scholarly journals Changing the Clinical Paradigm of Hydroxyurea Treatment for Sickle Cell Anemia Through Precision Medicine

2020 ◽  
Vol 109 (1) ◽  
pp. 73-81
Author(s):  
Min Dong ◽  
Patrick T. McGann
Keyword(s):  
Precision Medicine ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Hydroxyurea Treatment ◽  
Clinical Paradigm

scholarly journals Splenomegaly in Children with Sickle Cell Anemia Receiving Hydroxyurea in Sub-Saharan Africa

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 993-993
Author(s):  
Leon Tshilolo ◽  
George A. Tomlinson ◽  
Patrick T. McGann ◽  
Teresa S. Latham ◽  
Peter Olupot-Olupot ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Growth Parameters ◽  
Sub Saharan Africa ◽  
Advisory Committees ◽  
Splenic Enlargement ◽  
Hydroxyurea Treatment ◽  
Lower Blood ◽  
Sub Saharan

Introduction. Children with sickle cell anemia enrolled in Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) received open-label hydroxyurea at maximum tolerated dose (MTD) in four countries within sub-Saharan Africa (Tshilolo et al, NEJM 2019;380:121-131). Unlike children in the United States or Europe, a substantial proportion of REACH participants had splenomegaly at enrollment, and more developed splenomegaly while receiving hydroxyurea. Splenic enlargement in association with hydroxyurea treatment in sub-Saharan Africa is previously unrecognized, and its causes and consequences remain unclear. Methods. Palpable splenomegaly was evaluated at both the mid-clavicular and mid-axillary lines at each scheduled and unscheduled sick visit. The size of the spleen, defined as the greatest distance (cm) below the subcostal margin, was recorded in the REDCap trial database at all four clinical sites. Cross-sectional analysis was performed at baseline enrollment using four spleen categories (Not Palpable, 1-4 cm, ≥5 cm, or Splenectomy) with correlations for age, sex, site, growth parameters, alpha-thalassemia trait and G6PD deficiency. This analysis was repeated using the largest spleen size over the first two years on hydroxyurea, but examining two-year laboratory values and also the hydroxyurea dose at MTD, time to MTD, dose-limiting toxicities, and clinical outcomes including acute splenic sequestration, malaria infections, and sepsis. Results. A total of 606 children started hydroxyurea study treatment, including 6 (1.0%) with previous splenectomy, 59 (9.7%) with previous splenic sequestration, and 99 (16.3%) with palpable splenomegaly at enrollment (52 children with 1-4 cm and 47 with ≥5 cm). Large spleens (≥5 cm) were commonly observed at baseline at all clinical sites except Uganda, which identified only 1 child. Compared to those with no palpable spleen, children with large spleens at baseline had similar age and growth parameters, but were significantly more likely to have alpha-thalassemia (78.7% versus 56.2%, P=0.004) and also G6PD deficiency among males (28.0% versus 17.6%, P=0.32). Children with large spleens at enrollment also had a lower hemoglobin (Hb = 6.5 versus 7.3 g/dL, P<0.001) and lower platelet count (platelets = 227 versus 410 x 109/L, P<0.001), but equivalent fetal hemoglobin (HbF = 10.2 versus 9.4%, P=0.82). On hydroxyurea treatment with escalation to MTD, 262 children (43.7%) had palpable splenomegaly recorded, including 120 (20.0%) with spleens ≥5 cm. These large spleens were observed at all four clinical sites, with DRC having the most (52) and Uganda with the least (14). After 24 months of hydroxyurea treatment, laboratory differences were noted according to the cumulative occurrence of splenomegaly including a significantly lower hemoglobin and platelet count, higher absolute reticulocyte count, and lower hydroxyurea dose at MTD (Table). Large spleens were associated with a high cumulative incidence of laboratory dose-limiting toxicities, as well as a significantly higher risk of having clinically symptomatic malaria and receiving blood transfusions (Table). A total of 31 children (5.2%) on hydroxyurea treatment received elective splenectomy, including one partial splenectomy using arterial embolization. Conclusion. Children with sickle cell anemia living in sub-Saharan Africa have an increased risk of having palpable splenomegaly, which is further increased while receiving hydroxyurea treatment. Large spleen at baseline were associated with lower blood counts, consistent with hypersplenism. On hydroxyurea treatment, children with large spleens had significantly lower blood counts and more dose-limiting toxicities, which lowered their eventual hydroxyurea dose at MTD but still led to robust HbF responses. Children with large spleens were also at higher risk of developing malaria infections, receiving transfusions, and requiring surgical splenectomy. Splenic enlargement in association with hydroxyurea treatment was common in children with sickle cell anemia in the REACH trial; its cause remains unclear but the consequences include substantial laboratory toxicity and clinical morbidity. Investigating the etiologies and management of children with chronically enlarged spleens is crucial before expanding hydroxyurea access across Africa for sickle cell anemia. Disclosures Ware: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Other: Research Drug Donation; Nova Laboratories: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: DSMB; Agios: Membership on an entity's Board of Directors or advisory committees; Addmedica: Other: Research Drug Donation.

