Treatment Of Sickle Cell Disease Research Articles

Impact of Psychiatric Comorbidity on Readmissions of Sickle Cell Disease -a Nationwide Readmissions Database Study

Introduction: While advances in the management of sickle cell disease (SCD) treatment have improved outcomes, readmission rates among patients remain a significant concern. A previous study with the National Readmission Database (NRD) 2016 found that alcohol use, tobacco use, opoid use ,substance use and depression were associated with SCD readmission even though the general rate of readmission has decreased over the years. This study aims to update the literature, and further determine the predictors associated with increased readmission among individuals with SCD. Methods: Using the Nationwide Readmissions Database (NRD), we evaluated readmissions for SCD for the year 2016-2020. On the basis of International Classification of Diseases, TenthRevision, Clinical Modification (ICD-10-CM) codes, we identified SCD hospitalizations (D57.0, D57.1, D57.2, D57.4, D57.8), and comorbid conditions. Usingamultivariateregressionanalysis,weestimatedtheindependent predictors of 30-day readmissions of SCD. We used STATA® Version 18.0 Software (STATACORP, TEXAS, USA) for analysis. The p-value was set at p < 0.05 for statistical significance. Results: A total of 262,571 index admissions for adult patients with a primary diagnosis of SCD were admitted within the study period; 61,687 patients (23.6%) were readmitted within 30 days. A total of 886 and 105 deaths were reported respectively among index admissions and readmissions. Compared to index admissions, readmissions had decreased THC of 2147 U.S. dollars (95%CI: -2678 - -1615), while we found no significant change in the LOS between index admissions and readmissions. Common causes of increased rate of readmissions were SCD with mood disorder (HR=1.15, 95%CI: 1.11-1.20) , anxiety disorder (HR= 1.16, 95%CI: 1.11-1.20) and opioid use (HR=1.42, 95%CI: 1.35-1.50). Conditions associated with lower rates of readmission are Alcohol use disorder (HR 0.76, 95%CI: 0.62-0.94) and cannabis use ( HR=0.94, 95%CI: 0.88-0.99). Discussion: Our findings suggest that among individuals admitted with a primary diagnosis of SCD, having concurrent mood and anxiety disorders, and opioid use disorder increases rates of readmission. Interestingly, we observed that alcohol use disorder and cannabis use was associated with lower rates of readmission in SCD patients. Optimizing the comorbid conditions in patients with SCD may reduce readmission rates. However, further studies are required to establish the relationship between psychiatric comorbidity and healthcare resources utilization among SCD patients.

Increased Hydroxyurea Adherence Associated with Pediatric, Adolescent and Young Adult Sickle Cell Anemia Care at US Military Healthcare Facilities: A Cross-Sectional Study

Sickle Cell Anemia (SCA) causes significant acute complications, chronic complications, and premature mortality. The foundational treatment for SCA is hydroxyurea (HU) which reduces acute and chronic complications. Several barriers prevent patient HU adherence and thus treatment benefit. We performed a cross-sectional study of 206 pediatric, adolescent, and young adult (AYA) patients with HgbSS or HgbS-beta-thalassemia-zero in the United State Military Health System who were prescribed HU to evaluate for to factors associated with HU adherence. These patients have access to military or civilian pediatric hematology care at no or low cost. We categorised patient's adherence dichotomously according to the American Society of Hematology quality metric for HU adherence. The adherence group, 26% of the study population, had a younger mean age, 11.7 versus 14.9 (p = 0.0003), and was more likely to receive hematology care in the MHS. Logistic regression analysis of HU adherence, adjusted for age and gender demonstrated the patients receiving pediatric hematology care at a military healthcare facility had 2.96 (1.47-5.99, 95% CI) the odds of adherence compared to patients receiving pediatric hematology care at civilian healthcare facilities. The monthly base pay of the patient's sponsor, a strong indicator of socioeconomic status was not associated with HU adherence odds ratio 1.00 (0.99-1.01, 95% CI). Among Pediatric and AYA patients with SCA in the MHS: HU adherence appears equitable throughout the range of sponsor rank; and hematology care at military facilities is associated with increased HU adherence.

Preliminary Pharmacodynamic Results from a Multicenter Phase 2/3 Study of Next-Generation HbS Polymerization Inhibitor GBT021601 for the Treatment of Patients with Sickle Cell Disease

Introduction: Sickle cell disease (SCD) is a lifelong inherited disorder resulting in polymerization of sickle hemoglobin (HbS) that leads to red blood cell sickling/damage. SCD is characterized by chronic hemolytic anemia, vaso-occlusive crises, and cumulative organ damage. Voxelotor is a first-in-class HbS polymerization inhibitor approved in the US for the treatment of SCD in patients aged ≥4 years and in Europe for the treatment of hemolytic anemia due to SCD in patients aged ≥12 years as monotherapy or with hydroxyurea. GBT021601 is a next-generation HbS polymerization inhibitor with improved pharmacokinetic properties that increases hemoglobin (Hb)-oxygen affinity and stabilizes Hb in the oxygenated state to inhibit polymerization. GBT021601 has the potential for higher Hb occupancies at lower doses than voxelotor and could potentially reduce treatment burden while improving clinical outcomes. Here we report preliminary pharmacodynamic (PD) data from an ongoing phase 2/3 study of orally administered GBT021601 (NCT05431088) in patients with SCD. Methods:This is a 3-part, multicenter, phase 2/3 study: Part A is a randomized, open-label, 12-week, dose-finding study of GBT021601 in adult participants; Part B is a randomized, double-blind, placebo controlled 48-week study and will evaluate GBT021601 vs placebo in adult and adolescent participants; and Part C will evaluate open-label GBT021601 in pediatric participants. Herein, we present Week 6 and Week 12 data from Part A, which enrolled patients aged 18-65 years with SCD (HbSS or HbSB 0 genotype) and had Hb 5.5-10.5 g/dL at screening. Eligible patients were randomly assigned 1:1 to GBT021601 100 mg or 150 mg and received a loading dose twice daily for 4 days followed by once-daily maintenance doses through Week 12. The primary endpoint was change from baseline (BL) in Hb at Week 12. Clinical laboratory parameters, including RBC count, Hb, hematocrit (Hct), and mean corpuscular volume (MCV), were assessed. PD assessments included red blood cell (RBC) deformability (Oxygenscan, expressed as elongation index [EI]) as a function of partial pressure of oxygen [pO 2]). Results: At data cutoff (June 20, 2023), 28 of the 35 patients who received treatment in Part A of the study completed 12 weeks of treatment. The 100-mg group consisted of 17 patients, with a mean (range) age of 29.1 (18-49) years. The 150-mg group had 18 patients, with a mean (range) age of 30.2 (18-59) years. Most patients (32/35 [91.4%]) were homozygous for SCD (HbSS genotype). At BL, 16/35 patients (45.7%) were taking hydroxyurea. Patients treated with 100- and 150-mg doses of GBT021601 showed robust improvements from BL in several RBC parameters at 6 and 12 weeks ( Table). After 12 weeks of treatment, the mean (SD) increase in Hb from BL was 2.67 (1.52) g/dL for the 100-mg group (n=12) and 3.17 (1.82) g/dL for the 150-mg group (n=11). Additionally, the mean (SD) Hct gradually increased 7.87 (4.25) % in the 100-mg (n=12) and 9.61 (4.60) % in the 150-mg group (n=11), and RBC counts increased by 1.32 (0.79) 10 12/L in the 100-mg group (n=12) and 1.53 (0.60) 10 12/L, in the 150-mg group (n=11), thus approaching the normal range for these RBC parameters. At 12 weeks, mean (SD) MCV decreased from BL by 8.91 (6.49) fL in the 100-mg group (n=12) and 12.70 (9.05) fL in the 150-mg group (n=11). Ektacytometry results with GBT021601 showed marked improvement in RBC deformability with increases from BL in median EI max at Week 6 (100 mg: 0.37 to 0.55 [n=7]; 150 mg: 0.42 to 0.55 [n=7]) and Week 12 (100 mg: 0.37 to 0.53 [n=6]; 150 mg: 0.42 to 0.50 [n=8]) and an increase in median EI min from BL at Week 6 (100 mg: 0.09 to 0.42 [n=7]), which was indicative of improvement in RBC deformability. The median point of sickling during deoxygenation decreased from BL at Weeks 6 and 12 with dosing of GBT021601, indicating HbS polymerization was likely delayed ( Figure). Conclusions: In patients with SCD, GBT021601 maintenance doses of 100 mg and 150 mg led to increased Hb, increased Hct, and improvements in RBC deformability by 6 weeks, which were maintained through to Week 12. Analyses of PD data show promising evidence of efficacy with near normalization of Hb and oxygenscan parameters consistent with the improved mechanism of the drug. PD data from Part A of this phase 2/3 study demonstrated blood parameters approaching normal ranges and support for the ongoing clinical development of GBT021601 as a potential treatment for individuals with SCD.

