Hydroxyurea Research Articles

The rs368698783 (G>A) Polymorphism Affecting LYAR Binding to the Aγ-Globin Gene Is Associated with High Fetal Hemoglobin (HbF) in β-Thalassemia Erythroid Precursor Cells Treated with HbF Inducers

The human homologue of mouse Ly-1 antibody reactive clone protein (LYAR) is a putative novel regulator of γ-globin gene transcription. The LYAR DNA-binding motif (5′-GGTTAT-3′) is located within the 5′-UTR of the Aγ-globin gene. The LYAR rs368698783 (G>A) polymorphism is present in β-thalassemia patients and decreases the LYAR binding efficiency to the Aγ-globin gene. The objective of this study was to stratify β-thalassemia patients with respect to the rs368698783 (G>A) polymorphism and to verify whether their erythroid precursor cells (ErPCs) differentially respond in vitro to selected fetal hemoglobin (HbF) inducers. The rs368698783 (G>A) polymorphism was detected by DNA sequencing, hemoglobin production by HPLC, and accumulation of globin mRNAs by RT-qPCR. We found that the LYAR rs368698783 (G>A) polymorphism is associated with high basal and induced production of fetal hemoglobin in β-thalassemia patients. The most striking association was found using rapamycin as an HbF inducer. The results presented here could be considered important not only for basic biomedicine but also in applied translational research for precision medicine in personalized therapy of β-thalassemia. Accordingly, our data suggest that the rs368698783 polymorphism might be considered among the parameters useful to recruit patients with the highest probability of responding to in vivo hydroxyurea (HU) treatment.

Polymorph II of hydroxyurea 150 years after its first synthesis

Form II of hydroxyurea (HU) has been crystallized in the presence of urea in methanol solvent. The isoenergetic novel form II is isolated 150 years after its first synthesis (form I).

Gallbladder status among children with chronic hemolytic anemia attending Assiut University Children's Hospital

BackgroundOne among the numerous comorbidities of chronic hemolytic anemia (CHA) is bladder stones. The extensive use of abdominal ultrasound in kids documented raised detection rate of gallstones.Aim and objectivesTo see the frequency of gallbladder diseases among kids with CHA and to see the risk factors of gallbladder diseases among patients with CHA attending Assiut University Children's hospital.Patients and methodsThis cross-sectional study included 50 kids with CHA aged from 1 to 18 years, who were admitted to the Hematology Unit at Assiut University Children's Hospital (from the start of December 2018 to the end of November 2019). All patients were evaluated by full history, general and abdominal examination, laboratory assessment, and ultrasound findings to find the probable risk factors for gallstones.ResultsThe age of patients ranged from 1 year up to 18 years. The commonest age of bladder diseases detection was at 6 years. Twenty-one (42%) cases had gallbladder diseases. Bladder diseases were symptomatic in –81 with abdominal pain in affected kids. Thalassemia major was recorded more frequently (72%) in the studied group with 20 and 8% reporting sickle cell anemia and spherocytosis, respectively. The frequency of blood transfusion had statistical significance with gallbladder affection.ConclusionFrom this study, it can be concluded that the type of hemolytic disease, frequency of blood transfusion, history of hydroxy urea intake, and splenomegaly were risk factors for gallbladder affection in children with chronic hemolytic disease.

Clinical and laboratory characterization of adult sickle cell anemia patients in Kinshasa.

Sickle cell anemia (SCA) is a monogenic hemoglobinopathy associated with severe acute and chronic complications, with the highest incidence worldwide in Sub-Saharan Africa. The wide variability in clinical manifestations suggest that a uniform response to hydroxurea may not be attained. In view of a potential treatment with hydroxyurea (HU), we assessed the variability of clinical and hematological manifestations in a cohort of adults with SCA in Kinshasa, capital of the DR Congo in Central Africa. A cross-sectional study was conducted in a hospital dedicated to SCA management in Kinshasa. Clinical history of patients was recorded, a complete physical examination performed. The diagnosis was confirmed by means of DNA analysis. A full blood count and hemolysis markers were measured. The severity of the disease was evaluated by means of a previously reported score. The study group consisted of 166 genetically confirmed SCA patients. The SCA severity was mild in 28.9%, moderate in 64.5% and severe in 6.6%. The disease severity score increased with patient's age (p ≤ 0.001). The severity was higher in males compared to females (p = 0.012). In males, the severity score was correlated with the presence of priapism (p = 0.045), a manifestation not previously incorporated in the severity score. The severity score was inversely correlated with the fetal hemoglobin (HbF) rate (p = 0.005). Malnutrition (BMI <18.5 kg/m2) was present in 47% of patients and was related to the male sex, hip disease (aOR 3.11; p = 0.019) and severe phenotype (aOR 3.53; p = 0.012). Leg ulcers were more frequent in males than in females (p = 0.001; OR 24.3) and were correlated with the number of days of hospitalization (p = 0.029). Hip disease was related to the increasing age (p = 0.008). In this selected, hospital-based populations of adults with SCA, severe disease was rare, which may be due to survival bias. However, two thirds had moderate severity of the disease, mostly with a low HbF, and they may benefit from HU treatment. In the Central-African setting the separation between vaso-occlusive and hyperhemolytic sub-phenotypes was not applicable.

PARP1 recruits DNA translocases to restrain DNA replication and facilitate DNA repair.

Replication fork reversal which restrains DNA replication progression is an important protective mechanism in response to replication stress. PARP1 is recruited to stalled forks to restrain DNA replication. However, PARP1 has no helicase activity, and the mechanism through which PARP1 participates in DNA replication restraint remains unclear. Here, we found novel protein-protein interactions between PARP1 and DNA translocases, including HLTF, SHPRH, ZRANB3, and SMARCAL1, with HLTF showing the strongest interaction among these DNA translocases. Although HLTF and SHPRH share structural and functional similarity, it remains unclear whether SHPRH contains DNA translocase activity. We further identified the ability of SHPRH to restrain DNA replication upon replication stress, indicating that SHPRH itself could be a DNA translocase or a helper to facilitate DNA translocation. Although hydroxyurea (HU) and MMS induce different types of replication stress, they both induce common DNA replication restraint mechanisms independent of intra-S phase activation. Our results suggest that the PARP1 facilitates DNA translocase recruitment to damaged forks, preventing fork collapse and facilitating DNA repair.

Metabolomics Study of Serum Samples of β-YAC Transgenic Mice Treated with Tenofovir Disoproxil Fumarate.