Hydroxyurea corrects the dysregulated L-selectin expression and increased H2O2 production of polymorphonuclear neutrophils from patients with sickle cell anemia

Blood ◽  
2002 ◽  
Vol 99 (7) ◽  
pp. 2297-2303 ◽  
Author(s):  
Malika Benkerrou ◽  
Charlotte Delarche ◽  
Lamia Brahimi ◽  
Michèle Fay ◽  
Etienne Vilmer ◽  
...  
Keyword(s):  
Adhesion Molecules ◽  
Sickle Cell ◽  
Adhesion Molecule ◽  
Sickle Cell Anemia ◽  
Plasma Levels ◽  
Polymorphonuclear Neutrophil ◽  
H2o2 Production ◽  
Soluble Adhesion Molecules ◽  
Hydroxyurea Treatment ◽  
History Of

Impaired polymorphonuclear neutrophil (PMN) functions during sickle cell anemia (SCA) may have a pathogenic role in the onset of vasoocclusive events. We used flow cytometry to study, in whole blood, the adhesion molecule expression and respiratory burst of PMNs from children with SCA. Three different clinical groups were studied: (1) patients with no history of vasoocclusive events (n = 15); (2) patients with a history of vasoocclusive events (n = 17); and (3) patients receiving hydroxyurea therapy for severe vasoocclusive events (n = 9). Unstimulated PMNs showed decreased L selectin expression and increased H2O2 production whatever the severity of the disease, reflecting PMN activation. This could contribute to endothelial activation reflected by abnormal plasma levels of soluble adhesion molecules (soluble intercellular adhesion molecule-1, sE selectin, and sL selectin). After stimulation with bacterial N-formyl peptides (N-formyl-methionyl-leucyl-phenylalanine [fMLP]), PMNs from untreated patients with a history of vasoocclusive events showed dysregulated L selectin shedding and increased H2O2 production. Furthermore, in these patients, tumor necrosis factor priming followed by fMLP stimulation induced an H2O2 production significantly higher than in the other patient groups and controls. These impairments could immobilize PMNs on the endothelium, thereby inducing reduced blood flow and fostering microvascular occlusion and vascular damage. In contrast, children treated with hydroxyurea showed near-normal basal and poststimulation H2O2 production as well as normal L selectin shedding after stimulation but no change in plasma levels of soluble adhesion molecules. To our knowledge, this is the first report showing major qualitative changes of PMN abnormalities upon hydroxyurea treatment in SCA patients. This strongly suggests that PMNs are a primary target of this drug.

scholarly journals Optimizing hydroxyurea therapy for sickle cell anemia

Hematology ◽  
2015 ◽  
Vol 2015 (1) ◽  
pp. 436-443 ◽  
Author(s):  
Russell E. Ware
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Fetal Hemoglobin ◽  
Maximum Tolerated Dose ◽  
Sub Saharan Africa ◽  
Future Research ◽  
Published Evidence ◽  
Treatment Indications ◽  
Hydroxyurea Treatment ◽  
Hydroxyurea Therapy