Engagement with Incharge App - a Mobile Health Intervention to Improve Adherence to Hydroxyurea Among Individuals with Sickle Cell Disease

Introduction: Sickle cell disease (SCD) affects around 100,000 people in the United States, causing acute vaso-occlusive events and chronic end-organ damage. Hydroxyurea (HU) is a proven treatment for SCD that reduces acute and chronic complications. Despite extensive evidence and guideline recommendations, many people with SCD do not receive optimal HU therapy. Our group has shown that using the InCharge Health app, a SCD-specific app co-developed with patients (Alberts et al, JMIR mHealth uHealth, 2020), for at least 24 weeks, increases adherence to HU up to 29%, but engagement with the app varied among users. This study reports user's perceptions of the app relative to their degree of app utilization, thus informing future app adaptations to optimize app engagement and potentiate its effect. Methods: The InCharge Health app features included daily reminders, adherence and pain progress tracking, communication with providers and other patients, hospital mode deactivation, educational resources, and an accountability partner. Participants used the InCharge Health app and completed the validated Mobile Application Rating Scale (MARS, Stoyanov SR, JMIR mHealth uHealth, 2015) after 24 weeks of app use. The MARS evaluates the quality of mobile health apps by eliciting users' perceptions of engagement, functionality, aesthetics, and information quality. App utilization data (% of the study days) were obtained from the backend of the app and defined as low (<25%), medium low (25-50%), medium high (50-75%), and high (>75%). HU percentage of days covered (PDC), the percentage of days covered by filled HU prescriptions during the study period, was used as a proxy for medication adherence. Baseline pain frequency 12 months before study enrollment was obtained using the Adult Sickle Cell Quality of Life Measurement Information System. After 24 weeks, the ease of use, importance, and helpfulness of app features were evaluated and stratified based on the level of app usage. Results: A total of 208 participants enrolled, median age 26.3 years (range, 15 to 45), 52% (108/208) females, 87% (181/208) with HbSS/Sβ 0-thalassemia. Fifty-eight percent (121/208) of participants were low app utilizers, 19.2% (40/208) medium low, 15.9% (33/208) medium high, and 6.7% (14/208) high app utilizers (Table 1). As app usage increased, users reported lower pain frequency and pain severity. After 24 weeks, all groups increased PDC, which sustained post-study, and the magnitude of an increase was proportional to the amount of app use (Table 1). The mean (SD) daily use was 2.3 (4.8) minutes/day, and daily duration of app use increased with the total app use. Conversely, the interval between app usage decreased with total app use (Table 2). The most used app features included pain tracking (56.2%, 117/208) and weekly progress report (20.7%, 43/117). The least used features were connecting to educational resources (7.2%, 15/208) and communicating with treating providers (6.3%, 13/208, Table 2). Overall, 57.7% (120/208) rated the app moderately or very interesting, 63.0% (131/208) reported using it daily to 2 to 3 days/week, 83.2% (173/208) found the app easy to learn, simple, or intuitive. Low users found the app less interesting and had more concerns of the time and effort it took to use the app (Table 2). Across all groups, daily reminders were considered the most important and useful feature. Fewer high users considered daily reminders the most important feature, however high users more often deemed other features as most important. HU information was found to be the most important by high users, but this varied between the other user levels. High users also found adherence tracking most important with more users valuing it as app usage increased. Adherence and pain progress tracking were found helpful in all groups except the medium-high users. Importantly, more than 50% of all groups intended to continue using the app beyond the study period. Conclusions: The InCharge Health app promoted increased HU adherence proportional to its engagement. All users considered daily reminders the most beneficial and crucial feature, while pain tracking was widely utilized. Distinct app consumption and preference patterns were observed according to app usage level. Plans are underway to improve the app functionality and interface to allow real-time customization to boost app engagement and further adherence enhancement among individuals with SCD.

Patterns of Nonadherence to Hydroxyurea in Pediatric Sickle Cell Disease

Background: Sickle cell disease (SCD) affects an estimated 100,000 American children and adults (CDC, 2017). Hydroxyurea is the first-line disease-modifying treatment for SCD. Daily oral hydroxyurea significantly reduces the frequency of pain and serious medical complications associated with SCD, including dactylitis and acute chest syndrome (Wang et al., 2011). However, adherence to hydroxyurea is less than optimal at 74% among pediatric patients, with 20% of children who are prescribed hydroxyurea taking less than 50% of their prescribed doses (Louiselle et al., 2016). Suboptimal hydroxyurea adherence is associated with increased risk for medical complications, diminished quality of life, and higher health care costs and utilization (e.g., Badawy et al., 2017; Thornburg et al., 2010). Factors associated with hydroxyurea nonadherence in pediatric SCD include female sex, older age, more adherence barriers (e.g., difficulty obtaining refills), lower socioeconomic status, and lower parent treatment knowledge. Purpose: This study aims to characterize trajectories of pediatric hydroxyurea adherence to identify subgroups that may be at highest risk for hydroxyurea nonadherence (e.g., sociodemographic factors), critical time periods for adherence support interventions (e.g., adolescence), and minimal adherence thresholds to optimize hydroxyurea efficacy. Methods: Retrospective chart review across two institutions (i.e., Cincinnati Children's Hospital Medical Center and Nemours Children's Hospital, Delaware) are ongoing. Participants will include patients with SCD ages 2 to 21 years who were prescribed hydroxyurea from March 2007 to February 2017. Researchers are extracting the following data from patient electronic medical records (EMRs) to estimate hydroxyurea adherence: hemoglobin F levels (HbF), mean corpuscular volume (MCV), and absolute neutrophil count (ANC). Additional clinical information will be extracted from patient EMRs including demographic information, SCD genotype, SCD complications, acute care utilization, medical and social complexity, and concomitant medication use. Descriptive statistics will be used to summarize demographic and clinical characteristics of the sample. MCV will be the primary measure of hydroxyurea adherence and Hgb F and ANC will be secondary measures. If the final sample size is sufficiently large, we will conduct group-based trajectory modeling (GBTM) to analyze patterns of hydroxyurea adherence changes over time and identify hydroxyurea adherence trajectory subgroups. Multinomial logistic regression analyses will be used to analyze potential predictors of hydroxyurea adherence trajectory subgroup membership. Results: Preliminary results revealed that as of February 2017, 88% of eligible patients (based on age) were prescribed hydroxyurea.Data from the first 30 completed chart reviews indicates that half of the sample was female (sex assigned at birth), all identified as Black or African American, all but two participants had HbSS, and the mean age 13.0 years ( SD=8.0, range=2.47 to 26.81). Average MCV across an average of 21 time points ( SD=14.2, range=5-74) was 94.3 ( SD=11.2, range=58.4-114.2). As of February 2017, 53% of individuals had MCV values at or above 100. Specifically, 60% of 5-9 year olds, 47% of 10-15 year olds, and 46% of 16+ year olds had MCV values at or above 100. Average Hgb F across an average of 21 time points ( SD=15.3, range=3-81) was 22.9 ( SD=9.3, range=2.6-44.8). As of February 2017, 50% of individuals had HbF values at or above 20.0. Specifically, 55% of 5-9 year olds, 32% of 10-15 year olds, and 55% of 16+ year olds had HbF values at or above 20.0. Average ANC (at non-ill visits) across an average of 20.0 time points ( SD=13.6, range=5-71) was 3,965 ( SD=1,227; range=1,600-6,910). As of February 2017, 31% of individuals had ANC values less than 3,000. Specifically, 20% of 5-9 year olds, 34% of 10-15 year olds, and 30% of 16+ year olds had ANC values less than 3,000. Discussion:Results from this study have the potential to help researchers and clinicians better understand patterns and correlates of hydroxyurea adherence in pediatric SCD patients that can be targeted in future interventions.

