Hydroxyurea to Treat Pediatric Sickle Cell Disease in Haiti - a Preliminary Report

Abstract Introduction. Haiti is the poorest nation in the Western Hemisphere, and the prevalence of sickle cell disease (SCD) in thatnation is twice that among African-Americans in the United States. Patients with SCD in Haiti have limited access to preventative care and disease management measures due to scarce healthcare resources. Hydroxyurea (HU) is a compelling option for the amelioration of complications of SCD in Haiti due to its relatively low cost, proven safety, and well-documented efficacy. Hydroxyurea programs have been implemented in India and in several African settings, however little data existto demonstrate the acceptability or feasibility of such an effort in Haiti. Study Design/Objectives. This is an open label, single arm pilot study with the primary objective of examining the acceptability and feasibility of the use of HU to treat children with SCD in an existing pediatric SCD program in Port-au-Prince, Haiti. Acceptability was defined as enrollment of a minimum of two-thirds of patients who are offered participation in the study. Feasibility was defined as two thirds of the enrolled patients being compliant with a defined minimum number of mandated study visits, lab draws, and HU doses. Secondary objectives include documenting the effect of HU on renal, hepatic, and bone marrow function as well as describing the incidence of clinical events in Haitian sickle cell patients taking HU. Methods. Patients with HbSS disease, age 2-15 years, who met minimum hematologic, renal, and hepatic parameters, were eligible for the study. Patients were approached for inclusion into the study consecutively during three separate enrollment periods from November 2015 through June 2016. The starting dose of Hydroxyurea (capsule and suspension form were available) was 20mg/kg which was increased to a maximum dose of 25mg/kg. Study visits occurred every 4 to 8 weeks at which point laboratory and clinical efficacy parameters, as well as potential adverse effects history were collected and dose modifications occurred. The study period for each patient will last 1 year. Akron Children's Hospital (ACH) IRB and the Haitian National Ethics Board approved the study. Funding for this project is provided through grants from the American Academy of Pediatrics and the ACH Foundation. Results. The study is ongoing with the enrollment period being closed as of June 2016. Forty-three patients have been enrolled, with a mean length of participation of 17.6 weeks (range 0-32 weeks).Forty-seven patients were offered participation in the study and 45 signed consent and underwent the screening process, generating an acceptability measure of 95.7%. Two out of the 45 screened patients were excluded based on results from screening labs (1 non-HbSS on confirmatory electrophoresis, 1 severe anemia) resulting in the final enrollment of 43 patients (23M:20F, mean age 9 years). Feasibility is being actively assessed.There have been no serious adverse events and no deaths. Three out of 43 enrolled patients were lost to follow-up and removed from the study due to missing 3 consecutive study visits (see figure 1). Compliance with mandated study visits was high among the enrolled patients with an attendance of 92.9% of the visits. Percent attainment of mandated laboratory tests is shown in table 1. No patients have had HU dose interruptions based on abnormal lab tests. Sixteen study patients have 6 month hematologic laboratory data available at this time: mean Hemoglobin and MCV have increased from 7.1 to 7.9g/dL and 90.6 to 107.1fL, respectively, and mean WBC and platelet count have decreased from 18.0 to 12.4(10^9/mL) and 557 to 413(10^9/mL), respectively. Conclusion. Results suggest that HU isan acceptable option for treating children with sickle cell disease in Haiti. Our preliminary data show that HU is feasible, safe, and effective in this setting. Challenges exist in ensuring reliable laboratory follow-up and will likely have to be addressed on an individual clinic and laboratory basis. Disclosures No relevant conflicts of interest to declare.

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Effect of Hydroxyurea on Elevated Pulmonary Artery Pressures in Children with Sickle Cell Disease

Blood ◽

10.1182/blood.v118.21.4841.4841 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4841-4841

Author(s):

Farzana Pashankar ◽

Deepa Manwani ◽

Margaret Lee ◽

Nancy S. Green

Keyword(s):