Abstract Hydroxyurea has proven efficacy in numerous clinical trials as a disease-modifying treatment for patients with sickle cell anemia (SCA) but is currently under-used in clinical practice. To improve the effectiveness of hydroxyurea therapy, efforts should be directed toward broadening the clinical treatment indications, optimizing the daily dosage, and emphasizing the benefits of early and extended treatment. Here, various issues related to hydroxyurea treatment are discussed, focusing on both published evidence and clinical experience. Specific guidance is provided regarding important but potentially unfamiliar aspects of hydroxyurea treatment for SCA, such as escalating to maximum tolerated dose, treating in the setting of cerebrovascular disease, switching from chronic transfusions to hydroxyurea, and using serial phlebotomy to alleviate iron overload. Future research directions to optimize hydroxyurea therapy are also discussed, including personalized dosing based on pharmacokinetic modeling, prediction of fetal hemoglobin responses based on pharmacogenomics, and the risks and benefits of hydroxyurea for non-SCA genotypes and during pregnancy/lactation. Another critical initiative is the introduction of hydroxyurea safely and effectively into global regions that have a high disease burden of SCA but limited resources, such as sub-Saharan Africa, the Caribbean, and India. Final considerations emphasize the long-term goal of optimizing hydroxyurea therapy, which is to help treatment become accepted as standard of care for all patients with SCA.

Red Blood Cell Deformability Demonstrated with the Oxygenscan: Exploring the Association with Hydroxyurea Treatment, Co-Inherited α-Thalassemia, and Frequency of Pain in Children with Sickle Cell Anemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4834-4834
Author(s):  
Amina Nardo-Marino ◽  
Jesper Petersen ◽  
Andreas Glenthoej ◽  
John N. Brewin ◽  
Joergen Kurtzhals ◽  
...  
Keyword(s):  
Blood Cell ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Red Blood Cell ◽  
Hemoglobin F ◽  
Positive Correlation ◽  
King's College ◽  
Hydroxyurea Treatment ◽  
Pain Frequency ◽  
Rbc Deformability

Background Sickle hemoglobin (hemoglobin S, HbS) is a structural variant of adult hemoglobin. HbS polymerizes when oxygen tensions are low, leading to red blood cell (RBC) deformation, so-called "sickling". In sickle cell anemia (SCA), loss of RBC deformability is considered to be a primary factor responsible for vaso-occlusion and hemolysis. Until recently no laboratory tests to measure RBC deformability in SCA have been readily available. Study Aims In this study we examine RBC deformability, measured with the oxygenscan module of the Laser Optical Rotational Red Cell Analyzer (Lorrca) ektacytometer, in children with SCA treated with or without hydroxyurea (HU). Furthermore, we investigate the relationship between RBC deformability and pain frequency, as well as genetic and laboratory measures known to be associated with disease severity in SCA. Methods We included children aged 0-16 years with a confirmed diagnosis of SCA (HbSS) from the pediatric sickle cell clinic at King's College Hospital in London. Children were excluded if they had received any blood transfusions within 3 months of study inclusion. Children on HU were only included if treatment had been initiated >3 months prior to recruitment and the dose was stable. Children and their parents or guardians reported frequency of pain as: daily, weekly, monthly, yearly, or never. Laboratory measurements, including total hemoglobin (hb), hemoglobin F (HbF), and reticulocyte percentage, were performed on the same day as a sample was taken for oxygenscan analysis. Data on co-inheritance of α-thalassemia was recorded if available. EDTA blood samples were kept at approximately 4°C and transported from King's College London to Copenhagen University Hospital (Herlev and Gentofte Hospital), where they were analyzed within 48 hours of sampling using the Lorrca oxygenscan (RR Mechatronics, the Netherlands). The oxygenscan measures RBC deformability expressed as an elongation index (EI) during deoxygenation and reoxygenation, with EImax expressing RBC deformability at normal oxygen concentrations, EImin expressing RBC deformability after deoxygenation, and the point of sickling (POS) expressing the point at which >5% decrease in EI is observed, representing the pO2 at which sickling begins. All statistical analyses were performed in Stata V16.0 (StataCorp. 2019, USA), using the two-sided t-test, one-way ANOVA, and Pearson's correlation when appropriate. Results We included 47 children aged 0-16 years (mean age 7.9 years) in the study, 24 (51%) receiving HU. Children in the HU group presented with significantly higher HbF percentage compared to the non-HU group (15.6% and 10.9%, p=0.03). Children receiving HU had higher EImax and EImin, and lower POS values, compared to children in the non-HU group, although results were not significant (Table 1). There was a positive correlation between HbF and EImax (r= 0.57, p=0.0001) and HbF and EImin (r= 0.56, p=0.0001), and a negative correlation between HbF and POS (r=-0.37, p=0.01), as well as a positive correlation between total hb and EImax (r=0.35, p=0.02). There was no significant correlation between any oxygenscan parameters and reticulocyte percentage. Data on α-thalassemia was available for 23 children. EImax and EImin values were higher in heterozygous children compared to children without co-inherited α-thalassemia, and POS values were lower, but results were not significant (Table 2). We found no significant association between any oxygenscan parameters and pain frequency (Table 3). Conclusion In this study we identified a strong correlation between all oxygenscan parameters and HbF percentage, as has been reported previously. We found higher EImax and EImin and lower POS values in children receiving HU treatment and children with co-inherited heterozygous α-thalassemia, suggesting increased RBC deformability in these children. These results were not significant, however, which may in part be due to lack of power in the study. Also, it is possible that children in the HU group would have presented with lower EImax and EImin and higher POS values prior to HU initiation, with treatment response leading to results similar to those found in the non-HU group. Finally, our results suggest that there is no association between oxygenscan parameters and self-reported frequency of pain in children with SCA. Disclosures No relevant conflicts of interest to declare.

