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Key Points Cardiac abnormalities in children and young adults with sickle cell anemia are common.Timely initiation of treatment with hydroxyurea may lead to reverse cardiac remodeling and improvement in these cardiac abnormalities., Visual Abstract, Cardiac abnormalities such as left ventricular hypertrophy, left ventricular dilation, and pulmonary hypertension in sickle cell anemia have been previously described. Hydroxyurea, a disease-modifying therapy for sickle cell anemia, has been used for several decades. Longitudinal assessment of echocardiographic abnormalities in children and young adults with sickle cell anemia receiving hydroxyurea therapy is lacking. The goal of this retrospective study was to determine the prevalence of echocardiographic abnormalities in children and young adults with sickle cell anemia and to examine the effects of hydroxyurea on reverse cardiac remodeling. We reviewed the records of patients with sickle cell anemia who underwent routine cardiac screening at Cohen Children’s Medical Center between 2010 and 2017, followed by retrospective longitudinal analysis of echocardiograms performed on patients receiving treatment with hydroxyurea. Data on a total of 100 patients with sickle cell anemia were analyzed; 60 (60%) were being treated with hydroxyurea. Twenty-five (41.6%) of the patients on hydroxyurea had been treated for 1 year. Serial echocardiograms of patients receiving hydroxyurea were then analyzed. Left ventricular dilation and hypertrophy improved significantly with hydroxyurea treatment. In addition, the left ventricular volume and mass correlated negatively with duration of treatment with hydroxyurea. Our study provides evidence that prolonged hydroxyurea therapy may lead to reverse cardiac remodeling. Future studies should attempt to follow up this patient cohort for a longer duration.

We previously found that neurodevelopmental deficits commonly occurred in three-year-olds with sickle cell disease (SCD), but clinical significance was uncertain because a comparison group was lacking. Our objective in the current study was to prospectively compare neurodevelopment in three-year-old children with SCD to an age-appropriate control group. The Brigance Preschool Screen II is a neurodevelopmental screening examination which can be administered in 15-20 min. SCD patients (Group 1) were compared with community controls of similar age and ethnicity enrolled in daycare/preschool (Group 2). SCD patients who were receiving hydroxycarbamide treatment were also compared (Group 3). Two hundred forty-five three-year-olds were evaluated: Group 1, 111; Group 2, 114; and Group 3, 20. The below cut-off rate on the Brigance test was higher in Group 1 (73%) than in Group 2 (61%; P = 0·04). In multivariate analysis of Group 1 patients, only lower household income and more persons living in the home were independent predictors of this. Patients with SCD and matched controls had high rates of 'failing' the Brigance test. The below cut-off rate in untreated children with SCD was associated with low household income and increased number of persons living in the home.

Patients with sickle cell disease (SCD) are living longer and subsequently more apt to develop cardiopulmonary dysfunction. N-terminal pro-brain natriuretic peptide (NT-proBNP) levels have been used in adults with SCD to assess for pulmonary hypertension and mortality. While the incidence of PH is low in pediatrics, it is reasonable to presume that NT-proBNP levels can be used to assess risk for the development of cardiopulmonary morbidity. We hypothesized that NT-proBNP levels would be increased in patients with SCD compared to age-adjusted healthy children; additionally, these levels would be associated with labs indicative of hemolysis and would demonstrate evidence of obstructive lung disease and cardiac dysfunction. We retrospectively evaluated patients with SCD, 8-18 years old, at a large, tertiary care children's hospital. NT-proBNP levels were assessed in correlation with hemolytic lab work, spirometry, and echocardiographic data. The age group 8-14 years old, 75% of our cohort's population, had a median NT-proBNP of 70 pg/ml, greater than their age-adjusted counterparts (52 pg/ml). NT-proBNP levels were associated with an increased degree of hemolysis when compared with hemoglobin (Hb) (r = -0.43, p < .0001), reticulocyte count (r = .25, p = .01) and lactate dehydrogenase levels (r = .47, p < .0001). An inverse trend was found between NT-proBNP and spirometric data. Finally, a positive correlation was found between NT-proBNP and diastolic left ventricular size (r = .28, p = .047]. The correlations found suggest that NT-proBNP may be used prospectively to identify patients with SCD at increased risk for the development of cardiopulmonary dysfunction.

Adults infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have had high rates of thrombosis. A novel condition in children infected with SARS-CoV-2, multisystem inflammatory syndrome in children (MIS-C), has limited data on their prothrombotic state or need for thromboprophylaxis.We aimed to analyze the prothrombotic state using coagulation profiles, rotational thromboelastometry (ROTEM) parameters and clinical outcomes, to determine if this could aid in risk stratification for thromboprophylaxis.This analysis included patients (21 years of age) with a diagnosis of MIS-C (n = 40) and controls (presenting with suspicion of MIS-C but later ruled out; n = 26).MIS-C patients had higher levels of inflammatory markers including D-dimer (p .0001), compared with controls, along with evidence of hypercoagulability on ROTEM with elevated evaluation of fibrinogen activity (FIBTEM) maximum clot firmness (MCF) (p .05). For MIS-C patients with D-dimers1000 ng/ml, there was a significant correlation of FIBTEM MCF (p .0001) with a mean value of 37.4 (standard deviation 5.1). D-dimer2144 ng/ml was predictive of intensive care unit admission (area under the curve [AUC] 0.80; 95% confidence interval, 0.60-0.99; p .01; sensitivity: 82%, specificity: 75%), and elevated FIBTEM MCF (AUC 1 for2500 ng/ml). MIS-C patients (50%) received enoxaparin thromboprophylaxis (in addition to aspirin) with significant improvement in their inflammatory and ROTEM parameters upon outpatient follow-up; none developed symptomatic thrombosis.Despite an observed prothrombotic state, none of the MIS-C patients (on aspirin alone or in combination with enoxaparin) developed symptomatic thrombosis. ROTEM, in addition to coagulation profiles, may be helpful to tailor thromboprophylaxis in critically ill MIS-C patients.

Introduction: Youth with sickle cell disease (SCD) and their families are susceptible to stress and depression associated with chronic illness and social factors disproportionately affecting under-resourced U.S. communities. The COVID-19 pandemic has adversely impacted psychosocial and economic well-being, especially in some of these same communities. Our concurrent HABIT multi-site randomized trial aims to improve hydroxyurea adherence in youth with SCD ages 10-18 years through an intervention led by community health workers(NCT03462511). Subjects enrolled as youth-primary caretaker dyads; adults were mostly parents. We hypothesized that some HABIT subjects had depressive symptoms at baseline, and many had additional stressors during the pandemic. Methods: Two self-reported assessment tools were used, with options of English or Spanish: 1) PROMIS® pediatric (8a, v1.0) or adult (4a, v1.0) depression measures, completed at HABIT enrollment, nearly all between May 2018 - March 2020 ("baseline"); 2) A pandemic-related open-access survey originated by Johns Hopkins University on established core adult mental health assessed risks and behaviors.[1] Questions were closely adapted for use by youth. The pandemic survey assessed recent mental health symptoms and substance or domestic abuse. Two validated food insecurity screening questions were added.[2] Of 92 HABIT subjects, 84 were offered survey participation between May - July, 2020. Participants completed both assessment tools via electronic linkage to REDCap data capture. Analyses used chi square or Fisher exact test. Results: In all, 75% (63 of 84) responded to the pandemic survey; 31 were youth-parent dyads and one unpaired parent. Baseline demographics were: Youth (N=31): mean age 12.9±1.9 years, 48.4% female, 80.6% grade 6-12, 45.3% hospitalized within the prior 12 months; Caretakers (N=32): mean age 44.0±9.6 years, 87.5% Black, 18.8% Latinx, 37.50% married or living with a partner, 59.4% with at least some college education. At baseline, youth mean PROMIS® Depression T-Score was 49.9±10.1 (normal Conclusions: In this sample of subjects from the HABIT Trial, at baseline a higher proportion of youth had depressive symptoms compare to their primary caretakers. During the initial pandemic peak in the Northeast, disrupted work arrangements and especially school cancellation were widespread. Fewer youth but similar proportions of caretakers reported feeling depressed and/or anxious. Both groups commonly reported loneliness or not feeling hopeful for the future. History of mental health conditions, current substance use/abuse or verbal abuse were uncommon. Concordant with concerns for under-resourced communities, a sizeable minority of families reported food insecurity. Under the limitations of using 2 different assessment tools, in this modest sample the majority of youth with SCD but not caretakers were mildly-moderately depressed at baseline and that, during the pandemic, the 2 groups reported similar proportions of mental health symptoms. These findings suggest that screening for mental health symptoms, social disruption and food insecurity may be warranted in this high-risk group overall and during the pandemic. References: 1) COVID-19 and mental health measurement working group, Johns Hopkins Bloomberg School of Public Health, March 18, 2020 2) Barnidge E., et al., Screening for Food Insecurity in Pediatric Clinical Settings. J. Community Health 42(1):51-57, 2017 The HABIT Trial is supported by 5R01NR017206-04 (Green, Smaldone). The authors have no conflicts to disclose. Disclosures Smith-Whitley: Novartis: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Prime: Other: Education material; Celgene: Membership on an entity's Board of Directors or advisory committees. Aygun:bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; National Institute of Nursing Research: Research Funding; Patient-Centered Outsomes Research Institute: Research Funding; National Heart, Lung, and Blood Institute: Research Funding.

The coagulopathy of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is well documented in adults, with increases in D-dimer and prothrombin time found to be strong predictors of mortality, and anticoagulation shown to decrease this mortality. Viscoelastic parameters such as elevations in maximum clot firmness (MCF) on rotational thromboelastometry (ROTEM) have correlated with a hypercoagulable state in adults with SARS-CoV-2. We report our experience in children infected with SARS-CoV-2, with noted elevations in D-dimer and MCF on ROTEM (indicating hypercoagulability). Exploration of viscoelastic testing to provide additional laboratory-based evidence for pediatric-specific risk assessment for thromboprophylaxis in SARS-CoV-2 is warranted.