β-thalassemia is one of the most common monogenic disorders and a life-threatening health issue in children. A cost-effective and safe therapeutic approach to treat this disease is to reactivate the γ-globin gene for fetal hemoglobin (HbF) production that has been silenced during infancy. Hydroxyurea (HU) is the only FDA approved HbF inducer. However, its cytotoxicity and inability to respond significantly in all patients pose a need for an HbF inducer with better efficacy. The study describes the serum metabolic alteration in β-YAC transgenic mice treated with Tenofovir disoproxil fumarate (TDF) (n = 5), a newly identified HbF inducer, and compared to the mice groups treated with HU (n = 5) and untreated control (n = 5) using gas chromatography-mass spectrometry. Various univariate and multivariate statistical analyses were performed to identify discriminant metabolites that altered the biological pathways encompassing galactose metabolism, lactose degradation, and inositol. Furthermore, the decreased concentrations of L-fucose and geraniol in TDF-treated mice help in recovering towards normal, decreasing oxidative stress even much better than the HU-treated mice. The proposed study suggested that TDF can reduce the deficiency of blood required for β-thalassemia and can be used for the preclinical study at phase I/II for fetal hemoglobin production.

Erythrocyte type 1 equilibrative nucleoside transporter expression in sickle cell disease and sickle cell trait.

Hypoxia-mediated red blood cell (RBC) sickling is central to the pathophysiology of sickle cell disease (SCD). The signalling nucleoside adenosine is thought to play a significant role in this process. This study investigated expression of the erythrocyte type 1 equilibrative nucleoside transporter (ENT1), a key regulator of plasma adenosine, in adult patients with SCD and carriers of sickle cell trait (SCT). Relative quantitative expression analysis of erythrocyte ENT1 was carried out by Western blot and flow cytometry. Patients with SCD with steady state conditions, either with SS or SC genotype, untreated or under hydroxycarbamide (HC) treatment, exhibited a relatively high variability of erythrocyte ENT1, but with levels not significantly different from normal controls. Most strikingly, expression of erythrocyte ENT1 was found to be significantly decreased in patients with SCD undergoing painful vaso-occlusive episode and, unexpectedly, also in healthy SCT carriers. Promoting hypoxia-induced adenosine signalling, the reduced expression of erythrocyte ENT1 might contribute to the pathophysiology of SCD and to the susceptibility of SCT individuals to altitude hypoxia or exercise to exhaustion.

The impact of Hydroxyurea on the rates of Vaso–occlusive crises in patients with sickle cell disease in Saudi Arabia: a single–center study

BackgroundVaso–occlusive crises (VOCs) are acute and common painful complication of sickle cell disease (SCD), and are the main reason behind the frequent emergency department visits among SCD patients. Hydroxyurea (HU) is an old and commonly used medication that demonstrated its effectiveness in reducing the risk of VOCs and the incidence of hospitalization. Although multiple studies have examined the impact of HU on the rates of VOCs, few have explored its effectiveness among SCD patients in Saudi Arabia.MethodsThis was a single–center retrospective cohort study in which the electronic medical records of patients with SCD who have not had any previous exposure to HU prior to the initiation of HU treatment for ≥12 months were recruited. Paired t–test was conducted to examine the difference in the rates of VOCs, and levels of hemoglobin (Hgb), hematocrit (HCT), and platelet counts (PLT Ct) prior to the initiation of HU therapy and 12 months later. Multiple linear regression was conducted to examine whether age, gender, use of opioid analgesics, Hgb, HCT, and PLT Ct levels predict higher or lower rates of VOCs.ResultsOne hundred and fifty–six patients met the inclusion criteria and were included in the analysis. About 51% of the patients were males, and their mean age was 12.69 years. The mean HU dosage was 16.52 mg/kg/day, and the mean reduction in the rate of VOCs was 1.36 events per patient per year (95% CI [1.03–1.70], p < 0.0001) after the initiation of HU. Females were more likely to have greater reduction in the rates of VOCs in comparison to their male counterparts (β–estimate = 12.85, 95% CI [0.759–24.93], p = 0.0374).ConclusionThe use of HU results in a significant reduction in the rates of VOCs and emergency department visits. Future studies with robust research designs should be conducted to further examine the impact of HU on VOCs, hospitalization, and length of stay as well as compare HU to other newly approved medications for SCD, such as crizanlizumab.

Minimizing the Voltage Deficit of Tin Halide Perovskite Solar Cells with Hydroxyurea‐Doped PEDOT:PSS

Tin halide perovskite solar cells (TPSCs) have made great strides recently with an inverted device structure, in with poly(3,4‐ethylenedioxythiphene):poly(styrenesulfonate) (PEDOT:PSS) has been already widely applied as the hole transport layer (HTL) due to its optical transparency, easy processability, and good mechanical expandability. Nevertheless, the TPSCs still suffer from a severe voltage deficit from the carrier recombination loss and energy‐level mismatch. Herein, hydroxyurea (HYU)‐doped PEDOT:PSS to suppress the voltage loss at the PEDOT:PSS/perovskite interface is applied. It has been revealed that HYU effectively tunes the conductivity and hole mobility of PEDOT:PSS. The interfacial nonradiative carrier recombination is effectively suppressed. The target device shows a 20% increase in the open‐circuit voltage together with an increased power conversion efficiency rising from 8.10% to 10.17%. Therefore, this work provides a feasible strategy to minimize the voltage deficit in TPSCs from the HTL side, which is highly important to further boost the performance of TPSCs.

A multicenter, open-label study for efficacy and safety evaluation of anagrelide in patients with treatment-naïve, high-risk essential thrombocythemia as a primary treatment.

As the discussion of first-line anagrelide treatment is ongoing, we aimed to prospectively examine the efficacy and safety of anagrelide in cytoreduction therapy-naïve high risk essential thrombocythemia (ET) patients in Korea. Seventy patients from 12 centers were treated with anagrelide monotherapy for up to 8 weeks, followed up until 24 months. At week 8, 50.0% of the patients were able to achieve platelet < 600 x 109/L, and by 12 months, 55/70 (78.6%) patients stayed on anagrelide, and 40.0% patients showed platelet normalization. 14 patients required additional hydroxyurea (HU) for cytoreduction. The median daily dose of needed HU was 500mg (range 250mg - 1500mg). The efficacy was independent of the somatic mutation status. There were 4 thromboembolic events and 7 bleeding events during the follow-up period. The most common adverse events associated with anagrelide use were headache, followed by palpitation/chest discomfort, edema and generalized weakness/fatigue. 7 patients wished to discontinue anagrelide treatment due to adverse events (3 due to headache; 2 due to edema; 1 due to palpitation and 1 due to skin eruption). All in all, first-line anagrelide treatment showed a favorable response with tolerable safety profiles regardless of somatic mutation status.

