The Pediatric Clinician's Approach to Referring Children and Adolescents with Sickle Cell Disease for Potentially Curative Therapies.

“It Was Bootstrap All the Way”: Exploring the Barriers and Facilitators to the Development of Non-Hematology Sickle Cell Disease Experts in the United States

Examining the Role of Sickle Cell Disease Patients As Teachers in the Emergency Department: Patient Directed Physician Education

Shared Decision Making or Physician Advocate for a Particular Treatment Option: A Spectrum of Approaches to Decision Making about Disease Modifying Therapies in Sickle Cell Disease

Do Jehovah's Witnesses with Sickle Cell Disease Avoid the Healthcare System?

In this issue of the American Journal of Hematology, Green, Singh, and Baer report an interesting case of a 76-year-old patient with Beta 0/S sickle cell disease (SCD) diagnosed with primary myelofibrosis (PMF).1 This patient had mild SCD, most likely due to concomitant hereditary persistence of fetal hemoglobin and PMF, which was an unexpected finding in a routine complete blood count. Hemoglobin values, white blood cell count and differential were not uncommon for a homozygous SS or Beta 0/S patient. Even the platelet count values above 1000 ×106/μL that led to the diagnosis are sometimes observed in patients with hemoglobinopathies who have had a surgical or functional splenectomy. This case highlights the importance of comparing biological abnormalities with previous results to avoid failing to diagnose hematological neoplasms that can occur in SCD patients. This case seems to be the first in which primitive myelofibrosis was reported in an adult patient with SCD. However, several myeloid malignancies had been previously reported in SCD, leading to the hypothesis that SCD may lead to the development of hematologic malignancies, even in the absence of disease-modifying treatments. An international survey of 16 613 SCD patients at 52 institutions conducted by the International Association of Sickle Cell Nurses and Physician Assistants (IASCNAPA) identified one patient with acute myeloid leukemia (AML) and another with chronic myeloid leukemia (CML).2 Two recent epidemiology reports from California and the United Kingdom have suggested that patients with SCD have a higher risk of hematologic malignancies than the general population.3, 4 A review of 27 years of population-based data from California (with a median follow-up of 22 person-years data) showed that SCD patients had a risk of leukemia more than twice as high as that of the general population. Patients with severe SCD (defined by those who had an average of ≥ 3 hospital or emergency department visits per year) had a risk nearly four times higher than the general population. The risk factor for SCD patients developing AML was 3.59.3 A review of linked hospital and mortality records from the United Kingdom found that the rate of myeloid leukemia in the SCD population was 10 times higher than that observed in a control population.4 Neither of these two large studies provides data on the etiology of leukemia, nor does either consider the use of disease-modifying treatments or hematopoietic stem cell (HSC) transplant. A recently published review from Li et al. reported 15 SCD patients with myeloid neoplasms. Of these, 4 cases were reported by the authors and 11 were found in a review of the literature. Seven patients had a myelodysplastic syndrome (MDS) with an excess of blast or transformed to acute leukemia, three had AML with no myelodysplasia mentioned, and four with CML.5 Improvements in treatment and care in the last 50 years have extended the life expectancy in SCD, to the extent that many patients now survive to an age at which they are at an increased risk for cancer.6 Aging is associated with a functional decline of HSC as well as an increased risk of myeloid malignancies.7 An association between hydroxyurea (HU) exposure in SCD patients and leukemia is unproven and large studies did not show a significant increased risk of leukemia.8, 9 The study from California conducted from 1988 to 1999 and from 2000 to 2014 did not show an increased risk of leukemia after the approval of HU by the FDA in 1997.3 Moreover, the study of SCD patients treated with HU suggest that HU could decrease hematopoietic stress and slow down the rapid aging of these patients' HSC.10 Recently, the largest lentiviral vector-mediated β-globin replacement gene therapy trial in SCD reported two cases of adult patients diagnosed with myeloid neoplasms. One patient was diagnosed 3 years after transplant, the other 5 years after transplant.11-13 Both patients had been treated with bone marrow (BM) HSC and the original lentiviral transduction process, which likely accounted for their unsatisfactory responses. The less effective original process did not produce a sufficient percentage of modified HSC, and this process also failed to produce sufficient response at the peripheral red cell level; these deficiencies likely accounted for the unsatisfactory clinical outcomes of the earliest stage of the trial. These two patients' myeloid neoplasms shared cytogenetic and molecular similarities, with monosomy 7 and mutations in the oncogenes RUNX1 and