Effect of Hydroxyurea Therapy on the Incidence of Infections in Ugandan Children with Sickle Cell Anaemia

Abstract Hydroxyurea is efficacious against sickle cell anaemia (SCA)-related complications in African children. Prior studies demonstrated conflicting results on the effect of hydroxyurea on risk of infection, the most common cause of morbidity and mortality in African children with SCA. We evaluated the incidence of infections before and after starting hydroxyurea in 117 children aged 1-5 years with SCA enrolled in the Zinc for Infection Prevention in Sickle cell anaemia (ZIPS) clinical trial that received zinc or placebo treatment for one year (Clinicaltrials.gov, NCT03528434). Children were enrolled between March 2018 and November 2019 and initiated on hydroxyurea (20 mg/kg/day) if they met Uganda SCA guideline criteria for hydroxyurea treatment at any time during the study. We compared the incidence of infections before and after hydroxyurea therapy, adjusting for zinc treatment. Overall, the mean duration on hydroxyurea was 223.8 (85.2) person days. The mean(SD) incidence of any severe/invasive infections (infections meeting strict clinical and laboratory or radiological diagnostic criteria) was 6.2(9.0) vs. 1.9(2.3) infections per child per year before and after hydroxyurea (incidence rate ratio [IRR]: 0.40, 95%CI: 0.29-0.54, p<0.001), including a decrease in the incidence of bacteremia [IRR: 0.05] malaria, [IRR 0.28], cellulitis [IRR: 0.24], gastroenteritis [IRR: 0.41], pharyngitis [IRR: 0.59] and sinusitis [IRR: 0.38] (all p<0.05). Similarly, the incidence of clinically defined infections (infections meeting clinical but not laboratory/radiological criteria) decreased after hydroxyurea, (IRR: 0.49, 0.41-0.59), influenced primarily by large reductions in the incidence of lower and upper respiratory tract infections (p<0.001 for both). As expected, hydroxyurea treatment was also associated with a decrease in complications of SCA, including vaso-occlusive crises, hospitalizations and transfusions (all p<0.001). There was no interaction between zinc and hydroxyurea therapy on risk of infection and SCA-related complications. In Ugandan children with SCA, hydroxyurea therapy not only decreases the incidence of SCA-related complications, but also substantially reduces the incidence of infections. Research to understand the underlying mechanisms of protection from hydroxyurea against infection and exploration of its potential use for infection prevention is warranted. Disclosures 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.

Download Full-text

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.

Download Full-text

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.

Download Full-text

The Iron Status of Sickle Cell Anaemia Patients in Ilorin, North Central Nigeria

Advances in Hematology ◽

10.1155/2015/386451 ◽

2015 ◽

Vol 2015 ◽

pp. 1-5 ◽

Cited By ~ 3

Author(s):

Musa A. Sani ◽

James O. Adewuyi ◽

Abiola S. Babatunde ◽

Hannah O. Olawumi ◽

Rasaki O. Shittu

Keyword(s):

Sickle Cell ◽

Serum Ferritin ◽

Transferrin Receptor ◽

Sickle Cell Anaemia ◽

Iron Status ◽

Serum Transferrin ◽

Cross Sectional ◽

Serum Transferrin Receptor ◽

Iron Deficient ◽

The Mean

Objectives. Sickle cell anaemia (SCA) is one of the commonest genetic disorders in the world. It is characterized by anaemia, periodic attacks of thrombotic pain, and chronic systemic organ damage. Recent studies have suggested that individuals with SCA especially from developing countries are more likely to be iron deficient rather than have iron overload. The study aims to determine the iron status of SCA patients in Ilorin, Nigeria.Methods. A cross-sectional study of 45 SCA patients in steady state and 45 non-SCA controls was undertaken. FBC, blood film, sFC, sTfR, and sTfR/log sFC index were done on all subjects.Results. The mean patients’ serum ferritin (589.33 ± 427.61 ng/mL) was significantly higher than the mean serum ferritin of the controls (184.53 ± 119.74 ng/mL). The mean serum transferrin receptor of the patients (4.24 ± 0.17 μg/mL) was higher than that of the controls (3.96 ± 0.17 μg/mL) (p=0.290). The mean serum transferrin receptor (sTfR)/log serum ferritin index of the patients (1.65 ± 0.27 μg/mL) was significantly lower than that of the control (1.82 ± 0.18 μg/mL) (p=0.031).Conclusion. Iron deficiency is uncommon in SCA patients and periodic monitoring of the haematological, biochemical, and clinical features for iron status in SCA patients is advised.