Modulation of MicroRNA Expression In Sickle Reticulocytes Is Associated with Hydroxyurea Treatment and Fetal Hemoglobin Induction

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2650-2650
Author(s):  
Aisha L Walker ◽  
Shirley Steward ◽  
Michael Wang ◽  
Matthew P Smeltzer ◽  
Russell E. Ware
Keyword(s):  
Real Time ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Mirna Expression ◽  
Real Time Pcr ◽  
Mixed Model ◽  
Cross Sectional ◽  
Mixed Model Analysis ◽  
Hydroxyurea Treatment ◽  
Hbf Induction

Abstract Abstract 2650 Background: Hydroxyurea has both laboratory and clinical efficacy for children, adolescents, and adults with Sickle Cell Anemia (SCA), and its benefits are primarily due to its ability to increase fetal hemoglobin (HbF). However, HbF induction by hydroxyurea is highly variable among patients, and its mechanism of HbF reactivation remains unclear. MicroRNAs (miRNA) are small non-coding RNAs that can regulate gene expression by inhibiting transcription or translation of targeted proteins. Recently, miRNAs have been implicated in cellular regulation and differentiation including hematopoiesis and hemoglobin switching. In an effort to elucidate the mechanisms behind hydroxyurea-mediated HbF induction, we tested the hypothesis that hydroxyurea modulates miRNA expression in sickle reticulocytes in vivo and this modulation is associated with changes in HbF levels. Methods: As part of the prospective Hydroxyurea Study of Long-term Effects (HUSTLE, NCT00305175), total RNA was purified from CD71+ reticulocytes isolated from the peripheral blood of SCA patients, either prior to hydroxyurea treatment or after reaching stable maximum tolerated dose (MTD); non-SCA adults were included as controls. Initially, differential miRNA expression associated with disease and/or hydroxyurea exposure was determined by microarray and then confirmed by real-time PCR in a cross-sectional analysis of hydroxyurea-treated (n=13) and untreated (n=22) SCA patients, plus controls (n=8). Subsequently to identify hydroxyurea-mediated changes in miRNA expression and its association with HbF induction, miRNA levels were measured by real-time PCR in paired samples collected from patient reticulocytes at baseline and at hydroxyurea MTD (n=41). Statistical correlation to HbF levels used Spearman correlation coefficient and mixed model analysis. Results: Microarray analysis identified 108 miRNAs expressed in CD71+ reticulocytes, 10 of which were significantly different in SCA patients with or without hydroxyurea exposure and normal controls. Real-time PCR confirmed that miRNA expression of human miRNA (hsa-mir) 29a, 130b, 215, and 494 were upregulated, while hsa-mir-223 was downregulated, in untreated SCA patients compared to non SCA controls. Additional analysis of 41 paired samples showed that 3 miRNAs, hsa-mir 148a, 151-3p, and 494, were significantly upregulated with hydroxyurea treatment (Table 1). At MTD, HbF levels increased