Background The Spectra Optia allows automated performance of red blood cell reduction and isovolemic hemodilution (IHD) prior to standard red cell exchange (RCE), and is primarily intended for patients with sickle cell disease (SCD) undergoing chronic RCE. Data on the safety of inducing transient further anemia and the benefits of IHD-RCE is limited and occasionally contradictory. Study design and methods In this retrospective crossover analysis of six patients with SCD who underwent chronic exchange with standard RCE (Cobe Spectra) followed by IHD-RCE (Spectra Optia), we compared safety and benefit outcomes with IHD-RCE vs standard RCE. Results There were statistically but not clinically significant drops in blood pressure in the post-IHD phase. With IHD-RCE, there were significant reductions in red blood cell (RBC) usage and/or lower fraction of cells and significant increases in postprocedure hematocrit (Hct) associated with increased preprocedure Hct. There were no differences achieved in the time interval between procedures or in the net RBC gain with IHD-RCE. Overall, there were also no significant differences in pre- and postprocedure percentage of hemoglobin S, reticulocyte count, interval daily hemoglobin A decrement, or postprocedure white blood cell, neutrophil, or platelet counts. Conclusions Our study supports that IHD-RCE can be safely used in patients with stroke risk and compared to standard RCE, results in benefits of lower RBC usage and/or fraction of cells remaining and higher postprocedure Hct associated with higher preprocedure Hct. These findings support wider use of IHD-RCE, especially in the current environment with reduced availability of minority units.

Background Children with sickle cell disease (SCD) are at risk for neurocognitive deficits, which can lead to effects on academic performance and later job attainment. However, screening in children at high risk for poor academic performance (PAP) in a clinic setting has been limited. The goal was to identify young children with SCD at high risk for PAP via administration of a standardized screening tool at the clinic visit. Procedure Parents of 20 patients were asked to complete the Behavior Assessment System for Children, 3rd edition (BASC-3) Parent Rating Scale. Children ages six to nine years and all SCD genotypes were included. Those patients who scored at least 1 standard deviation below the mean were considered high risk. Statistics was used to associate demographic, academic, and laboratory data with risk status (RS). Results Four of 20 patients (20%) were found to be at risk by the BASC-3. A significant association was found between those with a history of PAP and RS (P = 0.001). A trend toward association was found between baseline hemoglobin, reticulocyte count, and RS. Children not at risk had a higher hemoglobin level and lower reticulocyte count (P = 0.37 and P = 0.20, respectively). Those on hydroxyurea were significantly less likely to score as at risk (P = 0.014), whereas those with siblings may be at greater risk (P = 0.037). Conclusion(s) A parent-directed screening tool may identify children with SCD in need of additional school support. Further prospective studies are necessary to understand correlations found between hemoglobin, reticulocyte count, and hydroxyurea treatment and risk for PAP.

The aim of the study was to reveal the prevalence of concomitant endometriosis in malignant and borderline ovarian tumours. A retrospective analysis was performed of 530 patients with malignant ovarian tumours and 131 with borderline ovarian tumours, who underwent surgery in our hospital between 1995 and 2011. Forty-eight (7.3%) of 661 patients with malignant and borderline ovarian tumours were associated with endometriosis. Of the 48 endometriosis cases, 73% of those were atypical. Infertility was noted in 38% of patients with endometriosis-associated ovarian tumours. The most frequently endometriosis-associated subtypes were endometrioid (33%) and clear cell (18%) histologies. Of endometriosis-associated endometrioid and clear cell ovarian tumours, 70% were early stage and 60% were premenopausal. The prevalence of concomitant endometriosis in borderline tumours (12%) was found to be significantly higher than that found in the malignant ones (6%; p = .02). Of 32 endometriosis-associated malignant ovarian tumours, 69% were FIGO stages I and II. In conclusion, ovarian endometriosis is seen with both malignant and borderline ovarian tumours, the association being significant with borderline tumours. Fortunately, the endometriosis-associated malignant ovarian tumours are mostly early stage. Impact statement What is already known on this subject? Epidemiologic data suggest that endometriosis has malignant potential. However, a subgroup of women with endometriosis at a high risk for ovarian cancer is yet to be clarified. Currently, endometriosis and ovarian cancer association does not seem to have a clinical implication. What do the results of this study add? The findings of this study revealed that nearly 75% of endometriosis-associated ovarian tumours were of atypical endometriosis. Half of endometriosis-associated ovarian tumour cases were of endometrioid/clear cell histology and 70% were early-stage. Endometriosis was significantly associated with borderline ovarian tumours and the endometriosis-associated malignant ovarian tumours were mostly early stage. What are the implications of these findings for clinical practice and/or further research? Additional studies need to be conducted to develop screening approaches for malignant transformation or an association in women with endometriosis. Till that time, a change of current clinical practices cannot be justified. However, counselling and treating women with endometriosis who are at high risk for cancer coexistence or conversion is encouraged.

Background: Sickle cell disease (SCD) is characterized by painful vaso-occlusive events (VOEs), progressive vasculopathy, hemolytic anemia, and organ damage resulting in frequent hospitalizations and decreased quality of life (QoL). The ongoing phase 1/2 HGB-206 study is evaluating the efficacy and safety of LentiGlobin for SCD (bb1111) gene therapy and has demonstrated complete resolution of severe VOEs, near-normalization of key hemolysis markers, and normalization of total hemoglobin up to 24 months post-LentiGlobin infusion in Group C. In addition, LentiGlobin for SCD also showed clinically meaningful improvements in QoL in adult patients. Here we present patient-reported QoL outcomes up to 24 months post-LentiGlobin infusion in Group C of the HGB-206 study. Methods: Patients (≥12-≤50 years of age) with severe SCD and recurrent severe VOEs underwent plerixafor mobilization and apheresis followed by myeloablative busulfan conditioning and LentiGlobin infusion. In addition to laboratory and clinical assessments, patients were monitored for patient-reported outcomes (PROs) at baseline and every 6 months post-infusion through Month 24 using PRO Measurement Information System (PROMIS)-57, a QoL-monitoring tool that has been validated in SCD. PROMIS-57 uses a collection of short forms to assess 7 PROMIS domains of relevance to patients' physical, mental, and social wellbeing (Depression, Anxiety, Pain Interference, Fatigue, Sleep Disturbance, Physical Function, Satisfaction with Participation in Social Roles) as well as a 0-10 Pain Intensity numeric rating scale (NRS). Available data were analyzed for 25/35 Group C patients (median age: 25 [19-38]; 40% female) who completed PROMIS-57 assessments at baseline with up to 24 months of follow-up as of February 17, 2021. For each domain, patients from the overall population were stratified into 2 subgroups depending on whether their baseline score was "better or near" or "worse" than the population norm, to account for potential differences over time in QoL changes relative to baseline status, and their means and standard deviations were plotted over time. The US general population norm is a standardized T-score of 50 for all domains and a 2.6 for Pain Intensity NRS. Meaningful change, a minimal response deemed meaningful to the patient, was interpreted at group level as at least a 5-point change from baseline for domains and a 2-point change for the NRS, as based on PROMIS guidelines and published literature. Results: In general, patients with baseline scores "worse" than the population norm reported improvements in all domains at Month 6 up to Month 24. Of note, mean pain interference decreased from 64.2 (n=16) to 44.5 (n=5), pain intensity decreased from 6.5 (n=15) to 1.8 (n=5) from baseline to Month 24 and fatigue decreased from 64.6 (n=8) to 46.9 (n=1) from baseline to Month 18, respectively (Figure). In patients with baseline scores "better or near" population norm, scores generally remained stable through Month 24. For example, mean pain interference scores were 46.4 (n=8) and 45.9 (n=4), pain intensity scores were 2.0 (n=9) and 2.8 (n=4), and fatigue scores were 47.7 (n=16) and 43.4 (n=9) at baseline and last visit, respectively. When considering mean differences, values for patients overall showed meaningful change in all domains and the Pain Intensity NRS, with the exception of Anxiety. Expected variability due to the small sample size limits interpretation. Mean values over time will be presented for all domains. Summary: In Group C of the HGB-206 study, patients with baseline scores "worse" than population norm had improved scores across all PROMIS-57 domains that were established early post-infusion and sustained up to Month 24. Patients with baseline scores "better or near" population norm were stable, and not worse up to Month 24. Mean values for patients overall indicate meaningful change at latest follow-up for all domains and Pain Intensity NRS, with the exception of Anxiety. These data show LentiGlobin for SCD not only improved hematologic parameters and resulted in complete resolution of severe VOEs, as presented elsewhere, but also provide sustained and clinically meaningful QoL benefit for patients. Continued follow-up and analysis of patient-reported outcomes is needed to evaluate the long-term impact of LentiGlobin for SCD. Figure 1 Figure 1. Disclosures Walters: Vertex pharmaceuticals: Consultancy; BioLabs, Inc: Consultancy; Ensoma, Inc.: Consultancy; AllCells, Inc: Consultancy. Kwiatkowski: Silence Therapeutics: Consultancy; Sangamo: Research Funding; Bioverativ: Research Funding; Apopharma: Research Funding; Bristol Myers Squibb: Consultancy; Imara: Consultancy, Research Funding; Celgene: Consultancy; Agios: Consultancy; bluebird bio,Inc.: Consultancy, Research Funding. Aygun: Patient Centered Outcomes Research Institute: Research Funding; bluebird bio, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; National Heart, Lung, Blood Institute: Research Funding; National Institute of Nursing Research: Research Funding; Global Blood Therapeutics: Consultancy. Gallagher: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Zhang: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Ho: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Thompson: Graphite Bio: Research Funding; Agios: Consultancy; Novartis: Research Funding; Global Blood Therapeutics: Current equity holder in publicly-traded company; Beam: Consultancy; CRISPR Therapeutics: Research Funding; Celgene/BMS: Consultancy, Research Funding; Biomarin: Research Funding; Baxalta: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Vertex: Research Funding; Editas: Research Funding. Kanter: Fulcrum Therapeutics, Inc.: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Forma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beam: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Graphite Bio: Consultancy; GuidePoint Global: Honoraria; Fulcrum Tx: Consultancy.

