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

Blood ◽  
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.

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

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 17-17
Author(s):  
Banu Aygun ◽  
George A. Tomlinson ◽  
Patrick T. McGann ◽  
Leon Tshilolo ◽  
Thomas N. Williams ◽  
...  
Keyword(s):  
Sickle Cell Anemia ◽  
Research Funding ◽  
Reticulocyte Count ◽  
Sub Saharan Africa ◽  
Laboratory Monitoring ◽  
Hydroxyurea Treatment ◽  
Thalassemia Trait ◽  
Treatment Responses ◽  
Sub Saharan ◽  
Hydroxyurea Therapy

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.

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

Blood ◽  
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.

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

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

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

Genetic Variants That Influence Fetal Hemoglobin Expression from Hydroxyurea Treatment

Blood ◽  
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.

scholarly journals Effects of Hydroxyurea Treatment on Malaria Infections in Sub-Saharan Africa

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 522-522
Author(s):  
Peter Olupot-Olupot ◽  
George A. Tomlinson ◽  
Teresa S. Latham ◽  
Patrick T. McGann ◽  
Brigida Santos ◽  
...  
Keyword(s):  
Risk Factor ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Blood Smear ◽  
Malaria Risk ◽  
Sub Saharan Africa ◽  
Advisory Committees ◽  
Hydroxyurea Treatment ◽  
Sub Saharan ◽  
Research Drug

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.

scholarly journals Hydroxyurea to Reduce Stroke Risk in Tanzanian Children with Sickle Cell Anemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 20-21
Author(s):  
Emmanuela E. Ambrose ◽  
Luke R. Smart ◽  
Primrose Songoro ◽  
Idd Shabani ◽  
Protas Komba ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Dose Escalation ◽  
Stroke Prevention ◽  
Stroke Risk ◽  
Sub Saharan Africa ◽  
Costal Margin ◽  
Screening Programs ◽  
Therapeutic Benefits ◽  
Sub Saharan