Download Full-text

Chronic Pain Is An Independent Predictor of Lower 6 Minute Walk Distance In Patients with Sickle Cell Disease: Results From Walk-PHaSST Study

Blood ◽

10.1182/blood.v116.21.2658.2658 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2658-2658

Author(s):

Lakshmanan Krishnamurti ◽

Ruchika Goel ◽

Oswaldo Castro ◽

Robyn J. Barst ◽

Erika Berman Rosenzweig ◽

...

Keyword(s):

Chronic Pain ◽

Exercise Capacity ◽

Sickle Cell ◽

Acute Pain ◽

Research Funding ◽

History Of ◽

Pain Crisis ◽

The Mean ◽

Minute Walk Distance ◽

Minute Walk

Abstract Abstract 2658 Introduction: Six minute walk distance (6MWD), is a measure of exercise capacity commonly used as an endpoint in pulmonary hypertension (PH) clinical trials. Many patients with sickle cell disease (SCD) have acute pain crises or chronic pain syndromes that impair their quality of life. While patients with SCD who are undergoing screening for PH are generally screened in steady state, i.e., when they have not had a recent pain crisis, the impact of chronic pain on exercise capacity in this group of patients has not been previously evaluated. Methods: walk-PHaSST was a multi-center screening study designed to identify subjects with SCD at increased risk for symptomatic PH, defined by a tricuspid regurgitant velocity (TRV) ≥ 2.7 m/sec and 6MWD between 150–500 meters, for enrollment in a double-blind placebo controlled trial of sildenafil. The primary endpoint was the change in 6MWD after 16 weeks of treatment. We examined the relationship between subjects' self-reported acute and chronic pain and baseline 6MWD in the screened SCD patients in walk-PHaSST. Results: For 90% of subjects, the information about pain was reported by the patient or parent/family member. Documentation of pain management and utilization of services was verified from medical records in 10% of subjects. Ninety four percent of all subjects reported having a history of acute sickle cell pain crises; 6% reported never having had an acute pain crisis. For the subjects who reported a history of acute pain crises, the ‘typical’ acute pain rating on a scale of 0 to 10 was ≥ 7 (maximum 10) for 77% of this subset of subjects. A total of 342 (50%) subjects reported not having had any pain crises in the preceding week. Of 720 subjects screened medical history and 6 MWD was available in 673 patients. Of these 633 (94%) subjects did not report having had a pain crisis requiring an emergency department visit or hospitalization in the preceding week. A total of 39% of subjects reported chronic sickle cell related pain; no rating was reported for chronic pain. 88% of patients reported using medications for pain control while 15% reported using non-drug therapy including physical therapy in 3%, alternative therapy in 2%, acupuncture in 2% and hypnosis in < 1% of patients. The mean 6MWD for the screened population was 439 meters (median 438 m, range 123–713 m). A total of 171/673 (26%) subjects had a 6MWD >500 meters, which was above the screening cut-off for enrollment in the main interventional trial. By univariate analysis, subjects reporting chronic pain had a significant lower odds ratio for walking > 500 meters (OR 0.637, 95% C.I 0.44–0.99); a similar observation was seen with those subjects with a history of acute pain crises (OR 0.47, 95% C.I 0.24–0.91). Multivariable logistic regression analysis revealed a significant inverse relationship between chronic pain but not acute pain and 6MWD after adjusting for age, TRV, gender, hematocrit and smoking history (See Table 1). The mean 6MWD decreased by 27 meters with self reported chronic pain after adjusting for TRV, age, gender, hematocrit and 6MWD. Conclusions: TRV is a known predictor of 6MWD. However, these data suggest that patient self reported sickle cell related chronic pain is also an independent predictor of 6MWD. This relationship raises interesting questions about the potentially confounding effects of pain on exercise capacity as assessed by the 6MW test. Further study is warranted to investigate an association between chronic pain and exercise capacity in SCD as well as exploration of appropriate endpoints for future clinical trials in patients with SCD and suspected symptomatic PH. Disclosures: Barst: Pfizer: Consultancy, Research Funding. Rosenzweig:Pfizer: Research Funding. Badesch:Pfizer: Honoraria, Research Funding. Hassell:Novartis: Research Funding.