Blood Transfusion Vs. Hydroxyurea for Stroke Prevention in Children With Sickle Cell Anemia: A Systematic Review and Meta-Analysis.

Sickle cell anemia (SCA) is a hereditary condition that can lead to severe complications in children such as acute coronary syndrome, splenic sequestration, renal failure, and stroke. Blood transfusion and hydroxyurea (HU) therapy are used to prevent stroke in children with sickle cell disease (SCD). Preliminary data show considerable variation and inconsistency in the use of these two therapeutic interventions. Therefore, this systematic review was carried out to compare the effects of blood transfusion to HU therapy in preventing stroke for children with sickle cell disease. There was an extensive literature search in reliable and authentic databases like PubMed, Medline, Scopus, Cochrane, and Science Direct to obtain relevant articles. This study used the standards and guidelines from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). During the systematic review, data were obtained focusing on the following parameters: the size of the sample in the study, the age of the subjects involved in the study, the type of Intervention, and the outcome. After an initial search of 163 papers, 25 studies were included. The results of the research give the first evidence that HU is effective in the treatment of cerebrovascular problems in children with SCD. However, it is unclear under what circumstances HU may prevent a second stroke. It can be concluded that children with SCAcan effectively avoid primary strokes through chronic blood transfusions and HU.

Characteristics and Clinical Outcomes in Patients (Pts) With Polycythemia Vera (PV) Receiving Ruxolitinib (RUX) After Hydroxyurea (HU): A Longitudinal Analysis From REVEAL

Background: Resistance or intolerance to first-line HU occurs in ~24% of pts with PV; RUX is a recommended second-line treatment (tx). In the large, real-world, multicenter, prospective Observational Study of pts with Polycythemia Vera in US Clinical Practices (REVEAL; NCT02252159), demographics, disease burden, clinical management, and pt-reported outcomes data of pts with PV were collected from 227 community or academic centers between 2014 and 2019. This analysis describes the characteristics and clinical outcomes of pts with PV who switched to RUX after HU tx. Methods: This analysis included pts (≥18 y) with a clinical diagnosis of PV who were treated with HU at least 3 mo prior to study enrollment and did not switch to an alternative therapy during the observation period (index: study enrollment date) or who switched to RUX after previous HU tx (index: RUX initiation date). Descriptive statistics were used to describe demographics, disease characteristics, and tx patterns. Blood count, Myeloproliferative Neoplasm-Symptom Assessment Form total symptom score (MPN-SAF TSS), and spleen length measurements were analyzed at index and at 3 and 12 mo post index for pts who switched to RUX. Results:Characteristics of pts who switched to RUX vs who were treated with HU Out of 2510 pts enrolled in REVEAL,1053 were eligible for this analysis and comprised of 906 pts treated with HU and 147 who switched to RUX (Table 1). Median age for both groups at index was similar (RUX, 67 y; HU, 70 y); 44.2% and 51.8% were women in the RUX and HU groups, respectively. In RUX vs HU, median (range) time to index date from PV diagnosis was 6.9 (0.3-36.3) vs 4.8 (0.1-36.5) y. The median (range) duration of HU tx prior to index date was 27.6 (0.1-221.0) mo in the RUX and 26.7 (3.0-435.7) mo in the HU group. Main reasons for HU discontinuation prior to RUX tx were lack of efficacy (n=53, 36.1%), adverse events (n=47, 32.0%), and disease progression (n=10, 6.8%). Pts who switched to RUX vs HU had higher mean (SD) MPN-SAF TSS (27.5 [17.7] vs 17.3 [15.1]) and higher percentage of pts (n=40, 27.2% vs n=84, 9.3%) with a palpable spleen. At index, 26 (18.1%) vs 65 (7.8%) pts who switched to RUX vs HU had an elevated white blood cell (WBC) count, with mean (SD) of 16.1 (16.3) vs 9.2 (6.2) ×109/L, respectively. Mean (SD) number of phlebotomies (PHL) 6 mo prior to index date was 1.3 (2.3) in the RUX and 0.7 (1.45) in the HU groups. In RUX vs HU, 27.2% vs 19.3% had a thrombotic event (TE) history prior to index date. Tx patterns and clinical outcomes in pts who switched to RUX (n=147) Ninety-two pts (62.6%) received the recommended initial dose of RUX (10 mg BID); additional initial doses were 5 mg BID (n=19), 20 mg BID (n=16), 15 mg BID (n=10), and other (n=10). Seventy-two (49.0%) required a dose modification. The median (range) RUX tx duration was 22.6 (3.0-54.5) mo; most pts (89.1%) received RUX for ≥6 mo. At the end of study, 118 pts (80.3%) were still on RUX. Compared with index, MPN-SAF TSS, proportion of pts with palpable spleen, and spleen length decreased at 3- and 12-mo follow-up (Table 2). The number of pts with hematocrit >0.45 L/L decreased from 49 at index to 19 and 16 at 3 and 12 mo, respectively (Table 2). The number of pts with WBC counts >10×109/L decreased from 87 at index to 66 and 48 at 3 and 12 mo, respectively (Table 2). Pts with no blood count test at 3- or 12-mo follow-up more likely had controlled hematocrit/WBC at index. Mean (SD) number of PHL decreased from 1.3 (2.3) at index (6 mo prior) to 0.5 (1.3) after 6 mo; 110 pts (74.8%) no longer required PHL 12 mo after index date. The TE rate after index date was numerically lower in RUX vs HU (2.7% vs 4.2%) after a median follow-up of 26 and 44 mo, respectively. Conclusion: This analysis of REVEAL, the largest real-world cohort of PV pts to date, demonstrated that pts who switched from HU to RUX had more severe disease burden vs those who were treated with HU. RUX tx resulted in significant improvements in PV-related symptoms, correlating with reduction in spleen size and sustained improvement in hematologic parameters. This resulted in a reduction of PHL within 6 mo, with most pts becoming PHL-free at 12 mo. There was also a trend towards lower rates of TEs with RUX. This longitudinal analysis validates the efficacy of RUX for the tx of PV after HU exposure in the real-world and suggests monitoring of PV pts on HU to identify those who are likely to benefit from transition to RUX in order to meet tx goals and become PHL-free. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Assessing Multi-Level Barriers to Medication Adherence in Youth with Sickle Cell Disease Using Pharmacy-Based Prescription Refill Data

