Abstract: Background: Sickle cell disease (SCD) is a genetic disorder that causes significant medical and neurologic morbidity in children. Hydroxyurea (HU) is the primary medication used to prevent these complications. National Heart, Lung, and Blood Institute (NHLBI) guidelines recommend offering HU to children as young as 9 months of age with SCD (HbSS or HbSB0 thalassemia) using a shared decision-making approach. Although HU has proven efficacious it remains underutilized and caregivers report that they are not always actively involved in the decision to initiate this therapy. Reasons for limited HU uptake likely include lack of clinician knowledge and training and negative caregiver perceptions. Thus, we developed the Engage-HU trial as a novel approach to address HU utilization barriers. A critical consideration for this trial was that SCD primarily affects individuals of African and Hispanic/Latino descent. In these minority populations, intervention trials are sometimes terminated early because of recruitment difficulties related to mistrust of research, caregiver burden, and transportation issues. As such, the Engage-HU trial design included best-practice strategies for recruiting people of color in research. This study describes these strategies, the initial recruitment plan, preliminary recruitment outcomes and strategies, and our procedural adaptations. Study Design and Methods: Engage-HU is a randomized control trial (NCT03442114) to assess how clinicians can engage caregivers in a shared discussion that considers their values and preferences and includes evidence that supports HU. Engage-HU compares two dissemination methods for clinicians to facilitate shared decision-making with caregivers of young children with SCD: 1) the American Society of Hematology Pocket Guide, and 2) the HU Shared-Decision Making (H-SDM) Toolkit. The study aims to recruit 174 caregivers and evaluate the effectiveness of the dissemination methods on patient-centered outcomes (caregiver confidence in decision-making and perceptions of experiencing shared decision-making) as well as HU uptake and child health outcomes. Eligible children are aged 0 to 5 years, candidates for HU, and their caregiver has not made a decision about HU in the past 3 months. The trial is being conducted at 9 sites in the United States and uses a stepped-wedge design. Data will be analyzed based on the intent-to-treat principle. All participants will remain in the arm of the study to which they were randomized, regardless of whether or not they receive the assigned dissemination method. The primary endpoints are caregiver decisional uncertainty and caregiver perception of shared decision-making measured using validated tools. Data will be analyzed using a linear mixed effects regression model with a robust variance estimator and maximum likelihood estimation with observations clustered within site. The Engage-HU trial includes adaptations to increase recruitment such as tailored messaging, a relational recruitment approach, streamlined data collection, and a Stakeholder Advisory Committee. However, even with these adaptations, the first 6-months of the trial yielded lower than anticipated recruitment. Rather than terminate the trial or accept low enrollment, the research team implemented a series of recruitment strategies to address barriers including helping to improve research coordinator knowledge of the study purpose and adjusting no-show and follow-up procedures (e.g., calls to families after missed appointments and reminder calls before appointments). Site clinicians and clinic staff were provided with additional training so they could give more context about Engage-HU to caregivers and the study principal investigator led monthly "all coordinator" calls to provide support by sharing updates and experiences about successful recruitment. Implementation of these strategies resulted in triple the number of enrollments over the next 7-months compared to the previous 6-months (Table 1). Our goal in sharing this information is to provide lessons learned that can be implemented in future trials with the systematically underserved SCD population. It is also anticipated that methods described here may also inform clinical approaches to better engage caregivers of young children around critical clinical conversations, such as initiating medications like HU. Disclosures King: Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bioline: Consultancy; RiverVest: Consultancy; Novimmune: Research Funding; Celgene: Consultancy; Tioma Therapuetics: Consultancy; Amphivena Therapeutics: Research Funding; WUGEN: Current equity holder in private company; Cell Works: Consultancy; Incyte: Consultancy. Smith-Whitley:Prime: Other: Education material; Celgene: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Neumayr:Emmaus: Consultancy; Bayer: Consultancy; CTD Holdings: Consultancy; Pfizer: Consultancy; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Micelle: Other: Site principal investigator; GBT: Other: Site principal investigator; PCORI: Other: site principal investigator; Novartis: Other: co-investigator; Bluebird Bio: Other: co-investigator; Sangamo Therapeutics: Other; Silarus: Other; Celgene: Other; La Jolla Pharmaceuticals: Other; Forma: Other; Imara: Other; National Heart, Lung, and Blood Institute: Other; Health Resources and Services Administration: Other; Centers for Disease Control and Prevention: Other; Seattle Children's Research: Other. Yates:Novartis: Research Funding. Thompson:Novartis: Consultancy, Honoraria, Research Funding; CRISPR/Vertex: Research Funding; BMS: Consultancy, Research Funding; Baxalta: Research Funding; Biomarin: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding.