Download Full-text

Pharmacokinetics-Based Individualized Dosing Strategy to Predict Maximum Tolerated Dose of Hydroxyurea in Children with Sickle Cell Anemia

Blood ◽

10.1182/blood.v126.23.982.982 ◽

2015 ◽

Vol 126 (23) ◽

pp. 982-982

Author(s):

Patrick T. McGann ◽

Min Dong ◽

Russell E. Ware ◽

Alexander A Vinks

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Research Funding ◽

Maximum Tolerated Dose ◽

Serum Concentrations ◽

Individualized Dosing ◽

Clinical Benefits ◽

Dosing Strategy ◽

Sampling Times ◽

Hydroxyurea Therapy

Abstract Background: Hydroxyurea is the primary disease-modifying therapy for adults and children with sickle cell anemia (SCA). Recent NHLBI guidelines include a recommendation for expanded hydroxyurea use, particularly for young children. The laboratory and clinical benefits of hydroxyurea therapy are optimized when escalated to maximum tolerated dose (MTD), but the process of dose escalation requires expertise and frequent laboratory tests. The time to reach MTD using traditional empirical escalation usually takes >6 months, which can delay the laboratory and clinical benefits. In addition, all children with good adherence at MTD will respond to hydroxyurea, but with substantial interpatient variability in both the MTD itself and the %HbF levels achieved, suggesting important individual differences in pharmacokinetics (PK) that contribute to this phenotypic variability. Objective: The primary objective of this study was to develop an individualized Bayesian adaptive dosing strategy to reduce the time required to reach hydroxyurea MTD for children with SCA. Achieving this objective required the development of a population PK model and identification of the most informative sampling times for Bayesian estimation order to reduce the number of observations required for robust estimation of hydroxyurea PK parameters for individual patients. Methods: PK data at baseline from 96 children with SCA enrolled in the prospective Hydroxyurea Study of Long-term Effects (HUSTLE, NCT00305175) were used to develop a population PK model using nonlinear mixed effects modeling (NONMEM 7.2). Patient demographics and clinical chemistry measurements were included for covariate analyses. The final model was validated by bootstrap analysis and visual predictive check. To identify the optimal sampling times and number of samples required to robustly estimate individual PK parameters and total hydroxyurea exposure (AUC), a D-optimal design analysis was performed using the final PK model with constraints of clinical feasibility. Results: Hydroxyurea PK profiles were best described by a one compartment model with Michaelis Menten elimination and a transit absorption model. Hydroxyurea serum concentrations showed substantial interpatient variability with AUC on Day 1 ranging from 40.0 to 149.2 mg*h/L. The average AUC at MTD (mean ± SD) was 115.7 ± 34.0 mg*h/L, so this value was chosen as the target hydroxyurea AUC for the final PK model-based approach. Of the tested covariates, body weight and cystatin C were identified as significant predictors of hydroxyurea clearance, but neither serum creatinine nor estimated creatinine clearance was identified as predictors of hydroxyurea clearance. D-optimal design indicated that three serum concentrations collected at 15-20 minutes, 50-60 minutes, and 3 hours after oral administration would accurately estimate systemic hydroxyurea exposure. Figure 1 demonstrates an example from a patient, demonstrating the PK profile obtained using the sparse sampling technique (Panel A) and the modeling to predict a dose that would target a AUC of 115 mg*h/L (Panel B). Conclusions: We have established a PK model-based individualized dosing strategy to predict hydroxyurea MTD in children with SCA. Our selective sampling strategy requires only three serum samples to be collected over 3 hours and is therefore more feasible and practical, particularly for very young children, than traditional hydroxyurea PK analysis that requires frequent blood collections over 6-8 hours. This novel Bayesian approach is being prospectively evaluated in the Therapeutic Response Evaluation and Adherence Trial (TREAT, ClinicalTrials.gov NCT02286154). In TREAT, hydroxyurea concentrations are measured using HPLC after a single oral dose of 20 mg/kg, requiring only 3 fingerstick blood samples over 3 hours for accurate assessment of each patient's unique hydroxyurea PK profile. The predicted MTD is then calculated based on the amount of drug required to meet the target AUC. This strategy has the potential to individualize therapy and optimize the dose titration of hydroxyurea therapy for children with SCA, such that the laboratory and clinical benefits at MTD are achieved more quickly. Disclosures Off Label Use: Hydroxyurea is not FDA-approved for children with sickle cell anemia. Ware:Bristol Myers Squibb: Research Funding; Biomedomics: Research Funding; Eli Lilly: Other: DSMB membership; Bayer Pharmaceuticals: Consultancy.