PTPN11, which are typically associated with the development of AML. These cytogenetic and molecular abnormalities were not found in first patient's pre-conditioning BM samples. It was concluded that both these events were likely not related to the gene therapy procedure. The first case was considered to be a secondary myeloid neoplasm related to busulfan conditioning.13 In the second case, the myeloid neoplasm clone developed from genetically modified HSC, which was not affected by busulfan conditioning, because the transgene had been found in the genome of the blast cells of this patient. It was concluded that this AML was likely not related to gene therapy, because the vector insertion in the AML cells took place in the VAMP4 gene, which has no known role in any cellular process related to cancer and because no disruption of gene expression was found in nearby genes.14 The Center for International Blood and Marrow Transplant Research (CIBMTR) reported that four patients developed a myeloid neoplasm (2 AML, 2 MDS) out of 910 patients with SCD transplanted from January 2008 to December 2017.15 For three cases, it happened after a haplo-identical transplant and an HLA-matched sibling one for the last one. These four patients rejected the transplant after receiving a nonmyeloablative conditioning regimen. An NIH study on 76 SCD adult patients, transplanted from 2004 to 2018 with nonmyeloablative conditioning, showed that of the 19 patients who rejected their grafts, 3 patients developed MDS/AML within 5 years after transplant. For two of these patients, the pathological clone showed p53 pathogenic mutations, which were present before transplant.16 This progression from baseline high-risk p53 clonal abnormalities to myeloid malignancy occurred only in patients who did not engraft or rejected the graft. By contrast, none of the 57 patients who engrafted developed MDS/AML. It is important to note that there were no reports of post-transplant malignant neoplasms in patients treated with myeloablative regimens, neither in the CIBMTR study nor in the French study of 234 geno-identical allotransplants performed between 1988 and 2012.15, 17 If myeloid leukemia cases were simply coincidental with SCD, their cytogenetics and molecular characteristics should be similar to de novo myeloid neoplasms observed in the general population. However, the study by Li et al. showed cytogenetic profiles with complex abnormalities in all the 10 non-CML cases for which cytogenetic information was available. Cytogenetic abnormalities –5/5q– and/or –7/7q– were component in 9 of these cases. Molecular diagnostic tests were available for four patients and mutations in the p53 gene were found in three of them.5 These morphologic features and this cytogenetic profile are often associated with alkylating agents and/or ionizing radiation; this association prompts consideration of these therapies as causes of myeloid neoplasm in this patient population.18 However, of the 10 patients with complex cytogenetic abnormalities, only 2 had had a previous HSC transplantation and HU, 4 had been treated with HU, and the remaining 4 received only transfusion and supportive care. The p53 mutations were found in one who received HU and then an HSC transplant, one patient treated with HU, and one treated with transfusion and supportive care only. These non-CMLs with complex karyotypic abnormalities, which are not secondary myeloid neoplasms suggest other causes than those of SCD pathophysiology.5 Aging HSC acquires mutations that sometimes provide a selective advantage. Next-generation DNA sequencing can be used to detect expanded peripheral blood progeny of a mutant clone and clonal hematopoiesis of indeterminate potential (CHIP), which is a risk factor for subsequent hematologic malignancy.19 Hematopoiesis in patients with SCD is associated with erythroid hyperplasia, reticulocytosis, and ineffective erythropoiesis starting at the immature erythroblast stage in the BM.20 The effects of SCD on the stem and progenitor cells have not been fully determined.10 Because of chronic hemolysis, vaso-occlusive crises, hematopoietic stress, ischemia–reperfusion, endothelial damage, tissular hypoxia inflammation, and compromised apoptosis, SCD may promote accelerated aging of hematopoiesis and potentially oncogenic somatic mutations.21-24 These mutations are extremely rare in children, and therefore, pose a very low risk of cancer, but they increase substantially in adult patients and appear to present a significant cancer risk.5, 7, 25 An increase in the prevalence of clonal hematopoiesis in SCD patients after 40 years old, was recently described by whole-genome sequencing studies.26, 27 Real-world evidence studies will be needed to confirm that while patients with SCD have a higher risk of hematologic malignancies than the general population, the absolute risk is low. Studies that assess the incidence of CHIP throughout the lifetimes of SCD patients treated with disease modifier therapies or various transplant modalities will be critical in assessing the impacts of those treatments on hematopoiesis, and in determining, which therapeutic strategy offers the most benefit to patients with severe SCD.

