research is focused on initiation and progression to acute leukemia starting from clonal hematopoiesis and progressing through MDS to AML.
Regarding the events that arose after gene therapy, there are usually two explanations: consequence to the gene therapy itself; however, the integration analysis didn’t confirm this hypothesis. The next question is: “is there an increase risk of leukemia in this context”? He explained that when a clonal mutation occurs, it gives proliferation advantage over the other hematopoietic stem cells (HSCs). These clonal cells multiply but don’t participate to the peripheral mature blood cell pool. There is also a high relative risk for these clonal HSCs to transform into leukemic cells. Recently, other effects of this altered hematopoiesis have been described: immune dysfunction, increased inflammation and cardiovascular disease. Clonal hematopoiesis is an age associated phenomenon. The set of genes are limited (DNMT3A and TET2). There is another set of genes with multiple mutations occurring called atypical. Therefore, clonal hematopoiesis may directly impact the efficacy and long-term complications seen in SCD after allogeneic and autologous gene therapy. It may also have an impact on systemic disease manifestations by potentiating the adverse pulmonary, cardiovascular and hematologic manifestations of SCD.
Dr. Lindsley showed TopMed data where the percentage of clonal cells is higher when we use more sensitive techniques to analyze the data. He also raised important questions such as: are the clonal cells real and do these engraft? It seems to be the case in a study he has done (not in SCD patients). He showed data where these clones engrafted, even small ones, persisted over time (7-10 years) and they were associated with altered cytokines levels (increased IL-12 and increasing cGVHD). There was no donor cell leukemia in recipients.
Dr. Lindsley suggests the benefits of a large consortium collaboration where a uniformly conducted analysis of frequency, age distribution, and clinical effect of clonal hematopoiesis in patients with SCD can be conducted.
There was a suggestion to study clonal hematopoiesis in a large cohort that allow for comparison of a US cohort to an African cohort. Discussion also occurred around ideas for a project to study samples in H3Africa and to do a biorepository in general for all patients.
Dr. Lakeia Bailey spoke about the “perception by the public to the gene therapy experience”. She started by saying that it is about “Ethics”. That majority of patients accept gene therapy for a severe illness. The concern is about the informed consent; and when the topic is complicated, there is a little chance to receive sufficient information, especially when published news are about “unwanted DNA deletion” for CRISPR for example. When not informed, the patient would rather stick to the disease she/he knows Dr. Bailey said. Other problems are rumors and misunderstanding in a community that has been severely discriminated against.
Some of the rumors and constant chatter started with HU use leading to cancer and leukemia. With transplant as a therapy, some of the community rumors have included “Man’s blood and semen found to contain only donor’s DNA after bone marrow transplant” giving rise to questions such as “Will my son still be my son?”.
She mentioned that the gene therapy was perceived sometimes in the community as responsible for transmitting HIV/AIDS since a “gutted” HIV retrovirus was utilize as the vector. She showed elegantly how SCD has had an effect on science, not only the science having impacted SCD; she also added that what should not happen is that “the science moving forward while the patients are left behind”. At the end, Dr. Bailey mentioned that fertility is not addressed in this group of patients who have historically been mistreated.
The last hour was a general discussion between all attendees.
There was emphasis on spending enough time on the informed consent for research studies and not pressuring individuals to enroll into the clinical trial.
The major part of the discussion was about the health care systems of delivering care to individuals with SCD. Some members felt that the past elimination of the Centers of Excellence was not the right decision. A suggestion was to create a partnership between ASH and the NIH to create clinical research infra-structure supporting clinical care. Examples such as Hemophilia and Cystic Fibrosis were cited repeatedly.
At the end of the meeting, Drs. Hoots and El Kassar thanked the members of the committee and the speakers for their participation and for sharing their insight and announced that the next SCDAC meeting will take place in the beginning of the calendar year 2022.