Background: The ongoing Phase 1/2 HGB-206 study (NCT02140554) of LentiGlobin for SCD (bb1111) GT uses a modified human β-globin gene that expresses an anti-sickling hemoglobin (HbA T87Q). The relationships between biological outcomes, clinical outcomes, and clonality in the initial cohort (Group A) and the cohort treated after substantial changes were made to the study protocol and manufacturing process to improve clinical benefit (Group C) are presented here. Methods: Patients (pts; ≥18 in Group A and ≥12-≤50 yrs in Group C) with SCD and recurrent severe vaso-occlusive events (VOEs), overt stroke, or tricuspid regurgitant jet velocity of >2.5 m/s, were enrolled. The initial protocol (cell collection and target busulfan dose) and manufacturing process in Group A was modified to improve cell dose, transduction efficiency, HbA T87Q expression, and clinical benefit. CD34+ cells (collected by bone marrow [BM] harvesting in Group A and plerixafor mobilization/apheresis in Group C) were transduced with BB305 lentiviral vector (LVV). LentiGlobin was infused after myeloablative busulfan conditioning. Transduction, SCD-related outcomes, clonality, and safety were assessed; data are median (min-max) unless otherwise stated. Results: As of 17 February 2021, there were 61.5 (55.5-66.1) months of follow-up post-LentiGlobin infusion in Group A (n=7) and 17.3 (3.7-37.6) months in Group C (n=35). After protocol and manufacturing modifications, median drug product vector copy number (DP VCN) and transduction efficiency were increased in Group C (3.7 c/dg with 80.3% transduced cells) compared with Group A (0.6 c/dg with 27.7% transduced cells). Peripheral blood (PB) VCN stabilized by Month 6 post-infusion and was sustained throughout follow up in both groups; however, the median PB VCN was correspondingly higher in Group C than in Group A (1.45 c/dg vs 0.09 c/dg). A higher DP VCN, %LVV+, and PB VCN in Group C generated increased HbA T87Q of 5.2 (2.6-8.8) g/dL (n=30) compared with HbA T87Q of 0.5 (0.1-1.8) g/dL (n=7) in Group A at Month 6. This was associated with near pancellular expression of HbA T87Q at ≥6 months post-infusion in Group C with a mean of 87% of red blood cells containing β A-T87Q by 18 months (n=14). Group C featured significantly higher median unique insertion sites (UIS) than Group A (p = 1.43 x 10 -12;Fig 1), consistent with increased polyclonality. Critically, median UIS also correlated strongly with PB VCN (Spearman rho = 0.97; Fig 1) and HbA T87Q at Month 6 post-infusion and was associated with improved clinical efficacy in Group C, with complete resolution of severe VOEs and near normal levels of key hemolysis markers. In Group C, the only treatment (tx) emergent serious adverse events (TESAEs) reported in >1 pt were abdominal pain, nausea, opioid withdrawal syndrome, and vomiting (n=2, 5.7% each). No events of malignancy were reported in Group C. One event of sudden death, considered unlikely related to LentiGlobin, occurred >18 months post-tx in a patient with significant baseline SCD-related cardiopulmonary disease. In Group A, the most common TESAE was sickle cell anemia with crisis (n=4, 57%). Two events of acute myeloid leukemia (AML) were reported in Group A pts at 3 and 5 years post-tx, both of which were considered unlikely related to the LVV. Both pts had classic AML driver mutations identified post-diagnosis. One pt died of AML and the second pt is receiving therapy for AML. The modifications made in Group C are anticipated to reduce risk of AML. To monitor safety, BM and PB will be screened for the presence of AML driver mutations prior to treatment, and patients already treated will have regular cytogenetic screening in addition to BB305 LVV integration site analysis. Summary: Alterations to the protocol and manufacturing process in HGB-206 resulted in improved cell dose, transduction efficiency, HbA T87Q expression, and clinical outcomes in Group C compared with Group A. Polyclonality was strongly correlated to PB VCN and HbA T87Q production, indicating that superior engraftment of LVV-transduced cells leads to favorable clinical outcomes. The safety profile post-LentiGlobin for all treated patients with SCD remains generally consistent with the risks of autologous stem cell transplant, myeloablative busulfan conditioning, and underlying SCD. Figure 1 Figure 1. Disclosures Thompson: Baxalta: Research Funding; Biomarin: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; CRISPR Therapeutics: Research Funding; Vertex: Research Funding; Editas: Research Funding; Graphite Bio: Research Funding; Novartis: Research Funding; Agios: Consultancy; Beam: Consultancy; Global Blood Therapeutics: Current equity holder in publicly-traded company. Kwiatkowski: Bluebird Bio: Other: Consultancy Fees; Imara: Other: Consultancy Fees; Celgene: Honoraria; Silence Therapeutics: Honoraria; Agios: Honoraria; ApoPharma: Research Funding; Novartis: Research Funding; Bluebird Bio: Research Funding; Sangamo: Research Funding; Terumo BCT: Research Funding. Aygun: National Heart, Lung, Blood Institute: Research Funding; Global Blood Therapeutics: Consultancy; National Institute of Nursing Research: Research Funding; Patient Centered Outcomes Research Institute: Research Funding; bluebird bio, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Schmidt: GeneWerk GmbH, Heidelberg, Germany: Current equity holder in publicly-traded company; German Cancer Research Center, Heidelberg, Germany: Current Employment. Pierciey: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Whitney: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Rogers: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Nnamani: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Foos: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Miller: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Zhang: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Lynch: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Walters: Vertex pharmaceuticals: Consultancy; Ensoma, Inc.: Consultancy; BioLabs, Inc: Consultancy; AllCells, Inc: Consultancy. Kanter: Fulcrum Therapeutics, Inc.: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Forma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beam: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Graphite Bio: Consultancy; GuidePoint Global: Honoraria; Fulcrum Tx: Consultancy. Bonner: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company.

Hydroxyurea has proven clinical benefits and is recommended to be offered to all children with sickle cell anemia (SCA), but the optimal dosing regimen remains controversial. Induction of red blood cell fetal hemoglobin (HbF) by hydroxyurea appears to be dose-dependent. However, it is unknown whether maximizing HbF% improves clinical outcomes. HUSTLE (NCT00305175) is a prospective observational study with a primary goal of describing the long-term clinical effects of hydroxyurea escalated to maximal tolerated dose (MTD) in children with SCA. In 230 children, providing 610 patient-years of follow up, the mean attained HbF% at MTD was >20% for up to 4 years of follow-up. When HbF% values were ≤20%, children had twice the odds of hospitalization for any reason (p20% was associated with fewer hospitalizations without significant toxicity. These data support the use of hydroxyurea in children, and suggest that the preferred dosing strategy is one that targets a HbF endpoint >20%.

Introduction: Transcranial Doppler (TCD) screening data from Uganda, Tanzania, and Nigeria have documented elevated velocities in >20% of children with sickle cell anemia (SCA) not receiving hydroxyurea treatment. Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) has demonstrated the safety, feasibility, and benefits of hydroxyurea for children with SCA living in sub-Saharan Africa, especially when escalated to maximum tolerated dose (MTD). Whether hydroxyurea also confers protection against stroke risk in this setting remains unproven, though hydroxyurea-associated increases in hemoglobin and fetal hemoglobin, plus decreases in TCD arterial flow velocities, should lower the risk of both primary and secondary stroke. The availability of TCD equipment and appropriately trained and certified TCD examiners to perform this non-invasive and inexpensive procedure is an important limitation in low-resource settings. Methods: REACH teams in Angola, Democratic Republic of Congo, Kenya, and Uganda identified two local persons at each site to receive formal TCD training and certification from two experienced and certified super-users, one from Uganda and one from the US. Initial training included hands-on teaching at each site by the Ugandan trainer, followed by didactic teaching and hands-on examinations at a central African location with both trainers and all four REACH teams. Follow-up training included monthly web-based teaching sessions of TCD technique and discussion of centrally reviewed exams. Each local examiner had at least 30 completed examinations reviewed, critiqued, and discussed together with the trainers before becoming formally certified as a REACH TCD examiner. After certification, all REACH participants taking hydroxyurea at a stable dose were eligible for TCD using a standardized protocol with identical Sonara/tek advanced non-imaging TCD ultrasound units with 2MHz probes and version 7 software (Natus, Middleton, WI). Time-averaged maximum velocities (TAMV) were measured in the middle cerebral artery, distal internal carotid artery, and the bifurcation. The highest TAMV was recorded and categorized as normal ( Results: Between November 2018 and March 2020, a total of 481 children in REACH received TCD screening; the average age was 9.3 ± 2.6 years, on hydroxyurea for 43 ± 8 months at an average dose of 23.5 ± 5.0 mg/kg/day with good response (Hb = 8.4 ± 1.3 g/dL, HbF = 23.9 ± 5.0%). There were 16 (3.3%) inadequate exams, defined as no vessel flow in either hemisphere; 5 inadequate exams were in children with prior stroke at hydroxyurea initiation and 1 with stroke on treatment. Of 465 adequate exams, the overall median TAMV was 128 cm/sec (IQR 25 cm/sec) with 449 normal velocities (96.6% overall, range by site 95.1-99.2%), 16 conditional velocities (3.4% overall, range by site 2.3-4.9%), and no abnormal velocities. In univariate analysis, maximum TAMV was inversely correlated with hemoglobin (r = -0.29, p Conclusions: Robust TCD screening capability was developed in REACH with detailed training, certification, and oversight of local personnel, most of whom had no prior experience. Compared to untreated children, very few REACH participants had elevated TAMV velocities, confirming that hydroxyurea lowers TCD velocities and reduces stroke risk for children with SCA in sub-Saharan Africa. The observed associations between TAMV and both hemoglobin and fetal hemoglobin document the importance of escalating hydroxyurea to achieve and maintain an optimized dose. In low-resource settings, TCD screening efforts by trained and certified examiners should be aligned with hydroxyurea treatment protocols that feature dose escalation, to provide a feasible and effective stroke prevention program. TCD screening of African children with SCA will allow early identification of stroke risk and optimized hydroxyurea dosing, thereby reducing morbidity and mortality in this vulnerable population. Disclosures Aygun: National Heart, Lung, and Blood Institute: Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; Patient-Centered Outsomes Research Institute: Research Funding; National Institute of Nursing Research: Research Funding.