Background: Across chronic diseases, suboptimal adherence to prescribed therapies compromises therapeutic benefits. In sickle cell disease (SCD), adherence to hydroxyurea (HU) in adolescents and young adults is often poor. Poor adherence may be either intentional or unintentional related to lack of capacity or resources. We used prescription refill data to examine barriers to adherence in two samples of 10-18 year old youth with SCD, known to be poorly adherent to HU, who participated in the multi-site "Hydroxyurea Adherence for Personal Best in SCD" (HABIT) feasibility and efficacy trials. Methods: Parents provided written consent to contact their pharmacy(ies) for release of their child's HU prescription records for the year prior to study entry and duration of participation in the HABIT 6-month feasibility [2013-2015] (NCT02029742) and 12-month efficacy [2017-2021] (NCT03462511) trials. Refill data were retrieved by fax, email or in person. HU dose prescriptions were verified by electronic health record review at each study site. Data collected were pharmacy name, HU dispensation dates, formulation (capsule/tablet versus suspension), concentration (mg/capsule or tablet or mg/ml suspension), prescribed HU dose, number of capsules/tablets or volume of HU suspension dispensed, directions for use and number of days for which drug was dispensed, and number of times the HU prescription was filled. Data retrieval was considered complete if the interval for participants' HU dispensed reflected 80% or greater of the trial prescribing period (1.5 years feasibility; 2 years efficacy). Using the World Health Organization Multidimensional Adherence Model, we categorized factors as patient-related (prescription of HU suspension reflecting problems with swallowing capsules/tablets); treatment-related (complex HU regimen defined as different dosing patterns on different days of the week), and health care system related (prescription of HU capsule other than 500 mg reflecting potential need for prior authorization, use of more than one pharmacy, lack of dosing directions for HU dispensed; dispensing less than 30 days of HU during a dispensing period). Data were analyzed using descriptive statistics; sample barriers were compared using chi-square. Results: Of 78 enrolled participants (28 feasibility trial, 50 efficacy trial), pharmacy data were available for 92.3% (27 feasibility trial, 45 efficacy trial; mean age 13.6±2.2 years, 72.2% Black, 30.6% Hispanic) (Table 1). On average, refill data collected spanned 81.9% of the trial period (74% feasibility trial; 86.7% efficacy trial). On average, HU prescriptions were filled 10.6±5.6 times within 18 months and 16.0±7.6 times within 24 months for feasibility and efficacy participants, respectively. The most frequently identified potential barriers to adherence in this sample were lack of dosing directions (66.7%), complex HU regimens (47.2%) and lack of direction specificity (i.e., the day(s) HU dose should be different) when complex regimens were prescribed (47.1%) (Table 2). Over 20% of youth were prescribed liquid HU formulation, while HU capsules/tabs other than 500 mg/capsule were infrequently prescribed (27.8%). No significant differences in barriers were seen between the two trials reflecting a period of 8 years. Discussion: Use of individual patient prescription refill data provides insight into multi-level barriers at the patient-, treatment- and health system-related levels, each of which is likely unintentional. Despite recent availability of HU capsules/tablets in varying concentrations, complex HU regimens, often lacking specific dosing directions, were common in this socially vulnerable multi-site sample. These findings suggest that barriers to adherence occur at all levels and did not change across the two trial periods. Reducing adherence barriers likely require development and testing of multi-level interventions which simplify medication schedules, incorporate more recent dose formulations of HU capsules/tablets when needed, provide explicit dosing directions on bottle labels and facilitate convenient HU access including dispensing greater than 30 day quantity of HU via pharmacy or mail order. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Cannabidiol Attenuates Chronic and Acute Hyperalgesia in Sickle Mice By Reducing Inflammation and Oxidative Stress

Pain is a major comorbidity of sickle cell disease (SCD) leading to hospitalization, opioid use and reduced survival. It can present as both chronic pain and/or unpredictable episodes of intense acute pain. Hydroxyurea (HU) is the mainstream FDA approved treatment for SCD, but its effect on reducing pain remains to be understood. A larger number of people with SCD use cannabis products for pain relief compared to those with other conditions. Cannabidiol (CBD) is one of the major constituents of Cannabis sativa, second to tetrahydrocannabinol, and has gained attention for its ability to treat pain without intoxicating side effects. CBD has been shown to decrease inflammation, oxidative stress, and inhibit mast cell activation, all of which occur in SCD. Thus, we hypothesize that CBD will ameliorate both chronic and acute hyperalgesia in humanized homozygous BERK sickle mice (called sickle) by inhibiting mast cell activation and decreasing inflammation and oxidative stress. To simulate the clinical condition, we treated female sickle mice intraperitoneally with [i] vehicle (1:1:18 DMSO:Tween-20:saline), [ii] HU (50 mg/kg/d HU), [iii] CBD (20 mg/kg/d) or [iv] HU + CBD and determined their effect on chronic and acute hyperalgesia (pain). Sickle mice treated with synthetic CBD alone or cotreatment with HU+CBD daily showed significantly reduced chronic mechanical (p<0.001) and cold (p<0.001) hyperalgesia compared to baseline after 7 days of treatment, which was maintained for up to 14 days. HU decreased mechanical (p<0.01) but not cold hyperalgesia after 14 days compared to baseline. Thus, CBD independently attenuates chronic hyperalgesia, whereas HU may have a modest effect on chronic pain. Following the initial 14 days of treatment above, we incited acute hyperalgesia by treating sickle mice with hypoxia/reoxygenation (H/R; 3 hours of hypoxia at 8% O2 and 92% N2, followed by 1 hour of reoxygenation at normoxia) on days 15 (H/R-1) and 18 (H/R-2). We observed that CBD, HU, and HU+CBD treatments were able to prevent an increase in H/R-incited hyperalgesia (acute response). CBD alone and HU+CBD significantly reduced mechanical (p<0.001) and cold hyperalgesia (p<0.001) compared to baseline following incitement of both H/R-1 and H/R-2, and up to 25 days, the last period of observation. HU alone did not show a significant decrease in mechanical or cold hyperalgesia compared to baseline following incitement of either H/R event, except for cold hyperalgesia 72h post-H/R-2 (p<0.05). CBD and HU+CBD treatments also reduced non-evoked cold avoidance compared to baseline in sickle mice, which spent significantly more time (p<0.01) in a cold chamber (4°C) 7d after H/R-2 (day 25), but HU alone did not. Thus, HU has a modest or no effect on different features of sickle pain, while CBD is able to ameliorate both chronic and acute pain. We next investigated the mechanism of CBD's analgesic effect in sickle mice. Following 9 days of daily treatment, we observed that CBD decreased total and degranulating mast cells (p<0.05 and p<0.01, respectively) in the skin compared to vehicle, and a reduction in tryptase (p<0.05), a marker of mast cell activation, in the skin secretagogue. CBD treatment decreased substance P (p=0.05) and malondialdehyde, (p<0.05), markers of neuroinflammation and oxidative stress respectively, in the skin secretagogue, and serum amyloid P (p<0.05), a marker of inflammation, in plasma. CBD significantly decreased inflammatory cytokines IL-3, which promotes mast cell proliferation, TNFα, a hallmark feature of cytokine storm, and MIP-1α and RANTES, which contribute to leukocyte recruitment. Thus, CBD attenuates inflammation, neuroinflammation and oxidative stress in sickle mice and may ameliorate leukocyte activities, a hallmark feature of SCD. We demonstrate that CBD is effective in attenuating chronic hyperalgesia and preventing acute pain by decreasing inflammation and oxidative stress. The effect of HU on reducing pain following H/R and chronic pain are modest and specific to certain characteristic features of sickle pain. Importantly, HU does not appear to interfere with the analgesic effect of CBD in sickle mice, which shows promise for CBD treatment in persons with SCD on HU. The availability of a >99% CBD-extract (Epidiolex) approved by the FDA to treat some forms of epilepsy may help facilitate clinical trials for assessing the effects of CBD on pain in persons with SCD.