an average of 17% from a mean of 8.9 ± 6.1% at baseline (range 0.0–22.9%) to a mean of 25.9 ± 9.0% at MTD (range 9.4–55.9%).Significant associations between hsa-mir 26b miRNA expression and HbF levels were identified, both at baseline (rs= -.34; p=0.03) and at MTD (rs= -.32; p=0.04). Using mixed model analysis, change in hsa-mir 151-3p expression was significantly associated with the change in HbF (p=0.047) from baseline to MTD. Conclusion: We identified specific miRNAs that are significantly associated with sickle cell anemia, hydroxyurea treatment, and hydroxyurea-mediated HbF induction. These studies suggest that miRNA regulation, specifically hsa-mir 26b and 151-3p, may be involved in hydroxyurea-mediated HbF induction in patients with sickle cell anemia. Future studies to identify the relevant protein targets may lead to a better understanding of hydroxyurea's mechanisms of action and patient response to the drug including the observed inter-patient variability in HbF response. Results from real-time PCR shows differential miRNA expression in non-SCA controls compared to untreated SCA patients from cross-sectional analysis, and upregulation of 3 miRNAs in SCA patients at baseline compared to MTD from paired-sample analysis. Negative fold change indicates a downregulation. Disclosure: Off Label Use: Hydroxyurea used to treat sickle cell anemia in children. Disclosures: Off Label Use: Hydroxyurea used to treat sickle cell anemia in children.

scholarly journals Shared decision making for hydroxyurea treatment initiation in children with sickle cell anemia

2014 ◽  
Vol 62 (2) ◽  
pp. 184-185 ◽  
Author(s):  
Lori E. Crosby ◽  
Lisa M. Shook ◽  
Russell E. Ware ◽  
William B. Brinkman
Keyword(s):  
Decision Making ◽  
Shared Decision Making ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Treatment Initiation ◽  
Shared Decision ◽  
Hydroxyurea Treatment

scholarly journals Hydroxyurea treatment decreases glomerular hyperfiltration in children with sickle cell anemia

2012 ◽  
Vol 88 (2) ◽  
pp. 116-119 ◽  
Author(s):  
Banu Aygun ◽  
Nicole A. Mortier ◽  
Matthew P. Smeltzer ◽  
Barry L. Shulkin ◽  
Jane S. Hankins ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Glomerular Hyperfiltration ◽  
Hydroxyurea Treatment

scholarly journals Proteomics Pathways of Sickle Cell Anemia (P2SCA): A Comprehensive Analysis By Liquid Chromatography Mass Spectrometry of Erythrocyte Membrane Proteins Characterized from the Muhimbili Sickle Cell Programme, Tanzania

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3653-3653
Author(s):  
Haddy KS Fye ◽  
Paul Mrosso ◽  
Frédéric B Piel ◽  
Simon Davis ◽  
Roman Fischer ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Liquid Chromatography ◽  
Erythrocyte Membrane ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Liquid Chromatography Mass Spectrometry ◽  
Potential Implication ◽  
Chromatography Mass Spectrometry ◽  
Hydroxyurea Treatment ◽  
Significant Difference