Introduction: Hydroxyurea is a potent therapeutic agent for sickle cell anemia (SCA), and treatment at maximum tolerated dose (MTD) is becoming the standard of care. Hydroxyurea exerts its disease-modifying effects primarily through induction of fetal hemoglobin (HbF), although the cellular and molecular mechanisms by which hydroxyurea increases HbF expression remain unclear. Children with SCA treated with hydroxyurea at MTD have substantial phenotypic variation, however, as some have higher HbF responses than others. We hypothesized that unknown quantitative trait loci modulate the pharmacological induction of HbF, so we performed a large genome wide association study (GWAS) of hydroxyurea-associated HbF responses for children with SCA treated prospectively with dose escalation to MTD. Methods: We analyzed genomic DNA from 831 children with SCA enrolled in pediatric research trials from the US (HUSTLE, SWiTCH, TWiTCH), the Caribbean (EXTEND, SACRED) and sub-Saharan Africa (REACH, NOHARM); all of these trials reported robust treatment responses with average HbF >20%. Study participants received hydroxyurea with dose escalation to MTD based on mild myelosuppression. Whole blood DNA was genotyped using the H3Africa SNP array (Illumina) with whole exome sequencing (WES) using NimbleGen VCRome 2.1 capture reagents and the Illumina HiSeq2500 platform. A transformed z-score for each study cohort gave a standardized measure of HbF induction relative to their steady-state level and their treatment HbF level at MTD. These standardized z-score HbF values were then used as a continuous variable for association testing using single-locus mixed model (EMMAX) adjusted for population stratification, using age, hydroxyurea dose at MTD, and sex as co-variates. We first performed an initial GWAS discovery using hydroxyurea response data from four distinct African populations (n=377). Single nucleotide variants (SNVs) with nominal significance (p Results: In the discovery GWAS step, no variant passed genome wide significance (p Conclusions: This large GWAS using global cohorts of children with SCA and robust prospective HbF phenotype data has identified genetic predictors of HbF hydroxyurea treatment responses. Three novel genetic loci, PTPRD, RPH3AL, and ELL2 have SNVs associated with lower HbF responses. PTPRD is a protein tyrosine phosphatase receptor involved in cellular processes such as cell growth and differentiation, while RPH3AL, a rabphilin 3A like protein, is known to be involved in calcium-ion-dependent exocytosis. ELL2 is an elongation factor for RNA polymerase II and could modify RNA processing under the cytostatic effects of hydroxyurea. These genes and variants will be investigated to determine how they impact individual HbF responses to hydroxyurea treatment. Disclosures Aygun: National Heart, Lung, and Blood Institute: Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; National Institute of Nursing Research: Research Funding; Patient-Centered Outsomes Research Institute: Research Funding.

Background Sickle cell disease (SCD) is caused by abnormal sickle hemoglobin (HbS) and results in chronic hemolytic anemia, painful vaso-occlusive events (VOEs), and progressive vasculopathy that lead to significant morbidity. While acute vaso-occlusive pain is a defining clinical feature, chronic daily pain also contributes significantly to poor quality of life in many adult patients. The ongoing Phase 1/2 HGB-206 Study (NCT02140554) evaluating safety and efficacy of LentiGlobin for SCD (bb1111) gene therapy (GT) uses a modified human β-globin gene that produces GT-derived anti-sickling hemoglobin (HbAT87Q). Data from Group C patients including red blood cell (RBC) physiology, clinical outcomes, and patient-reported pain intensity are presented here. Methods Patients (≥12 and ≤50 years) with SCD and stroke or severe VOEs, including acute episodes of pain and acute chest syndrome (ACS), were enrolled. CD34+ cells collected by plerixafor mobilization/apheresis were transduced with BB305 lentiviral vector. LentiGlobin was infused following myeloablative busulfan conditioning. Patients were monitored for laboratory evaluations including Hb levels and hemolysis markers, SCD-related outcomes, pain intensity using the Patient Reported Outcomes Measurement Information System (PROMIS)-57, and adverse events (AEs). Data are median (min-max) unless otherwise stated. Results As of 3 March 2020, 40 Group C patients (23.5 [12-38] years) initiated cell collection; 25/40 were treated with LentiGlobin and followed for 12.1 (2.8-24.8) months. Neutrophil and platelet engraftment were achieved at 19 (12-27) days and 28 (19-136) days, respectively. All patients stopped RBC transfusions by 90 days post-treatment. In 16 evaluable patients with ≥6 months of follow-up, total Hb at last visit was 11.5 (9.6-16.2) g/dL, with HbAT87Q contribution of 5.2 (2.7-9.4) g/dL, HbS of 6.1 (4.9-7.8) g/dL, and median HbS ≤ 60% of total Hb. Exploratory assays showed near pancellular expression of HbAT87Q ≥6 months post-treatment (N=9 patients), with ~90% of RBCs containing βA-T87Q by 18 months, and reduction in sickling propensity comparable to sickle cell trait. At last visit post-treatment, key hemolysis markers were trending towards normalization with median (quartile [Q]1-Q3) lactate dehydrogenase of 212 (201-287) U/L, reticulocyte count of 178 (146.5-236.3) ×109/L, and total bilirubin of 19 (15.4-27.4) µmol/L (all for n=25). In 14 patients with ≥6 months of follow-up and history of vaso-occlusive crisis (VOC) or ACS, the annualized VOC+ACS rate was 4.0 (2.0-14.0) in the 2 years prior to treatment. Post-treatment, no ACS or serious VOCs were observed in these patients. One non-serious Grade 2 VOC occurred ~3.5 months after LentiGlobin infusion, resulting in a 99.5% (95% confidence interval, 92.4%-100%) mean reduction in the annualized VOC+ACS rate post-treatment (Figure 1). Patients with PROMIS-57 pain intensity scores "worse" than the population norm at baseline reported clinically meaningful improvements in pain reduction at 12 months post-treatment (n=5). Patients with scores near or "better" than the population norm at baseline (n=5) remained stable over time (Figure 2). The most common non-hematologic Grade ≥3 AEs post-treatment were stomatitis (n=15) and febrile neutropenia (n=11). Serious AEs reported in ≥2 patients post-treatment were nausea, opioid withdrawal syndrome, and vomiting (all for n=2); 3 patients had LentiGlobin-related nonserious Grade ≤2 AEs. There has been one death, unlikely related to LentiGlobin, >18 months post-treatment in a patient with significant baseline SCD-related cardiopulmonary disease. There have been no events of graft failure, vector-mediated replication-competent lentivirus, or clonal dominance. Summary LentiGlobin for SCD GT results in near pancellular βA-T87Q expression and reduced HbS expression, which impacts the pathophysiology of SCD as demonstrated by reduced RBC sickling and hemolysis and increased total Hb. Complete resolution of VOC/ACS was observed in almost all patients, with 99.5% mean reduction in the annualized VOC+ACS rate post-treatment. In addition, patients overall reported an improved pain intensity score. The safety profile post-LentiGlobin remains generally consistent with myeloablative single-agent busulfan conditioning and underlying SCD. Longer follow-up and additional patients will be presented. Disclosures Thompson: CRISPR/Vertex: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Biomarin: Research Funding; Baxalta: Research Funding; BMS: Consultancy, Research Funding. Walters:AllCells, Inc: Consultancy; Veevo Biomedicine: Consultancy; Editas: Consultancy. Kwiatkowski:Agios: Consultancy; bluebird bio, Inc.: Consultancy, Research Funding; Apopharma: Research Funding; Novartis: Research Funding; Terumo Corp: Research Funding; Sangamo: Research Funding; Celgene: Consultancy; Imara: Consultancy; Bristol Myers Squibb: Consultancy. Aygun:Patient-Centered Outsomes Research Institute: Research Funding; National Heart, Lung, and Blood Institute: Research Funding; National Institute of Nursing Research: Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding. Schmidt:German Cancer Research Center, Heidelberg, Germany: Current Employment; GeneWerk GmbH, Heidelberg, Germany: Other: Equity ownership. DelCarpini:bluebird bio, Inc.: Current Employment, Other: Ownership Interest and Salary. Pierciey:bluebird bio, Inc.: Current Employment, Other: Ownership Interest and Salary. Miller:bluebird bio, Inc.: Current Employment, Other: Ownership Interest and Salary. Gallagher:bluebird bio, Inc.: Current Employment, Other: Ownership Interest and Salary. Chen:bluebird bio, Inc.: Consultancy. Goyal:bluebird bio, Inc.: Current Employment, Other: Ownership Interest and Salary. Kanter:Wells Fargo: Honoraria; Cowen: Honoraria; Jeffries: Honoraria; AGIOS: Membership on an entity's Board of Directors or advisory committees; Medscape: Honoraria; GLG: Honoraria; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; BEAM: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy; bluebird bio, inc: Consultancy, Honoraria; Novartis: Consultancy; Guidepoint Global: Honoraria.