Download Full-text

Ndepth: Novel Dose Escalation to Predict Treatment with Hydroxyurea

Blood ◽

10.1182/blood.v126.23.3419.3419 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3419-3419

Author(s):

Alex George ◽

Bogdan R. Dinu ◽

Russell E. Ware

Keyword(s):

Sickle Cell ◽

Dose Escalation ◽

Alternative Treatment ◽

Research Funding ◽

Young Patients ◽

Prediction Equation ◽

Published Data ◽

Safety And Efficacy ◽

Dose Prediction ◽

Hydroxyurea Therapy

Abstract Several clinical trials have demonstrated that hydroxyurea therapy offers significant benefits for infants, children, and adolescents with sickle cell anemia. Patients on hydroxyurea who achieve a stable maximum tolerated dose (MTD), defined by a target level of mild marrow suppression, have greater laboratory and clinical benefits than those maintained on a lower dose. A complicating factor in achieving MTD is the significant inter-patient variability in MTD, but no way currently to predict the MTD for individual patients. As such, MTD is commonly achieved by gradual dose escalation in a resource-intensive process that often takes six to twelve months and delays optimal treatment benefits. Using published data from a cohort of previously untreated patients escalated to hydroxyurea MTD, we developed an equation to predict individualized MTD for patients initiating therapy. The primary objective of the Novel Dose Escalation to Predict Treatment with Hydroxyurea (NDEPTH, ClinicalTrials.gov 02042222) clinical trial is to determine the safety and efficacy of the dose-prediction equation. The study is designed as a prospective, open-label, randomized controlled trial consisting of two treatment arms: a Standard Treatment Arm utilizing a current published dose-escalation protocol for achieving hydroxyurea MTD and an Alternative Treatment Arm utilizing a dose-prediction equation to determine MTD, calculated prior to initiation of treatment. The primary endpoint of the study will be time to MTD for each arm. Additional endpoints include analyses of safety and biological responses to hydroxyurea therapy At the planned interim analysis of this study, we have recruited ten participants to each arm of the study. Kaplan-Meier analysis of these twenty participants indicates that there is a trend approaching significance (p = 0.071) for subjects on the dose-prediction arm to reach MTD faster than those on the dose-escalation arm, with a median time to MTD of 112 days versus 309 days respectively. Additionally, the dose-prediction equation has a high degree of accuracy (R2 = 0.66; p = 0.001) in predicting the actual MTD for all enrolled participants, with a mean predicted dose of 26.4 ± 1.6 mg/kg and actual dose of 27.1 ± 4.1 mg/kg. Children on the dose-prediction Alternative Treatment Arm have had a higher incidence of excessive myelosuppression requiring temporary dose cessation in three subjects, but no clinical adverse events. These interim results suggest that the dose-prediction equation is safe and effective in determining MTD for young patients with SCA initiating hydroxyurea therapy. Final analysis of the safety and efficacy of the dose-prediction equation will be performed upon completion of the study. Disclosures Off Label Use: This abstract describes the use of hydroxyurea in pediatric sickle cell patients. Hydroxyurea is not currently approved by the FDA for this purpose.. Ware:Bayer Pharmaceuticals: Consultancy; Eli Lilly: Other: DSMB membership; Bristol Myers Squibb: Research Funding; Biomedomics: Research Funding.

