Establishing Sickle Cell Disease Stroke Prevention Teams in Africa is Feasible: Program Evaluation Using the RE-AIM Framework.

We used the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework to evaluate a Stroke Prevention Team's readiness to prevent strokes in children with sickle cell anemia living in northern Nigeria. The NIH sponsored Stroke Prevention Trial in Nigeria included a goal of a sustainable stroke prevention program. The program's 1-year reach for transcranial Doppler screening was 14.7% (4710/32,000) of which 6.0% (281/4710) had abnormal velocities (≥200 cm/s). All participants with abnormal transcranial Doppler velocities were started on hydroxyurea (effectiveness). The leaders of all 5 hospitals agreed to adopt the program. After 1 year, program-implementation and maintenance rates were 100%, demonstrating the program's feasibility and short-term sustainability.

Level of utilization and provider-related barriers to the use of hydroxyurea in the treatment of sickle cell disease patients in Jos, North-Central Nigeria.

BACKGROUND: Hydroxyurea is underutilized by sickle cell health-care providers in Nigeria despite available evidence of its effectiveness in reducing the manifestations and complications of sickle cell disease (SCD). OBJECTIVES: To assess the level of utilization and provider-related barriers to the use of hydroxyurea in SCD therapy in Jos, Nigeria. METHODS: A cross-sectional study conducted among 132 medical doctors providing care for SCD patients. Data on sociodemographics, utilization and barriers to hydroxyurea use were obtained. The barriers were fed cumulatively into the logistic regression model as predictors of utilization. RESULTS: Of the 132 care providers, 88 (67%) had been in medical practice for ≥6years. The level of utilization of hydroxyurea was 24.2%. The significant barriers that predicted the non-utilization of hydroxyurea included lack of expertise (OR=5.1; 95% CI=2.65-9.05), lack of clinical guidelines (OR=3.84; 95% CI=2.37-14.33), fear of side-effects (OR=0.50; 95% CI=0.22-0.68) and doubt about its effectiveness (OR=0.30; 95% CI=0.20-0.90). CONCLUSION: The level of utilization of hydroxyurea in the treatment of SCD among the care providers is sub-optimal with the lack of expertise in its use identified as the most prominent barrier. There is an urgent need for the training of sickle cell care-providers and the development of clinical guidelines on hydroxyurea use.

Early initiation of hydroxyurea (hydroxycarbamide) using individualised, pharmacokinetics-guided dosing can produce sustained and nearly pancellular expression of fetal haemoglobin in children with sickle cell anaemia.

Hydroxyurea (hydroxycarbamide) is an effective treatment for sickle cell anaemia (SCA), but clinical responses depend primarily upon the degree of fetal haemoglobin (HbF) induction and the heterogeneity of HbF expression across erythrocytes. The number and characteristics of HbF-containing cells (F-cells) are not assessed by traditional HbF measurements. Conventional hydroxyurea dosing (e.g. fixed doses or low starting doses with stepwise escalation) produces a moderate heterocellular HbF induction, but haemolysis and clinical complications continue. Robust, pancellular HbF induction is needed to minimise or fully inhibit polymerisation of sickle haemoglobin. We treated children with hydroxyurea using an individualised, pharmacokinetics-guided regimen starting at predicted maximum tolerated dose (MTD). We observed sustained HbF induction (mean >30%) for up to 6 years, which was not dependent on genetic determinants of HbF expression. Nearly 70% of patients had ≥80% F-cells (near-pancellular), and almost half had ≥90% F-cells (pancellular). The mean HbF/F-cell content was ~12 pg. Earlier age of initiation and better medication adherence were associated with high F-cell responses. In summary, early initiation of hydroxyurea using pharmacokinetics-guided starting doses at predicted MTD can achieve sustained near-pancellular or pancellular HbF expression and should be considered an achievable goal for children with SCA treated with hydroxyurea at optimal doses. Clinical trial registration number: NCT02286154 (clinicaltrials.gov).

Hydroxyurea treatment and neurocognitive functioning in sickle cell disease from school age to young adulthood.

Neurocognitive impairment is common in sickle cell disease (SCD) and is associated with significant functional limitations. In a cross-sectional analysis, we examined the association between hydroxyurea (HU) treatment and neurocognitive functioning from school-age to young adulthood in individuals with SCD. A total of 215 patients with HbSS/HbSß0 -thalassaemia (71% HU treated) and 149 patients with HbSC/HbSß+ -thalassaemia (20% HU treated) completed neurocognitive measures at one of four developmental stages: school-age (age 8-9 years), early adolescence (age 12-13 years), late adolescence (age 16-17 years) and young adulthood (ages 19-24 years). For participants with multiple assessments, only the most recent evaluation was included. In multivariable analysis adjusted for social vulnerability, HU treatment and sex, older age was associated with a reduction in overall intelligence quotient (IQ) of 0·55 points per year of life [standard error (SE) = 0·18, false discovery rate adjusted P value (PFDR) = 0.01] for patients with HbSS/HbSß0 -thalassaemia. Earlier initiation of HU (n = 152) in HbSS/HbSß0 -thalassaemia was associated with higher scores on neurocognitive measures across most domains, including IQ [estimate (SE) 0·77 (0·25)/year, PFDR = 0·01], after adjusting for social vulnerability, sex and treatment duration. These results support the early use of HU to limit the detrimental neurocognitive effects of SCD, while highlighting the need for additional measures to further mitigate neurocognitive deterioration.

Perception to hydroxyurea therapy in patients with sickle cell disease: Report from 3 centers.

Background: Hydroxyurea (HU) is an hemoglobin F inducing agent used in the treatment of sickle cell disease (SCD). Aim: The aim of this study is to determine the perception of HU by people living with SCD. Materials and Methods: A pretested questionnaire was self-administered to known cases of SCD attending pediatrics and adult hematology clinics in three participating centers. Mothers of children <18 years responded on their behalf. Results: There were 101 responders, 49 (48.5%) males and 52 (51.5%) females, of which 24 (23.8%) were children <18 years and 77 (76.2%) were adults. The majority (n = 73, 72.3%) knew their phenotype. Up to 63 (62.4%) had crises in the past 3 months. Only 35 (34.7%) had heard of HU, many through their doctor (n = 16, 45.7%), 8 (22.9%) through online resources, and 7 (20%) from friends. Only 12 (11.9%) had been exposed to HU therapy, of which 5 (41.7%) had discontinued therapy mostly due to side effects (n = 2, 40%). The seven patients (58.3%) on continuous HU therapy for a duration of 6 months to over 5 years, all reported reduced hospital admissions and frequency of crises as benefits of the drug, whereas 4 (57.1%) had stopped requiring blood transfusion since starting therapy. Of those who had never taken HU, 53 (52.5%) believed that HU should be used in treating SCD and majority (n = 32, 60.4%) would want to be commenced on the drug. However, 8 (15.1%) would decline therapy (mostly due to perceived associated side effects; n = 4; 50%). Six (11.3%) were unsure if they would want the drug and 7 (13.2%) would have to discuss the decision first with their family. There were 8 (8.9%) responders who did not think HU will be beneficial in SCD and would decline treatment, while 26 (29.2%) were unsure of both the benefits of the drug or of commencing therapy. Conclusion: The findings from this study suggest that HU is beneficial for patients with SCD; however, the awareness of this medication among SCD patients is still low in our environment. Some SCD patients would decline the use of HU due to perceived side effects. We recommend that more awareness on HU be created and coordinated multi-center studies on the efficacy of HU in the Nigerian population be carried out.

RésuméContexte: L'hydroxyurée (HU) est un agent inducteur de l'hémoglobine F utilisé dans le traitement de la drépanocytose (SCD). Objectif: le but de cette L'étude vise à déterminer la perception de l'HU par les personnes atteintes de SCD. Matériel et Méthodes: un questionnaire pré-testé a été auto-administré aux cas connus de SCD fréquentant des cliniques de pédiatrie et d'hématologie pour adultes dans trois centres participants. Les mères d'enfants de moins de 18 ans ont répondu en leur nom. Résultats: Il y avait 101 répondants, 49 (48,5%) hommes et 52 (51,5%) femmes, dont 24 (23,8%) étaient des enfants de moins de 18 ans et 77 (76,2%) étaient des adultes. La majorité (n = 73, 72,3%) connaissait leur phénotype. Jusqu'à 63 (62,4%) ont eu des crises au cours des 3 derniers mois. Seulement 35 (34,7%) avaient entendu parler de HU, beaucoup par l'intermédiaire de leur médecin (n = 16, 45,7%), 8 (22,9%) par des ressources en ligne et 7 (20%) par des amis. Seulement 12 (11,9%) avaient été exposés à un traitement par HU, dont 5 (41,7%) avaient arrêté le traitement principalement en raison d'effets secondaires (n = 2, 40%). Les sept patients (58,3%) sous traitement HU continu pendant une durée de 6 mois à plus de 5 ans, tous ont signalé une réduction des hospitalisations et de la fréquence des crises comme bienfaits du médicament, alors que 4 (57,1%) avaient cessé de nécessiter une transfusion sanguine depuis le début du traitement. De ceux qui n'avaient jamais prises HU, 53 (52,5%) estimaient que HU devrait être utilisée dans le traitement de la drépanocytose et la majorité (n = 32, 60,4%) souhaiterait commencer le médicament. Cependant, 8 (15,1%) refuseraient le traitement (principalement en raison des effets secondaires associés perçus; n = 4; 50%). Six (11,3%) ne savaient pas siils voudraient le médicament et 7 (13,2%) devraient d'abord discuter de la décision avec leur famille. Il y avait 8 répondants (8,9%) quine pense pas que l'HU sera bénéfique dans la drépanocytose et refuserait le traitement, tandis que 26 (29,2%) n'étaient pas certains des avantages du médicament ou commencer la thérapie. Conclusion: Les résultats de cette étude suggèrent que l'HU est bénéfique pour les patients atteints de SCD; cependant, la conscience de ce médicament chez les patients SCD est encore faible dans notre environnement. Certains patients SCD refuseraient l'utilisation de l'HU en raison du côté perçu effets. Nous recommandons qu'une plus grande sensibilisation à l'HU soit créée et coordonne des études multicentriques sur l'efficacité de l'HU au Nigéria. population être effectuée.

Single laser trapping for optical folding and rotation of red blood cells in sickle cell disease in response to hydroxyurea treatment.

Optical folding and rotation behavior of red blood cells (RBCs) in polarized laser tweezers are considerably important for understanding the biophysical and biomechanical properties using the fast probing method. Here, a dual-mode polarized single-laser tweezers technique with distinct principal axes exhibiting different polarization states is presented and designed to investigate the deformation, optical folding, and rotation of single living cells with one measurement. RBC optical folding and rotation speed are measured in patients with sickle cell disease (SCD), including follow up of patients after hydroxyurea (HU) treatment for at least three months. Folding angle and rotation speed are significantly lower in patients with SCD and do not significantly differ in patients treated by HU compared with the healthy control group. The RBC folding angle and rotation speed in patients treated with HU drug increase linearly at lower laser powers and rapidly at higher powers, and increase much slowly in patients not treated with HU. The difference in the folding angle and rotation speed of RBCs could be useful for drug response in SCD or predicting pain crisis in SCD.

Experience with combination of hydroxyurea and low-dose thalidomide in transfusion-dependent beta thalassemia patients.

Hydroxyurea (HU) and thalidomide have been reported to improve clinical and hematological parameters in transfusion-dependent beta thalassemia (TDT). Therefore, we retrospectively analyzed the combination of HU and thalidomide in 140 transplant ineligible TDT, ≥ 10 years old, visiting our thalassemia clinic between October 2014 and November 2019. Responses were defined as maintenance of hemoglobin ≥9gm/dl without transfusion as complete response (CR) and with at least 50% reduction in transfusion burden as partial response (PR). Patients with less than 50% transfusion burden reduction for consecutive 6 months of therapy were defined as non-responders (NR), and treatment was discontinued thereafter. Primary end point was overall response rate (ORR) at last follow-up. At median follow-up of 22.6 (95% CI 16.4-28.7) months, 76 (57.2%) patients achieved CR and 19 (14.3%) achieved PR, accounting to an ORR of 71.5%. Among responders at last follow-up, a significant increase in the post-treatment hemoglobin (0.88±0.37gm/dl, p<0.0001) and drop in serum ferritin (-1490.5ng/ml, p<0.0001) were observed. Median time to CR was 124 (95% CI 75.3-172.6) days. Median longest continuous CR was 791 (95% CI 662.2-919.7) days. Common toxicities observed were sedation (25%), hyperbilirubinemia {(23.57%, grade 3/4 =17 (12.14%)}, and constipation (22.8%). Nearly three-fourth of the patients has responded with majority having CR. Adverse events are a concern; hence, regular close monitoring is a prerequisite.

Hydroyxurea improves cerebral oxygen saturation in children with sickle cell anemia.

Neurologic complications are common in patients with sickle cell anemia (SCA), but conventional tools such as MRI and transcranial Doppler ultrasonography (TCD) do not fully assess cerebrovascular pathology. Cerebral tissue oximetry measures mixed oxygen saturation in the frontal lobes (SCT O2 ) and provides early prognostic information about tissue at risk of ischemic injury. Untreated patients with SCA have significantly lower SCT O2 than healthy controls that declines with age. Hydroxyurea is effective in preventing many SCA-related complications, but the degree to which it preserves normal neurophysiology is unclear. We analyzed participants enrolled in the Therapeutic Response Evaluation and Adherence Trial (TREAT, NCT02286154), which enrolled participants initiating hydroxyurea using individualized dosing (new cohort) and those previously taking hydroxyurea (old cohort) and was designed to monitor the long-term benefits of hydroxyurea. Cerebral oximetry was performed at baseline and annually. For the new cohort (median starting age = 12 months, n = 55), mean baseline SCT O2 was normal before starting hydroxyurea (mean 65%, 95% CI 58-72%) and significantly increased after 2 years (mean 72%, 95% CI 65-79%, p < .001). The SCT O2 for patients receiving long-term hydroxyurea (median age = 9.6 years) was normal at study entry (mean 66%, 95% CI 58-74%) and remained stable across 2 years. Both cohorts had significantly higher SCT O2 than published data from predominantly untreated SCA patients. Cerebral oximetry is a non-invasive method to assess cerebrovascular pathology that complements conventional imaging. Our results indicate that hydroxyurea suggests protection against neurophysiologic changes seen in untreated SCA.

OCCURRENCE OF UNUSUAL HAEMOGLOBINOPATHIES IN BALOCHISTAN: HB SD AND HB SE - PRESENTATION WITH OSTEOMYELITIS.

OBJECTIVE: To describe two cases of unusual variants of sickle cell disease. CASE DESCRIPTION: We present two cases of sickle cell disease variants (haemoglobinopathies), from unrelated families, in the state of Balochistan (Pakistan). One was diagnosed with sickle cell disease in the haemoglobin electrophoresis, whereas the other was diagnosed with sickle cell SE disease. Both were diagnosed based on the presentation of osteomyelitis. COMMENTS: Haemoglobin SD disease (Hb SD) and haemoglobin SE disease (Hb SE) are rare haemoglobinopathies in the world. The lack of available literature suggests that both are variants of sickle cell disease (SCD), with heterogeneous nature. The prevalence of sickle cell disease with compound heterozygotes was found at a variable frequency in the population of the Asian Southeast. The frequency of osteomyelitis in SCD is 12 to 18%, but its occurrence among variant haemoglobinopathies is little reported. Both reported cases presented with osteomyelitis as a characteristic of the disease presentation.

Effect of hydroxyurea exposure before puberty on sperm parameters in males with sickle cell disease.

Sperm parameters are known to be impaired in men with sickle cell disease (SCD). Although treatment with hydroxyurea (HU) has an impact on sperm quality, sperm preservation is impossible before puberty. This study's primary objective was to analyze and compare sperm parameters in male patients with SCD exposed (or not) to HU before puberty. Twenty-six sperm samples from 15 patients (median age, 17 years; range, 16-23) treated with HU during childhood were compared with 46 samples from 23 HU-naïve patients (20 years; 16-24). The median age at HU initiation was 6 years (1-14 years), the median duration of HU treatment was 4 years (0.5-10), and the mean dose of HU was 22.4 ± 3.7 mg/kg per day. Although we observed substantial quantitative and qualitative semen abnormalities in all patients, there were no significant differences in semen volume, sperm concentration, total sperm count, or spermatozoa motility, morphology, and vitality between the HU-exposed and HU-naïve groups. At the time of the semen analysis, 100% of the patients in the HU-exposed group and 52% of the patients in the HU-naïve group received transfusion therapy. The specific effect of HU on spermatogenesis in very young infants and the putative value of transfusion for reversing the toxicity of HU warrant further investigation.

Potent and orally active purine-based fetal hemoglobin inducers for treating ß-thalassemia and sickle cell disease.

Reactivation of fetal hemoglobin (HbF) expression by therapeutic agents has been suggested as an alternative treatment to modulate anemia and the related symptoms of severe ß-thalassemia and sickle cell disease (SCD). Hydroxyurea (HU) is the first US FDA-approved HbF inducer for treating SCD. However, approximately 25% of the patients with SCD do not respond to HU. A previous study identified TN1 (1) as a small-molecule HbF inducer. However, this study found that the poor potency and oral bioavailability of compound 1 limits the development of this inducer for clinical use. To develop drug-like compounds, further structure-activity relationship studies on the purine-based structure of 1 were conducted. Herein, we report our discovery of a more potent inducer, compound 13a, that can efficiently induce γ-globin gene expression at non-cytotoxic concentrations. The molecular mechanism of 13a, for the regulation HbF expression, was also investigated. In addition, we demonstrated that oral administration of 13a can ameliorate anemia and the related symptoms in SCD mice. The results of this study suggest that 13a can be further developed as a novel agent for treating hemoglobinopathies, such as ß-thalassemia and SCD.

Computer Algorithm-Based Hydroxyurea Dosing Facilitates Titration to Maximum Tolerated Dose in Sickle Cell Anemia.

Adults with sickle cell disease (SCD) experience acute and chronic complications and die prematurely. When taken at maximum tolerated dose (MTD), hydroxyurea prolongs survival; however, it has not consistently reversed organ dysfunction. Patients also frequently do not take hydroxyurea, at least in part because of physician discomfort with prescribing hydroxyurea. We sought to develop a computer program that could easily titrate hydroxyurea to MTD. This was a single-arm, open-label pilot study. Fifteen patients with homozygous SCD were enrolled in the protocol, and 10 patients were followed at baseline and then for 1 year after hydroxyurea initiation or dose titration. Fetal hemoglobin significantly increased in all 10 patients from 8.3% to 25.1% (P < .001). Nine patients were titrated to MTD in an average of 7.9 months, and the tenth patient's hydroxyurea dose was increased to 33 mg/kg/day. Computer program dosing recommendations were the same as manual dosing decisions made using the same algorithm for all patients and at all times. We also evaluated markers of cardiopulmonary, liver and renal damage. Although cardiopulmonary function did not significantly improve, direct bilirubin and alanine aminotransferase levels significantly decreased (P < .001 and P < .01, respectively). Last, although kidney function did not improve, degree of proteinuria was significantly reduced (P < .05). We have developed a computer program that reliably titrates hydroxyurea to MTD. A larger study is indicated to test the program either as a computer program or a downloadable application.

Occurrence of unusual haemoglobinopathies in balochistan: hb sd and hb se - presentation with osteomyelitis / Ocorrência de hemoglobinopatias incomuns no baluchistão: hb sd e hb se - apresentação com osteomielite

ABSTRACT Objective: To describe two cases of unusual variants of sickle cell disease. Case description: We present two cases of sickle cell disease variants (haemoglobinopathies), from unrelated families, in the state of Balochistan (Pakistan). One was diagnosed with sickle cell disease in the haemoglobin electrophoresis, whereas the other was diagnosed with sickle cell SE disease. Both were diagnosed based on the presentation of osteomyelitis. Comments: Haemoglobin SD disease (Hb SD) and haemoglobin SE disease (Hb SE) are rare haemoglobinopathies in the world. The lack of available literature suggests that both are variants of sickle cell disease (SCD), with heterogeneous nature. The prevalence of sickle cell disease with compound heterozygotes was found at a variable frequency in the population of the Asian Southeast. The frequency of osteomyelitis in SCD is 12 to 18%, but its occurrence among variant haemoglobinopathies is little reported. Both reported cases presented with osteomyelitis as a characteristic of the disease presentation.

RESUMO Objetivo: Descrever dois casos de variantes raras da hemoglobinopatia falciforme. Descrição do caso: Apresentamos aqui dois casos de hemoglobinopatias variantes das células falciformes, de famílias não relacionadas, no estado do Baluchistão (Paquistão), sendo um diagnosticado como doença da hemoglobina SD na eletroforese de hemoglobina, enquanto o outro com doença da hemoglobina SE. Ambos foram diagnosticados a partir da apresentação de osteomielite. Comentários: Hemoglobina SD (Hb SD) e hemoglobina SE (Hb SE) são hemoglobinopatias raras no mundo. A escassez de literatura disponível sugere que ambas são variantes da doença falciforme (DF) com natureza heterogênea. A prevalência de hemoglobinopatia falciforme com heterozigosidade composta foi encontrada com frequência variável na população do sudeste asiático. A frequência de osteomielite na DF é de 12 a 18%, mas sua ocorrência entre as hemoglobinopatias falciformes variantes é pouco relatada. Os dois casos reportados apresentaram osteomielite como característica de apresentação da doença.