The introduction of gene therapies into the clinical care landscape for individuals living with sickle cell disease (SCD) represents a momentous achievement with the potential to rewrite the story of the world's most prevalent heritable blood disorder. This disease, which was first described in 1910 and did not see a US Food and Drug Administration-approved therapeutic until 1998, is poised to be among the first to realize the promise of gene therapy and genome editing. However, the future of these treatments now rests on how evidence of safety, outcomes, and acceptance in clinical practice unfolds in SCD. Furthermore, historic injustices involving the exploitation of individuals from minoritized racial and ethnic groups in medical contexts necessitate extreme care in ensuring readiness among individuals with SCD considering genetic therapies. To address a gap in resources focused on patient readiness for gene therapy. The Cure Sickle Cell Initiative organized the Patient Readiness and Resilience Working Group in September 2020. Membership was comprised of behavioral health clinicians and scientists with expertise in SCD, adults with lived experience with SCD, and a caregiver. Over 2 years, the working group developed consensus recommendations and created resources to guide implementation of pregene therapy patient readiness assessments. Recommendations centered on strategies to enhance delivery of education about gene therapy and assess knowledge and understanding, interest and motivation, and psychosocial risk and resilience factors. Five goals of a pregene therapy patient readiness assessment were identified: (1) gathering information about a patient's understanding of and perceived readiness for gene therapy; (2) encouraging an open dialogue; (3) providing a conceptualization of psychosocial factors that may influence participation in gene therapy; (4) identifying patient strengths that can be used to promote psychosocial well-being before, during, and after gene therapy; (5) identifying and addressing psychosocial risks. Patient readiness and psychosocial factors will have tangible implications for the success of gene therapy at individual and collective levels. Health care institutions, industry, payers, policymakers, and clinicians all shoulder responsibility for ensuring that patients with SCD are adequately prepared for gene therapy and supported in ways that optimize readiness and access. Resources described here may be leveraged as a guide to support implementation of pregene therapy assessments of patient readiness and resilience in SCD.

Planning Mental Health and Social Support Prescreening Assessments for Adult Sickle Cell Disease Patients: Evaluating Readiness for Curative Therapy