Download Full-text

Correlation of Voxelotor Exposure with Hemoglobin Response and Measures of Hemolysis in Patients from the HOPE Study

Blood ◽

10.1182/blood-2019-130802 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1020-1020 ◽

Cited By ~ 2

Author(s):

Jo Howard ◽

Elliott Vichinsky ◽

Jennifer Knight-Madden ◽

Margaret Tonda ◽

Carla Washington ◽

...

Keyword(s):

Sickle Cell ◽

Research Funding ◽

Organ Damage ◽

Advisory Board ◽

Pharmacodynamic Modeling ◽

Employment Equity ◽

Double Blind ◽

Hydroxyurea Treatment ◽

Travel Grant ◽

Equity Ownership

Background: Sickle cell disease (SCD) is an inherited disorder in which pathology is driven by hemoglobin (Hb) polymerization and red blood cell sickling, leading to chronic hemolysis and anemia as well as episodic vaso-occlusion. These manifestations of SCD contribute to the cumulative organ damage that leads to disability and accelerated mortality. Voxelotor is a first-in-class therapy in development for the treatment of SCD that has been shown to increase Hb levels and reduce markers of hemolysis, consistent with inhibition of sickle Hb polymerization. The objective of this analysis was to evaluate the association between Hb response and markers of hemolysis in voxelotor-treated patients. Methods: The HOPE trial is a phase 3, randomized, placebo-controlled, double-blind, multicenter study comparing the efficacy and safety of voxelotor (1500 mg and 900 mg daily) versus placebo for ≥24 weeks in patients aged 12 to 65 years with SCD. The primary endpoint is the percentage of patients with a Hb response at week 24, defined as a >1.0 g/dL increase in Hb. Secondary endpoints include change in markers associated with hemolysis: absolute reticulocyte count and percentage of reticulocytes, indirect bilirubin level, and lactate dehydrogenase (LDH) level. The per-protocol population was defined as those who completed the week 24 visit of the assigned treatment regimen and who did not initiate hydroxyurea treatment between baseline and week 24. Pharmacokinetic/pharmacodynamic modeling was used to correlate voxelotor exposure with Hb response and measures of hemolysis. Results: A total of 229 patients (n=74, voxelotor 1500 mg; n=79, voxelotor 900 mg; n=76, placebo) were included in the per-protocol analysis. Among patients receiving voxelotor 1500 mg, all measures of hemolysis were consistently lower for those with changes in Hb of >1 g/dL compared with those with changes of ≤1 g/dL (Table 1). In the 900 mg group, percentage of reticulocytes, bilirubin, and LDH were lower for those with changes in Hb of >1 g/dL compared with those with changes of ≤1 g/dL; this pattern was not seen for absolute reticulocytes in this cohort. Generally, the degree of reduction in hemolysis markers was greater in the 1500 mg arm compared with the 900 mg arm. Linear relationships between voxelotor exposure and Hb and LDH response were observed. In addition, saturable relationships between reticulocytes and bilirubin were also observed. Conclusions: Among patients treated with voxelotor, those with Hb changes of >1.0 g/dL had the greatest reductions in the markers of hemolysis. In addition, patients with Hb changes of >1 g/dL and who received voxelotor 1500 mg had lower hemolytic markers than those who received voxelotor 900 mg, suggesting that exposure to a higher dose of voxelotor results in a greater decrease in hemolysis markers. Taken together, these results suggest that the mechanism by which voxelotor raises Hb is related to a reduction in hemolysis, which may modify the morbidity of SCD by improving hemolytic anemia. Disclosures Howard: Imara: Consultancy, Other: Travel grant; Global Blood Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant; Resonance Health: Other: Travel grant. Vichinsky:Global Blood Therapeutics: Consultancy; Agios: Research Funding; Pfizer: Research Funding. Knight-Madden:Global Blood Therapeutics: Research Funding; Nova Laboratories: Advisory Board on SCD 2017, Research Funding; Global Blood Therapeutics: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; Addmedica: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; BlueBird Bio: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; Abbott Nutrition: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; Abbot International: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; Nova Laboratories: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; Pfizer: Other: Advisory Board on SCD 2017. Tonda:Global Blood Therapeutics: Employment, Equity Ownership. Washington:Global Blood Therapeutics: Employment, Equity Ownership. Tong:Global Blood Therapeutics: Employment, Equity Ownership. Lehrer-Graiwer:Global Blood Therapeutics: Employment, Equity Ownership. Gordeuk:Emmaus: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Imara: Research Funding; Global Blood Therapeutics: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Ironwood: Research Funding; Inctye: Research Funding; Pfizer: Research Funding; Inctye: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Modus Therapeutics: Consultancy, Honoraria; Global Blood Therapeutics: Consultancy, Honoraria, Research Funding; Emmaus: Consultancy, Honoraria; Ironwood: Research Funding; Modus Therapeutics: Consultancy, Honoraria; Imara: Research Funding; Pfizer: Research Funding.