Acute vaso-occlusive episodes (VOE) are the most common reason for presentation to the Emergency Department (ED) and inpatient admission in people living with sickle cell disease (SCD). The goal of this study was to compare the hospital admission rate for VOE from our centre's day hospital (Pediatric Ambulatory Chemotherapy and Transfusion Unit; PACT) versus the ED, and to determine which factors influence admission rate. The study included a total of 370 visits involving 140 children with SCD with a mean age of 10·9 ± 5·5 years. The timing from triage to the first analgesic was significantly different between the PACT and the ED (median, 32 vs. 70 min, P < 0·0001). The initial choice of opioid dosage adhered to our centre's guidelines 84% of the time in the PACT v. 45% in the ED for morphine (P = 0·0003) and 100% in the PACT vs. 43% (P = 0·002) for hydromorphone. The admission rate from the ED (57%) was significantly higher than that of the PACT (29%) even when accounting for differences in baseline variables (P = 0·0001). In conclusion, the odds of being admitted were 3·8 times higher if the patient was treated in the ED. Timely administration and appropriate dosing of intravenous opioids may change this outcome in the future.

Background Hydroxyurea (HU) is recommended as standard practice for youth with sickle cell disease (SCD). Yet, despite its efficacy, HU adherence in adolescents and young adults is often poor. Poor medication adherence increases disease burden, healthcare cost and widens health disparities. Adolescence is a critical time to improve adherence through improved chronic disease self-management. This study aims to test the efficacy of an intervention delivered to youth/parent dyads by community health workers (CHWs), augmented by tailored text messages on HU adherence (primary outcome). Secondary outcomes are intervention sustainability, youth health-related quality of life, self-management responsibility concordance, acute hospital use and self-reported disease symptoms. Methods Hydroxyurea Adherence for Personal Best in Sickle Cell Disease, “HABIT,” is a 12 month multi-center randomized controlled trial. One hundred four youth, 10 to 18 years of age prescribed HU who meet eligibility criteria, enrolled with their parent as dyads, will be randomized 1:1 to either the HABIT intervention or to usual clinical care plus education handouts. All subjects will complete clinic visits at months 0, 2, 4, 6 (efficacy component), 9 and 12 (sustainability component) for assessment of HbF biomarker, other hematologic parameters, and to complete questionnaires. In addition, dyads assigned to the HABIT intervention will work with CHWs to identify a daily habit (e.g., brushing teeth) on which to build a HU adherence habit. Tailored daily text message reminders to support the habit will be developed by the dyad in collaboration with the CHWs and sent to parent and youth. At the 6 month visit, the intervention will end and the sustainability portion of the trial will begin. All data analyses will be based on intention to treat with all randomized subjects included in the analyses. Discussion Prior retrospective studies demonstrate that a majority of adolescents are poorly adherent to HU. If efficacious, the HABIT intervention has the potential to improve the lives of youth with SCD. Trial registration Clinicaltrials.gov NCT03462511. Registered March 6, 2018, last updated July 26, 2019.

Summary Background For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions. Methods TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4–16 years and had abnormal TCD flow velocities (≥200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant's maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307. Findings Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140–146) in children who received standard transfusions and 138 cm/s (135–142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10–8·98). Non-inferiority (p=8·82 × 10 −16 ) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions). Interpretation For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke. Funding National Heart, Lung, and Blood Institute, National Institutes of Health.

Although hemoglobin SC (HbSC) disease is usually considered less severe than sickle cell anemia (SCA), which includes HbSS and HbS/β(0) -thalassemia genotypes, many patients with HbSC experience severe disease complications, including vaso-occlusive pain, acute chest syndrome, avascular necrosis, retinopathy, and poor quality of life. Fully 20 years after the clinical and laboratory efficacy of hydroxyurea was proven in adult SCA patients, the safety and utility of hydroxyurea treatment for HbSC patients remain unclear. Recent NHLBI evidence-based guidelines highlight this as a critical knowledge gap, noting HbSC accounts for ∼30% of sickle cell patients within the United States. To date, only 5 publications have reported short-term, incomplete, or conflicting laboratory and clinical outcomes of hydroxyurea treatment in a total of 71 adults and children with HbSC. We now report on a cohort of 133 adult and pediatric HbSC patients who received hydroxyurea, typically for recurrent vaso-occlusive pain. Hydroxyurea treatment was associated with a stable hemoglobin concentration; increased fetal hemoglobin (HbF) and mean corpuscular volume (MCV); and reduced white blood cell count (WBC), absolute neutrophil count (ANC), and absolute reticulocyte count (ARC). Reversible cytopenias occurred in 22% of patients, primarily neutropenia and thrombocytopenia. Painful events were reduced with hydroxyurea, more in patients >15 years old. These multicenter data support the safety and potentially salutary effects of hydroxyurea treatment for HbSC disease; however, a multicenter, placebo-controlled, Phase 3 clinical trial is needed to determine if hydroxyurea therapy has efficacy for patients with HbSC disease.

Introduction: Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) is an open-label study of hydroxyurea for children with sickle cell anemia (SCA) in sub-Saharan Africa (Angola, DR Congo, Kenya, and Uganda). Initial results documented the feasibility, safety, and benefits of hydroxyurea for SCA in sub-Saharan Africa but guidance for optimizing hydroxyurea therapy is needed. We describe 5 years of hydroxyurea dosing and monitoring in the largest prospective cohort of children with SCA receiving hydroxyurea to date. Methods: Children 1-10 years of age with SCA were enrolled. The hydroxyurea dose was fixed at 15-20 mg/kg/day for the first 6 months with monthly complete blood counts (CBCs) to ensure safety. From month 6-24, the dose was escalated (5 mg/kg every 8 weeks) to maximum tolerated dose (MTD), defined as mild myelosuppression with absolute neutrophil count (ANC) 7.0 g/dL, or platelets Results: A total of 606 children initiated hydroxyurea and currently 555 (92%) remain on treatment, with average treatment duration of 48 ± 12 months and a total of 2,441 patient-years of hydroxyurea treatment. Over 85% achieved MTD with an average hydroxyurea dose of 22.5 ± 5.0 mg/kg/day, ranging from 19.0 mg/kg/day in Angola to 25.4 mg/kg/day in Uganda. With dose increases over time, the most recent average dose is 23.9 ± 5.4 mg/kg/day (site range 22.9-24.6 mg/kg/day). Lab benefits have been sustained; Hb increased from 7.3 g/dL at baseline to 8.4 g/dL at MTD and remains 8.3 g/dL at Month 60. Similarly, the average HbF increased from 11% baseline to 25% at MTD and remains 23% at Month 60. The average ANC decreased from 6.8 x 109/L at baseline to 3.2 x 109/L at MTD and remains 3.5 x 109/L at Month 60. Lab toxicities are infrequent, transient, and mostly incidental. Of 19,730 CBCs obtained during the treatment phase, 421 (2.1%) in 225 participants included a DLT. The most common DLT was thrombocytopenia (33%), with only 4 platelet counts Conclusions: Hydroxyurea is safe, well-tolerated, and effective for children with SCA living in sub-Saharan Africa. Treatment responses are robust and sustained in REACH across all 4 clinical sites and unaffected by baseline Z-score. Hydroxyurea optimization requires periodic dose escalation for weight gain and titration to mild myelosuppression. Deletional α-thalassemia trait significantly influences the hydroxyurea dose and treatment responses, but the lab benefits with optimized dosing are still robust regardless of the α-globin genotype. Lab toxicities from hydroxyurea are uncommon and typically asymptomatic, suggesting that routine CBC monitoring is needed only at 3-month intervals once a stable dose is achieved, more to optimize the dose than to identify incidental toxicities. This approach to optimizing hydroxyurea therapy will allow more widespread utilization in low-resource settings with limited laboratory monitoring. Disclosures Aygun: National Heart, Lung, and Blood Institute: Research Funding; National Institute of Nursing Research: Research Funding; Patient-Centered Outsomes Research Institute: Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Children with sickle cell anemia (SCA) and conditional transcranial Doppler (TCD) ultrasound velocities (170-199 cm/sec) may develop stroke. However, with limited available clinical data, the current standard of care for conditional TCD velocities is observation. The efficacy of hydroxyurea in preventing conversion from conditional to abnormal TCD (≥200 cm/sec), which confers a higher stroke risk, has not been studied prospectively in a randomized trial. Sparing Conversion to Abnormal TCD Elevation (SCATE #NCT01531387) was a National Heart, Lung, and Blood Institute-funded Phase III multicenter international clinical trial comparing alternative therapy (hydroxyurea) to standard care (observation) to prevent conversion from conditional to abnormal TCD velocity in children with SCA. SCATE enrolled 38 children from the United States, Jamaica, and Brazil [HbSS (36), HbSβ(0) -thalassemia (1), and HbSD (1), median age = 5.4 years (range, 2.7-9.8)]. Because of the slow patient accrual and administrative delays, SCATE was terminated early. In an intention-to-treat analysis, the cumulative incidence of abnormal conversion was 9% (95% CI = 0-35%) in the hydroxyurea arm and 47% (95% CI = 6-81%) in observation arm at 15 months (P = 0.16). In post hoc analysis according to treatment received, significantly fewer children on hydroxyurea converted to abnormal TCD velocities when compared with observation (0% vs. 50%, P = 0.02). After a mean of 10.1 months, a significant change in mean TCD velocity was observed with hydroxyurea treatment (-15.5 vs. +10.2 cm/sec, P = 0.02). No stroke events occurred in either arm. Hydroxyurea reduces TCD velocities in children with SCA and conditional velocities.