Background: Sickle cell disease (SCD) is a chronic hemolytic disease with multisystem involvement leading to significant morbidities and mortalities. SCD confers a significant burden on patients (pts), including a high impact on quality of life (QoL). The impact of the COVID-19 pandemic on pts with SCD has not been well characterized. Aims: The Real World Assessment Survey for Sickle Cell Disease in the Kingdom of Saudi Arabia (KSA) (ROARS) is a cross-sectional survey of pts with SCD and treating healthcare professionals (HCPs), which was designed to understand several aspects of the burden of SCD in KSA. In this study, we examined the impact of the COVID-19 pandemic on SCD pts based on findings from ROARS. Methods: Between September and December 2021, pts with SCD (age: 5-65 years) and HCPs (>2 years SCD experience, SCD load >50 pts, >50% of clinical practice time spent treating SCD pts) were surveyed (in person or via caregiver if pts were between 5-14 years of age) using the structured, bilingual ROARS questionnaires (English/Arabic) through personal quantitative web-assisted telephone interviews. ROARS was developed by SCD experts from KSA and Novartis, and includes the global health domain of Patient-Reported Outcomes Measurement Information System (PROMIS), a validated tool for assessing QoL among SCD pts and caregivers of different age ranges. Questions covered topics such as disease impact on QoL, symptoms, disease complications, treatment goals, treatment strategies, and COVID-19. Descriptive statistics were used to summarize the results. Results: A total of 1011 pts (pediatric: n=504; adult: n=507) and 64 HCPs (hematologists: n=31; non-hematologists: n=33) completed the survey. Data were collected from 11 cities, with 90% of respondents from Eastern and South-Western provinces of KSA where the SCD prevalence is highest. The top 5 complications reported by both pediatric and adult pts were fever (52%), joint issues (49%), swollen and/or painful fingers/toes (47%), infections (37%), and tight chest pain (35%). A high proportion of pts (80%) felt that the pandemic had an impact on their medical care (Figure) (adults: 85%;[PM(1] pediatric: 76%). The impact of COVID-19 on medical care was particularly evident in pts treated with hydroxyurea compared to untreated pts (adults: 91% and 79%; pediatric: 84% and 74%). When survey results were stratified by the number of vaso-occlusive crises (VOCs), 85% of adult pts reported an impact of the pandemic on their medical care, regardless of the VOC frequency (<5 or ≥5); among pediatric pts, 72% with ≥5 VOCs and 83% with <5 VOCs reported an impact. Mental/emotional impact of the pandemic was reported by 66% of pts (adults: 68%; pediatric: 64%). The majority of pts missed or cancelled their appointments due to COVID-19 (adults: 81%; pediatric: 74%). Overall, 39% of the pts reported the impact of the pandemic as severe (Figure). From the HCPs’ perspective, 86% felt that COVID-19 affected their medical service, and 78% thought it affected their pts’ mental/emotional well-being. Overall, 16% of HCPs thought the pandemic significantly impacted their pts. Image:Summary/Conclusion: The ROARS survey among Saudi pts with SCD found that the majority of pts, especially adults, felt the COVID-19 pandemic had an impact on their medical care and emotional well-being. The impact of COVID-19 was also reflected in a decline in pt care, as reported by HCPs. In future, it would be interesting to understand the impact of the pandemic on vaccinated vs unvaccinated SCD pts.

Sickle cell disease (SCD) is a complex multisystem debilitating disease. Despite its complexity, health care providers who are not SCD experts receive little formal education on SCD. An open-access, educational website, "Emergency Department Sickle Cell Disease: Crisis Management and Beyond," was created to provide education about SCD to emergency department (ED) providers who are not SCD experts but who provide care for patients with SCD. Electronic surveys were used to conduct a formal evaluation of the accuracy and relevance of the website's content, as well as the effectiveness of the education modules in improving knowledge among health care providers. The evaluation consisted of (1) individual module pre- and post-knowledge assessment, (2) content validity assessment of educational modules, (3) overall website content assessment, and (4) overall website assessment (Health on the Net core principles). A convenient sample of ED providers, accelerated bachelor of science in nursing students, SCD experts, and website experts completed the anonymous surveys. Descriptive statistics and paired t tests were used to compare mean difference in post- minus pre-knowledge test scores. Knowledge scores statistically improved for nursing students (p value less than 0.0001). Emergency department providers showed a mean improvement of 3.2 points on the eight-item knowledge assessment. Both SCD experts and ED providers agreed that the module content was clear and easy to understand, accurate, comprehensive, relevant, and met module objectives. Participants agreed that the website was clear, easy to navigate, and visually appealing. Website experts stated that the website met much of the Health on the Net criteria. The website is a useful resource for providers and nursing students, especially those who serve or plan to serve in EDs.

Paths Grant: Using the Hub and Spoke Model to Improve Access to Care for Adults Living with Sickle Cell Diseases

Sickle Cell Disease Management Practices across Nigeria: A Cross-Sectional Analysis

Pilot Results from an Integrated Pediatric Pulmonary Clinic on Outcomes in Children with Sickle Cell Disease

A pause in gene therapy: Reflecting on the unique challenges of sickle cell disease