Blood Transfusion Ameliorates Free Haem-Induced Loss of Thrombomodulin and Endothelial Cell Activation in Paediatric Sickle Cell Anaemia

Background Sickle cell anaemia (SCA) is responsible for major paediatric morbidity including risk of stroke in up to 10% of children. Mainstays of therapy include hydroxyurea (HU) and chronic blood transfusion (BT), with BT considered gold standard for stroke prevention. However, the biological mechanisms through which BT is significantly superior to HU in reducing stroke risk have not been clearly defined. SCA complications are due in part to free haem-mediated damage, leading to endothelial cell (EC) activation, tissue factor (TF) expression and release of von Willebrand Factor (VWF), which binds platelets and sickle RBCs. Recently loss of EC Thrombomodulin (TM) has been shown to promote EC activation and VWF release and soluble TM (sTM) plays a role in disseminated intravascular coagulation and COVID-19. Hypothesis We hypothesize free haem alters EC TM expression, promoting EC activation and VWF release. Intravascular hemolysis and free haem may be reduced in children on chronic BT, maintaining EC quiescence and enhancing protection against stroke compared with HU. Methods Following ethical approval and informed consent 180 SCA children (median age 12 years, 49% male) were recruited. Steady-state plasma samples were collected prior to BT (n=84) or at outpatient clinic for HU (n=96). Paired crisis samples were obtained in a subset of HU (n=30). EC activation markers and Weibel Palade Body (WPB) proteins were evaluated by ELISA, VWF multimers were assessed by 1.8% agarose gels and ADAMTS13 activity assessed by FRET. Free haem levels were quantified and thrombin generation (TG) assays performed. Factor VIII:C was measured in the National Coagulation Centre at St James's Hospital. Human umbilical vein endothelial cells (HUVEC) were exposed to cell-free haem (Hemin), hydroxyurea, cytokines (IL-1β and TNFα) or patient plasma; VWF was measured in the supernatant and HUVEC TM expression assessed by flow cytometry. Results VWF:Ag and VWF propeptide (VWFpp) levels were significantly increased in HU compared to BT children, suggesting acute EC activation (median plasma VWF:Ag levels 1.29 v 1.03 IU/ml; p=0.0005, median VWFpp levels 1.63 v 1.17 IU/ml p=0.006). Furthermore, plasma levels of other WPB stored proteins were also significantly elevated in the HU cohort, including Angiopoietin-2 (Ang-2) (4214 v 2337 pg/ml, p<0.0001 and Osteoprotegerin (OPG) (1825 v 1507 pg/ml p=0.006). Abnormalities of high-, intermediate- and low molecular weight VWF multimers were noted in HU but not BT. While putative inhibitors of ADAMTS13 were increased in HU, including Platelet Factor 4 and Interleukin-6, ADAMTS13 activity did not differ between groups. FVIII:C levels were significantly elevated in 65% of the total cohort and were higher in HU than BT (1.62 IU/ml v 1.30 IU/ml p<0.0001). Free haem levels were increased in HU versus BT (12.5 v 9.5μM p=0.0003), as well as levels of LDH and reticulocyte %, pointing to increased intravascular hemolysis. EC markers and FVIII:C correlated strongly with hemolytic indices. In addition to increased EC activation, increased endogenous thrombin potential (ETP), peak thrombin and velocity index were observed in HU versus BT, pointing to enhanced TG, possibly driven by elevated circulating TF. TG parameters correlated with plasma FVIII:C levels. Exposure of HUVEC to free haem in vitro resulted in a significant decrease in surface TM expression and increased VWF secretion (p<0.05). Conversely exposure to hydroxyurea or cytokines did not alter TM expression. Exposure of HUVEC to plasma from crisis but not paired steady-state plasma induced EC activation and VWF release compared with control plasma. Importantly, free haem levels ≥20 μM were observed in 25% HU children in steady state and 40% in crisis, compared with 0% of BT. Furthermore, significantly elevated sTM levels in SCA children with a history of cerebrovascular disease compared to those without (5.7 v 4.6 ng/ml p=0.02), suggesting that sTM may predict end-organ dysfunction. Conclusions We have shown in a large cohort of SCA children that EC activation, TG and intravascular haemolysis are increased in HU-treated children compared with BT. Free haem induces loss of EC TM and VWF release in vitro, leading to EC activation. Elevated sTM levels were a biomarker of end-organ damage. These data suggest that reduction of free haem in children undergoing regular BT is a key mechanism through which EC quiescence is maintained in paediatric SCA.