Transcranial Doppler (TCD) With Transfusions Changing to Hydroxyurea (TWiTCH) trial is a randomized, open-label comparison of hydroxycarbamide (also termed hydroxyurea) versus continued chronic transfusion therapy for primary stroke prevention in patients with sickle cell anaemia (SCA) and abnormal TCD. Severity and location of iron overload is an important secondary outcome measure. We report the baseline findings of abdominal organ iron burden in 121 participants. At enrollment, patients were young (9·8 ± 2·9 years), predominantly female (60:40), and previously treated with transfusions (4·1 ± 2·4 years) and iron chelation (3·1 ± 2·1 years). Liver iron concentration (LIC; 9·0 ± 6·6 mg/g dry weight) and serum ferritin were moderately elevated (2696 ± 1678 μg/l), but transferrin was incompletely saturated (47·2 ± 23·6%). Spleen R2* was 509 ± 399 Hz (splenic iron ~13·9 mg/g) and correlated with LIC (r(2) = 0·14, P = 0·0008). Pancreas R2* was increased in 38·3% of patients but not to levels associated with endocrine toxicity. Kidney R2* was increased in 80·7% of patients; renal iron correlated with markers of intravascular haemolysis and was elevated in patients with increased urine albumin-creatinine ratios. Extra-hepatic iron deposition is common among children with SCA who receive chronic transfusions, and could potentiate oxidative stress caused by reperfusion injury and decellularized haemoglobin.

Background Sickle cell anemia (SCA) is an inherited hematological disorder that causes a large but neglected global health burden, particularly in Africa. Hydroxyurea represents the only available disease‐modifying therapy for SCA, and has proven safety and efficacy in high‐resource countries. In sub‐Saharan Africa, there is minimal use of hydroxyurea, due to lack of data, absence of evidence‐based guidelines, and inexperience among healthcare providers. Procedure A partnership was established between investigators in North America and sub‐Saharan Africa, to develop a prospective multicenter research protocol designed to provide data on the safety, feasibility, and benefits of hydroxyurea for children with SCA. Results The Realizing Effectiveness Across Continents with Hydroxyurea (REACH, ClinicalTrials.gov NCT01966731) trial is a prospective, phase I/II open‐label dose escalation study of hydroxyurea that will treat a total of 600 children age 1–10 years with SCA: 150 at each of four different clinical sites within sub‐Saharan Africa (Angola, Democratic Republic of Congo, Kenya, and Uganda). The primary study endpoint will be severe hematological toxicities that occur during the fixed‐dose treatment phase. REACH has an adaptive statistical design that allows for careful assessment of toxicities to accurately identify a safe hydroxyurea dose. Conclusions REACH will provide data that address critical gaps in knowledge for the treatment of SCA in sub‐Saharan Africa. By developing local expertise with the use of hydroxyurea and helping to establish treatment guidelines, the REACH trial results will have the potential to transform care for children with SCA in Africa. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.

Serial phlebotomy was performed on sixty children with sickle cell anaemia, stroke and transfusional iron overload randomized to hydroxycarbamide in the Stroke With Transfusions Changing to Hydroxyurea trial. There were 927 phlebotomy procedures with only 33 adverse events, all of which were grade 2. Among 23 children completing 30 months of study treatment, the net iron balance was favourable (-8·7 mg Fe/kg) with significant decrease in ferritin, although liver iron concentration remained unchanged. Therapeutic phlebotomy was safe and well-tolerated, with net iron removal in most children who completed 30 months of protocol-directed treatment.

The intracellular parasites Babesia microti and Babesia duncani can be transmitted by blood transfusion and cause severe life-threatening hemolytic anemia in high-risk patients, including those with sickle cell disease. The rarity of the diagnosis, as well as its similar clinical presentation to delayed hemolytic transfusion reaction, may lead to a delay in diagnosis, as well as inappropriate treatment with steroids or other immunosuppressive agents. The morbidity caused by this disease in especially vulnerable populations justifies the need for a universal blood-screening program in endemic areas.

Background Humanism and professionalism are virtues intrinsic to the practice of medicine, for which we lack a standard, evidence-based approach for teaching and evaluation. Pediatric hematology-oncology (PHO) fellowship training brings new and significant stressors, making it an attractive setting for innovation in humanism and professionalism training. Procedure We electronically surveyed a national sample of PHO fellows to identify fellows' educational needs in humanism and professionalism. Next, we developed a case-based, faculty-facilitated discussion curriculum to teach this content within pilot fellowship programs. We assessed whether fellowships would decide to offer the curriculum, feasibility of administering the curriculum, and satisfaction of fellow and faculty participants. Results Surveys were completed by 187 fellows (35%). A minority (29%) reported that their training program offers a formal curriculum in humanism and/or professionalism. A majority desires more formal teaching on balancing clinical practice and research (85%), coping with death/dying (85%), bereavement (78%), balancing work and personal life (75%), navigating challenging relationships with patients (74%), and depression/burn out (71%). These six topics were condensed into four case-based modules, which proved feasible to deliver at all pilot sites. Ten fellowship programs agreed to administer the novel curriculum. The majority (90%) of responding fellows and faculty reported the sessions touched on issues important for training, stimulated reflective communication, and were valuable. Conclusions Pediatric hematology-oncology fellows identify numerous gaps in their training related to humanism and professionalism. This curriculum offers an opportunity to systematically address these educational needs and can serve as a model for wider implementation. Pediatr Blood Cancer 2015;62:335–340. © 2014 Wiley Periodicals, Inc.

Background More than 90% of children with sickle cell anemia (SCA) lose splenic function by the age of 2 yrs. Splenic function may improve with hydroxyurea, but previous studies are conflicting. We prospectively evaluated the effect of hydroxyurea on splenic filtrative function. Methods Children with SCA enrolled in the Hydroxyurea Study of Long-Term Effects (HUSTLE-NCT00305175) underwent clinical evaluations including Tc99m liver–spleen (LS) scans before hydroxyurea initiation and after 3 yrs of treatment to maximum tolerated dose (MTD). LS scans were classified as follows: no uptake

Background: Isovolemic hemodilution (IHD-RCE), an add-on to standard red cell exchange (RCE), was recently FDA-approved on select apheresis devices. Equipoise exists as to the degree of red cell unit reduction and time interval extension between procedures with IHD-RCE. Also, concern has been raised that the transient hematocrit (Hct) decrease and potential hypotension with IHD-RCE causes ischemic brain injury, especially with Moya Moya disease. Again, there is equipoise, with only one of 4 studies reporting increased hypotension and no studies of ischemic brain injury with IHD-RCE. We therefore conducted a retrospective crossover study of efficacy and safety of IHD-RCE in our sickle cell disease patients, three of whom had Moya Moya, and report follow-up brain MRI/MRA data, heretofore not reported in the literature. Study design: This was a retrospective review of patients who crossed over from standard RCE (Cobe Spectra) to IHD-RCE (Spectra Optia). The IHD phase used normal saline for replacement fluid. Minimum (post-IHD) hematocrits (Hcts) and post-procedure Hcts were based upon pre-procedure Hcts as per Matevosyan et al, JCA 2012. Pre-procedure CBCs, reticulocyte counts, and serum ferritins were drawn within 72 hours of the procedure and post-procedure CBCs drawn immediately post-procedure. All red cell units were leuko-reduced, CEK matched, and less than 15 days old when possible. Methods: The same number of procedures were analyzed for standard RCE and IHD-RCE, with the RCE procedures most recent to crossover to IHD-RCE used for comparison. Means of continuous variables were calculated for each patient; means and standard deviations of the patient means are shown, unless otherwise indicated. Paired t-testing was used to compare IHD-RCE to RCE († in tables indicates p-value < 0.05) Results: Patients: All 6 patients (3 M, 3 F) were black; 5 had HbSS and 1 had SB+thal. The indication for RCE was stroke prophylaxis in four, 3 of whom had Moya-Moya disease, and frequent vaso-occlusive crisis (VOC) in two. Mean patient age at the time of first IHD-RCE was 15 ± 2 years, and a mean 26 ± 12 procedures of each procedure type was analyzed for IHD-RCE to RCE comparisons. Patient total blood volume (TBV) significantly increased from the RCE to IHD-RCE periods and was accounted for in the analysis. Procedure-centric measures (Table 1). Despite increasing TBV, red cell unit usage did not increase, and the volume of donor red cells transfused per mL TBV significantly decreased with IHD-RCE. There was no increase in inter-procedural interval. Patient-centric efficacy measures (Table 2): Despite the decreased volume of donor red cells transfused per mL TBV, and similar post- and pre-procedure HbS %s between IHD-RCE and RCE, the pre-procedure Hct was slightly (5%) increased with IHD-RCE. Procedural safety-related measures (Table 3): Although there were statistically significant drops in systolic and diastolic blood pressures (BP) post-IHD compared to pre-procedure BP, the degrees (about -6%) were mild. By procedure end, there were no overall significant differences in BP from pre-procedure BP. In addition, there was no overall significant change in heart rate post-IHD or post-procedure. Actual patient adverse events (Table 4): One patient had a single possibly IHD-related Grade 2 symptomatic (dizziness) vasovagal event, occurring at procedure end and resolved with normal saline bolus. All 4 patients on IHD-RCE for stroke prophylaxis had follow-up MRI/MRA after switching to IHD-RCE. One patient showed new silent strokes and vasculopathy but her prior MRI/MRA predated her standard RCE period. One patient who had progressed on standard RCE had no progression on IHD-RCE. The other two patients had stable MRI/MRA. Conclusion: When reducing pre-procedure Hct by 20-24% during the IHD phase, our data confirm the 11-13% reduction in red cell unit usage with IHD-RCE reported by Sarode et al, JCA 2011 and Hequet et al, Transfusion 2019, but do not support an increased inter-procedural interval of 16 days as per Sarode et al. Most patients had a mild (< 15%) and asymptomatic drop in systolic and diastolic BPs with IHD-RCE; a minority also had a very mild ( Disclosures No relevant conflicts of interest to declare.