Sickle Cell Disease ◽

Pulmonary Artery ◽

Sickle Cell ◽

Conflicts Of Interest ◽

Laboratory Data ◽

Fetal Hemoglobin ◽

Total Daily Dose ◽

Cell Disease ◽

Biomarker Analysis ◽

Significant Change

Abstract Abstract 4841 Background: Pulmonary hypertension (PHT) is a significant complication of sickle cell disease. Studies in children report a 16–30% prevalence of elevated pulmonary artery pressures, as estimated by measurement of tricuspid regurgitant jet velocity (TRV) on echocardiography. The pathogenesis of elevated pulmonary artery pressures is multifactorial, with hemolysis induced endothelial dysfunction playing a major role. More recent studies highlight the role of inflammation in the pathogenesis. Hydroxyurea is a well established treatment for sickle cell disease. It acts primarily by induction of fetal hemoglobin, thereby reducing hemolysis, with possible additional effects on vascular and endothelial function. The aim of this study was to determine if early detection and treatment with hydroxyurea will decrease elevated pulmonary artery pressures in children with sickle cell disease. Methods: The study was conducted at 3 centers. Children with Hb SS and Hb Sb0 thalassemia between the ages of 5–21 years, with a screening echocardiogram showing a TRV ≥ 2.5 m/sec were identified. An echocardiogram was repeated to confirm elevated TRV. Subjects with persistent elevation of TRV ≥ 2.5 m/sec on repeat echocardiogram, were consented and started on hydroxyurea at 20 mg/kg/d with escalation to a maximum tolerated dose or a total daily dose of 30 mg/kg/d. Laboratory data and echocardiograms were repeated at 6 and 12 months to measure effect of hydroxyurea on TRV. Additionally blood and urine samples were also collected pre treatment, at 6 and 12 months post treatment for biomarker analysis, which will be performed later. Baseline and 6 month laboratory and echocardiogram data were compared using paired t test. Results: Twelve patients were enrolled. Mean age was 12.25 years (range 6–19 years) with a M:F ratio of 2:1. Average follow up is 11 months. Patients tolerated hydroxyurea well, and in 90% of patients the dose was escalated to 30 mg/kg/d. 1 patient achieved MTD at 20 mg/kg/d. Two patients went off study at 4 and 5 months respectively. As shown in Table 1, six months after starting hydroxyurea there was a significant increase in mean oxygen saturation, hemoglobin, mean corpuscular volume and fetal hemoglobin. There was a significant decrease in mean reticulocyte count, LDH and white blood cell count. There was no significant change in TRV six months after treatment with hydroxyurea. Conclusion: Hydroxyurea significantly decreased measures of hemolysis in children with sickle cell disease. Six months after treatment with hydroxyurea, there was no significant change in estimated pulmonary artery pressures measured on echocardiography. The study is ongoing to see if hydroxyurea affects pulmonary artery pressures with a longer duration of treatment. Disclosures: No relevant conflicts of interest to declare.

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Prevalence of Sickle Cell Disease, Hemoglobin S, and Hemoglobin C Among Haitian Newborns: Feasibility of Newborn Screening for Hemoglobinopathies in Haiti

Blood ◽

10.1182/blood.v120.21.4235.4235 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4235-4235

Author(s):

Genevieve Arty ◽

Rotz Seth ◽

Prasad Bodas ◽

Lucia De Zen ◽

Francesco Angelo Zanolli ◽

...

Keyword(s):