ASCENT1: A Phase 2 Trial to Evaluate the Efficacy and Safety of Oral Decitabine-Tetrahydrouridine (NDec) in Patients with Sickle Cell Disease

Background: Sickle cell disease (SCD) is driven by the polymerization of mutated hemoglobin (HbS) in red blood cells (RBCs). Fetal hemoglobin (HbF) mitigates the effects of HbS polymerization, but the HbF gene expression is silenced in infancy by DNA methyltransferase 1 (DNMT1). Decitabine induces HbF expression by direct inhibition of DNMT1. NDec is an innovative combination treatment with decitabine, the active component, and the pharmacokinetic enhancer tetrahydrouridine (THU). Hydroxyurea (HU), the current standard of SCD care, indirectly induces HbF by inducing bone marrow stress. As the indirect effect of HU on HbF is clinically variable, the direct HbF induction of NDec is hypothesized to provide a sustainable treatment option for patients with SCD. In a previous trial in high-risk patients with SCD by Molokie R et al. (2017), oral decitabine (0.16 mg/kg) and THU vs placebo significantly increased total Hb, HbF, proportion of HbF-enriched RBCs (%F-cells) and improved RBC health markers, without triggering grade ≥3 non-hematologic toxicity. NDec formulations were further investigated in 2 phase 1 trials in healthy people. The ASCENT1 trial (NCT05405114) aims to study the efficacy and safety of once- or twice-weekly NDec vs placebo in patients with SCD. This study will provide proof of concept and determine the optimal dose for future trials. Study design: ASCENT1 is a randomized, placebo-controlled phase 2 trial with an additional exploratory open-label HU block (Figure). To ease the operational aspects for patients and sites, trial design, visit schedule and trial materials were developed together with patient groups, study nurses and coordinators. The HU non-eligible block will include those who are HU-naïve or who cannot be treated with HU for any reason. Participants randomized to NDec in the HU active block will discontinue HU during a 4-week washout period. Study population: All SCD genotypes are eligible for inclusion; other criteria are ≥18 years of age, 2-10 documented vaso-occlusive crises (VOCs) ≤12 months before screening, Hb ≥5.0-≤10.5 g/dL and reticulocyte count >1.5x upper limit of normal at screening. HU active participants are eligible only if deemed inadequately controlled by investigators despite being prescribed HU in the preceding 6 months and being on a stable dose >3 months. Exclusion criteria include chronic transfusion therapy or treatment 28 days before screening/during trial with hematopoietic growth factors and treatment with voxelotor, crizanlizumab or L-glutamine 12 weeks before signing informed consent. Study treatment and endpoints: HU non-eligible (n=60) and HU active (n=24) participants will be randomized 1:1:1 to NDec once weekly, NDec twice weekly (2 consecutive days) or placebo/open-label HU. The trial consists of a main and extension phase (24 weeks each). NDec will be administered orally, with a meal, according to body weight intervals to attain a decitabine dose level of 0.16−0.25 mg/kg and THU dose level of 8−12.5 mg/kg. The primary endpoint is change in total Hb (g/dL) from baseline (BL) to Week 24. Secondary efficacy endpoints include change in HbF (g/dL and %HbF of total Hb), change in %F-cells of total RBCs, and change in hemolysis markers from BL to Week 24. Secondary efficacy endpoints also include numbers of VOCs, acute chest syndrome and transfused RBC units from BL to Week 48. The secondary safety endpoint is the number of adverse events (grade ≥3) from BL to Week 52. Changes in patient-reported outcomes from BL to Week 48 will be assessed using 5 validated questionnaires for SCD. Statistical analysis: The primary endpoint will be analyzed using an ANCOVA model with treatment, historical VOC rate and sex as fixed factors, and BL Hb as covariate. Treatment policy estimand will be used to handle intercurrent events. Considerations: In this trial, VOCs are defined as ≥1 predefined clinical events requiring a medical visit, including home and telemedicine visits, for those with limited regular access to medical management at a clinic/hospital. NDec and HU both induce HbF and will not be given together due to a theoretical potentiation of hematologic toxicity. The exploratory HU active block enables preliminary comparisons of the efficacy and safety between NDec and HU. The extension phase allows for analyses that may require longer follow-up to show clinical benefits and sustainability of NDec in SCD. The recruitment to ASCENT1 started in summer 2022. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Characteristics, Blood Counts, Treatments, and Clinical Outcomes of 5871 Patients with Polycythemia Vera Treated in US Community Practices

Background: Cytoreduction with hydroxyurea (HU) is the recommended first-line (1L) treatment for high-risk polycythemia vera (PV) (age ≥60 years or history of thrombosis), but many patients (pts) have suboptimal response to HU. This study describes characteristics, blood counts, treatments, and clinical outcomes among pts with PV, including those with suboptimal response to HU, in 2 large networks of US community oncology practices. Methods: This was a retrospective observational study of adult pts with a documented new diagnosis of PV in the iKnowMed electronic health record database (01Jan2008-31Jan2020), which is implemented in The US Oncology Network and non-Network practices. Pts with ≥2 postdiagnosis visits during the study observation period (01Jan2008-31Jan2021) were included in the analysis. Suboptimal response to HU was defined as meeting ≥1 of the following criteria after ≥3 months of treatment: (1) white blood cell (WBC) count >10 × 109/L, (2) platelet count >400 × 109/L, and/or (3) hematocrit (HCT) >45%. Data on demographic/clinical characteristics and prior treatment were summarized with descriptive statistics. Duration of therapy and overall survival were assessed via the Kaplan-Meier method, which censored pts without subsequent treatment discontinuation/death records at the end of the study observation period. Results: 5871 pts (The US Oncology Network, n=3022; non-Network, n=2849) met all eligibility criteria and were included in the analysis. Mean (SD) age at diagnosis was 66.1 (13.6) years (70% ≥60 years), 44% of pts were female, 87% were White, and 49% were current or former tobacco users. At diagnosis, 6% of pts had a history of thrombotic event, and 71% had high-risk PV; 38% (1535/4021), 34% (1361/4014), and 67% (2696/4010) of evaluable pts had elevated WBC (>10 × 109/L), platelets (>400 × 109/L), and HCT (>45%), respectively. Over half of pts with high-risk PV (55%; 2303/4185) received a cytoreductive agent as 1L treatment (90% HU), and 45% did not receive cytoreductive therapy. Among those with low-risk PV, 32% (540/1686) received a cytoreductive agent as 1L treatment (89% HU), and 68% did not receive cytoreductive therapy. Five-year survival probability was 82% among all pts, 79% for pts with high-risk PV (age ≥60 years or history of thrombosis), and 96% for those with low-risk PV. Overall, 56% of patients had a suboptimal response for blood count control after 3 months of treatment; this remained roughly the same at 6 months (Table). Among pts who received 1L HU, median (Q1, Q3) time from diagnosis to HU initiation was 29.0 (0.0, 252.5) days for those with high-risk PV and 103.0 (0.0, 683.5) days for those with low-risk PV; median (Q1, Q3) duration of HU was 26.7 (8.1, 54.6) and 35.6 (9.3, 68.5) months, respectively. Among pts treated with 1L HU who had evaluable blood counts, 42% (1078/2548) had a suboptimal response at 3 months, 64% of whom (691/1078) continued to have a suboptimal response at 6 months (WBC >10 × 109/L and/or platelets >400 × 109/L, 50%; HCT >45%, 36%). Median duration of 1L HU treatment for pts with suboptimal response was 26.6 (95% CI: 24.0, 29.3) months. Among pts with suboptimal response to 1L HU, 5-year survival probability was 82% overall (high risk, 78%; low risk, 99%). Pts with suboptimal response appeared to have a lower 5-year survival probability than pts with optimal response (81.5% [95% CI: 77.7%, 85.5%] vs 84.3% [95% CI: 81.2%, 87.4%]). This difference between pts with suboptimal vs optimal response was statistically significant in non-Network (74.5% [95% CI: 67.7%, 82.0%] vs 85.1% [95% CI: 81.1%, 89.3%]; P=0.008) but not in The US Oncology Network practices (86.7% [95% CI: 82.3%, 91.2%] vs 83.6% [95% CI: 79.1%, 88.3%]; P=0.109). Besides this difference observed in the 5-year survival probability, pt characteristics and outcomes were similar between the 2 networks, although additional data (eg, pt/disease characteristics; phlebotomy use, supportive care) are needed to better understand differences between networks. Conclusions: The prevalence of elevated blood counts at diagnosis and follow-up while on HU treatment is consistent with previous real-world evidence. About 1 in 6 pts with a suboptimal response to HU died within 5 years, and there was a trend toward shorter survival among those with suboptimal response compared with pts with blood count control. HU dose adjustments or alternative treatments may be needed for pts with suboptimal response to HU. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Sickle Cell Disease (SCD) Burden on Patients Treated With Hydroxyurea (HU): Results from the Real-World Assessment Survey for SCD in Saudi (ROARS)