Introduction. Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) is a prospective multicenter open-label trial that has already demonstrated hydroxyurea treatment at maximum tolerated dose (MTD) is safe, feasible, and offers major benefits for children with sickle cell anemia living in sub-Saharan Africa (Tshilolo et al, NEJM 2019;380:121-131). One unexpected benefit was a significant reduction in the number of malaria infections, including those with Grade 3 severity or above, across four trial sites in varied epidemiological settings. The overall rate of symptomatic malaria infections decreased from 46.9 events per 100 patient-years during screening to 22.9 events per 100 patient-years on treatment, an incidence rate ratio of 0.49 (95% confidence intervals [CI] = 0.37-0.66). This decreased rate of malaria was observed during the first 12 months of treatment, but declined further between Months 12-36, after the children had dose escalation to achieve hydroxyurea MTD at 22.5 mg/kg/day. Potential mechanisms of malaria protection remain unknown at this time, but could relate to both patient characteristics as well as treatment-related laboratory changes in hemoglobin (Hb), mean corpuscular volume (MCV), absolute neutrophil count (ANC), or fetal hemoglobin (HbF). Methods. Malaria infections were recorded in the REACH REDCap electronic database. Using several methods for recurrent events, with time-varying predictors as well as landmark analysis, associations with infections recorded during study treatment were assessed for multiple variables including trial site, high or low malaria season, age, gender, spleen status, hydroxyurea dose, MTD status, latest laboratory values (Hb, MCV, ANC, and HbF, all measured at least 15 days prior to the onset of the infection), as well as genetic modifiers alpha-thalassemia and G6PD deficiency. Univariate relationships were assessed using the Anderson-Gill model, followed by multiple regression to estimate Hazard Ratios (HR) with 95% CI's. Additional analyses were performed using a gap-time model that resets the clock after each infection, as well as using only the first infection in each participant; the subset of 200 acute blood-smear proven malaria infections was also analyzed separately. Results. A total of 635 children were enrolled in REACH and eligible for analysis, of whom 606 started hydroxyurea treatment. There were 333 malaria infections recorded during 1580 patient-years of observation, including 50 during screening and 283 on treatment, of which 200 had documented positive blood smears at the clinical site. Significant associations for malaria risk were identified with higher ANC (HR = 1.06 per 1 x 109 neutrophils/L, CI = 1.02-1.10, P=0.005), higher MCV (HR = 1.01 per fL, CI = 1.00-1.02), and palpable splenomegaly (HR 1-4cm = 1.73, CI = 1.22-2.45, P= 0.002, HR ≥5cm = 1.52, CI = 1.04-2.21, P=0.03). In multiple regression, the latest ANC and MCV, as well as splenomegaly remained significant but higher HbF was also associated with more malaria (HR = 1.02 per %HbF, CI = 1.00-1.03, P=0.03). These trends were consistent when using the landmark, gap-time and first infection analytical approaches. Analysis of only documented blood-smear positive malaria infections again identified higher ANC, MCV, and splenomegaly as risk factors, but found no association with HbF. Achieving MTD was found to confer significant protection against documented malaria infections (HR = 0.62, CI=0.39-1.00, P=0.048). Conclusion. Hydroxyurea treatment in children with sickle cell anemia living in sub-Saharan Africa is associated with a decreased risk of malaria infections, particularly after achieving MTD. The mechanisms by which hydroxyurea protects against malaria are likely multi-factorial, but do not appear to be related to HbF induction, as higher HbF values were not protective and in some analyses were a risk factor. However, a higher ANC was significantly associated with malaria risk in all models and analyses; since hydroxyurea treatment lowers the ANC, dose escalation to MTD may confer protection against malaria infection by reducing inflammation. Spleen status is also crucial and the role of splenomegaly as a risk factor for malaria requires further investigation. Disclosures Ware: Novartis: Other: DSMB; Agios: Membership on an entity's Board of Directors or advisory committees; 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; Addmedica: Other: Research Drug Donation; Bristol Myers Squibb: Other: Research Drug Donation; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees.

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 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.

Elevated tricuspid valve regurgitation jet velocity (TRV ≥ 2.5 m/s) is associated with mortality among adults with sickle cell disease (SCD), but correlative biomarkers are not studied according to treatment exposure or genotypes. To investigate the associations between biomarkers and TRV elevation, we examined the relationship between TRV and hemolytic, inflammatory, and cardiac biomarkers, stratified by disease-modifying treatments and SCD genotype. In total, 294 participants with SCD (mean age, 11.0 ± 3.7 years) and 49 hereditary spherocytosis (HS; mean age, 22.9 ± 19.75 years) were included for comparison and enrolled. TRV was elevated in 30.7% of children with SCD overall: 18.8% in HbSC/HbSβ+ -thalassemia, 28.9% in untreated HbSS/HbSβ0 -thalassemia, 34.2% in HbSS/HbSβ0 -thalassemia hydroxyurea-treated, and 57% in HbSS/HbSβ0 -thalassemia chronic transfusion treated. TRV was elevated in 10.7% and 27.8% in HS children and adults, respectively. In children with SCD, elevated TRV was correlated with hemoglobin (odds ratio [OR] = 0.78, P = 0.004), lactate dehydrogenase (LDH; OR = 2.52, P = 0.005), and N-terminal pro-brain natriuretic peptide (NT-pro BNP; OR = 1.003, P = 0.004). In multivariable logistic regression, adjusting for genotype, sex, hemolytic index, and treatment, hemoglobin concentration remained the only significant variable associated with elevated TRV in untreated HbSS/HbSβ0 -thalassemia participants. TRV was not associated with inflammatory markers, other markers of hemolysis, or NT-pro BNP in untreated HbSS/HbSβ0 -thalassemia. Neither hemoglobin nor LDH was associated with TRV in HbSC/HbSβ+ -thalassemia. These results suggest that elevated TRV is influenced by the degree of anemia, possibly reflecting sickling as part of the disease pathophysiology. Prospective studies should monitor hemoglobin concentration as children with SCD age into adulthood, prompting initiation of TRV screening and monitoring.

Neonatal chondrodysplasia punctata (CDP) is characterized by epiphyseal stippling and midfacial hypoplasia. CDP is usually inherited, but can be acquired because of maternal vitamin K deficiency. We describe an infant with CDP born to a teenager with sickle cell anemia and transfusional iron overload. The mother had severe liver fibrosis, elevated liver iron concentration (34 mg Fe/g), and coagulopathy, but no gestational use of warfarin. Fetal abnormalities were attributed to vitamin K deficiency secondary to liver dysfunction from iron toxicity. Treatment of iron overload among women with sickle cell anemia of childbearing potential is important to avoid possible CDP in newborns.

Background Chronic transfusions help prevent primary stroke in children with sickle cell anemia (SCA) and abnormal transcranial Doppler (TCD) velocities. However, the effects of transfusions on TCD velocities and brain MRI/MRA findings are incompletely described. Procedure We reviewed TCD and brain MRI/MRA results in 27 children with SCA and abnormal TCD velocities receiving transfusions to prevent primary stroke. All TCDs were performed by a single examiner, immediately prior to a scheduled transfusion. We also examined the effects of laboratory and clinical parameters on TCD responses to transfusion therapy. Results For the whole cohort, the average pre-transfusion HbS on transfusions was 31.7 ± 12.3%. The most significant decline in TCD velocities occurred within 10 months of starting transfusions. Follow-up TCD values trended upward with increasing pre-transfusion %HbS levels while on treatment. Half of the children had persistent conditional/abnormal TCD velocities despite transfusions and 28% had new/progressive stenosis on MRA, but none had primary stroke during 73 patient-years of follow-up. Conclusions For children with SCA and abnormal TCD velocities, transfusions lower TCD velocities and help prevent stroke, but do not always result in normal velocities or protect against progression of cerebral vasculopathy. Improved adherence to transfusion goals may improve on-treatment TCD velocities. Pediatr Blood Cancer 2013;60:1499–1502. © 2013 Wiley Periodicals, Inc.

Elevated foetal haemoglobin (HbF) levels are protective against some manifestations of sickle cell anaemia but the impact on retinopathy is unknown. We report on 123 children with HbSS, 10.6% of whom developed retinopathy. Independent of hydroxycarbamide, children with a HbF

Summary Silent cerebral infarction (SCI) is the most common neurological abnormality among children with sickle cell anaemia (SCA). The effect of hydroxycarbamide (also termed hydroxyurea) on the development and progression of SCI is unclear. We evaluated brain magnetic resonance imaging/angiography (MRI/MRA) in children with SCA receiving long-term hydroxycarbamide therapy. Fifty participants (median 9·4 years, range 1·1–17·3) enrolled in the Hydroxyurea Study of Long-Term Effects (HUSTLE; NCT00305175) underwent brain MRI/MRA and laboratory evaluations before hydroxycarbamide initiation and after 3 and 6 years of treatment to maximum tolerated dose. SCI and vascular stenosis were evaluated. At baseline, 3 and 6 years, SCI were present in 19/50 (38%), 20/49 (41%), and 7/17 (41%), respectively. At 3 years, one child developed a SCI lesion, and another progressed (single lesion to multiple). Lower haemoglobin (Hb) (80 g/l vs. 86 g/l, P = 0·049), fetal Hb (5·0% vs. 10·4%, P

The global burden of sickle cell disease (SCD) is now being increasingly realized. SCD poses a significant public health problem in sub-Saharan Africa, the Middle East, some regions of India, the Caribbean, and Brazil. In many of these regions, progress in the management of SCD has been slow. Long-term North-South and South-South partnerships between SCD professionals, funding agencies, governments, and industry are needed to help reduce the high disease burden in developing countries, through widespread SCD education, relevant research and implementation of evidence-based cost-effective interventions. A group of SCD professionals have responded with action by forming a global network.