Health Equity in Sickle Cell Research and Access to Therapy

Sickle cell disease (SCD) is a global public health disorder that affects millions of people across the globe. It is a monogenic disorder caused by an A-to-T point mutation in the β-globin gene that produces abnormal hemoglobin S (Hb S), which polymerizes in the deoxygenated state, resulting in physical deformation or sickling of erythrocytes. Sickle erythrocytes promote vaso-occlusion and hemolysis, which are two major cellular hallmarks of the disease. Rapid advances made in understanding the molecular genetics of SCD in the early part of the 20th century have not been matched by comparable progress towards understanding its clinical complications, and developing effective therapies. Contemporary reevaluation of SCD as the product of multiple gene interactions promises to overcome the historical constraints of the single-gene disease paradigm that has inevitably impeded translation of research discoveries into clinical benefit. Two landmark papers in the late 1940s by the Nobel laureates Linus Pauling and Janet Watson provided the molecular bases for SCD and a rational strategy to treat the disease. The publication by Pauling et al., Sickle Cell Anemia, a Molecular Disease, in Nature in 1949 established SCD as the first molecular human disease, and it established the inheritance pattern of the disorder and of monogenic diseases generally. In addition, that seminal work laid the foundation for the explosion of knowledge in human molecular genetics decades later that gave birth to a new discipline called gene therapy. The publication by Watson The Significance of the Paucity of Sickle Cells in Negro Infants provided the concept that fetal hemoglobin (Hb F) ameliorates the clinical presentation of SCD for the first time in 1948, ushering in one of the most intensely studied areas of SCD research. Advancements in Genetics, Cellular and Molecular Mechanisms, and Therapy of SCD in the two decades following the seminal works by Pauling and Watson were driven primarily by studies on the erythrocyte, involving polymerization of Hb S and antisickling hemoglobin variants, rheology, and red cell membrane. A highlight amongst these studies was the landmark work by Kan and Dozy published in the article DNA Sequence Adjacent to the Human Beta-Globin Structural Gene: Relationship to Sickle Mutation. That study described the presence of single-nucleotide polymorphisms in the human genome for the first time, and it initiated a new avenue of research that led to the discovery of the multicentric origin of the sickle mutation, and it laid the foundations for genetic association studies in SCD, which are currently a major focus of several investigations. The scope of SCD research expanded beyond the erythrocyte in the 1980s to encompass vascular biology, notably the endothelium, coagulation, and inflammation. Twenty years later, the most compelling evidence that these factors play a critical role in the pathogenesis of SCD is the demonstration that tumor necrosis factor induced adhesion of leukocytes to the vascular endothelium provides the initial cellular events of vaso-occlusion in a mouse model of SCD. Paradigm-shifting insights into the mechanisms of globin gene expression spearheaded by the discovery of the locus control region (LCR) by two groups in the 1990s heralded a new era in SCD research. First, these insights helped to create developmentally regulated and clinically relevant transgenic mouse models of SCD. Second, they permitted the development of efficacious DNA vectors for gene therapy of SCD that continue to improve as novel elements of gene delivery systems become available and are incorporated into newer generation vectors. The current special issue of Anemia contains original research articles about progress made towards Hb F induction using novel pharmacological agents and artificial zinc finger transcription factors, and a web-based tool to evaluate adherence to hydroxyurea therapy. The latter tool represents efforts to integrate new technology to improve the clinical care of individuals with SCD. Also included in this issue is the first report from a Congolese group of the association of Hb F levels with clinical severity in this population. Several articles report alteration in redox environment and link this phenomenon to impaired hematopoietic progenitor and stem cell function improved by treatment with n-acetyl cysteine in transgenic SCD mice, reduced migration of endothelial progenitors cells derived from children who have SCD, and lastly an association of oxidative stress markers with an atherogenic index in adults with sickle nephropathy. What is known about the deleterious effects of sickling on the genitourinary tract and the role of cyclic nucleotide signaling is reviewed. Finally, articles report two endothelial dysfunction including increased activity of the elastase cathepsin K, and age-dependent increase, in vascular permeability, that culminates in pulmonary edema in middle-aged SCD mice. The wide variety of experimental studies in this special issue represents potentially new therapeutic tools, ranging from novel approaches for Hb F induction, improved stem cell function and a biomarker to predict risk for SCD nephropathy. Furthermore, the findings of endothelial dysfunction via upregulated cathepsin activity may represent a new pharmacologic target to block accelerated arterial disease observed in children with SCD. The reports in this issue will aid research efforts to close the gap between understanding SCD genetics and developing effective new clinical care approaches and therapeutic options. Betty S. Pace Solomon F. Ofori-Acquah Kenneth R. Peterson