Sickle Cell Health Awareness, Perspectives, and Experiences (SHAPE) Survey: Perspectives of Physicians in Gulf Cooperation Council Countries on Sickle Cell Disease

Introduction: Sickle cell disease (SCD) is a genetic disorder that adversely impacts patients' physical and emotional well-being, yet research on the impact of SCD on quality of life is limited. The prevalence of SCD across Gulf Cooperation Council (GCC) countries ranges 0.24-5.8% (Abu-Shaheen et al. Expert Rev Hematol 2022). The Sickle Cell Health Awareness, Perspectives, and Experiences (SHAPE) survey aimed to broaden understanding of the global burden of SCD. This analysis reports the experiences of physicians in GCC countries treating patients with SCD who participated in the SHAPE survey within the context of insights obtained globally. Methods: Physicians from Brazil, Canada, France, Germany, the UK, the US, and 2 countries in the GCC (Saudi Arabia and the United Arab Emirates [UAE]) completed a 12-minute online survey comprising close-ended questions about their experiences of treating patients with SCD. Physicians practicing for 3-35 years and currently caring for ≥10 patients with SCD were eligible. Results:Of 219 physicians globally who responded, 30 (13.7%; Saudi Arabia and the UAE, n=15 each) were from GCC countries. Physicians in GCC countries on average were caring for 16 patients with SCD and had 16 years of experience treating patients with SCD. The most common symptoms of SCD reported to physicians in GCC countries were bone aches (95%) in patients aged ≤11 years, fatigue/tiredness and bone aches (92% each) in patients aged 12-17 years, and bone aches (100%) in patients aged ≥18 years. Bone aches and yellow eyes/skin/nails were symptoms reported by a significantly higher proportion of patients in all age groups to physicians in GCC countries than all surveyed physicians (Figure 1). Most physicians agreed early treatment of SCD can help with managing/preventing severe symptoms (80% in GCC countries vs 87% globally) and that treating hemolytic anemia can improve most aspects of SCD including, reducing end-organ damage (87% vs 84%). A significantly greater proportion of physicians in GCC countries, compared with all surveyed physicians, reported they were confident in their knowledge of the consequences of hemolytic anemia (93% vs 50%), and they were significantly more likely to attribute the development of SCD complications such as chronic anemia, kidney damage, and blood clots to hemolytic anemia (Figure 2). A significantly greater proportion of physicians in GCC countries, compared with all surveyed physicians, agreed end-organ damage is unavoidable (87% vs 59%), and they were reluctant to discuss the potential future challenges/complications of SCD with a patient or their family (57% vs 37%). Most physicians agreed they were optimistic about future treatments for SCD (73% in GCC countries vs 81% globally). A significantly greater proportion of physicians in GCC countries reported considering the cost/benefit ratio to the patient and/or health care system before recommending a treatment compared with all surveyed physicians (87% vs 64%). Physicians in GCC countries, compared with all surveyed physicians, reported a significantly smaller proportion of patients were treated with hydroxyurea (24% vs 43%) and opioids (10% vs 29%). The top concerns physicians in GCC countries had were their patients not understanding the long-term effects/progression of SCD (47%), only seeking treatment/care when experiencing crises (47%), and lack of community support for patients (40%). Physicians reported wanting more support to educate their patients about the long-term effects of SCD (93% in GCC countries vs 83% globally). Conclusions: Physicians in GCC countries identified the symptom(s) most frequently reported by patients aged ≤11 years and ≥18 years as bone aches, and by patients aged 12-17 years as bone aches and fatigue/tiredness. Most physicians in GCC countries agreed end-organ damage is unavoidable, but over half were reluctant to discuss the potential future complications of SCD with patients and their families. Findings from the SHAPE survey underline the need for treatments that target specific SCD symptoms and delay end-organ damage, as well as the need of physicians in GCC countries for greater support when treating patients with SCD.

Feasibility of Constructing an Interactive Mapping Tool to Visualize Sickle Cell Disease Geographic Distribution and Medical Care Utilization in the United States

Introduction: It is recognized that many people living with sickle cell disease (SCD) face significant structural obstacles to establishing and maintaining long-term hematology care. For example, some people with SCD care may lose access as a result of a geographic move; others may lose access by aging out of the pediatric care setting. These scenarios could be addressed by providing resources in areas with addressable populations and unmet medical need. However, deploying SCD treatment resources is frustrated by the lack of an established tool that can estimate the number of people living with SCD or gaps in services available in a given geography. We hypothesized that we could build a tool using a combination of publicly available demographic data combined with hospital claims data. Methods: Using CDC estimations for SCD affecting 1 in 365 African American and 1 in 16,300 Hispanic births, we estimated SCD prevalence based on data from the 2021 US Census, segmented by age, race, and county. We added a distinction between rural and urban counties using classification from the Consumer Financial Protection Bureau (CFPB), which designates rural counties as “a county that is neither in a metropolitan statistical area nor in a micropolitan statistical area that is adjacent to a metropolitan statistical area.”. PowerBI was used to generate a heat map to visualize the data at a state and county level, with the ability to filter by patient age and urban vs. rural designation. Finally, using hospital claims data for SCD “with crisis” (i.e., claims referencing ICD10 codes: D5700; D5701; D5702; D57211; D57212; D57219; D57811; D57812; D57819) and SCD “without crisis” (i.e., claims referencing ICD10 codes: D571; D5720; D5740; D5742; D5744; D5780), Pearson correlation was used to determine if an association existed between our estimated SCD prevalence and SCD related hospital claims for claim years 2021, 2022 and partial 2023. Results: Our model estimates a total of 127,297 people living with SCD in the United States, with 97% (123,454) being Black and 3% (3,843) being Hispanic (Table 1). 88% (111,977) were predicted to be under age 65, and 28% (35,675) were predicted to be under age 19. The majority (95%, 120,875) lived in urban counties. Most rural counties with SCD patients are located in the South and Southeast US (Figure 1). There was a strong positive correlation between our predictions of SCD prevalence at the state level and SCD-related hospital claims (coefficient of 0.903217 [95%CI: 0.944-0.836], p<0.001). For claim years 2021, 2022 and 2023 (partial) there were 1.6 claims per 1 SCD patient across the United States. While there were 1.6 claims per patient in urban counties, there were 0.7 claims per 1 patient in rural counties, consistent with a relative lack of access to care in rural areas compared to urban areas. Conclusions: Although not a direct measurement, and possibly overestimating the number of people >age65 living with SCD, our estimate suggests that there may be several thousand more people living with SCD than what is generally believed (100,000 per US CDC). Our estimates are partially validated by our finding that hospital claims data correlate strongly with our estimates of SCD prevalence at the state level. Although only a relatively small population of people living with SCD reside in rural counties, lower utilization of hospital services, as measured by hospital claims data, suggest that rural populations may have an unmet medical need that is particularly striking. Although working with claims data and disease estimates based on census data introduces significant limitations, it is feasible that this type of analysis could help to direct resources to areas with greatest unmet medical need.

Assessment of Neurocognitive Functioning in Sickle Cell Disease and Thalassemia and the Association with Silent Cerebral Infarcts and Cerebral Hemodynamics and Oxygen Metabolism

Introduction Neurocognitive impairment is a significant problem in patients with sickle cell disease (SCD), affecting various life domains such as academic achievement, career progress, and general life quality. The cause of this impairment is not yet fully understood, however, it has been linked to silent cerebral infarcts (SCIs) and irregularities in blood perfusion and oxygenation, particularly in children with SCD. Previous research has identified cognitive deficits in adults with SCD, but the relationship with SCIs has not been thoroughly explored in this age group. This study aimed to examine the neurocognitive functioning among adult patients with three types of inherited chronic anemia (severe SCD, mild SCD, and thalassemia) and healthy controls. Additionally, we investigated potential associations of neurocognitive performance with cerebral perfusion and oxygenation, and SCIs. Methods This study included 70 severe SCD patients (60 HbSS, 10 HbSβ 0), 22 mild SCD patients (14 HbSC, 8 HbSβ +), 16 thalassemia patients (6 NTDT, 10 TDT), and 29 healthy controls. We assessed neurocognitive functioning through eight tasks divided into seven neurocognitive domains such as attention, processing speed, nonverbal IQ, working memory, verbal learning, visual memory, and fine motor dexterity. Each task score was standardized using published norm data, converted into Z-scores, and used to compute the mean Z-score per domain. SCIs were assessed and segmented using FLAIR MRI scans. Cerebral blood flow (CBF) and oxygen extraction fraction (OEF) were derived using time-encoded pseudo-continuous arterial spin labeling (te-pCASL) and T 2-relaxation-under-spin-tagging (TRUST) techniques, respectively. Cerebral metabolic rate of oxygen (CMRO 2) was calculated from the CBF, OEF and oxygen content (calculated from hemoglobin and arterial saturation). One-sample t-tests or one-sample Wilcoxon-signed rank tests were used to compare the seven neurocognitive domains of each group with normative test data and ANOVA was used to compare these domains between participant groups. Independent-sample t-tests or Mann-Whitney U tests were used to compare the neurocognitive domains between patients with and without SCIs. Lastly, correlation analyses explored the relationships between the neurocognitive domains and SCI volume, CBF, OEF, and CMRO 2. Results In the severe SCD group, only processing speed and fine motor dexterity were significantly impaired after adjusting for multiple comparisons (Table 1 & Figure 1). Mild SCD patients exhibited lower scores in processing speed, working memory, and fine motor dexterity compared to the norms. In contrast, after adjustment for multiple comparisons, thalassemia patients and healthy controls only showed significantly lower scores in fine motor dexterity (Table 1). When comparing groups, SCD patients had significantly slower processing speed compared to thalassemia patients and healthy controls. Surprisingly, SCD patients without SCIs exhibited poorer fine motor dexterity than those with SCIs (p=0.03), while no such associations were identified in other groups. Finally, no associations were found between the neurocognitive domains and SCI volumes, CBF, OEF and CMRO 2. Conclusion Our results show slower processing speed in SCD patients compared to thalassemia patients and healthy controls, aligning with previous studies. However, unlike previous research, we did not find additional neurocognitive deficits in SCD patients. This could be due to variations in patient selection, environmental factors, socioeconomic status, or recent enhancements in SCD treatment approaches, such as the early administration of hydroxyurea and/or blood transfusion. Interestingly, all groups showed diminished fine motor dexterity, potentially due to the ongoing digital transition. A key observation from this study was the lack of association between neurocognitive performance and SCIs, hemodynamics, and oxygen metabolism, suggesting that SCIs and oxygenation might not be the only factors contributing to impaired processing speed. Our results suggest that recent developments in medical treatments could have improved the neurocognitive function of SCD patients residing in Western countries. However, concerning the domain of processing speed, further studies are required to investigate other SCD-related factors that might influence this particular area.

Grndad and Disease Modifying Therapy (DMT): Shifts in Dmt Are Seen at the Adolescent/Young Adult Transition in Sickle Cell Disease in a Multi-Site Prospective Registry

The ability to characterize the modern person living with SCD in the US has been limited by the lack of a well-curated longitudinal registry. The Globin Research Network for Data and Discovery ( GRNDaD) registry aims to overcome this challenge by collecting data from the now 53 IRB-approved centers across the US in collaboration with the National Alliance of Sickle Cell Centers (NASCC) and the HRSA-funded Sickle Cell Disease Treatment Demonstration Project Grant. Here, we describe the use of disease-modifying therapy in (actively consented) adults and children with Hgb SS/ SB 0 thalassemia (SCA) from 37 sites. Methods: Each site consents subjects and enters extensive baseline data including SCD complications and labs, subjects also complete patient-reported outcomes (PROs)-both at baseline and annually. Each subject is expected to have an annual follow-up where data is extracted from the Electronic Health Record (EHR). All data is stored in REDCap and, for this abstract, data were extracted into R on all active subjects (data entry in the last two years) who have complete minimum data collected. Median values were compared using Mann-Whitney U tests. Disease-modifying therapy (DMT) in this study comprises hydroxyurea (HU), chronic red blood cell (RBC) transfusions, crizanlizumab, L-glutamine, and voxelotor. Results: There are 2501 active patients in GRNDaD. Twenty-six percent of subjects are pediatric </= 18 years of age, 55.5% are female and 66.7% have HgbSS or HgbSB 0 thalassemia (SCA). Here, we report data on people with SCA only, whose minimum data were complete (n=1272). Table 1 shows DMT by age. 187 (21%) adults and 31 (8.5%) children were not on DMT. Figure 2 is a box plot of the absolute neutrophil count (ANC) comparing adults and children who are and are not taking HU. Adults on HU had significantly lower ANCs than those not on HU (median = 4.4 (IQR: 3.07, 6.3) v 6.6 (IQR:4.07, 8.14), p<0.001) (Figure). Similar findings were observed for children ( median = 3.5 (IQR:2.5, 5.7) Vs 8.1 (5.8, 12.8) , p =0.04) Both children and adults on HU had higher MCVs than those not on HU (median for peds: 91.5 (IQR: 85.1, 98.75) v 86 (IQR: 83.3, 86.1), p=0.05, median for adults: 96.5 (IQR: 89, 107) v 90 (IQR: 86.1, 95.1), p<0.001). We compared hemoglobin for those on and off HU, and on and off voxelotor, excluding patients on chronic transfusion therapy. There was a statistically significant difference in hemoglobin when comparing on or off of HU (median 8.9 g/dl (IQR 7.95, 9.9) v 8.2 g/dl (IQR: 7.2, 9.7, p =0.047)). There were no statistically significant differences in hemoglobin when comparing subjects on or off of voxelotor (median = 8.4 g/dl (IQR: 7.5, 9.6) vs 7.9 (IQR: 7.4, 9.8), p =0.57). In the adults, there were statistically significantly more males than females on HU, but there were no differences seen in the pediatric cohort. Examining DMT by age group, chronic RBC transfusion use doubled from the 11-17 age group to the 18-29-year age group (12% to 25%) and HU use decreased (83%-59%) over this same period. Limitations: This cohort may over-represent those on DMT as those enrolled in GRNDaD were more likely to have clinic visits. Discussion: GRNDaD has doubled the number of sites consenting subjects and entering data over the last year. The number is expected to increase again in the next 12 months, as an additional 15 sites are already IRB-approved with a goal to include all SCD centers in NASCC. This cross-sectional description of the current population of people living with SCD and treated in NASCC-recognized SCD centers in the US shows that the majority of those with SCA are receiving DMT. There is a noticeable decrease in HU use during the transition period with an increase in the use of chronic transfusion therapy. Newer DMT has had limited uptake in this cohort. The next steps will be to provide longitudinal data on this population and examine associations of DMT and important clinical outcomes including PROs.

Defining curative endpoints for sickle cell disease in the era of gene therapy and gene editing.

A growing number of gene therapy- and gene editing-based treatments for patients with sickle cell disease (SCD) are entering clinical trials. These treatments, designed to target the underlying cause of SCD, have the potential to provide functional cures, which until now were possible only through allogeneic hematopoietic stem cell transplant. However, as these novel approaches advance from early- to late-stage clinical trials, it is essential to identify physiologically and clinically relevant endpoints that can demonstrate the achievement of a functional cure for SCD. Here, we present an overview of the pathophysiology of SCD and current treatment options, review ongoing SCD clinical trials using gene therapy or gene editing approaches, and identify the most relevant endpoints for demonstrating the attainment of a functional cure for SCD.

Gene-addition/editing therapy in sickle cell disease

Gene therapy is an innovative strategy that offers potential cure for patients with sickle cell disease, and no appropriate donor for transplant consideration. While we await long term data from these clinical trials, we remain optimistic that gene therapy will become a standard of care for curative treatment in sickle cell disease. As gene therapy becomes a standard of treatment in sickle cell disease, we must also acknowledge the potential for financial burden to patients. We also must acknowledge the prevalence of sickle cell disease in low-resource settings. Hopefully, as we learn more about gene therapy, we can assess ways to overcome the financial toxicity that comes with this therapy.

Use of Disease-Modifying Treatments in Patients With Sickle Cell Disease

Despite hydroxyurea being an established treatment for sickle cell disease (SCD), it remains underused. The recent approval of the disease-modifying treatments (DMTs) l-glutamine, crizanlizumab, and voxelotor underscores the need to understand the uptake of DMTs in the current treatment landscape. To explore characteristics that may be associated with DMT use and to describe observed patterns of yearly DMT use from 2014 to 2021. This cross-sectional study used administrative claims data from Optum's deidentified Clinformatics Data Mart Database from January 1, 2014, to September 30, 2021, to identify adults and children with SCD. Data were analyzed from August 1, 2022, to August 28, 2023. Use of DMTs. Patient characteristics across groups with varying patterns of DMT use and yearly patterns of prescription fills for hydroxyurea, crizanlizumab, voxelotor, and l-glutamine. A total of 5022 beneficiaries with SCD (2081 [41.4%] aged 18-45 years; 2929 [58.3%] female) were included in sample A (144 [2.9%] inconsistent users, 274 [5.5%] incident users, 892 [17.8%] consistent users, and 3712 [73.9%] non-DMT users). Inconsistent users had a higher prevalence of vaso-occlusive crises (mean [SD], 3.7 [4.7]), splenic complications (6 of 144 [4.2%]), pulmonary complications (36 of 144 [25.0%]), kidney disease (21 of 144 [14.6%]), acute chest syndrome (18 of 144 [12.5%]), and health care visits (eg, mean [SD] inpatient visits, 7.0 [10.7]) compared with the other use groups. Non-DMT users had the lowest prevalence of vaso-occlusive crises (mean [SD], 0.8 [2.4]), acute chest syndrome (109 of 3712 [2.9%]), and inpatient (mean [SD], 2.0 [6.6]) and emergency department (mean [SD], 0.7 [3.1]) visits and the highest proportion of adults 65 years and older (593 of 3712 [16.0%]). In sample B (6387 beneficiaries with SCD), hydroxyurea use modestly increased from 428 of 2188 participants (19.6%) in 2014 to 701 of 2880 (24.3%) in 2021. Use of l-glutamine increased briefly but gradually decreased throughout the study period. In 2021, out of 2880 participants, 102 (3.5%) had at least 1 fill for crizanlizumab and 131 (4.6%) had at least 1 fill for voxelotor. Overall, total DMT use increased from 428 of 2188 participants (19.6%) in 2014 to 815 of 2880 patients (28.3%) in 2021. In this cross-sectional analysis of adults and children with SCD, uptake of DMTs remained low from 2014 to 2021, despite the approval of newer therapies. Notable differences in patient characteristics across varied DMT exposure types necessitate further exploration into factors that facilitate DMT use and the creation of strategies to enhance DMT uptake.

The ongoing challenge of RBC alloimmunization in the management of patients with sickle cell disease

RBC transfusion remains a cornerstone in the treatment of sickle cell disease (SCD). However, as with many interventions, transfusion of RBCs is not without risk. Allogeneic RBC exposure can result in the development of alloantibodies, which can make it difficult to find compatible RBCs for future transfusion and increases the likelihood of life-threatening complications. The development of RBC alloantibodies occurs when a patient's immune system produces alloantibodies against foreign alloantigens present on RBCs. Despite its longstanding recognition, RBC alloimmunization has increasingly become a challenge when caring for patients with SCD. The growing prominence of alloimmunization can be attributed to several factors, including expanded indications for transfusions, increased lifespan of patients with SCD, and inadequate approaches to prevent alloimmunization. Recognizing these challenges, recent observational studies and preclinical models have begun to elucidate the immune pathways that underpin RBC alloimmunization. These emerging data hold promise in paving the way for innovative prevention strategies, with the goal of increasing the safety and efficacy of RBC transfusion in patients with SCD who are most vulnerable to alloimmunization.

Systematic, Point-of-Care Newborn Screening and Treatment for Sickle Cell Disease in Rural Mali, West Africa: Results from an Ongoing Implementation Project

Introduction: Sickle cell disease (SCD) is highly prevalent across sub-Saharan Africa and is a significant source of under-5 mortality. Accurate characterization of the disease prevalence is difficult to determine due to the absence of systematic newborn screening in most African countries. Mali is a land-locked West African country with a high burden of sickle cell disease. Despite the critical need for early diagnosis of SCD to improve survival, wide scale diagnostic efforts utilizing IEF or HPLC in sub-Saharan Africa have been limited by a paucity of laboratory equipment and trained personnel, unreliable supply chain for consumables, and overall expense. Point-of-Care (POC) testing for SCD is advancing rapidly and has the potential to reduce these barriers. This analysis will review the results of an ongoing POC newborn screening program for SCD at a single rural hospital in Mali and will evaluate the acceptance rates and basic outcomes of resource-adapted treatment. Methods: Between March 2019 and March 2023, all newborns at Koutiala Women's and Children's Hospital in Koutiala, Mali were offered screening for SCD with the HemoTypeSC ™ POC test kit (Silver Lake Research, California, USA). After verbal consent, heel-stick samples were procured within the first 24 hours of life. The samples were processed according to the package insert. The results were available within 10 minutes and were provided to the caregiver prior to discharge. Newborns who were found to have sickle cell disease were referred to the SCD treatment program where they were offered ongoing access to basic treatment measures such as antibiotic prophylaxis, malaria prevention, and hydroxycarbamide therapy. Parents of infants with HbSS who had not been seen in the clinic for follow-up within at least 6 months were contacted by phone at the time of this analysis to provide an update on their clinical status. Families of infants with HbS trait or HbC trait received appropriate genetic counseling. Statistical analysis was performed using a paired t-test. Results: 11,938 infants were born over the study period and 11,818 (99%) received POC screening. Screening results revealed Hb S trait; n=1,119 (9.47%), Hb C trait; n=1,285 (10.87%), Hemoglobin SS; n=81 (0.69%), Hemoglobin SC; n=100 (0.85%), and homozygous C; n=20 (0.54%). In all, 181 infants (1.54%) were found to have sickle cell disease and were offered follow-up care in the SCD treatment program at Koutiala Hospital. In addition, 2,404 infants (20.34%) were found to be carriers of either HbC trait or HbS trait. The mean age of those children diagnosed with HbSS and HbSC at the time of this analysis was 22.20mo (3-42mo) and 21.46mo (4-37mo), respectively. 89% (n=72) of the infants with HbSS received ongoing disease management. Penicillin prophylaxis was accepted in 82% (n=59) of the children in this cohort. Additionally, 44% (n=32) were started on hydroxycarbamide at a low, fixed dose (20ml/kg/day) based on disease severity parameters. Mean MCV for those children receiving hydroxycarbamide was 89.06fL (+/- 9.5fL) and for the non-hydroxycarbamide group was 79.83fL (+/- 14.3fL) (p= 0.025). While the most common reason for clinical follow-up was routine treatment, patients were also seen for fever, malaria treatment, and bone pain episodes. Based on clinical records and phone follow-up, there were two confirmed deaths (2.5%) in the HbSS cohort. One infant died of non-SCD complications on the first day of life and the other died at 6 months of age without returning to the clinic for follow-up treatment. Conclusions: This program is the first to examine the impact of systematic POC infant screening and treatment for SCD in rural Mali, West Africa. The low cost and rapidity of POC testing resulted in a high rate of newborns screened and positively impacted the success of clinical follow-up. POC testing results were comparable when reviewed alongside historical IEF-based screening at Koutiala Hospital (Table 1). The higher percentage of infants screened by POC when compared to IEF may have been slightly affected by an increase in the general awareness of SCD amongst the regional population. There was a high acceptance rate of ongoing clinical care (89%) and low death rate (2.5%) within the HbSS cohort which may be attributable to early access to diagnosis and treatment. Results from a larger patient size and longer treatment duration will provide more insight into the benefits of POC screening in this setting.

A Comprehensive Echocardiographic Portrait of Adult Sickle Cell Disease Patients in the Modern Era

Background Cardiovascular complications, especially pulmonary hypertension, are a known cause of mortality in patients with sickle cell disease (SCD). With advances in medicine and the introduction of various disease-modifying medications, the incidence and prevalence of cardiovascular complications are poorly documented. Aim To determine rates of cardiovascular complications in patients with SCD in the modern era of disease-modifying medications in a single center. Method We performed a retrospective observational single-center study of patients with SCD: all genotyped and ≥16 years old who had a recent echocardiogram performed during the study period of 2019-2023. Demographics, echocardiogram results, and laboratory findings were collected and analyzed. Descriptive statistics are presented in percentages, medians, and interquartile ranges. An unpaired Student's t-test and Fisher's exact test were used to determine, where appropriate, the level of significant differences among continuous and categorical variables, respectively, with p value <0.05 considered statistically significant. Data was analyzed using GraphPad Prism version 9.0.2. Results As of June 2023, 80 patients (38 male and 42 female, median age 30 years) had undergone a routine transthoracic echocardiogram. Sixty-five patients had the HbSS genotype, 8 HbSC, and 7 HbSB null. Sixty-one patients had received at least one treatment, and 19 (24%) were on concurrent therapy. Hydroxyurea was the common SCD-modifying therapy that the patients received (51 patients), followed by L-glutamine and voxelotor (11 each) and crizanlizumab (9 patients). In total, 56 (70%) patients had at least one cardiac abnormality. The most common cardiac abnormality was left atrial dilatation (41%), followed by left ventricular hypertrophy (33%), right atrial dilation (24%), and left ventricular dilatation (23%). Pulmonary hypertension was present in 30 (38%) patients with tricuspid regurgitation velocity (TRV) ≥2.5 msec (Table 1). The cohort of patients with pulmonary hypertension tended to be older (median age 31 years, p=0.0357), have a higher creatinine level (median 0.8, p=0.0414), and have coexisting echocardiographic abnormalities such as left atrial dilatation (70% vs. 24%, p<0.0001) or right atrial dilatation (40% vs. 14%, p=0.0136) than SCD patients without pulmonary hypertension (Table 2). Conclusion We present a comprehensive echocardiographic assessment of patients with SCD. Despite advances in the treatment of SCD, there remains a high prevalence of cardiac involvement in SCD patients. We found out that 70% of the patients we reviewed had at least one cardiac abnormality on echocardiography. Left atrial dilatation and left ventricular hypertrophy were the most common cardiac abnormalities noted. Pulmonary hypertension was observed in 37.5% of patients with co-existing right and left atrial enlargement. Larger studies are needed to corroborate these findings.

Optimization of Lentiviral ß-Globin Vectors in a Forward Orientation to Enhance Therapeutic Effectiveness for Sickle Cell Disease