Sickle Cell Disease ◽

Newborn Screening ◽

Sickle Cell ◽

The United States ◽

Case Finding ◽

Small Sample ◽

Western Hemisphere ◽

Cell Disease ◽

Sickle Hemoglobin ◽

Hplc System

Abstract Abstract 4235 Background In the United States, four decades of advances in the treatment of sickle cell disease have reduced mortality rates of affected children from greater than 50% to well below 5%. The greatest impacts have come from inexpensive, non-burdensome interventions. The effectiveness of these interventions relies on universal newborn screening, case-finding, and targeted intervention. We sought to determine the prevalence of sickle cell disease among Haitian newborns and demonstrate feasibility of a hemoglobinopathy screening effort at a large scale. Haiti, the poorest country in the Western Hemisphere, lacks newborn screening. One study examined incidence of hemoglobinopathy traits (HbS and HbC) among infants of recent Haitian immigrants in Maimi, FL, USA, and reported an incidence of 8% and 4.7%. The study was limited by small sample size, and a population that might differ from native Haitians. Another study examining the prevalence of sickle hemoglobin among healthy adult volunteers in Northern Haiti, reported at 15.5%. Testing methods did not distinguish trait from homozygous disease, though volunteers were clinically well. In a previously published pilot study, our group sought to address these limitations through direct screening of newborns. We screened 259 newborns. We demonstrated prevalence of S trait, SS disease, and SC disease of 10%, 1.5%, and 1.5% respectively. In this report we present an update and demonstrate the scalability and feasibility of our approach in a much larger population. Methods 2459 consecutive newborns at Saint Damien Pediatric Hospital in Port-Au-Prince, Haiti in 2010 were screened for detection of hemoglobin types F,A,S,C,D, and E to establish prevalence of Sickle Hemoglobin. Heel-prick specimens were obtained and placed on filter paper (S&S 903, Schleicher & Schuell, New Hampshire, USA) and sent to Pordenone Hospital, Italy. Screening was performed using the Variant HPLC system (Bio-Rad Laboratories, California, USA), then Variant NBS HPLC system (Bio-Rad Laboratories, California, USA). Our project has evolved from screening only, to active case finding and provision of comprehensive disease management. The program is driven by local physician leaders and supported by a multinational team of academic and clinical staff. Results Among 2459 screened neonates 2258 specimens were able to be tested. 201 were unable to be tested due to technical issues with samples. Of the 2258 samples tested, 247 had HbS, fifty-seven had HbC, ten had HbSS, and three had HbSC. This yields a prevalence of 10.9%, 2.5%, 0.44% and 0.13% respectively. This corresponds to the prevalence of HbSC or HbSS of one in one hundred seventy three newborns. Conclusions Sickle cell disease is highly prevalent in Haiti, warranting universal screening and treatment efforts. We have demonstrated feasibility of newborn screening in Haiti. We recognize that challenges will exist in expanding this project to remote settings. Further, given that 78% of children in Haiti are born outside of hospitals, challenges to screening these patients remain. Nonetheless, this project provides valuable data at a scale suitable to inform clinical decision-making as well as health policy development. Disclosures: No relevant conflicts of interest to declare.

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Intermittent Use Of Sufadoxine-Pyrimethamine To Prevent Malaria In Patients With SCD In Malaria Endemic Regions: Findings From The Sickle Cell Disease Research and Control Center Of Bamako, Mali

Blood ◽

10.1182/blood.v122.21.1006.1006 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1006-1006

Author(s):

Dapa Aly Diallo ◽

Aldiouma Guindo ◽

Boubacari Ali Touré ◽

Yaya Sarro ◽

Baba Fané ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Conflicts Of Interest ◽

Sub Saharan Africa ◽

Health District ◽

Cell Disease ◽

Serious Adverse Events ◽

Control Center ◽

Disease Research ◽

And Control

Abstract Sickle cell disease (SCD) is a chronic disorder affecting erythrocytes and is especially prevalent throughout Sub-Saharan Africa where malaria is thought to be a significant cause of morbidity and mortality in affected individuals. In the absence of effective malaria vaccine, one of the affordable alternatives to prevent malaria at present is chemoprophylaxis. In order to evaluate the effectiveness of a monthly intermittent prophylaxis treatment (IPT) with sulfadoxine-pyrimethamine (SP) during high malaria transmission season in patients with sickle cell disease, two groups of SCD patients from two different sites were compared. The first group constituted of patients followed at the Sickle Cell Disease Research and Control Center of Bamako where IPT is routinely administered while the second group consisted of individuals enrolled in the health district in the same locality but no malaria prophylaxis. In this area, the incidence of resistance of P.falciparum to SP is estimated < 10%. SP combination was administrated as follows: sulfadoxine 25mg/kg and pyrimethamine 1.25mg/kg. For both groups, diagnosis of malaria was performed by using the rapid diagnosis test for the presence of P.falciparum. From 2011 to 2012, 687 SCD patients (457 from the Sickle Cell Disease Research and Control Center and 115 from the health district) were enrolled. The observed prevalence of malaria infection in the group receiving a monthly IPT by SP (1.5%) was much lower than the group (6%) for which IPT was not offered (P=0.01). When data was stratified by hemoglobin genotypes, malaria was found to occur entirely in SS and SC patients and no malaria cases were observed in S/β-thalassemia patients. SP was well tolerated since no patient in SP arm reported pruritus and no serious adverse events including death were recorded during the study. In malaria endemic areas where the incidence of resistance to SP is low, anti-malarial prophylaxis with this combination therapy significantly reduced the incidence of malaria in SCD patients with good safety and a lower cost. Disclosures: No relevant conflicts of interest to declare.