Introduction: Sickle cell anemia (SCA) is highly prevalent in sub-Saharan Africa with >300,000 annual births, and substantial morbidity and mortality due to limited resources. The burden of stroke in this population is of particular concern, given the devastating clinical and neurocognitive sequelae of these events. Hydroxyurea, a potent disease modifying therapy for SCA, is safe and feasible for low-resource and malarial endemic countries within sub-Saharan Africa and when used at maximum tolerated dose (MTD), decreases the incidence of acute painful vaso-occlusive events, infections, malaria, transfusions, hospitalizations, and death. Whether hydroxyurea can prevent primary stroke in SCA within Africa has not yet been determined, due in part to lack of stroke screening programs using transcranial Doppler (TCD) ultrasonography. If effective, hydroxyurea would have even more therapeutic benefits for children with SCA, particularly in settings where blood is not available, affordable, or safe. We designed the Stroke Prevention with Hydroxyurea Enabled through Research and Education (SPHERE) trial to determine the stroke risk among Tanzanian children using TCD screening and to investigate the effects of hydroxyurea to reduce that risk. Methods: The SPHERE trial (NCT03948867) is a single center prospective phase 2 open-label screening and treatment pilot study at Bugando Medical Centre, a teaching and referral hospital in Mwanza, Tanzania. Children 2-16 years old with SCA consented to TCD screening by locally trained and certified examiners; recent febrile illness, red cell transfusion, or hospitalization were temporary exclusions. Study participants with maximum Time-Averaged Mean Velocity (TAMV) on TCD exam categorized as conditional (170-199 cm/sec) or abnormal (≥200 cm/sec) are offered hydroxyurea with escalation to MTD, while those with normal TCD screening exams will be rescreened annually. Hydroxyurea is initiated at ~20 mg/kg/day using 500 mg capsules and a weekly dosing calculator, then escalated every 8 weeks by 5 mg/kg/day up to 35 mg/kg/day. Children on hydroxyurea are seen monthly during dose escalation and every 3 months after reaching MTD. The primary endpoint is change in TCD velocity after 12 months of hydroxyurea therapy. Secondary endpoints include changes in splenic volume and filtrative function; change in renal function; incidence of infection, especially malaria; hydroxyurea pharmacokinetics; and genetic modifiers of disease including pharmacogenomics. Results: From April 2019 to April 2020, a total of 202 children underwent TCD screening, exceeding the projected enrollment pace and goal (Figure). The average age (mean ± SD) at enrollment was 6.8 ± 3.5 years, and 53% were female. A majority had previous dactylitis (75%), painful vaso-occlusive episode (93%), blood transfusion (68%), and malaria (89%). Recurrent hospitalization was common with 30% having >5 previous hospitalizations. Only 4% had previously used hydroxyurea. Baseline labs included hemoglobin = 7.8 ± 1.3 g/dL, HbF = 9.3 ± 5.4 %, and ANC = 5.5 ± 2.4 x 109/L. Baseline assessment revealed a palpable spleen in 46 children (23%), and most of these (29) were ≥5 cm below the costal margin. Abdominal ultrasonography documented splenic tissue in 91% of children with an average volume of 101 ± 123 mL (range 8-1045). TCD examinations were performed in all children at enrollment with average TAMV of 148 ± 27 cm/sec [median 144, IQR 130-169 cm/sec] with 76% normal, 21% conditional, 2% abnormal, and 1% inadequate exams. Of 47 children eligible for hydroxyurea for elevated TCD velocities, 45 successfully initiated treatment, while 1 lived too far away for regular visits, and 1 had low blood counts from acute splenic sequestration and died before initiating study treatment. Conclusion: Children with SCA in Tanzania have a high risk for primary stroke. Identification of elevated TCD velocities through screening by local trained certified examiners, coupled with initiation of hydroxyurea treatment with dose escalation to MTD, offers a feasible and affordable means by which to lower TCD velocities and reduce primary stroke risk. Now fully enrolled, SPHERE has built local clinical capacity, research infrastructure and high-quality TCD screening, and will prospectively determine the benefits of hydroxyurea for stroke prevention, as a prelude for expanding hydroxyurea access for children with SCA in Tanzania. Figure Disclosures No relevant conflicts of interest to declare.

scholarly journals Genetic Causes of Anemia in Malawian Children Less Than 5 Years of Age: Results from the Malawi Demographic and Health Survey

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 313-313 ◽  
Author(s):  
Patrick T. McGann ◽  
Anne M. Williams ◽  
Kathryn E. McElhinney ◽  
Laurel Romano ◽  
Julia Woodall ◽  
...  
Keyword(s):  
G6pd Deficiency ◽  
Research Funding ◽  
Sickle Cell Trait ◽  
Hemoglobin Concentration ◽  
Sub Saharan Africa ◽  
Rt Pcr ◽  
Entire Cohort ◽  
Genetic Causes ◽  
Alpha Thalassemia ◽  
Sub Saharan

Abstract CCHMC IRB Protocol Background: Anemia is an important contributor to morbidity and mortality among young children in sub-Saharan Africa. Although nutritional and environmental etiologies of anemia are common, the causes are multi-factorial and include inherited blood disorders that are thought to be prevalent across sub-Saharan Africa.There are few data across Africa, including Malawi, regarding the prevalence of inherited blood disorders and contributions to anemia burden. Methods: The Malawi Demographic and Health Survey (MHDS) was conducted between October 2015 and February 2016 by the Malawi National Statistical Office in collaboration with the Community Health Services Unit of the Ministry of Health. The MHDS included a sub-study to investigate the nutritional and genetic causes of anemia. For the substudy, 105 clusters were randomly selected from the MHDS sample. In each cluster, 21 households were randomly selected and all eligible children 6-59 months were enrolled. Following visits to each household for informed consent, children were brought to the field lab for assessment of anthropometry and venous blood collection. Hemoglobin concentration was measured by the Hemocue device, and 200µL was spotted onto dried bloodspots (DBS). The DBS were frozen, and samples were transported to the US for DNA extraction and genetic analyses. DNA was extracted from DBS using two 3mm punches and frozen at -85C. Genetic causes of anemia were determined using a combination of PCR-based techniques: HbS allele (rs334) using TaqMan RT-PCR analysis; G6PD deficiency (A- variant) using 3 TaqMan RT-PCR analyses for G202A (rs1050829) to distinguish A and B isoforms followed by A376G (rs1050828) to identify the A- variant, and gender (SRY_VIC, ABCD1_CCHS0H-FAM); and deletional -α3.7-thalassemia using a copy-number variant RT-PCR assay with probes inside and outside the α-globin region (Hs03947236_cn, HbA_Tri_CCPAD0C). Results:Of 1263 children for whom informed consent was obtained, 1137 ultimately had adequate bloodspots collected for molecular analyses. The mean (±SD) hemoglobin concentration for the entire cohort was 11.5±1.7 g/dL. Twenty nine percent of all children (355/1205) were anemic (Hb<11 g/dL). A majority of anemic children (212/355, 59.7%) had mild anemia (Hb 10-11 g/dL), while 134 (37.7%) had moderate anemia (Hb 7.0-9.9 g/dL) and 2.5% (9 children) had severe anemia (Hb<7 g/dL). The allele frequency for the G6PD A- variant was 0.19 for the entire cohort, while G6PD deficiency was present in 20.8% of males and 2.5% of females with a female carrier rate of 32.2%. Alpha-thalassemia trait was found in 33.5% of children, including 25.6% with a single α-globin gene deletion (α-/αα) and 8.0% of children with a two gene deletion (α-/α-). The HbS allele frequency was 0.05 with a carrier rate (sickle cell trait, HbAS) of 10.1%. The table summarizes the hemoglobin concentrations according to each inherited hematological condition (for the samples that had both genetic analyses and hemoglobin concentrations measured). Alpha-thalassemia status was associated with a significantly lower hemoglobin concentration compared to non-carriers. Further data on the frequency of other common nutritional deficiencies (iron, vitamin A) and infectious (malaria, hookworm) causes of anemia are currently being analyzed. Conclusions: Anemia is a common and multi-factorial problem in Malawian children. In addition to nutritional and other environmental factors, this study demonstrates that genetic causes of anemia are common in this cohort of children. As expected, alpha-thalassemia trait is associated with decreased hemoglobin concentration, while steady state G6PD deficiency and sickle cell trait are not associated with anemia. The importance and frequency of these inherited hematological disorders is underappreciated in Malawi and across sub-Saharan Africa and should be considered when evaluating the prevalence and management of anemia in African children. Larger scale surveillance of these disorders with careful geospatial mapping will be important to further describe the incidence, co-inheritance, and clinical significance of these common inherited hematological disorders. Table. Table. Disclosures Ware: Addmedica: Research Funding; Biomedomics: Research Funding; Global Blood Therapeutics: Consultancy; Nova Laboratories: Consultancy; Bristol Myers Squibb: Research Funding; Bayer Pharmaceuticals: Consultancy.

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

Blood ◽  
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.

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

2020 ◽  
Vol 382 (26) ◽  
pp. 2524-2533 ◽  
Author(s):  
Chandy C. John ◽  
Robert O. Opoka ◽  
Teresa S. Latham ◽  
Heather A. Hume ◽  
Catherine Nabaggala ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Dose Escalation ◽  
Sub Saharan Africa ◽  
Sub Saharan

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

Blood ◽  
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 &gt;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 (&lt;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&lt;0.0001), age (r = -0.23, p&lt;0.0001), and fetal hemoglobin (r = -0.12, p=0.027); and positively correlated with reticulocytes (r = 0.17, p&lt;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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