Abstract Annually, there are 312 000 births with Sickle Cell Anemia (SCA), which has been recognized as one of the most common inherited conditions in Africa and is currently emerging as a condition of prominence in much of the developed world due to migration patterns. Despite its growing importance, there has been a significant lag in the application of emerging methodologies to its research, in particular to support the discovery of disease-associated markers of potential implication in therapeutics and informing a more comprehensive understanding of the condition. To bring SCA in line with cutting-edge 'omics research, we conducted a study applying advanced mass spectrometry methods for the comprehensive characterization of the protein profiles of erythrocyte membranes. One hundred and twenty participants of confirmed Hemoglobin (Hb) phenotypes HbAA (18), HbAS (21) and HbSS (81) were enrolled from the Muhimbili Sickle Cell Programme in Tanzania. All consented individuals were confirmed to not be on hydroxyurea treatment and not having received a blood transfusion in the preceding 3 months. Whole blood was collected and mixed in 10 ml EDTA vials sent within 72 hours to the Target Discovery Institute (TDI), University of Oxford, UK. Once received, packed erythrocyte fractions were isolated and underwent a series of wash steps followed by erythrocyte lysis and the isolation of the ghost membranes by ultracentrifugation. The ghost cells were then prepared for liquid chromatography mass spectrometry (LCMS) analysis using a novel published method. Proteomics analysis on a Thermo Scientific Q-Exactive High Field MS identified 2,288 membrane or membrane associated proteins of which 1,605 showed significant difference between at least two of the Hb phenotypes with fold changes of up to 22. Specific comparisons identified 1,286 proteins showing significant (p value cut-off, 0.05) changes in expression between the HbAA and HbSS groups; 1,248 between the HbAS and HbSS groups and 278 between the HbAA and HbAS groups. A summary of 30 markers have been presented including a range of proteins of potential therapeutic impact. These were selected based on their ranked significance following statistical analysis, the overall distinction seen between the controls and the HbSS group and the robustness of their identification. The results obtained show significant changes in the presence or absence as well as levels of numerous proteins in the HbSS population compared to controls. This research is a significant contribution to the field of SCA research and forms the foundation to direct further study on the sickle erythrocyte membrane. The large number of proteins identified to be of association to individuals' Hb genotypes represents a significant breakthrough and could contribute to a better understanding of the pathophysiological mechanisms involved in the disease. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

Optimizing hydroxyurea therapy for sickle cell anemia

Hematology ◽  
2015 ◽  
Vol 2015 (1) ◽  
pp. 436-443 ◽  
Author(s):  
Russell E. Ware
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Fetal Hemoglobin ◽  
Maximum Tolerated Dose ◽  
Sub Saharan Africa ◽  
Future Research ◽  
Published Evidence ◽  
Treatment Indications ◽  
Hydroxyurea Treatment ◽  
Hydroxyurea Therapy

Hydroxyurea has proven efficacy in numerous clinical trials as a disease-modifying treatment for patients with sickle cell anemia (SCA) but is currently under-used in clinical practice. To improve the effectiveness of hydroxyurea therapy, efforts should be directed toward broadening the clinical treatment indications, optimizing the daily dosage, and emphasizing the benefits of early and extended treatment. Here, various issues related to hydroxyurea treatment are discussed, focusing on both published evidence and clinical experience. Specific guidance is provided regarding important but potentially unfamiliar aspects of hydroxyurea treatment for SCA, such as escalating to maximum tolerated dose, treating in the setting of cerebrovascular disease, switching from chronic transfusions to hydroxyurea, and using serial phlebotomy to alleviate iron overload. Future research directions to optimize hydroxyurea therapy are also discussed, including personalized dosing based on pharmacokinetic modeling, prediction of fetal hemoglobin responses based on pharmacogenomics, and the risks and benefits of hydroxyurea for non-SCA genotypes and during pregnancy/lactation. Another critical initiative is the introduction of hydroxyurea safely and effectively into global regions that have a high disease burden of SCA but limited resources, such as sub-Saharan Africa, the Caribbean, and India. Final considerations emphasize the long-term goal of optimizing hydroxyurea therapy, which is to help treatment become accepted as standard of care for all patients with SCA.

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