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Five years of experience with hydroxyurea in children and young adults with sickle cell disease

Blood ◽

10.1182/blood.v97.11.3628 ◽

2001 ◽

Vol 97 (11) ◽

pp. 3628-3632 ◽

Cited By ~ 132

Author(s):

Alina Ferster ◽

Parvine Tahriri ◽

Christiane Vermylen ◽

Geneviève Sturbois ◽

Francis Corazza ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Laboratory Data ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Significant Difference ◽

History Of ◽

Ischemic Attack

The short-term beneficial effect of hydroxyurea (HU) in sickle cell disease (SCD) has been proven by randomized studies in children and adults. The Belgian registry of HU-treated SCD patients was created to evaluate its long-term efficacy and toxicity. The median follow-up of the 93 patients registered is 3.5 years; clinical and laboratory data have been obtained for 82 patients at 1 year, 61 at 2 years, 44 at 3 years, 33 at 4 years, and 22 after 5 years. On HU, the number of hospitalizations and days hospitalized dropped significantly. Analysis of the 22 patients with a minimum of 5 years of follow-up confirm a significant difference in the number of hospitalizations (P = .0002) and days in the hospital (P < .01), throughout the treatment when compared to prior to HU therapy. The probabilities of not experiencing any event or any vaso-occlusive crisis requiring hospitalization during the 5 years of treatment were, respectively, 47% and 55%. On HU, the rate per 100 patient-years of severe events was estimated to be 3.5% for acute chest syndrome, 1.2% for aplastic crisis, 0.4% for splenic sequestration; it was 0% for the 9 patients with a history of stroke or transient ischemic attack followed for an average of 4 years. No important adverse effect occurred. Long-term chronic treatment with HU for patients with SCD appears feasible, effective, and devoid of any major toxicity; in patients with a history of stroke, HU may be a valid alternative to chronic transfusion support.

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Hydroxyurea Is Associated with Early Onset Malaria Episode in Treated Sickle Cell Disease Patients

Blood ◽

10.1182/blood.v128.22.4868.4868 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4868-4868

Author(s):

Aldiouma Guindo ◽

Yeya dit Sadio Sarro ◽

Boubacari Ali Toure ◽

Baba Fane ◽

Mody Coulibaly ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Conflicts Of Interest ◽

Malaria Incidence ◽

Treated Group ◽

Malaria Episode ◽

Cell Disease ◽

African Countries ◽

Control Center

Abstract Hydroxyurea (HU) is the only drug which has demonstrated efficacy in terms of reduced incidence of VOC and ACS, reduced need for hospitalization and reduced number of blood transfusion in sickle cell disease. African countries are among those with highest rate of both malaria and sickle cell disease. Despite of that the heterozygous form (HbAS) is known to protect against malaria, there is no documented studies on the clinical effect of HU on malaria. 36 patients aged 4 to 60 years old and treated by HU at the sickle cell disease research and control center of Bamako for at least 2 years. The treated group was compared to a matched untreated sickle cell patients group. During the follow-up, malaria incidence and onset to clinical episode of malaria were compared between treated SCD patients and untreated group. Results of the comparison show that there is no increased incidence of malaria in the treated group after 2 years follow-up (P=0.9). However, a reduction on the time to first malaria episode within the sickle cell population treated with HU was observed (P=0002).Based on this observed reduced time to first malaria episode in HU treated SCD patients, the use of HU in malaria endemic areas needs to be revaluated. It is howether clear that a more comprehensive approach would hopefully reduce the morbidity due to HU use for SCD affected children. Disclosures No relevant conflicts of interest to declare.

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Identification of Patient-Specific Factors Associated with Alloimmunization in Sickle Cell Disease

Blood ◽

10.1182/blood.v130.suppl_1.989.989 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 989-989

Author(s):

Ryan A Virden ◽

Kelsey Busken ◽

Richard Madsen ◽

Emily Coberly ◽

Bindu Kanathezhath Sathi

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Clinical Laboratory ◽

Conflicts Of Interest ◽

Statistical Significance ◽

Laboratory Data ◽

Patient Specific ◽

Continuous Variables ◽

Cell Disease ◽

Specific Factors

Abstract Background: Alloimmunization is a frequent complication of red blood cell (RBC) transfusion in sickle cell disease (SCD), arising from disparities between the recipient and donor RBC antigens. This potentially life-threatening complication impacts the utilization of chronic transfusion, a disease-modifying treatment in SCD. Many centers across the country use dedicated donor programs that match SCD recipients to a small group of racially and phenotypically-matched RBC donors in order to minimize exposure to foreign RBC antigens. The pathogenesis of alloimmunization remains an area of active research. Emerging data suggests that a pro-inflammatory state in the recipient plays a role in alloantibody (alloAb) generation. Some SCD patients develop an alloAb after minimal exposure to donor RBC units, whereas others do not. In a subset of these latter patients, multiple exposures to disparate RBC units will not lead to alloAb formation. To further understand this phenomenon, we sought to identify patient-specific factors in SCD that are associated with a higher risk of alloimmunization. Methods: We retrospectively analyzed clinical, laboratory, and transfusion-related data for all pediatric and adult SCD patients treated at the University of Missouri between 2000-2017. Descriptive statistics were expressed for continuous variables. Two-tailed Student's t-tests and Chi-squared analyses were used to determine statistical significance. Results: Of a total of 130 SCD patients identified, 89 patients (58 HbSS, 25 HbSC, and 6 HbSβ0/+ patients) had adequate transfusion, clinical, and laboratory data for inclusion in this study. The overall alloimmunization rate was 28%, with genotype-specific alloimmunization rates of 36% (HbSS), 4% (HbSC), and 50% (HbSβ0/+). Neither age nor gender significantly differed between the alloimmunized and non-alloimmunized groups. Alloimmunized SCD patients received, on average, 4 times more lifetime RBC units as compared to the non-alloimmunized group (264 units vs. 65 units, respectively, p = 0.002). Among all SCD patients, individuals who received more than 5 units per year of life were more likely to become alloimmunized (61% vs. 16%, p = 0.02, Figure 1). The most common alloantibodies identified in our patients were C, E, and Kell (Figure 2). Warm autoantibodies were identified in 36% of all alloimmunized patients versus only 5% of non-alloimmunized patients (p = 0.0001). Lastly, alloimmunization was associated with lower hemoglobin (8.66 ± 1.17 vs. 9.52 ± 1.54, p = 0.01) and higher creatinine (0.71 ± 0.36 vs. 0.56 ± 0.22, p = 0.02) among all SCD patients. In addition, higher LDH (549 ± 180 vs. 386 ± 127, p = 0.01) was observed in pediatric SCD patients who were alloimmunized. Both pediatric and adult SCD patients with the HbSS genotype demonstrated higher creatinine in the alloimmunized group (p = 0.03). An increased incidence of leg ulcers was found to be associated with alloimmunization (12% vs. 0%, p = 0.005, Table 1) amongst all of the clinical variables analyzed. Hydroxyurea therapy was not associated with a decreased prevalence of alloimmunization (Table 2). Conclusions: We identified an association between alloimmunization and higher LDH, lower hemoglobin, and higher creatinine in our SCD patient population. In addition, increased alloimmunization was seen in patients with a higher exposure to RBC units, both cumulatively and on a per life year basis. These data suggest that SCD patients with increased hemolysis or recipients of more than 5 RBC units per life year are associated with a higher risk of developing an alloAb. Larger studies will be required to define a causative relationship between this clinical SCD phenotype and a higher risk of alloimmunization. Disclosures No relevant conflicts of interest to declare.

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Renal Disease in Sickle Cell: Clinically Varied and Associated with Increased Mortality

Blood ◽

10.1182/blood.v120.21.90.90 ◽

2012 ◽

Vol 120 (21) ◽

pp. 90-90

Author(s):

Sabarish Ayyappan ◽

Paul Drawz ◽

Mehdi Nouraie ◽

Mariana E Hildesheim ◽

Yingze Zhang ◽

...

Keyword(s):

Renal Function ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Multivariate Analyses ◽

Conflicts Of Interest ◽

Laboratory Data ◽

Red Cell ◽

Cell Disease ◽

Cell Destruction ◽

Increased Risk

Abstract Abstract 90 The Walk-Phasst Study of sickle cell disease (SCD) affords a unique opportunity to examine renal function in a large number of adults with SCD. Extensive clinical and laboratory data were obtained on 463 adults with HbSS and 127 adults with HbSC. Where possible, correlates for estimated glomerular filtration rate (eGFR, calculated by the 4-value MDRD equation) and albuminuria/proteinuria were also evaluated in historical data, from SS adults in the CSCCD cohort and the Multicenter Study of Hydroxyurea (MSH) in sickle cell disease. Adjusted decline in eGFR was more rapid in SS compared with SC, at −2.6 and −0.92 ml/min/1.73 m2/year, respectively (p<0.001). In SS, similar declines in cross-sectional eGFR with age were seen in adults in the CSCCD (n=705) and MSH (n=298) cohorts, at −2.9 and −1.9 ml/min/year (BSA corrected), respectively. Multivariate analysis of the SS cohort in of Walk-Phasst revealed that depressed eGFR values were associated with an elevated estimated pulmonary arterial systolic pressure (as reflected in a higher tricuspid regurgitant jet velocity, measured by echocardiogram, p=0.007) and with evidence for inflammation (an elevated white blood cell count, p=0.018). In SC adults, in contrast, lower eGFRs were primarily associated with a diminished erythroid reserve (depressed absolute reticulocyte counts, P=0.005). Albuminuria (≥30 mg albumin/gm creatinine) was detectable in 66 and 41 % of adults with HbSS and HbSC in Walk-Phasst (185/287 evaluable SS and 25/61 evaluable SC, p=0.001). In Walk-Phasst, albuminuria in SS was associated with evidence of increased red cell destruction (lower total hemoglobin (P=0.07), higher LDH (P<0.001), and higher reticulocyte count (P=0.017)). In SC, albuminuria was associated with a higher LDH (P=0.01). 159/657 (24%) of adult SS subjects in the CSCCD cohort had trace to 4+ proteinuria, using a method (urine dipstick analysis) that is less sensitive and less quantitative than the albumin-to-creatinine ratio used in Walk-Phasst. Multivariate analyses again suggested a strong association between a depressed Hgb and proteinuria (P<0.001) in CSCCD, and LDH was also associated with proteinuria, in univariate analyses (P<0.001). In Walk-Phasst the absence of albuminuria in all subjects with SCD was associated with lesser mortality in multivariate analyses (Hazard ratio 0.62 (0.4–0.9, P=0.02). No similar association was seen between eGFR and mortality. Subjects with SS in Walk-Phasst had depressed serum bicarbonate levels, of 23.8±3.4 compared with 24.7±3.2mEq/dL in SC (p<0.005) and 24.8±3.3 mEq/dL in the non-CKD general population (Shah et al, 2009). In multivariate analyses, acidemia was associated with both increased destruction and decreased production of red cells, e.g. higher EPO (P=0.003) and total bilirubin levels (P<0.001), but lower reticulocyte counts (P=0.06). Impaired physiologic functioning in acidemic subjects with HbSS, manifest as a depressed 6MWD (P<0.001) and a lower eGFR (P<0.001), was seen. No effect of bicarbonate level on mortality in SCD patients was evident in Walk-Phasst. In conclusion, renal function is perturbed in sickle cell syndromes in several ways, including more rapid decrement in eGFR, highly prevalent albuminuria, and, in SS, marked abnormalities in acid-base balance. Albuminuria is associated with anemia in two large cohorts of sickle cell disease patients and, in Walk-Phasst, with evidence for enhanced red cell destruction. Importantly, albuminuria correlated with an increased risk for mortality in sickle cell disease. (We acknowledge the many contributions made by the Walk-PHASST Investigators: Badesch DB, Barst RJ, Castro OL, Girgis RE, Gibbs JS, Goldsmith JC, Hannoush H, Hassell KL, Kato GJ, Krishnamurti L, Lanzkron S, Machado RF, Morris CR, Novelli EM, Rosenzweig EB, Sachdev V, Schraufnagel DE, Taylor JG 6th.) Disclosures: No relevant conflicts of interest to declare.

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Hydroxyurea Utilization in Nigeria, a Lesson in Public Health.

Blood ◽

10.1182/blood.v110.11.80.80 ◽

2007 ◽

Vol 110 (11) ◽

pp. 80-80 ◽

Cited By ~ 11

Author(s):

Zakari Y. Aliyu ◽

Aliyu Babadoko ◽

Aisha Mamman

Keyword(s):

Health Care ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Clinical Studies ◽

The United States ◽

Cell Disease ◽

Hydroxyurea Treatment ◽

Transfusion Requirements ◽

The World

Abstract Hydroxyurea is a successful and cost effective drug therapy for sickle cell disease. Treatment with hydroxyurea is associated with a significant decrease in sickle cell complications, hospitalizations and transfusion requirements by about 50% and mortality reduction by 40% in clinical studies. The drug is unfortunately underutilized in sickle cell disease in the United States despite clear efficacy data and management experience. There is no data on the utilization of hydroxyurea in Africa, a part of the world with the highest global burden of sickle cell disease. We prospectively interviewed 206 consecutive adults and pediatric sickle cell patients as part of the Nigerian pulmonary hypertension screening study and reviewed over 1000 patients followed longitudinally at Ahmadu Bello university teaching hospital in Zaria, Nigeria. We also interviewed 10 hematologists (3 specialists and 7 hematologists in training) at the same university hospital. 65% of the 206 prospectively evaluated patients met the Multicenter Study of Hydroxyurea clinical indications for hydroxyurea treatment. No patient (zero percent) was on hydroxyurea therapy. All hematologists (100%) reported their discomfort with instituting hudroxyurea. Barriers to hydroxyurea utilization identified by practitioners included safety and toxicity profile (100%), patient compliance (100%), effective follow up (100%), drug availability (100%), affordability (100%) and specifically concern for reactivation of latent tuberculosis (50%) and carcinogenesis (100%) and teratogenicity (100%). Only 5% of patients had been informed of or were aware of hydroxyurea as a treatment option in sickle cell disease. Patient related barriers to hydroxyurea identified include lack of awareness (95%), cost (100%), availability (100%), need for frequent follow up (90%), pregnancy restrictions and need for concomitant contraceptive use (98%) and risk of infections (98%). Our study indicates the absolute lack of hydroxyurea utilization in a major health care center in Nigeria. Nigeria has the highest incidence of sickle cell disease in the world with about 150,000 children born with the disease annually. Sickle cell disease accounts for about 9 –16% of under-five mortality rates in the country. The sickle cell disease related morbidity, mortality and health systems financial burden remains very high in Nigeria and most of Africa. Local health care provider education and support and patient counseling and education are needed for the successful introduction of hydroxyurea in Nigeria. Clinical studies designed to assess the safety and efficacy of hydroxyurea in unique African settings is needed to facilitate the introduction and utilization of hydroxyurea in Nigeria and other parts of Africa.

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Health Status of Offspring Conceived During Hydroxyurea Therapy for Sickle Cell Disease.

Blood ◽

10.1182/blood.v114.22.1533.1533 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1533-1533

Author(s):

Saloni Tanna ◽

Betsy Clair ◽

Sejal Kuthiala ◽

Teresa A. Coleman ◽

Abdullah Kutlar

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Attention Deficit Disorder ◽

Life Support ◽

Conflicts Of Interest ◽

Case Reports ◽

National Registry ◽

Cell Disease ◽

Apgar Scores

Abstract Abstract 1533 Poster Board I-556 Hydroxyurea (HU) is an S-phase specific cytotoxic agent (pregnancy category D), approved for use in sickle cell disease (SCD) primarily due to its ability to augment production of fetal hemoglobin (HbF), which has been shown to reduce the frequency of pain crises and decrease the need for blood transfusions. In all animal species tested, HU produced an increase in congenital anomalies. Defects of the central nervous system, palate, and skeleton occurred in rats treated with HU in the ninth to twelfth gestational days. Embyonic cytotoxicity may be secondary to formation of reactive free radicals. Because of its teratogenic potential, patients with SCD are instructed to practice contraception while on HU therapy. However, risks associated with maternal or paternal HU exposure at the time of conception is unclear. Our review of the literature has only shown six case reports of HU exposure in pregnancy for the treatment of SCD. Two of these pregnancies were terminated with medical abortion, the remaining four cases described liveborn infants with normal phenotypes at 15 to 21 months of follow up. 236 patients followed at the Medical College of Georgia Sickle Cell Center have been on HU for a period of 6 months to 14 years. Despite precautionary counseling, we have identified seven women and three men with SCD who have conceived while on HU therapy. We analyzed the birth records of ten children conceived during HU therapy. The duration of HU therapy varied from 2 weeks to 3 years at the time pregnancy was diagnosed; gestational age when HU was discontinued ranged from 3 to 10.5 weeks. Some children were born prematurely or preterm, with birth weights ranging from 922 to 3178 grams. APGAR scores ranged from 2 to 9 for the first minute and 8 to 10 for the five minute score. One child who had been born severely premature at 26 weeks with a birth weight of 922 grams and APGAR scores of 2 and 8 at one and five minutes to a father who had been on HU at the time of conception was ultimately withdrawn from life support measures. The remaining nine children were assessed for appropriate development by questionnaires provided to parents as well as pediatric records when available. One child with APGAR scores of 5 and 9 has been diagnosed with mental retardation and attention deficit disorder. Developmentally, the other eight children have achieved appropriate milestones. Women with sickle cell disease are more likely to develop complications such as intrauterine growth retardation and preterm delivery than those without the disease. These findings suggest that children conceived on HU therapy are not significantly different from other infants born to parents with SCD who are not on HU. Our sample size is not large enough to observe the potential effects of in utero HU exposure. The small number of subjects is likely secondary to potential teratogenicity discouraging women to become pregnant as well as paucity of exposed pregnancies due to menstrual disturbances induced by HU. It is therefore important to develop and maintain a national registry to allow longer follow up of exposed children and more careful assessment of fetotoxic effects for those conceived during HU therapy for SCD. Disclosures No relevant conflicts of interest to declare.

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A phase 1/2 ascending dose study and open-label extension study of voxelotor in patients with sickle cell disease

Blood ◽

10.1182/blood-2018-08-868893 ◽

2019 ◽

Vol 133 (17) ◽

pp. 1865-1875 ◽

Cited By ~ 31

Author(s):

Jo Howard ◽

Claire Jane Hemmaway ◽

Paul Telfer ◽

D. Mark Layton ◽

John Porter ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Phase 1 ◽

Extension Study ◽

Cell Disease ◽

Open Label ◽

Serious Adverse Events ◽

Double Blind ◽

Open Label Extension ◽

Dose Study

Abstract New treatments directly targeting polymerization of sickle hemoglobin (HbS), the proximate event in the pathophysiology of sickle cell disease (SCD), are needed to address the severe morbidity and early mortality associated with the disease. Voxelotor (GBT440) is a first-in-class oral therapy specifically developed to treat SCD by modulating the affinity of hemoglobin (Hb) for oxygen, thus inhibiting HbS polymerization and downstream adverse effects of hemolytic anemia and vaso-occlusion. GBT440-001 was a phase 1/2 randomized, double-blind, placebo-controlled, single and multiple ascending dose study of voxelotor in adult healthy volunteers and patients with SCD, followed by a single-arm, open-label extension study. This report describes results of voxelotor (500-1000 mg per day) in patients with sickle cell anemia. The study evaluated the safety, tolerability, pharmacokinetic, and pharmacodynamic properties of voxelotor and established proof of concept by improving clinical measures of anemia, hemolysis, and sickling. Thirty-eight patients with SCD received 28 days of voxelotor 500, 700, or 1000 mg per day or placebo; 16 patients received 90 days of voxelotor 700 or 900 mg per day or placebo. Four patients from the 90-day cohort were subsequently enrolled in an extension study and treated with voxelotor 900 mg per day for 6 months. All patients who received multiple doses of voxelotor for ≥28 days experienced hematologic improvements including increased Hb and reduction in hemolysis and percentage of sickled red cells, supporting the potential of voxelotor to serve as a disease-modifying therapy for SCD. Voxelotor was well tolerated with no treatment-related serious adverse events and no evidence of tissue hypoxia. These trials were registered at www.clinicaltrials.gov as #NCT02285088 and #NCT03041909.

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