Abstract: Background: Hydroxyurea (HU) is the primary medication used to prevent the significant medical and neurologic morbidities of pediatric sickle cell disease (SCD; HbSS or HbSB0 thalassemia). Despite the benefits of HU, it remains under-utilized likely due to lack of clinician knowledge/training and negative caregiver perceptions. Thus, we developed the Engage-HU randomized controlled trial (NCT03442114) as a novel approach to address HU utilization barriers. Engage-HU is designed to assess how clinicians can engage caregivers in a shared discussion that considers their values, preferences, and scientific evidence about HU. The COVID-19 pandemic has resulted in significant changes to healthcare delivery for children with SCD, as they are at increased risk of severe illness from COVID-19 infection. Given their risk status, it was recommended that patients with SCD complete telehealth visits when possible. Some families also chose to delay care because they feared their child would get infected at hospitals/healthcare clinics that care for COVID-19 positive patients. Since the lives of all families enrolled in the Engage-HU trial have been affected to some extent, we incorporated measures to capture the impact of the COVID-19 pandemic and the usability of telemedicine implementation and services. Methods: Engage-HU is a randomized control trial comparing two dissemination methods for clinicians to facilitate shared decision-making with caregivers of young children with SCD. Study outcomes include caregiver confidence in decision-making and perceptions of experiencing shared decision-making as well as HU uptake and child health outcomes. Eligible children are 0 to 5 years, candidates for HU, and their caregiver has not decided about HU in the past 3 months. The trial is being conducted at 9 sites in the United States and uses a unidirectional crossover design. The primary endpoints are caregiver decisional uncertainty and caregiver perception of shared decision-making measured using validated tools. Data will be analyzed using the intent-to-treat principle, and all participants will remain in the arm to which they were randomized. A multiple group comparison analysis will be performed to assess significant response variable differences by group randomization. The Engage-HU study aims to recruit 174 caregivers who are considering initiating HU. The trial is being conducted at 9 sites in the United States. Data collection is ongoing, and 160 caregiver-participants have been enrolled to date. Since May 2020, caregiver-participants have completed the COVID-19 Exposure and Family Impact Scales (CEFIS), which contain 2 subscales (exposure to potentially traumatic aspects of the pandemic, impact on families), and the COVID-19 telemedicine use survey during a study visit. Results: Currently, 8 of the 9 sites have collected data from 48 caregivers (93.8% mothers), most of whom (93.8%) identify as African American/Black (see Figure 1). Correlations indicated that older caregivers experienced greater exposure (Mean = 7.0, SD = 4.1, range = 1-19) to potentially traumatic aspects of the pandemic (r = .31, p = .04). Distress related to COVID-19 varied widely across the sample, for both caregivers (Mean = 5.9, SD = 2.9, range = 1-10) and children (Mean = 4.1, SD = 3.4, range = 1-10). Scores on the telemedicine usability survey were generally high, indicating that caregivers are happy with the quality of care delivered via telehealth. However, caregivers (r = .30, p = .09) and children (r = .32, p = .07) experiencing more pandemic-related distress reported less satisfaction with telehealth. Conclusion: Although Engage-HU has resumed research operations, recruitment has not reached pre-pandemic targets, as fewer eligible patients are scheduled for routine care visits at SCD clinics. Our preliminary analyses suggest a significant continued impact of the pandemic on families and general satisfaction with the quality of healthcare delivered via telemedicine. These findings indicate that targeted screenings to identify and intervene for those who demonstrate more COVID-19 pandemic-related distress are needed. Figure 1 Figure 1. Disclosures Quinn: Forma Therapeutics: Consultancy; Aruvant: Research Funding; Novo Nordisk: Consultancy; Emmaus Medical: Research Funding. Yates: Agios Pharmaceuticals: Current Employment. Badawy: Sanofi Genzyme: Consultancy; Vertex Pharmaceuticals Inc: Consultancy; Bluebird Bio Inc: Consultancy. Thompson: bluebird bio, Inc.: Consultancy, Research Funding; Baxalta: Research Funding; Biomarin: Research Funding; Celgene/BMS: Consultancy, Research Funding; CRISPR Therapeutics: Research Funding; Vertex: Research Funding; Editas: Research Funding; Graphite Bio: Research Funding; Novartis: Research Funding; Agios: Consultancy; Beam: Consultancy; Global Blood Therapeutics: Current equity holder in publicly-traded company. Smith-Whitley: Global Blood Therapeutics: Current Employment. King: National Cancer Institute: Research Funding; National Heart, Lung, and Blood Institute: Research Funding; Health Resources and Services Administration: Research Funding; Global Blood Therapeutics: Research Funding. Meier: CVS Caremark: Consultancy; Forma Therapeutic: Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Membership on an entity's Board of Directors or advisory committees; Novartis,: Other: Data Safety Monitoring Board membership; NHLBI: Other: Data Safety Monitoring Board membership; Global Blood Therapeutics: Other: Steering Committee membership, grant funding; CDC,: Other: grant funding; Indiana Department of Health: Other: grant funding . Tubman: Global Blood Therapeutics: Consultancy, Research Funding; Novartis Pharmaceuticals: Honoraria, Research Funding; Forma Pharmaceuticals: Consultancy; Perkin Elmer: Honoraria. Crosby: Forma Therapeutics: Honoraria; PCORI: Research Funding; HRSA: Research Funding; Global Blood Therapeutics Panel: Honoraria; Children's Hospital of Philadelphia: Honoraria; Professional Resource Exchange: Patents & Royalties: $30-$60 every other year; SCDAA: Honoraria; NHLBI: Other: Payment for review of LRP Proposals, Research Funding. OffLabel Disclosure: Hydroxyurea has been FDA approved for the treatment of sickle cell disease for patients ages 2 years and above but NHLBI and ASH Guidelines recommend it be offered to children as young as age 9 months.

Abstract: Background: Sickle cell disease (SCD) is the most common genetic disorder in the United States, seen in 100,000 Americans. SCD complications include pain episodes, chronic anemia and long-term end organ damage, leading to significant impairment in health-related quality of life (HRQOL) across the lifespan. Hydroxyurea (HU) reduces morbidity and mortality, improves HRQOL and lowers healthcare utilization, yet adherence remains suboptimal. Limited evidence from cross-sectional studies demonstrates an association between lower HU adherence and worse HRQOL scores. Objective: To assess the longitudinal relationship of HU adherence to HRQOL domains, including fatigue and depression. We hypothesized that higher HU adherence over time would be associated with improvement in HRQOL domain scores, especially depression and fatigue. Methods: In this longitudinal cohort study (NCT04675645), patients were enrolled from the comprehensive sickle cell clinic at Lurie Children's Hospital of Chicago. Patients were eligible if they were ³8 years old, had SCD (any genotype), and on HU with a stable dose for ³2 months. Study assessments included PROMIS ® measures for depression and fatigue, self-report of adherence using visual analogue scale (VAS), and patient demographics. Assessments were completed at baseline and every 3 months with a total of 5 visits (0, 3, 6, 9 and 12 months). Laboratory markers of adherence collected from chart review, including fetal hemoglobin (HbF%) and mean corpuscular volume (MCV). We conducted bivariate correlations among demographic variables, adherence markers and HRQOL scores as well as among adherence variables (VAS, HbF, MCV) at each visit. We conducted different multilevel models (MLMs), fixed and random effects, to understand the extent to which between- and within-person variation in adherence was associated with HRQOL scores over the 12-month period. We report unstandardized betas (B) and 95% Confidence Intervals (CI) from the MLMs. Results: Twenty-three patients have been enrolled (96% HbSS, 65% females, 100% Black, median age 15 [range 9-22] years old). At baseline, participants had a median Hb level of 9.5 (IQR 8.3-10.3 g/dl) with a HbF of 16.4% (IQR 13.1-28.7%) and MCV of 106.5 fl (IQR 91.6-113.9 fl). Participants' MCV levels significantly correlated with HbF% and VAS at visit 1 (r=0.58, P & lt;0.01; r=0.6, P & lt;0.01), visit 2 (r=0.66, P & lt;0.01; r=0.63, P & lt;0.01), visit 4 (r=0.76, P & lt;0.01; r=0.72, P & lt;0.01) and visit 5 (r=0.71, P & lt;0.01; r=0.59, P & lt;0.05), respectively. Participants' VAS adherence levels significantly increased from visit 1 to visit 5 (median 72 [IQR 60-92] vs. 88 [IQR 75-95] , P=0.04, respectively) along with significant improvement in their fatigue scores (median 52.8 [IQR 35.1-70.5] vs. 30.8 [IQR 13.2-48.4] , P=0.001, respectively). Variation in fatigue and depression scores across the study period was due to between-person differences (38% and 71%, respectively) or within-person fluctuations (62% and 29%, respectively). Using fixed and random effect MLMs, between-person differences in HU adherence over 12 months using VAS and HbF% were significantly related to participants' reported depression (B -0.43, 95% CI -0.69 to -0.17, P & lt;0.01; B -0.58, 95% CI -1 to -0.15, P & lt;0.05, respectively) (Figure 1) and fatigue scores (B -0.42, 95% CI -0.68 to -0.16, P & lt;0.01; B -0.43, 95% CI -0.78. to -0.06, P & lt;0.05, respectively) (Figure 2). In contrast, we found no statistically significant effects of within-person variation in adherence, using VAS and HbF, on participants' reported fatigue and depression scores over 12 months, which could be due our small sample size. Conclusions: Children and adolescents who were more adherent to HU across the entire study period were less likely to experience fatigue and depression, compared to those who were less adherent. Participants' self-report and laboratory markers of adherence were significantly correlated across study visits. Within-person fluctuations in adherence were not associated with changes in fatigue and depression scores across the study period. Future multi-institutional studies with a larger sample size are needed to better understand the within-person effects of variation in HU adherence on HRQOL scores over time. Behavioral interventions, such as mHealth apps, that are focused on improving HU adherence among children and adolescents with SCD has the potential to improve HRQOL and other important health outcomes. Figure 1 Figure 1. Disclosures Badawy: Bluebird Bio Inc: Consultancy; Vertex Pharmaceuticals Inc: Consultancy; Sanofi Genzyme: Consultancy. Thompson: Biomarin: Research Funding; Baxalta: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; CRISPR Therapeutics: Research Funding; Vertex: Research Funding; Editas: Research Funding; Graphite Bio: Research Funding; Novartis: Research Funding; Agios: Consultancy; Beam: Consultancy; Global Blood Therapeutics: Current equity holder in publicly-traded company. Cella: FACIT: Membership on an entity's Board of Directors or advisory committees.

Abstract: Background . Sickle cell disease (SCD) is a chronic debilitating illness. SCD-related complications result in substantial impairment in quality of life (QOL). Our study objective was to assess the relationship of participants’ characteristics, QOL, hydroxyurea adherence, and SCD-related clinical outcomes in youth with SCD. Procedure . A single-center cross-sectional study. Thirty-four youth with SCD enrolled from clinic between January and December 2015. Participants completed PROMIS® measures and ©Modified Morisky Adherence Scale. Results . Participants had a mean age of 14.8 (SD 2.9) years and 41% were female. Participants’ age correlated with fatigue ( r s =0.48; P =0.006), pain ( r s =0.32; P =0.07), and anxiety ( r s =0.33; P =0.06) scores. Participants with chronic pain had worse upper extremity physical function ( P =0.05), pain ( P =0.04), anxiety ( P =0.05), and depression ( P =0.05). Males reported significantly higher hydroxyurea adherence (5.4 versus 3.6, P =0.02) compared to females. Participants with chronic pain had more frequent hospitalizations ( P =0.02), emergency room visits ( P =0.04), and longer total length of hospital stays over 12-month period ( P =0.01). Conclusions . Older and female participants had worse QOL scores, and males reported higher hydroxyurea adherence. Participants with chronic pain reported significant impairment in different QOL domains and had increased healthcare utilization. Future longitudinal studies examining the relationship between participants’ characteristics, QOL, hydroxyurea adherence, and SCD-related clinical outcomes are needed.

Abstract: Patients with sickle cell disease (SCD) and other anemias who receive blood transfusions are at risk of organ damage due to transfusional iron overload. Deferiprone is an iron chelator with a well‐established safety and efficacy profile that is indicated for the treatment of transfusional iron overload. Here, we report safety data from the large‐scale, retrospective Ferriprox® Total Care Registry, which involved all patients with SCD taking deferiprone following the 2011 approval of deferiprone in the United States through August 2020. A total of 634 patients who had initiated deferiprone treatment were included. The mean (SD) duration of deferiprone exposure in the registry was 1.6 (1.6) years (range 0 to 9.7 years). In the overall patient population ( N = 634), 64.7% ( n = 410) of patients reported a total of 1885 adverse events (AEs). In subgroup analyses, 54.6% ( n = 71) of pediatric patients and 67.3% ( n = 339) of adult patients reported AEs. The most common AEs reported in patients receiving deferiprone were sickle cell crisis (22.7%), nausea (12.1%), vomiting (8.7%), abdominal discomfort (5.4%), and fatigue (5.4%). Neutropenia was reported in four (0.6%) patients and severe neutropenia/agranulocytosis (defined as absolute neutrophil count 〈 0.5 × 10 9 /L) was reported in two (0.3%) patients. Of patients with evaluable data, all cases of neutropenia and severe neutropenia/agranulocytosis resolved with deferiprone discontinuation. Results from the nearly 10 years of real‐world data collected in the Ferriprox® Total Care Registry demonstrate that deferiprone is safe and well tolerated in patients with SCD or other anemias who have transfusional iron overload.

Abstract: Transfusional iron overload represents a substantial challenge in the management of patients with sickle cell disease ( SCD ) who receive chronic or episodic red blood cell transfusions. Iron‐induced cardiomyopathy is a leading cause of death in other chronically transfused populations but rarely seen in SCD . Study objectives were to: (i) examine the extent of myocardial and hepatic siderosis using magnetic resonance imaging ( MRI ) in chronically transfused SCD patients, and (ii) evaluate the relationship between long‐term (over the 5 years prior to enrolment) mean serum ferritin ( MSF ), spot‐ferritin values and liver iron content ( LIC ) measured using MRI and liver biopsy. Thirty‐two SCD patients (median age 15 years) with transfusional iron overload were recruited from two U.S. institutions. Long‐term MSF and spot‐ferritin values significantly correlated with LIC by MRI ‐R2* ( r  = 0·77, P   〈  0·001; r  = 0·82, P   〈  0·001, respectively). LIC by MRI ‐R2* had strong positive correlation with LIC by liver biopsy ( r  = 0·98, P   〈  0·001) but modest inverse correlation with cardiac MRI ‐T2* ( r  =   −0·41, P  = 0·02). Moderate to severe transfusional iron overload in SCD was not associated with aberrations in other measures of cardiac function based on echocardiogram or serum biomarkers. Our results suggest that SCD patients receiving chronic transfusions may not demonstrate significant cardiac iron loading irrespective of ferritin trends, LIC and erythropoiesis suppression.

Abstract: Patients with sickle cell disease (SCD) and thalassemia experience several complications across their lifespan that lead to impairment in different health-related quality of life (HRQOL) domains. There is increasing interest in curative therapies for patients with SCD and thalassemia, including hematopoietic stem cell transplant (HSCT) and gene therapy; however, the effect of these therapies on various HRQOL domains remains unclear. Our objective was to systematically evaluate the most recent evidence for the effect of HSCT and gene therapy on HRQOL in patients with SCD and thalassemia. A systematic search of medical literature databases was conducted. A total of 16 studies (thalassemia, n = 9; SCD, n = 6; both, n = 1) involving 517 participants met inclusion criteria (thalassemia, n = 416; SCD, n = 101). HSCT was associated with a small to large positive effects in most HRQOL domains (Cohen’s d; mean = 0.47; median = 0.37; range, 0.27-2.05). In thalassemia, HSCT was frequently associated with large positive effects in physical and emotional HRQOL domains (median d = 0.79 and d = 0.57, respectively). In SCD, HSCT was associated with large positive effects in all HRQOL domains. Emerging data suggest improvement in HRQOL outcomes across different domains following gene therapy in thalassemia and SCD. The quality of evidence was moderate in 13 studies (81%). HSCT has a positive impact on several HRQOL domains in patients with SCD and thalassemia; however, more longitudinal studies are warranted to assess the sustainability of these effects. Reporting HRQOL outcomes from ongoing gene therapy or gene-editing trials in SCD and thalassemia is key to better understand the benefits of such therapies.