The prevalence of SCD in the Kingdom of Saudi Arabia (KSA) is one of the highest in the world with up to 2.6% of the population affected. The Real-World Assessment Survey for Sickle Cell Disease in Saudi (ROARS) was conducted to evaluate the impact of SCD on the quality of life (QoL) of this population. Here, we present data on the QoL burden experienced by patients with SCD in KSA treated with hydroxyurea (HU). Between September and December 2021, patients in KSA with SCD (age: 5-65 years) were surveyed (caregivers were surveyed for patients 5-14 years) using structured, bilingual ROARS questionnaires (English/Arabic) through personal quantitative web-assisted telephone interviews. The survey includes the Patient-Reported Outcomes Measurement Information System (PROMIS) global health domain, a validated tool for assessing QoL among SCD patients and caregivers. The survey evaluated topics such as the impact of SCD on QoL, symptoms, impact of SCD on productivity at work/school, and treatment goals. A total of 1011 responses to the survey were collected; of these, 32.3% (n=327) of patients were currently being treated with HU (47% of adult and 17% of pediatric patients surveyed) and are the focus of this analysis. Amongst these patients, the median age (range) was 25 (5-83) years. Patients were responsible for reporting their SCD genotype: 58% of respondents were diagnosed with HbSS (n=189), 26% with HbSC (n=86), 2% with HbSβ0 thalassemia (n=8), and 5% with HbSβ+ thalassemia (n=15). Overall, 35% (adults, n=84; pediatric n=25) of patients in the eastern province were treated with HU, 27% (adult, n=71; pediatric, n=17) in the western province, 24% (adult, n=55; pediatric, n=24) in the southern province, and 14% (adult, n=29; pediatric, n=22) in the central province. Among HU-treated patients, 64% reported never ceasing/stopping treatment, 21% rarely ceased/stopped treatment and 15% of patients cease/stop treatment sometimes, often, or all the time. The most common reason for patients ceasing/stopping treatment was forgetting to take their medication (79%). Of patients who cease/stop treatment sometimes, often, or all the time (n=48), 17% of these stated that their medication was not available while 4% could not afford their medication. The mean (SD) number of VOCs reported by HU-treated patients in the 12 months prior to survey completion was 4.6 (4.09), while 32% (n=104) of these patients reported experiencing ≥5 VOCs in the same period. The most common SCD symptoms (other than VOCs) experienced by HU-treated patients were bone ache (reported by 92% of respondents), fatigue/tiredness (85%), headache (79%), anxiety (61%), joint stiffness (56%) and numbness/tingling (51%). Most HU-treated patients reported poor/fair or good health for all QoL metrics assessed (Figure 1). Almost half of patients (49%) reported that their SCD was impactful/extremely impactful on their emotional wellbeing. Of those treated with HU, 71% of patients reported that HU is effective in treating their SCD symptoms. However, 84% of patients report a desire for alternatives to their current pain management medication while 72% report concerns about the long-term side effects of HU. The most important treatment goals for these patients were improvement in quality of life (82%), improvement in overall symptoms (79%), and reduction in the number of severe pain crises and increase in the number of days free from severe pain crises (79%). A total of 48% of HU-treated patients were bothered by limitations in performing everyday activities; 48% and 55% of patients also reported that their SCD has prevented them from progressing in their career or education, respectively. Patients treated with HU reported missing a mean (SD) of 6.9 (10.4) hours of work in the 7 days prior to survey completion because of their SCD. Access to HU treatment continues to be a challenge, with approximately 70% of patients surveyed not receiving HU. Despite the observed clinical benefit in symptom control, patients receiving HU continue to experience disease burden including substantial impact on QoL and productivity at work/school (as evident from the treatment goals identified by patients). These data highlight the necessity of optimizing HU accessibility and treatment strategies to improve patient outcomes. These data also illustrate the need for novel therapeutic options and management strategies for patients with SCD to target patient-reported treatment goals. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Understanding Hydroxyurea Utilization in Sickle Cell Disease: Exploring Patient and Provider Attitudes and Beliefs