Sickle cell disease (SCD) is a monogenic hemoglobin (Hgb) disorder characterized by a single pointmutation in the β-globin gene which causes Hgb polymerization under low oxygen tension and sickling of red blood cells (RBCs) which in turn drives severe systemic injury. Gene addition technologies like hematopoietic stem cell (HSC) targeted lentiviral (LV) gene therapy are among the most promising curative strategies for SCD. To expand this approach, improvements in LV titer, transduction efficiency, along with suppression of native sickle-globin, are preferred to generate successful therapeutic outcomes. One such improvement targets LV orientation: the relationship between the DNA encoding the β-globin gene in the LV and the promoter driving healthy β-globin gene expression. We created a forward-oriented β-globin-expression vector with an improved titer that results in more efficient transduction of human CD34+ cells in vitro, in human reconstituting CD34+ cells in xenografted mice, and in rhesus reconstituting CD34+ cells(Uchida N. et al., 2019). We report here on further optimization of LVs that in addition to forward orientation, also express shRNA that decreases native β-globin and sickle-globin, which could enhance the assembly of corrected Hgb tetramers. Seven unique constructs which varied in anti-β-globin shRNA sequences, packaging elements, and regulatory elements, were transduced into MEL-BB88 cells and expanded for 2 weeks. gDNA was collected for vector copy number (VCN) analysis, and treated with 10 µM hemin to induce Hgb expression. Five days after hemin-induction, cells were harvested for benzidine staining and immunoblot analysis to validate globin expression. Sca-1+ HSC/progenitor (HSPC) BM cells were isolated from Towne's humanized SCD donor mice prior to stimulation for 48 h with cytokines, then transduced at an MOI of 24 twice, 24 h apart. To assess the in vivo engraftment potential of the transduced HSPCs, 2.5x10^6 cells were transplanted into lethally irradiated CD45.1 recipient mice. Peripheral blood (PB) was sampled at 2-week intervals for PBMC chimerism and lineage engraftment, Hgb electrophoresis, Lorrca OxygenScan and OsmoScan assays, and PB VCN. Whole BM from engrafted recipients was collected at 30 weeks and used for secondary transplantation assays which were again analyzed over 24 weeks for PB engraftment, VCN, and donor Hgb expression. LVs were produced at varying titers and all successfully transduced MEL-BB88 cells with VCNs between 1 and 5 that were maintained following hemin induction. Interestingly, variations in RRE elements dramatically affected human globin expression in vitro. Furthermore, the transplanted mice engrafted fully with HSPCs transduced with multiple vectors. Notably, mice transplanted with HSPCs transduced with vector CX0066p (LCR-Enhancer-P-HBB-shmiR-3g1.223 + 3g2.30a-R1) maintained a VCN of 0.2-0.4 in PB for the 30-week duration of the primary transplant. Cellulose acetate gels of RBCs from PB showed ~40% HbA in a background of HbS. The P50 right-shifted towards normal, RBC counts increased, WBC counts decreased, and OxygenScan parameters were all corrected towards controls and away from those values obtained from mice transplanted with mock transduced HSPCs. EI max and EI min increased while pO2@95% decreased. Lastly, the RBC sickling was corrected in an in vitro sickling assay. In conclusion, based on LV titer, MEL cell expression, transduction efficiency, engraftment of modified cells, in vivo globin expression, anti-sickling activity, and oxygen transport, these constructs provide outstanding Hgb expression and phenotype correction. Consequently, these candidates serve as a solid foundation for future human gene therapy products in the treatment of SCD.

Inclacumab Reduce Preexisting Red Blood Cell Adhesion to Activated Endothelial Cells: In-Vitro Assessment of the Microfluidic Platform Endothelium-on-a-Chip

Background: In 2019 FDA approved the use of an antibody anti P-selectin (Crizanlizumab) for the treatment of sickle cell disease (SCD) to reduce the vaso occlusive crisis (VOCs). New anti-adhesive treatments are being developed recently. Global Blood Therapeutics, Inc., acquired by Pfizer Inc. in October 2022, acquired Inclacumab from Roche and started two clinical trials now in phase 3 to evaluate the capacity of this humanized IgG4 monoclonal antibody anti P-selectin to reduce the VOCs in patients with SCD. In our recent work presented at EHA 23 in Frankfurt Germany, we showed that Inclacumab prevents the adhesion of RBCs to chronically and acutely heme activated human umbilical vein endothelial cells (HUVECs) with a statistically significant higher effect in comparison to Crizanlizumab. In this work we used a similar approach to test the capacity of Inclacumab in the reduction of preexisting adhesion events on acutely heme activated HUVECs. Methods:Whole blood EDTA samples from six SCD subjects all with HbSS genotypes were collected at University Hospital Cleveland Medical Center, Cleveland, OH, USA. To standardize the samples, we isolated RBCs by centrifugation and subsequential washes in Phospahte buffer s of the whole blood and resuspended in basal cell culture medium (EBM; Lonza, Morristown, NJ, USA) at a hematocrit of 20% with 10 mM of HEPES. HUVECs (Lonza, Morristown, NJ, USA) were introduced and maintained within the endothelialized microfluidic channels at physiological flow for at least 48-72 hours prior to experiments. We performed an acute short-term activation, where the blood samples were supplemented with 40 µM heme +/- 100 µg/ml injected through the microfluidic channels for 15 minutes, after the adhesion took place we washed the non-adherent cells with Inclacumab and Crizanlizumab and we compared with untreated washing buffer (both compounds were provided by Global Blood Therapeutics, Inc., a wholly owned subsidiary of Pfizer Inc. South San Francisco, CA, USA) A phase-contrast images of the remaining RBCs were acquired with an inverted microscope (DMi8 Leica Microsystems Inc. Deerfield, IL, USA) and quantified based on previous published methods (Figure 1A). Paired t-test was used to calculate statistical significance. Results: Acute short-term heme activation induces high level of RBCs adhesion. Both compounds Inclacumab and Crizanlizumab showed a reduction of the number of adherent RBCs to the activated heme, but only Inclacumab results statistically a significant higher reduction compared to untreated RBCs (Figure 1B). Conclusions: Inclacumab is able not only to prevent the adhesion of RBCs to acutely and chronically activated HUVECs but is able to remove the preexisting adhesion and results in significant higher reduction compared to untreated. RBCs adhesion assay on Endothelium-on-a-chip is a novel and efficient way to study the efficacy of the new antiadhesive drug and could be used to monitor patient response to new therapies in SCD. Figure1 : Effect of Inclacumab vs Crizanlizumab on removal of SCD RBC adhesion to heme activated HUVECs. A) Schematic of adhesion experiment and inverted microscope contrast of phase images 10X of adherent RBCs at acutely heme activated HUVECs. B) Inclacumab has statistically significant effect on remove adherent RBCs to acutely heme activated HUVECs (p=0.009, N=7) For all experiments, the heme concentrations were 40 µM and Inclacumab and Crizanlizumab were 100 µg/ml. Scale bare 20 µm. P-values were based on paired t-test. Error bars represent the standard error of the mean (SEM)