Download Full-text

Emergency Department Encounters, Hospitalizations and ED Reliance Among Medicaid Eligible Patients with Sickle Cell Disease in North Carolina

Blood ◽

10.1182/blood-2019-127196 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2113-2113

Author(s):

Paula Tanabe ◽

Nancy Crego ◽

Christian Douglas ◽

Emily Bonnabeau ◽

Marian Earls ◽

...

Keyword(s):

North Carolina ◽

Sickle Cell Disease ◽

Old Age ◽

Sickle Cell ◽

Research Funding ◽

Claims Data ◽

Age Group ◽

Cell Disease ◽

Old Patients ◽

The Mean

Introduction: Sickle cell disease (SCD) is a complex disease for which pain is the hallmark. Pain from vaso-occlusive episodes is the number one reason for ED visits and hospital admissions. This paper reports Medicaid claims data from NC for individuals with SCD, including: 1) ED encounters and re-encounters within 7, 14 and 30 days; 2) hospitalization and re-hospitalization within 7, 14 and 30 days; and 3) ED reliance (EDR) score. Methods: We examined Medicaid claims data from for patients with a diagnosis of SCD (ICD 9 CM codes: 282.6x, ICD 10 CM codes: D57.0x, D57.1, D57.2x, D57.4x, D57.8x) in North Carolina. Data is reported for a cohort of 2,790 patients with a diagnosis of SCD, age 1 to 65+ and enrolled at least 11 months in NC Medicaid between March 1, 2016 and February 28, 2017. ED re-encounters and re-hospitalizations within 7, 14 and 30 days were identified using the time between the date of service listed on the ED or hospital claim and the next date of service in the subsequent claim. Individual ED Reliance (EDR) score was calculated as the total number of ED encounters divided by the total ambulatory visits (outpatient + ED encounters) per enrollee, (ambulatory visits reported elsewhere). Similar to Kroner et al, an EDR of >0.33 was considered a high score. Inpatient claims were identified using a category of service code indicating hospitalization. Results: The participants in the sample (n=2790) were majority female (57.92%), lived in metropolitan areas (77.63%) and had a mean age of 23.05 years old (SD=16.06). Of the 9,075 total ED encounters, 69.86% of the total sample had an ED encounter during the 12-month study period. There was a mean of 3.25 (SD=7.38) and median of 1 (IQR = 0 - 3) ED encounters per patient for the sample. Those who were 18-30 years old had the highest mean and median ED encounters per patient (4.98, SD= 9.34 and 2, IQR 1 to 5). The 31-45 year old group had the second most, with 4.82 (SD= 11.03) total ED encounters. The percentage of the sample with an ED re-encounter within 7, 14, and 30 days was also highest among the 18-30 year old group (29.17%, 33.98% and 40.89%) followed by those 31-45 years old (23.71%, 28.49%, and 34.80%), respectively. The 31-45 age group had the second most hospitalizations/patient and re-hospitalizations. The mean EDR was highest among 18-30 year old patients (0.35) and 46.48% of this age group had an EDR of 0.33 or greater. In the 31-45 year-old age group, the mean EDR was 0.28 and 35.18% had an EDR of 0.33 or greater. The overall sample had a mean of 1.30 (SD= 2.75) hospitalizations/patient. The 18-30 year old age group also had the highest mean total hospitalizations (2.08, SD= 3.72) and mean re-hospitalizations within 7 (0.16; SD=0.77), 14 (0.41; SD=1.68), and 30 (0.82; SD=2.79) days. The 31-45 age group had the second most hospitalizations/patient and re-hospitalizations (Table 1). Conclusions: Overall, increasing age coincided with increased ED and inpatient utilization, as well as with the period of transition from pediatric to adult SCD care. Furthermore, high EDR was most prevalent in the 18-30 age group. Our study further supports the need for increased focus on acute care utilization in the 18-45 year-old age group and considerations for improved care transition interventions. Disclosures Tanabe: NIH: Research Funding; AHRQ: Research Funding. Shah:Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; GBT: Research Funding.

Download Full-text

Predictors of Hydroxyurea Use in Children with Sickle Cell Disease

Blood ◽

10.1182/blood-2018-99-111377 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4934-4934

Author(s):

Chisom Ifeoma Okwor ◽

Robert J Klaassen ◽

Mary-Ann Harrison ◽

Ken Tang ◽

Isabelle Laforest ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Research Funding ◽

Small Sample Size ◽

Small Sample ◽

Care Utilization ◽

Lower Income ◽

Cell Disease ◽

Hematological Indices ◽

Hydroxyurea Treatment

Abstract Background: Since hydroxyurea emerged as an effective therapy for sickle cell disease (SCD), there have been numerous studies that have demonstrated its safety and efficacy in children and adults with SCD. In their 2014 guidelines, the NHLBI recommended that hydroxyurea treatment should be offered to all infants and children with sickle cell anemia (HbSS and HbS/beta0 thalassemia) starting at 9 months of age. However, hydroxyurea is underused among children and adolescents with SCD and to date, there have been no studies that have identified the specific determinants that may predict hydroxyurea adherence in these patients. Objectives: 1. To identify predictors of hydroxyurea adherence in children with SCD. 2. To measure the rate of hydroxyurea use among CHEO patients with SCD who were born between January 1, 2003 and December 31, 2015; and 3. To compare the rates of SCD-related complications between patients who were not prescribed hydroxyurea, patients who were adherent to hydroxyurea and patients who were not adherent to hydroxyurea Methods: We extracted medical chart data to identify patients with SCD who were born between January 1, 2003 and December 31, 2015. Patients were classified as either "Not prescribed hydroxyurea" or "Prescribed hydroxyurea" based on clinical documentation and the presence of at least one hydroxyurea outpatient prescription. For those patients who were prescribed hydroxyurea, hematological indices were collected and analyzed over time to estimate adherence to hydroxyurea. To measure the adherence of children prescribed hydroxyurea, we examined the trends in the patient's hematological indices after their first prescription of hydroxyurea. Adherence was defined as increased hematological indices (from baseline) by greater than or equal to any 2 of the following: Mean corpuscular volume (MCV) by 10 fL; Hemoglobin levels (g/L) by 10 g/L and/or %HbF (fetal hemoglobin) by 10%. We measured the frequency of disease-related complications among CHEO patients with SCD according to their use of hydroxyurea and used multivariate analyses to evaluate immigration status, newborn screening status, SCD subtype, SCD complications, income, age and sex as predictors for hydroxyurea adherence. Results: Children with HbSS were more likely to have been prescribed hydroxyurea compared to children with HbSC (87.8% vs. 9.5%). Canadian citizenship, newborn hemoglobinopathy screening and lower familial income were associated with better hydroxyurea adherence (Table 1). Although the association was not statistically significant, patients were more likely to be prescribed hydroxyurea if they were from a lower income background (61.9% for lowest and second lowest quartiles vs. 38.1% for third and highest quintiles). Patients were also more likely to adhere to hydroxyurea if they did not have private medical insurance for hydroxyurea coverage (Table 1). Finally, hydroxyurea adherence was associated with reduced rates of health care utilization and SCD-related complications (Table 2). Conclusions: In line with previous studies of hydroxyurea for the treatment of SCD, patients who were adherent to hydroxyurea had fewer complications compared to those patients who were either non-adherent to or not prescribed hydroxyurea. Similarly, patients had fewer complications after being prescribed hydroxyurea compared to before they started hydroxyurea with a reduction in the rate of ED visits, acute chest syndromes, complications, transfusions and hospitalizations. Patients from non-immigrant families, patients who were identified through newborn hemoglobinopathy screening and patients from lower income families were more likely to be adherent to hydroxyurea. Although the results of this study were limited by its small sample size, further studies will clarify these determinants of hydroxyurea adherence among SCD patients and enable clinicians to improve hydroxyurea adherence for SCD patients. Disclosures Klaassen: Shire: Consultancy; Novartis: Research Funding; Hoffman-La Roche: Consultancy; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; Octapharma AG: Consultancy, Honoraria; Agios Pharmaceuticals Inc.: Consultancy; Cangene: Research Funding.

Download Full-text

Assessment of Some Haemostatic Parameters in Sickle Cell Anaemia Subjects Resident in Rivers and Bayelsa States

Journal of Advances in Medicine and Medical Research ◽

10.9734/jammr/2021/v33i1130925 ◽

2021 ◽

pp. 53-64

Author(s):

Barinaaziga S. Mbeera ◽

Susanna O. Akwuebu ◽

A. C. U. Ezimah ◽

Nancy C. Ibeh ◽

Evelyn M. Eze

Keyword(s):

Steady State ◽

Sample Size ◽

Sickle Cell ◽

Teaching Hospital ◽

Sickle Cell Anaemia ◽

Control Group ◽

Port Harcourt ◽

The Mean ◽

The University ◽

D Dimer

Aim: The aim of this study was to assess some haemostatic parameters in sickle cell anaemia subjects in Rivers and Bayelsa States. Study Design: This study is a cross-sectional observational study. Place and Duration of Study: This study was carried out at the University of Port Harcourt Teaching Hospital, Rivers State, and the Federal Medical Centre, Yenagoa, Bayelsa State, between the months of February and August, 2020. Methodology: A total of four hundred and fifty (450) subjects with age range of 1-50 years were randomly selected. There were about 200 registered patients (adults and children alike) at the sickle cell clinics of the University of Port Harcourt Teaching Hospital, and the Federal Medical Centre, Yenagoa, with an average of 4 new patients per month. The sample size was obtained using a prevalence of sickle cell anaemia of 2% and the sample size was calculated using Cochran sample size formula. Five milliliters (5ml) of venous blood sample was withdrawn from the peripheral vein in the upper limb of subjects using a standard venipuncture technique. The sample was rocked gently to mix and kept at room temperature and the haemostatic parameters (vWF, FVIII, D-dimer, L-arginine, fibrinogen, ADAMTS13) were assayed quantitatively with Bioassay Technozym kit using Microplate Reader (Labtech microplate auto ELISA plate reader, an IS0 13485:2003 CE and WHO compliance Co., Ltd. Shanghai International Holding Corp. GmbH; Europe) calibrated to a wavelength of 450 nm with strict adherence to the manufacturer's instructions, while PT and APTT were analysed with Fortress reagent and Uniscope SM801A Laboratory using water bath.Data management and statistical analyses were conducted using Statistical Analyses System SAS 9.4 (SAS Institute, Cary, North Carolina, USA) and p values less than .05were considered statistically significant. Results: The results showed the mean comparison of haemostatic parameters in sickle cell anaemia and control subjects. The comparison of haemostatic parameters showed significant(p<.05) increasesand decreases inVaso-Occlusive Crisis (VOC) and steady state respectively compared with the control group. There was statistically significantreduction in the mean comparison of L-Arginine (p<.01) in VOC) condition than steady state in relation to the control group in our study population, while D-Dimer, ADAMTS13 were also significantly reduced statistically (p<.01) in VOC condition than steady state compared with the control group. However, the mean FVIII inhibitor, Fibrinogen, PT (INR) and APTT were significantly higher (p<.01) in VOC than steady state when compared to controls with normal haemoglobin (HbAA).Correlations of haemostaticparameters by sickle cell anaemia subjects’ condition showed more significant positive correlations in VOC than steady state. Conclusion: This study showed a heightened hypercoagulability in Sickle Cell Snaemia(SCA)subjects, and further pave way for better understanding particularly the diagnostic variables underlying SCA, specific to each subject condition (steady state and VOC). Subjects with SCA, particularly during VOC, undergo significant haemostatic alterations that increase their risk of developing coagulation activation-related complications. Thus, though selected markers of coagulation were significantly different between the subject conditions, they were often significantly higher in the SCA.

Download Full-text