Introduction Hydroxyurea (HU), a first line sickle cell disease (SCD) modifying drug, has a 22%-48% utilization rate, according to national estimates (Lanzkron 2006, Stettler 2015, Knisely 2020). There are numerous factors identified as barriers to adherence of hydroxyurea such as access to care (Badawy 2017). Given the high frequency of SCD inpatient admissions at the University of Chicago Medical Center (UCMC) and thus the limited opportunity for outpatient care where disease modifying therapies can be initiated, we proposed a quality improvement project to monitor HU education and usage during inpatient encounters. Methods Our project was reviewed by the UCMC Institutional Review Board and approved to meet quality improvement (QI) determination. To address the question of HU initiation in SCD during inpatient encounters, we surveyed key stakeholders including patients with SCD and providers. We identified consecutive patients with SCD who were either established with primary care or hematology at UCMC (n=197) and distributed our deidentified survey through a REDCap secure link to patients with active email accounts (n=135). We designed a provider survey eliciting knowledge, beliefs, and perspectives on HU use in SCD and distributed this through REDCap to 182 frontline providers. We analyzed the data qualitatively, identifying patterns and common themes from aggregate responses and free text answers. Results The patient survey response rate was 31% (n=42/135). Forty-five percent (n=18) of patients agreed that they missed follow up appointments due to admissions. Approximately half of patient respondents indicated they were not taking HU (n=19). Additionally, of those patients, 72% (n=14) indicated they would be willing to deal with the side effects of HU if it improved their SCD symptoms and 32% (n=6) said they would consider initiation of HU during an inpatient encounter. Patient respondents cited the benefits of HU, including improving quality of life (33%; n=13), preventing pain episodes (43%; n=17), improving mortality (18%; n=7), and helping prevent hospitalizations (36%; n=14). In terms of further education, 35% (n=14) of patient respondents indicated they would like to learn more about HU. 88% (n=35) indicated they would like to learn more about other disease modifying therapies. The provider survey response rate was 73% (n=132/182), of whom, 40% (n=52) were IM or Med/Peds residents, 28% (n=37) were medicine attendings, and 11% (n=15) were Hematology/Oncology faculty or fellows. 98% (n=129) of respondents overall agreed that HU initiation should be offered to patients with SCD during inpatient encounters and that the benefits of HU in SCD outweighed the potential harms. Providers requested tools to facilitate prescribing HU during inpatient encounters, including bundled orders ("orderset") within the EMR (55%; n=73), an option for inpatient SCD consult services (28%; n=37), education sessions and materials (45%; n=59), and a linked outpatient hematology referral system (58%; n=77). Conclusion: Results from our patient survey demonstrate an unmet need for expanding access to HU into inpatient encounters and providing access to other disease modifying therapies and potential cures. Providers would be comfortable with initiation and monitoring of HU during inpatient SCD encounters. To facilitate this, providers request additional education and process resources. Results from both surveys inform a plan to address disparities in HU utilization rates among patients with SCD at UCMC, in addition to providing opportunities to enhance SCD care overall. The path forward will include building curricula for providers, educational handouts on disease modifying therapies for patients, generating a HU prescribing orderset embedded in the EMR, and innovating a SCD inpatient consult service at UCMC.

Optimizing Shared Decision Making about Hydroxyurea in Young Children with Sickle Cell Anemia

Introduction: The National Heart, Lung, and Blood Institute (NHLBI) recommends hydroxyurea (HU) be offered to all children with sickle cell anemia (SCA) age >9 months via shared decision-making (SDM). However, HU remains underutilized, largely due to parental concerns about safety and potential long-term effects. SDM was recommended because it can decrease parental uncertainty as families clarify their values/preferences and understand scientific evidence about HU. Funded by the Patient-Centered Outcomes Research Institute (PCORI), the Engage HU study (NCT03442114) compared two methods for optimizing SDM for HU in young children with SCA: the American Society of Hematology's (ASH) HU clinician pocket guide (usual care condition) and a HU SDM toolkit (toolkit condition) created by the research team. This study aimed to compare the impact of these on caregiver decisional uncertainty and caregiver perception of clinician use of SDM. Methods: Engage HU was a prospective, multi-site intervention trial with a unidirectional crossover design in which each clinic began enrolling in the usual care condition and then one-by-one crossed over to the toolkit condition. Inclusion criteria included children ages 0-5 years followed at 12 SCA centers in the US who were candidates for HU and whose caregivers had not decided about HU therapy within 3 months prior to enrollment. After receiving a flyer/letter, eligible caregivers were approached in clinic or by phone. Caregivers completed an e-consent form. Study visits were conducted in-person or via telehealth. Primary endpoints were caregiver decisional uncertainty (Decisional Conflict Scale-DCS) and caregiver perception of clinician use of SDM (Dyadic OPTION scale-OPTION). Lower scores on the DCS indicate less decisional uncertainty and higher scores on the OPTION indicate that the clinician demonstrated more SDM behaviors (e.g., asked about caregiver preferences/values). All survey data were collected using paper surveys or electronically via REDCap™. Data were analyzed using linear regression models in Stata version 17 for each main outcome of interest (DCS and OPTION Total Scores). Our primary predictor was group (toolkit versus usual care). The model was estimated using full information maximum likelihood estimation on the full analysis sample (N=132) to account for missing data. We also accounted for site-level variation, when the sites crossed from usual care to toolkit (i.e., the cluster), when data were collected (0=pre-COVID, 1=during COVID), and the impact of COVID-19 on caregivers (assessed using the COVID-19 Exposure and Family Impact Survey [CEFIS]). Results: A total of 176 caregivers of eligible children consented. Twelve SCA clinical sites participated; however, four sites were terminated early due to staff turnover or low accrual. Mean caregiver age was 30.19 (SD=6.97); most identified as female (93.1%), Black/African American (89.3%), or Mixed race (6.1%), and mothers (90.8%). Most children had HbSS (94.7%). Preliminary analyses were conducted on 132 caregivers with complete data (n=85 Usual Care; n=47 Toolkit). Regression analyses showed that participants in the toolkit condition had significantly lower DCS Total scores (i.e., lower decisional conflict) than those in usual care condition (b=-7.33, 95% CI=-13.3 to 1.31, p=.017). In addition, significant differences were found on the DCS subscales (see Table 1). Similarly, participants in the toolkit condition had significantly higher OPTION Total scores (i.e., parents reported that the clinician exhibited more SDM behaviors) than those in usual care (b=2.38, 95% CI=0.44 to 4.34, p=.016). Conclusions: Use of the HU toolkit compared to the usual care approach significantly improved SDM between providers and caregivers of children with SCA; however, given site team turnover, lower than expected accrual, and study interruption due to the COVID-19 pandemic, additional research is needed to confirm these preliminary findings. Future studies should also seek to identify context-specific factors (e.g., clinic processes) that are key to successful implementation of SDM with both younger and older children with SCA. This project was supported by an award fromPCORI contract number CDR-1609-36055 (PI: Crosby).Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal