Optimizing Hydroxyurea Therapy with Reduced Laboratory Monitoring for Children with Sickle Cell Anemia in Sub-Saharan Africa: The Reach Experience

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) <4.0 x 109/L on 2 consecutive CBCs without hematological toxicities. CBCs were performed monthly until MTD or a stable dose was achieved, then subsequently every 3 months. Dose limiting toxicities (DLT) requiring a temporary treatment hold were defined as ANC <1.0 x 109/L, Hb <4.0 g/dL, reticulocyte count <80 x 109/L unless Hb >7.0 g/dL, or platelets <80 x 109/L. Known genetic modifiers of SCA, including G6PD deficiency and α-thalassemia trait, were determined for all participants. 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 <20 x 109/L and no bleeding. Anemia was the second most common DLT (26%), most commonly associated with a high reticulocyte count and malarial infection, unrelated to hydroxyurea. Severe neutropenia (ANC <0.5 x 109/L) was rare (5 events) with no neutropenic infections. Over 2/3 of DLT events were identified incidentally during a scheduled visit when the study participant was asymptomatic, including all 5 severe neutropenic episodes. Weight-for-age and height-for-age Z-scores were not associated with higher rates of DLT during hydroxyurea treatment. Children with two-gene deletional α-thalassemia trait tolerated significantly lower hydroxyurea doses than the normal genotype (MTD dose 20.0 vs. 24.0 mg/kg/day, p <0.001) and had significantly different treatment responses at Month 60 including lower HbF (19.5 vs 24.3%, p <0.0001) and MCV (72 vs 99 fL, p<0.001) but higher hemoglobin (8.5 vs 8.1 g/dL, p=0.016). DLT frequency was unaffected by α-thalassemia status. Males with G6PD A- deficiency did not demonstrate significant differences in dosing, response, or toxicity. 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.

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Hydroxyurea Reduces the Transfusion Burden in Children with Sickle Cell Anemia: The Reach Experience

Blood ◽

10.1182/blood-2021-146632 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 11-11

Author(s):

Alexandra Power-Hays ◽

George A. Tomlinson ◽

Leon Tshilolo ◽

Brigida Santos ◽

Thomas N. Williams ◽

...

Keyword(s):

Sickle Cell Anemia ◽

Neutrophil Count ◽

Dose Escalation ◽

Research Funding ◽

Sub Saharan Africa ◽

Fixed Dose ◽

Alpha Thalassemia ◽

Hydroxyurea Treatment ◽

Thalassemia Trait ◽

Sub Saharan

Abstract Introduction: Many children with sickle cell anemia (SCA) require blood transfusions, which carry risks and utilize a scarce resource globally, particularly in Africa. Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) has documented the safety, feasibility, and benefits of hydroxyurea for children with SCA living in sub-Saharan Africa. In REACH, hydroxyurea escalated to maximum tolerated dose (MTD) significantly decreased vaso-occlusive events, malaria, and death; transfusions were decreased by ~70% over 30 months of treatment when compared to the 2-month screening period. Characterizing how hydroxyurea reduces transfusion needs in REACH could contribute to improved clinical understanding and lead to better outcomes, a decreased transfusion burden, and preservation of the blood supply in these limited-resource settings. Methods: Transfusions were recorded prospectively in the REACH REDCap electronic database. Using time-varying predictors and landmark analysis, transfusions during screening and treatment were analyzed by clinical site, calendar month, age, gender, splenomegaly, hydroxyurea dose, MTD status, baseline and latest laboratory values (Hemoglobin, MCV, HbF, absolute neutrophil count, and platelets, all measured at least 30 days prior to the transfusion), alpha thalassemia trait, and G6PD deficiency. Incidence rate ratios (IRR) were calculated for treatment periods compared to screening. Univariate relationships were assessed using the Anderson-Gill model, plus multiple regression to estimate Hazard Ratios (HR) with 95% confidence intervals (CI's). Results: A total of 635 children with SCA enrolled in REACH, and 606 started hydroxyurea treatment. During screening, 48 transfusions were given to 43 children, and during the treatment phase 405 transfusions were administered to 214 children over an average treatment time of 5.2 ± 1.3 years. The transfusion rate was 43.3 per 100 patient-years during screening, which decreased to 22.0 per 100 patient-years during the initial fixed dose treatment period (IRR = 0.50; 95%CI = 0.35-0.74, p<0.001 compared to screening) and then decreased further to 12.1 per 100 patient-years during the dose escalation period (IRR = 0.28; 95%CI = 0.21-0.39, p<0.001 compared to screening; IRR = 0.54; 95%CI = 0.43-0.73, p<0.001 compared to fixed-dose). For every 100 children treated for a year with hydroxyurea during dose escalation, there were 31.4 fewer transfusions compared to the untreated screening period. Comparison of the indications for transfusion between the screening and treatment periods revealed transfusions administered for anemia decreased from a rate of 26.1 to 5.1 per 100 patient-years (p<0.001), while transfusions for malaria trended toward a decrease from 7.2 to 3.8 per 100 patient-years (p=0.08). Lower transfusion rates on hydroxyurea were associated with higher hemoglobin concentration (HR = 0.72 per 1g/dL increase; 95%CI = 0.65-0.78, p <0.0001) and higher HbF levels (HR = 0.80 per 10% increase, 95%CI = 0.69-0.92, p=0.0071). Those with palpable splenomegaly had higher transfusion rates (HR = 1.58, 95%CI = 1.22-2.03, p=0.0094). Age, gender, alpha thalassemia trait, G6PD deficiency, and neutrophil count were not associated with differences in transfusion rates. Conclusion: Hydroxyurea significantly reduces blood transfusion administration in children with SCA in sub-Saharan Africa, especially when escalated to MTD. Transfusions for the sole indication of anemia decreased significantly on hydroxyurea treatment, likely due to higher treatment-associated hemoglobin levels and decreased hemolysis, and transfusions for malaria also trended toward a decrease. Splenomegaly remains a risk factor for transfusions despite hydroxyurea treatment. Overall, increased access to and implementation of hydroxyurea treatment for children with SCA across sub-Saharan Africa may not only improve individual patient outcomes through reduction in anemia, transfusion burden, and transfusion-associated complications including infections, but may also to help preserve the scarce blood supply for the benefit of the larger population. Disclosures Aygun: Global Blood Therapeutics: Consultancy; Patient Centered Outcomes Research Institute: Research Funding; National Heart, Lung, Blood Institute: Research Funding; National Institute of Nursing Research: Research Funding; bluebird bio, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stuber: ASH Research Collaborative: Consultancy. Ware: Bristol Myers Squibb: Research Funding; Addmedica: Research Funding; Hemex Health: Research Funding; Nova Laboratories: Research Funding; Novartis: Other: DSMB Chair; Editas: Other: DSMB Chair.

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Novel Use of Hydroxyurea in an African Region with Malaria (NOHARM): A Randomized Controlled Trial

Blood ◽

10.1182/blood.v130.suppl_1.759.759 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 759-759

Author(s):

Robert Opoka ◽

Christopher Ndugwa ◽

Teresa S. Latham ◽

Adam Lane ◽

Heather Ann Hume ◽

...

Keyword(s):

Adverse Events ◽

Sickle Cell ◽

Research Funding ◽

Malaria Incidence ◽

Controlled Trial ◽

Sub Saharan Africa ◽

Number Needed To Treat ◽

Hydroxyurea Treatment ◽

Sub Saharan ◽

Double Blinded

Abstract Background. Hydroxyurea treatment is recommended for children with sickle cell anemia (SCA) living in high-resource malaria-free regions, but its safety and efficacy in malaria-endemic settings such as sub-Saharan Africa, where the greatest sickle cell burden exists, remain unknown. In vitro studies suggest hydroxyurea could increase malaria severity, through upregulation of intracellular adhesion molecule 1 (ICAM-1) that facilitates parasite adhesion to endothelium. In addition, hydroxyurea-associated neutropenia could worsen infections that occur in low-resource settings. Methods. NOHARM (NCT01976416) was a randomized, double-blinded, placebo-controlled trial conducted in malaria-endemic Uganda. Children between the ages of 1.00-3.99 years were enrolled, and then received 12-months of blinded treatment with either hydroxyurea or placebo at 20 ± 2.5 mg/kg/day, with dose adjustments in both arms for weight gain and hematological toxicities. All participants received standard care for SCA including folic acid, penicillin prophylaxis, and pneumococcal vaccination. For malaria prophylaxis, children received insecticide-treated mosquito nets and monthly sulphadoxine-pyrimethamine. The primary outcome was incidence of clinical malaria. Secondary outcomes included SCA-related adverse events, clinical and laboratory effects, and hematological toxicities. After completing the blinded treatment phase, all participants were offered open-label hydroxyurea, as per local Ethics Committee recommendations. Results. Study participants (median age 2.2 years) received either hydroxyurea (N=104) or placebo (N=103) for 12-months. Malaria occurred at a low rate throughout the study. The malaria incidence did not differ between children on hydroxyurea [0.05 episodes/child/year, 95% CI (0.02, 0.13)] versus placebo [0.07 episodes/child/year (0.03, 0.16)]. The hydroxyurea/placebo malaria incidence rate ratio was 0.7 [(0.2, 2.7), p=0.61], and time to infection did not differ significantly between treatment arms. A composite SCA-related clinical outcome (vaso-occlusive painful crisis, dactylitis, acute chest syndrome, splenic sequestration, or blood transfusion) was less frequent with hydroxyurea (45%) than placebo (69%, p=0.001). For individual clinical events, vaso-occlusive pain and hospitalizations were significantly less frequent with hydroxyurea than placebo; the number needed to treat to prevent one hospitalization was 6.4, while the number needed to treat to prevent a SCA-related event was 2.5. Serious adverse events, sepsis episodes, and dose-limiting toxicities were similar between treatment arms. Specifically, low hemoglobin (<6.0 g/dL) occurred more frequently in children receiving placebo than hydroxyurea, while the frequencies of neutropenia, thrombocytopenia and reticulocytopenia did not differ significantly between treatment arms. Three deaths occurred (two hydroxyurea, one placebo, none from malaria). Children receiving hydroxyurea had significantly increased hemoglobin concentration and fetal hemoglobin, along with decreased leukocytes, neutrophils, and reticulocytes. Conclusions. In this prospective randomized double-blinded placebo-controlled trial of young children with SCA living in Uganda, hydroxyurea therapy was both safe and efficacious. Based on these NOHARM data, hydroxyurea treatment appears safe for children with SCA living in malaria-endemic sub-Saharan Africa, without increased risk for severe malaria, infections, or adverse events. Hydroxyurea provides predicted SCA-related laboratory and clinical efficacy, but the optimal dosing and monitoring regimens for affected children in Africa remain undefined. Disclosures Ware: Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding; Addmedica: Research Funding; Nova Laboratories: Consultancy; Global Blood Therapeutics: Consultancy.

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

Blood ◽

10.1182/blood-2019-129937 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 993-993

Author(s):

Leon Tshilolo ◽

George A. Tomlinson ◽

Patrick T. McGann ◽

Teresa S. Latham ◽

Peter Olupot-Olupot ◽

...

Keyword(s):

Board Of Directors ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Growth Parameters ◽

Sub Saharan Africa ◽

Advisory Committees ◽

Splenic Enlargement ◽

Hydroxyurea Treatment ◽

Lower Blood ◽

Sub Saharan

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

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Optimizing hydroxyurea therapy for sickle cell anemia

Hematology ◽

10.1182/asheducation-2015.1.436 ◽

2015 ◽

Vol 2015 (1) ◽

pp. 436-443 ◽

Cited By ~ 19

Author(s):

Russell E. Ware

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Fetal Hemoglobin ◽

Maximum Tolerated Dose ◽

Sub Saharan Africa ◽

Future Research ◽

Published Evidence ◽

Treatment Indications ◽

Hydroxyurea Treatment ◽

Hydroxyurea Therapy

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

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Genetic Variants That Influence Fetal Hemoglobin Expression from Hydroxyurea Treatment

Blood ◽

10.1182/blood-2020-143139 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 8-9

Author(s):

Anu Marahatta ◽

Jonathan M. Flanagan ◽

Thad A. Howard ◽

Nicole Mortier ◽

William Schultz ◽

...

Keyword(s):

Dose Escalation ◽

Genetic Variants ◽

Research Funding ◽

Fetal Hemoglobin ◽

Sub Saharan Africa ◽

Z Score ◽

Genome Wide ◽

Hydroxyurea Treatment ◽

Hbf Induction ◽

Treatment Responses

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<0.001) in the discovery step were then selected for replication using an additional African cohort (n=168). Variants that were significant in both the discovery and replication cohorts were then verified using a cohort of US (n=200) and Caribbean (n=86) children with SCA, identifying genomic loci with consistent associations for HbF induction across all cohorts. Results: In the discovery GWAS step, no variant passed genome wide significance (p<10-8) for the MTD HbF phenotype, including no significant associations with known genetic modifiers of endogenous HbF (BCL11A, HBS1L-MYB, HBG2). A total of 2057 low frequency and common SNVs had at least nominal association (p<0.001) with the hydroxyurea treatment responses, of which 44 were also significant (p<0.05) and with the same direction of association with HbF induction in the replication cohort. In the final verification step, these 44 significant variants were then tested in additional independent SCA cohorts with at least three demonstrating a strong effect (Table 1). The rs10978155 variant in the PTPRD gene and the rs55695413 variant in the RPH3AL gene were both consistently associated (p<0.05) with lower HbF treatment responses. Another variant (rs75442556) near the ELL2 gene approached statistical significance (p=0.08) in the verification cohort and was also associated with lower HbF expression. The allele frequencies for these PTPRD, RPH3AL, and ELL2 variants were 0.32, 0.017, and 0.25, respectively, and did not affect baseline HbF levels. Children with these PTPRD, RPH3AL, and ELL2 genetic variants still had substantial HbF induction, but achieved lower hydroxyurea MTD HbF levels on average by 2.9%, 9.8%, and 2.7%, respectively. 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.

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Optimizing hydroxyurea therapy for sickle cell anemia

Hematology ◽

10.1182/asheducation.v2015.1.436.3917688 ◽

2015 ◽

Vol 2015 (1) ◽

pp. 436-443 ◽

Cited By ~ 8

Author(s):

Russell E. Ware

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Fetal Hemoglobin ◽

Maximum Tolerated Dose ◽

Sub Saharan Africa ◽

Future Research ◽

Published Evidence ◽

Treatment Indications ◽

Hydroxyurea Treatment ◽

Hydroxyurea Therapy

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

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Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia

Blood ◽

10.1182/blood-2011-07-364190 ◽

2011 ◽

Vol 118 (18) ◽

pp. 4985-4991 ◽

Cited By ~ 89

Author(s):

Russell E. Ware ◽

Jenny M. Despotovic ◽

Nicole A. Mortier ◽

Jonathan M. Flanagan ◽

Jin He ◽

...

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Oral Absorption ◽

Fetal Hemoglobin ◽

Maximum Tolerated Dose ◽

Interpatient Variability ◽

Nucleotide Polymorphisms ◽

Hydroxyurea Treatment ◽

Treatment Responses ◽

Hydroxyurea Therapy

Abstract Hydroxyurea therapy has proven laboratory and clinical efficacies for children with sickle cell anemia (SCA). When administered at maximum tolerated dose (MTD), hydroxyurea increases fetal hemoglobin (HbF) to levels ranging from 10% to 40%. However, interpatient variability of percentage of HbF (%HbF) response is high, MTD itself is variable, and accurate predictors of hydroxyurea responses do not currently exist. HUSTLE (NCT00305175) was designed to provide first-dose pharmacokinetics (PK) data for children with SCA initiating hydroxyurea therapy, to investigate pharmacodynamics (PD) parameters, including HbF response and MTD after standardized dose escalation, and to evaluate pharmacogenetics influences on PK and PD parameters. For 87 children with first-dose PK studies, substantial interpatient variability was observed, plus a novel oral absorption phenotype (rapid or slow) that influenced serum hydroxyurea levels and total hydroxyurea exposure. PD responses in 174 subjects were robust and similar to previous cohorts; %HbF at MTD was best predicted by 5 variables, including baseline %HbF, whereas MTD was best predicted by 5 variables, including serum creatinine. Pharmacogenetics analysis showed single nucleotide polymorphisms influencing baseline %HbF, including 5 within BCL11A, but none influencing MTD %HbF or dose. Accurate prediction of hydroxyurea treatment responses for SCA remains a worthy but elusive goal.

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Hydroxyurea Therapy for Children With Sickle Cell Anemia in Sub‐Saharan Africa: Rationale and Design of the REACH Trial

Pediatric Blood & Cancer ◽

10.1002/pbc.25705 ◽

2015 ◽

Vol 63 (1) ◽

pp. 98-104 ◽

Cited By ~ 17

Author(s):

Patrick T. McGann ◽

Léon Tshilolo ◽

Brigida Santos ◽

George A. Tomlinson ◽

Susan Stuber ◽

...

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Sub Saharan Africa ◽

Sub Saharan ◽

Hydroxyurea Therapy

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Realizing Effectiveness across Continents with Hydroxyurea (REACH): A Prospective Multi-National Trial of Hydroxyurea for Sickle Cell Anemia in Sub-Saharan Africa

Blood ◽

10.1182/blood-2018-99-113818 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3-3

Author(s):

Leon Tshilolo ◽

George Tomlinson ◽

Thomas N. Williams ◽

Brigida Santos ◽

Peter Olupot-Olupot ◽

...

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Research Funding ◽

Advisory Board ◽

Sub Saharan Africa ◽

Primary Study ◽

Global Burden ◽

Average Dose ◽

Clinical Events ◽

Sub Saharan

Abstract 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 <4.0x109/L or absolute reticulocyte count <150x109/L. A total of 515 participants (85%) achieved MTD at an average dose of 22.5±4.9 mg/kg/day (IQR 18.5-26.1, range 11.8-34.0 mg/kg/day); the average time to MTD was 11 months from treatment initiation. The primary safety endpoint was hematological dose limiting toxicities (DLT) in the first 133 children at each site. Only 4.9% of REACH participants had DLT during the first 3 months of treatment, favorable to the predicted 20-30% based on smaller US pediatric studies with fewer patient-years of observation including HUG-KIDS, HUSOFT, and BABY HUG. Overall, hydroxyurea was well-tolerated with no excess lab toxicities, with 0.18 recorded toxicities/year during 111 patient-years of screening and 0.22 toxicities/year during 1438 patient-years of treatment. Lab benefits of hydroxyurea included clinically significant increases in hemoglobin concentration, mean corpuscular volume, and fetal hemoglobin, plus significant decreases in white blood cell count, neutrophils, and reticulocytes. Clinical benefits were also observed, as rates of vaso-occlusive pain, acute chest syndrome, and transfusions all decreased ~50% during the treatment phase. Unexpectedly, the rate and severity of malaria also decreased; malaria declined from 47.8 to 22.3 events per 100 patient-years, while clinically severe malaria (Grade 3 or above) fell from 9.9 to 2.5 events per 100 patient-years during treatment. Effects on all-cause mortality were also pronounced, with 3.6 deaths per 100 patient-years during screening decreasing to 1.1 deaths per 100 patient-years on hydroxyurea. 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.

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Building Capacity and Assessing Stroke Risk with Transcranial Doppler Ultrasonography in Sub-Saharan Africa: The Reach Experience

Blood ◽

10.1182/blood-2020-142318 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 17-18

Author(s):

Brigida Santos ◽

Maria Nakafeero ◽

Adam Lane ◽

Leon Tshilolo ◽

Thomas N. Williams ◽

...

Keyword(s):

Transcranial Doppler ◽

Research Funding ◽

Stroke Risk ◽

Fetal Hemoglobin ◽

Sub Saharan Africa ◽

Low Resource Settings ◽

Low Resource ◽

Hydroxyurea Treatment ◽

Hands On ◽

Sub Saharan

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 (<170 cm/sec), conditional (170-199 cm/sec), or abnormal (≥200 cm/sec) and correlated with laboratory and clinical parameters. 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<0.0001), age (r = -0.23, p<0.0001), and fetal hemoglobin (r = -0.12, p=0.027); and positively correlated with reticulocytes (r = 0.17, p<0.001). No gender difference was noted, but alpha thalassemia trait (2-gene deletion) was associated with significantly lower TCD velocities, while G6PD A- deficiency had no observed effects. 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.

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