Association of Exon 14 of the SOX6 Gene Sequence Variations with Response to Hydroxyurea Therapy in Patients Carrying Non Transfusion-Dependent Thalassemia.

Hydroxyurea (HU) activates the γ-globin gene, resulting in increased Hb F synthesis. The SOX6 gene is a member of the Sox (Sry-type HMG box) family of transcription factors, characterized by minor groove binding domain. The DNA binding domain of this gene is encoded by exon 14. We assessed the relationship between response to HU and exon 14 of the SOX6 gene sequence variations in patients with non transfusion-dependent thalassemia (NTDT). One hundred NTDT patients from southern Iran underwent HU therapy randomly participated in this cross-sectional study between February 2013 and October 2014. Based on response to HU therapy, the patients were divided into two groups: good and poor responder. Sequence variations of exon 14 of the SOX6 gene was assayed by the Sanger sequencing technique. From all evaluated single nucleotide polymorphisms (SNPs) as above, we found no significant association between sequence variations of exon 14 of the SOX6 gene and response to HU therapy (p > 0.05). It seems that no SNPs in exon 14 of the SOX6 gene is associated with response to HU in NTDT patients, but more studies are needed for further evaluation.

Managing patients with sickle cell disease in primary care.

Sickle cell disease (SCD) is a group of disorders affecting the hemoglobin in erythrocytes. SCD is associated with significant morbidity and mortality and occurs most commonly among people of African ancestry. In 2014, the National Heart, Lung, and Blood Institute updated its guidelines for the management of SCD. These guidelines were implemented to provide evidence-based recommendations to assist primary care clinicians in the proper management of patients with SCD. This article reviews the current practice guidelines for SCD, with attention to health maintenance and hydroxyurea.

Hydroxyurea Dose Escalation for Sickle Cell Anemia in Sub-Saharan Africa.

BACKGROUND: Hydroxyurea has proven safety, feasibility, and efficacy in children with sickle cell anemia in sub-Saharan Africa, with studies showing a reduced incidence of vaso-occlusive events and reduced mortality. Dosing standards remain undetermined, however, and whether escalation to the maximum tolerated dose confers clinical benefits that outweigh treatment-related toxic effects is unknown. METHODS: In a randomized, double-blind trial, we compared hydroxyurea at a fixed dose (approximately 20 mg per kilogram of body weight per day) with dose escalation (approximately 30 mg per kilogram per day). The primary outcome was a hemoglobin level of 9.0 g or more per deciliter or a fetal hemoglobin level of 20% or more after 24 months. Secondary outcomes included the incidences of malaria, vaso-occlusive crises, and serious adverse events. RESULTS: Children received hydroxyurea at a fixed dose (94 children; mean [±SD] age, 4.6±1.0 years) or with dose escalation (93 children; mean age, 4.8±0.9 years); the mean doses were 19.2±1.8 mg per kilogram per day and 29.5±3.6 mg per kilogram per day, respectively. The data and safety monitoring board halted the trial when the numbers of clinical events were significantly lower among children receiving escalated dosing than among those receiving a fixed dose. At trial closure, 86% of the children in the dose-escalation group had reached the primary-outcome thresholds, as compared with 37% of the children in the fixed-dose group (P<0.001). Children in the dose-escalation group had fewer sickle cell-related adverse events (incidence rate ratio, 0.43; 95% confidence interval [CI], 0.34 to 0.54), vaso-occlusive pain crises (incidence rate ratio, 0.43; 95% CI, 0.34 to 0.56), cases of acute chest syndrome or pneumonia (incidence rate ratio, 0.27; 95% CI, 0.11 to 0.56), transfusions (incidence rate ratio, 0.30; 95% CI, 0.20 to 0.43), and hospitalizations (incidence rate ratio, 0.21; 95% CI, 0.13 to 0.34). Laboratory-confirmed dose-limiting toxic effects were similar in the two groups, and there were no cases of severe neutropenia or thrombocytopenia. CONCLUSIONS: Among children with sickle cell anemia in sub-Saharan Africa, hydroxyurea with dose escalation had superior clinical efficacy to that of fixed-dose hydroxyurea, with equivalent safety. (Funded by the Doris Duke Charitable Foundation and the Cincinnati Children's Research Foundation; NOHARM MTD ClinicalTrials.gov number, NCT03128515.).