Improving Treatment Adherence in Patients with Sickle Cell Disease

BACKGROUND: Crizanlizumab is approved for treatment of sickle cell disease (SCD) patients with frequent pain crises and hospital admissions. Here, we address systemic factors that have led to sub-optimal adherence to monthly crizanlizumab infusions at our institution. Due to 340B status limitation, the drug was originally offered at a site affiliated to our hospital with little SCD team presence. In 2020, UW hospital (primary site of SCD care) acquired 340B status, but transferring crizanlizumab infusions to UW hospital was not prioritized. In 2022, our institution's crizanlizumab adherence was 22% 1. Patients receiving crizanlizumab were interviewed to identify adherence barriers. Top barriers included location (44%), scheduling (44%), and low knowledge about the medication (67%). A detailed analysis with SCD team input revealed barriers such as restriction on opioids for day treatment, scheduling delays after hospital admissions, onerous paper orders process, different EMRs, and poor communication/coordination between sites (Fig 1). METHODS: The hospital leadership was appraised of these barriers in a series of meetings by the SCD team and approval to administer crizanlizumab at UW hospital infusion center was granted. UW health pharmacy and infusion staff planned a transition phase with 5 patients transitioned each month between March-April 2023. Crizanlizumab orders were updated in the EMR, and infusion nursing staff received training about the drug. Smart phrases were created for patient education in after visit summaries (AVS). Day treatment with IV fluids and pain management was offered with infusions. SCD care coordinator and social worker helped with scheduling, transport, and childcare. Providers aimed to discuss treatment goals and pros/cons during visits. Goal was set to assess adherence at months 3 and 12 after implementation. Average rate of adherence was defined as percent of prescribed treatments taken by the patient over a specified time period. In case of hospitalization, adherence was defined as rescheduling and receiving the treatment. We aimed to improve adherence to 50% at 3 months and 75% at 12 months if crizanlizumab FDA approval is maintained. RESULTS: By mid-July 2023, 11 patients were transitioned to UW Hospital for crizanlizumab infusions. 10/11 patients received the drug during this period (1 patient taken off due to pregnancy). The average adherence rate increased from 22% to 71% at 3 months, exceeding the original goal. 5/10 patients had an adherence rate of 75% or more. Additionally, 70% received at least one visit from the SCD social worker (SW) during treatment and 70% saw their provider concurrently with at least one visit. All patients received day treatment with supportive IVFs and/or pain medications during the infusion visit (Fig. 2). Only 2/10 patients had 25% or less adherence which occurred due to scheduling errors that will be addressed moving forward. DISCUSSION: Our study aims to address both intentional and unintentional barriers to crizanlizumab adherence that included infusion location, scheduling, and patient education. Our team advocated for the transition of infusions to the main hospital where they receive all other SCD care. This provided patients with direct access to their SCD team during infusions. Care coordinator and social work involvement helped consolidate treatment-related orders to one EMR, standardize nursing and patient education, organize scheduling, and address social barriers. The adherence rate increased from 22% to 71% at 3 months after implementation. Although the current approval of crizanlizumab is under review, we believe the barriers addressed in this project can be extended to current SCD treatments and upcoming novel therapies. Splitting care sites due to insurance and logistical reasons can create barriers for this vulnerable population due to complex care coordination and psychosocial needs. The rapid improvement in crizanlizumab adherence displayed here is a testament to the impact of having a dedicated SCD team at one leading site to advocate for and address the unique barriers to healthcare experienced by people with SCD. Sources 1. Nixon G, Fallon M, Fulcer K, Curran W, Nazeef M, Pradhan R. How can infusion therapy adherence by improved in Sickle Cell Disease. American Society of Health-System Pharmacists; Dec. 2022. Las Vegas, NV.

FORTITUDE: A Phase 2 Open-Label Study in Progress to Evaluate Etavopivat for the Treatment of Anemia in Patients with Lower-Risk Myelodysplastic Syndromes

Background: Most patients with lower-risk myelodysplastic syndrome (LR-MDS) develop anemia and a high proportion of patients become dependent on red blood cell (RBC) transfusions. MDS-related anemia is associated with low hemoglobin (Hb) levels, iron overload and poor quality of life. Erythropoiesis-stimulating agents and other drugs, including lenalidomide, luspatercept and imetelstat (an investigational product), can lead to RBC transfusion independence and improve Hb levels in many patients; however, responses are generally transient and novel treatments are needed for this population. Etavopivat is an investigational, once-daily, selective erythrocyte pyruvate kinase (PKR) activator in development for the treatment of sickle cell disease (SCD) and anemia in patients with LR-MDS. In a phase 1 study in adult and adolescent patients with SCD by Saraf et al. HemaSphere. (2022), etavopivat 400 mg once daily was considered well tolerated and showed sustained Hb increases up to 12 weeks for most patients. Additional studies in healthy volunteers and patients with SCD support an acceptable safety profile together with improved RBC health and function during continuous treatment with etavopivat. In patients with LR-MDS, ineffective hematopoiesis may be due, in part, to insufficient ATP production, leading to increased erythroid lineage apoptosis. By activating PKR, etavopivat may improve RBC health and function by stimulating energy production (increasing ATP levels), increasing Hb levels (decreasing anemia), and decreasing erythroid lineage apoptosis. Aims:Describe the design of a multicenter, open-label, phase 2 study (FORTITUDE; NCT05568225) evaluating hematologic improvements in patients with very low-, low- and intermediate-risk MDS during treatment with etavopivat. Study design:Key eligibility criteria include age ≥18 years; very low-, low- and intermediate-risk MDS per the Revised International Prognostic Scoring System; and anemia defined by mean Hb <10.0 g/dL and <3 RBC transfusions <16 weeks prior to first dose for non-transfusion-dependent (NTD) patients or ≥3 units of RBCs for anemia <16 weeks prior to first dose for transfusion-dependent (TD) patients. Key exclusion criteria include MDS associated with del 5q cytogenetic abnormality and known TP53 abnormality, history of acute myeloid leukemia, and an absolute neutrophil count <0.5 × 10 9/L. Additional exclusion criteria include prior treatment with azacitidine; decitabine; erythropoietin, other hematopoietic growth factor treatment or lenalidomide within 30 days of Day 1 or anticipated to be required during the study; and luspatercept within 30 days of Day 1 for NTD patients and within 16 weeks of Day 1 for TD patients. Patients will receive etavopivat 400 mg once daily for at least 48 weeks. Treatment may be continued beyond 48 weeks in patients demonstrating clinical benefit. The primary objective of the study is to assess hematologic improvements based on an erythroid response over any continuous period ≥8 weeks within 24 weeks on etavopivat treatment in patients with LR-MDS. The primary endpoint will be based on the combined incidence of: ≥1.5 g/dL increase in Hb from baseline maintained for ≥8 consecutive weeks for NTD patients; absence of any transfusion for ≥8 consecutive weeks for low transfusion-burden patients; and reduction by ≥50% of RBC units for ≥8 consecutive weeks for high transfusion-burden patients. Safety, tolerability, pharmacokinetic, and pharmacodynamic properties of etavopivat will be evaluated. FORTITUDE is open for enrollment in Canada, France, Germany, and the USA. Planned enrollment includes approximately 15 patients in each of the three transfusion requirement-based groups (Figure). Statistical analysis: The primary endpoint (pooled incidence) will be tested with a one-sided Fisher's exact test at the significance level of 0.025 where 0.2 is the assumed null proportion. Summary:Etavopivat is a novel, investigational, once-daily, selective PKR activator with the potential to improve RBC health and lifespan. This phase 2 study will assess the safety of etavopivat and its impact on Hb levels and RBC transfusion burden in patients with LR-MDS and anemia.

HbF Inducing Eed Inhibitor Ftx-6058 Selectively and Reversibly Impacts Bone Marrow in Wild-Type Mice

Sickle cell disease (SCD) is a genetic disorder characterized by red blood cell sickling, hemolysis, vaso-occlusive crises (VOCs), and other complications resulting from a mutation in the HBB gene. Increasing fetal hemoglobin (HbF) levels has shown promise in mitigating disease-related pathophysiology. In individuals with SCD who exhibit hereditary persistence of fetal hemoglobin (HPFH) and have HbF levels ranging from 20% to 30%, a remarkable reduction in symptoms is observed, highlighting the protective effect of increased HbF in SCD. Preclinical and clinical findings indicate that compounds inhibiting the embryonic ectoderm development (EED) component of polycomb repressive complex 2 (PRC2) leads to elevations in HbF to therapeutic levels. These results suggest the potential for a substantial benefit for individuals living with SCD. To further understand the effects of PRC2 inhibition, this study aims to characterize the onset and reversibility of EED inhibition by FTX-6058. Results from in vivo studies in wild-type mice demonstrated upregulation of the mouse fetal hemoglobin ortholog mRNA (Hbb-bh1) as well as target engagement in bone marrow though quantification of H3K27 trimethylation during seven days of active dosing of FTX-6058. Target engagement and differential gene expression profiles in the bone marrow subsequently returned to baseline shortly after the dosing period. These findings demonstrate that inhibition of EED through FTX-6058 leads to a minimal, transient impact on the bone marrow in mice, and any transcriptional changes are rapidly reversible following cessation of dosing. A small molecule EED inhibitor has the potential to provide a new treatment for sickle cell disease without irreversibly altering the bone marrow.