Background Bone marrow transplantation (BMT) using human leukocyte antigen (HLA)-matched sibling donors can be curative for children with sickle cell anemia (SCA). However, minimal data exist regarding availability of HLA-identical matched siblings for transplant-eligible children, and family interest in pursuing transplantation. Methods We retrospectively analyzed a pediatric SCA cohort receiving chronic transfusions between July 2004 and January 2011. Data were analyzed regarding the number of full siblings and half-siblings, availability, and family interest in HLA testing the full siblings, and interest in proceeding with HLA-matched transplantation. Results Among 113 patients, 46 (41%) had at least 1 full sibling and 40 (35%) had an unaffected full sibling who could serve as a BMT donor. The families of 23 of these patients (58%) agreed to HLA-type sibling, 8 of whom (35%) were matched. Transfusion indications for families agreeing to HLA typing included stroke (46%) abnormal TCD (29%), acute chest syndrome (21%), and other CNS reasons (4%). Common reasons to decline HLA typing or transplantation included fear of the process, toxicities of the procedure, and comfort with current quality of life on transfusions. Only 8 of 113 (7%) were eligible for matched BMT, and only 3 (3%) underwent HLA-matched transplantation. Two unmatched children received haploidentical transplantation. Conclusions Most families of children with SCA on chronic transfusions choose to proceed with HLA typing. However, when a matched sibling was identified, most families declined to proceed with matched-sibling transplantation. Discussing BMT as a treatment option, offering HLA typing and identifying barriers may improve acceptance of this treatment modality. Pediatr Blood Cancer 2012; 58: 611–615. © 2011 Wiley Periodicals, Inc.

Hydroxyurea is a potent and safe disease-modifying therapy for sickle cell anemia (SCA), with available data proving laboratory and clinical efficacy for both children and adults. Although the global burden of SCA is greatest within sub-Saharan Africa, almost all studies with hydroxyurea to date have been conducted in the US and Europe. Since additional comorbidities may affect children with SCA in low-resource settings, including malnutrition, malaria, and other infections, prospective research is needed to develop locally appropriate guidelines for hydroxyurea use. To assess the feasibility, safety, and benefits of hydroxyurea for SCA in sub-Saharan Africa, we designed the prospective multi-center REACH trial (Realizing Effectiveness Across Continents with Hydroxyurea, NCT01966731). Four sites with high scientific and organizational capacity and geographical diversity (Luanda, Angola; Kinshasa, Democratic Republic of Congo; Kilifi, Kenya; and Mbale, Uganda) were selected to treat 600 children aged 1-10 years, using hydroxyurea capsules donated by Bristol-Myers Squibb. Open-label treatment at 15-20 mg/kg/day continued for six months unless hematological toxicity occurred, followed by escalation using weight and pre-defined laboratory criteria to maximum tolerated dose (MTD). Primary study endpoints included feasibility (enrollment, retention, adherence); safety (hematological toxicities, infections, MTD), and benefits (lab parameters, sickle-related clinical events, transfusions, death). We now present the main results of the REACH trial. Between July 2014 and December 2016, a total of 635 children with SCA were enrolled. The median age at enrollment was 5.4 years (IQR 3.4-7.4 years). During a two-month screening period, 29 children withdrew due to ineligibility (11), non-adherence (8), relocation (3), withdrawal of consent (3), or death (4). A total of 606 children initiated hydroxyurea at an average dose of 17.5±1.8 mg/kg/day. Study retention was excellent during treatment, with 5% overall drop-out due to study withdrawal or death. Study adherence was outstanding with 97% completed scheduled visits and 94% collected lab studies. After Month 6, the dose was escalated by 2.5-5.0 mg/kg/day every 8 weeks until mild marrow suppression, typically absolute neutrophil count The NHLBI-funded multi-national REACH trial provides the first prospective data on hydroxyurea treatment for children with SCA in sub-Saharan Africa. These results document the feasibility, safety, and benefits of daily oral hydroxyurea in the area of greatest global burden. With evidence that hydroxyurea can reduce sickle-related clinical events, transfusions, malaria, and even death, wider access to hydroxyurea in Africa can be planned to provide treatment where it is most needed. Disclosures Ware: Nova Laboratories: Consultancy; Addmedica: Research Funding; Bristol Myers Squibb: Research Funding; Biomedomics: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Agios: Other: advisory board; Global Blood Therapeutics: Other: advisory board.

Background Neurocognitive deficits have been described in school age children with sickle cell disease (SCD), even in the absence of stroke or silent infarcts. However, the age of onset and factors contributing to this problem have not been well studied. We hypothesized that in children with SCD the failure rate with Brigance screening would be higher than in the normal population. Methods We reviewed retrospectively the Brigance Preschool Screen-II test results in 3-year-old children with SCD. Findings were correlated with hemoglobinopathy genotype, hemoglobin level, transcranial Doppler ultrasound (TCD) velocities, and treatment with hydroxyurea, as well as with psychosocial factors. Results Eighty-eight children with SCD followed by the St. Jude Sickle Cell Center (mean age 3.5 years) had neurocognitive screening during their regular clinic visits. Forty-four (50%) children had scores below the normal cut-off value for their age (twice the national failure rate of 25%). Failures were associated with less parental education (P = 0.005 for maternal and P = 0.03 for paternal education levels) and with speech deficits (P = 0.01), but were not associated with sickle cell genotype or hemoglobin concentration. Conclusion These preliminary data suggest that psychosocial factors may have more profound effects on early childhood development than disease-related factors in this group of young sickle cell patients. A larger prospective study with appropriate controls is warranted to validate these findings, which have implications for the etiology and prevention of neurocognitive decline in children with SCD. Pediatr Blood Cancer 2011;56:620–624. © 2010 Wiley-Liss, Inc.

In the last decade, the care of patients with sickle cell disease (SCD) has undergone important advances with better understanding of disease pathophysiology and improvement in standards of care, especially among paediatric patients. Although many new drugs are currently being investigated and are at different stages of development, the pace of drug discovery and utilization has been slow and suboptimal. Hydroxycarbamide (hydroxyurea) has been investigated and utilized for at least two decades. Hydroxycarbamide's efficacy has been demonstrated, albeit with different levels of evidence, in paediatric and adult populations, and yet clinician and patient acceptance and use have been far from ideal. In this review we discuss the current usage of hydroxycarbamide and its possible future indications in SCD, as well as the use of new compounds that have very different mechanisms of action, which may prove safe and efficacious when used alone or in combination in patients with SCD.

Anti-D immunoglobulin is a common front-line treatment for childhood immune thrombocytopenia (ITP) that typically results in a rapid and significant increase in platelet count. Unpredictable treatment responses and interpatient variability limit more widespread use. We hypothesized that anti-D response variability is influenced by RHD gene zygosity and erythrocyte D antigen expression. We compared RHD zygosity and quantitative D antigen expression to anti-D treatment results. Hemizygous RHD subjects demonstrated significantly higher platelet increases and peak platelet counts than homozygous RHD subjects. Future studies should investigate the mechanisms by which RHD zygosity and D antigen expression affect platelet responses to anti-D immunoglobulin.

A 14-year-old girl had an abdominal mass with the characteristics of an ovarian germ cell tumor on computed tomography scan. The mass, arising from the left ovary, was completely resected and found to be osteosarcoma arising from a mature cystic teratoma. A metastatic lesion in the abdomen did not respond to 2 courses of cisplatin, doxorubicin, ifosfamide, and high-dose methotrexate, and was resected. Seven months after completion of chemotherapy, there were simultaneous local recurrence and lung metastases. Previously, 10 cases of ovarian osteosarcoma have been reported in the literature: 5 were primary osteosarcoma of the ovary, 4 were associated with teratomas, and 1 was part of a malignant mixed mesodermal tumor of the ovary. Of the 10, there are only 2 long-term survivors, both of whom were treated with adjuvant chemotherapy following complete resection.

Hemoglobin S/Black (Aγδβ)0-thalassemia is a rare sickle cell disease (SCD) variant. On the basis of limited descriptions in the literature, the disease is reported as a mild microcytic anemia with an uncomplicated course. We report the clinical and laboratory data of nine patients whose diagnoses were confirmed by DNA-based techniques. Despite having mild anemia and high fetal hemoglobin level postinfancy, these patients developed many of the classic complications of SCD, including vaso-occlusive crisis, acute chest syndrome, avascular necrosis, and cholelithiasis. On the basis of these findings, we recommend that patients with this rare disorder receive specialized hematology care according to SCD guidelines.

Despite documented laboratory and clinical benefits of hydroxyurea for children with sickle cell anemia (SCA), the drug's long-term safety and efficacy remains poorly defined. The HUSOFT trial and extension study examined feasibility, toxicity, and hematological efficacy of hydroxyurea in infants with SCA. This report describes HUSOFT participants who have continued hydroxyurea therapy for 15 years. With IRB approval, medical records were reviewed for clinical, laboratory, and growth parameters. Twenty-eight infants enrolled in the original 2-year HUSOFT study received open-label liquid hydroxyurea at 20 mg/kg/day; 17 completed the extension study with dose escalation to 30 mg/kg/day. Eight of these 17 (6 girls and 2 boys, all HbSS) have continued on daily hydroxyurea for at least 15 years (median age at last follow-up 17.6 years) without interruption. All hematologic indices (Hb concentration, mean corpuscular volume (MCV), fetal hemoglobin) showed sustained effect after 15 years. The median maximum tolerated dose of hydroxyurea has decreased from 30 to 26 mg/kg/day (range 19.5–31.2); neutropenia [absolute neutrophil count (ANC)