Hydroxyurea

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Russell E. Ware - One of the best experts on this subject based on the ideXlab platform.

  • Novel use Of Hydroxyurea in an African Region with Malaria (NOHARM): a trial for children with sickle cell anemia
    2018
    Co-Authors: Robert O Opoka, Russell E. Ware, Christopher M Ndugwa, Teresa Latham, Adam Lane, Phillip Kasirye, James S Hodges, Heather Hume, Chandy C John
    Abstract:

    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 sub-Saharan Africa, where the greatest sickle-cell burden exists, remain unknown. In vitro studies suggest Hydroxyurea could increase malaria severity, and Hydroxyurea-associated neutropenia could worsen infections. NOHARM (Novel use Of Hydroxyurea in an African Region with Malaria) was a randomized, double-blinded, placebo-controlled trial conducted in malaria-endemic Uganda, comparing Hydroxyurea to placebo at 20 ± 2.5 mg/kg per day for 12 months. The primary outcome was incidence of clinical malaria. Secondary outcomes included SCA-related adverse events (AEs), clinical and laboratory effects, and hematological toxicities. Children received either Hydroxyurea (N = 104) or placebo (N = 103). Malaria incidence did not differ between children on Hydroxyurea (0.05 episodes per child per year; 95% confidence interval [0.02, 0.13]) vs placebo (0.07 episodes per child per year [0.03, 0.16]); the Hydroxyurea/placebo malaria incidence rate ratio was 0.7 ([0.2, 2.7]; P = .61). Time to infection also 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 = .001). Children receiving Hydroxyurea had significantly increased hemoglobin concentration and fetal hemoglobin, with decreased leukocytes and reticulocytes. Serious AEs, sepsis episodes, and dose-limiting toxicities were similar between treatment arms. Three deaths occurred (2 Hydroxyurea, 1 placebo, and none from malaria). Hydroxyurea treatment appears safe for children with SCA living in malaria-endemic sub-Saharan Africa, without increased severe malaria, infections, or AEs. Hydroxyurea provides SCA-related laboratory and clinical efficacy, but optimal dosing and monitoring regimens for Africa remain undefined.This trial was registered at www.clinicaltrials.gov as #NCT01976416. Protocol approval was obtained from the institutional review boards of Makerere University School of Medicine, Indiana University, University of Minnesota, and Cincinnati Children's Hospital, as well as the Uganda National Drug Authority and Uganda National Council for Science and Technology.

  • novel use of Hydroxyurea in an african region with malaria noharm a trial for children with sickle cell anemia
    Blood, 2017
    Co-Authors: Robert O Opoka, Russell E. Ware, Christopher M Ndugwa, Teresa Latham, Adam Lane, Heather A Hume, Phillip Kasirye, James S Hodges, Chandy C John
    Abstract:

    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 sub-Saharan Africa, where the greatest sickle-cell burden exists, remain unknown. In vitro studies suggest Hydroxyurea could increase malaria severity, and Hydroxyurea-associated neutropenia could worsen infections. NOHARM (Novel use Of Hydroxyurea in an African Region with Malaria) was a randomized, double-blinded, placebo-controlled trial conducted in malaria-endemic Uganda, comparing Hydroxyurea to placebo at 20 ± 2.5 mg/kg per day for 12 months. The primary outcome was incidence of clinical malaria. Secondary outcomes included SCA-related adverse events (AEs), clinical and laboratory effects, and hematological toxicities. Children received either Hydroxyurea (N = 104) or placebo (N = 103). Malaria incidence did not differ between children on Hydroxyurea (0.05 episodes per child per year; 95% confidence interval [0.02, 0.13]) vs placebo (0.07 episodes per child per year [0.03, 0.16]); the Hydroxyurea/placebo malaria incidence rate ratio was 0.7 ([0.2, 2.7]; P = .61). Time to infection also 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 = .001). Children receiving Hydroxyurea had significantly increased hemoglobin concentration and fetal hemoglobin, with decreased leukocytes and reticulocytes. Serious AEs, sepsis episodes, and dose-limiting toxicities were similar between treatment arms. Three deaths occurred (2 Hydroxyurea, 1 placebo, and none from malaria). Hydroxyurea treatment appears safe for children with SCA living in malaria-endemic sub-Saharan Africa, without increased severe malaria, infections, or AEs. Hydroxyurea provides SCA-related laboratory and clinical efficacy, but optimal dosing and monitoring regimens for Africa remain undefined. This trial was registered at www.clinicaltrials.gov as #NCT01976416.

  • a clinically meaningful fetal hemoglobin threshold for children with sickle cell anemia during Hydroxyurea therapy
    American Journal of Hematology, 2017
    Co-Authors: Jeremie H Estepp, Russell E. Ware, Winfred C. Wang, Matthew P Smeltzer, Banu Aygun, Kerri Nottage, Guolian Kang, Christina M Abrams, Jane S. Hankins
    Abstract:

    Hydroxyurea has proven clinical benefits and is recommended to be offered to all children with sickle cell anemia (SCA), but the optimal dosing regimen remains controversial. Induction of red blood cell fetal hemoglobin (HbF) by Hydroxyurea appears to be dose-dependent. However, it is unknown whether maximizing HbF% improves clinical outcomes. HUSTLE (NCT00305175) is a prospective observational study with a primary goal of describing the long-term clinical effects of Hydroxyurea escalated to maximal tolerated dose (MTD) in children with SCA. In 230 children, providing 610 patient-years of follow up, the mean attained HbF% at MTD was >20% for up to 4 years of follow-up. When HbF% values were ≤20%, children had twice the odds of hospitalization for any reason (P  20% was associated with fewer hospitalizations without significant toxicity. These data support the use of Hydroxyurea in children, and suggest that the preferred dosing strategy is one that targets a HbF endpoint >20%.

  • Hydroxyurea therapy for sickle cell anemia
    Expert Opinion on Drug Safety, 2015
    Co-Authors: Patrick T Mcgann, Russell E. Ware
    Abstract:

    Introduction: Sickle cell anemia (SCA) is a severe, inherited hemoglobin disorder affecting 100,000 persons in the US and millions worldwide. Hydroxyurea, a once daily oral medication, has emerged as the primary disease-modifying therapy for SCA. The accumulated body of evidence over 30 years demonstrates that Hydroxyurea is a safe and effective therapy for SCA, but Hydroxyurea remains underutilized for a variety of reasons.Areas covered: In this review, we summarize the available evidence regarding the pharmacology, clinical, and laboratory benefits, and safety of Hydroxyurea therapy for the treatment of SCA. The purpose of this review is to provide the reader a comprehensive understanding of Hydroxyurea and to reinforce the fact that Hydroxyurea is a safe and effective medication for the treatment of SCA.Expert opinion: In our opinion, Hydroxyurea therapy should be considered standard-of-care for SCA, representing an essential component of patient management. Early initiation and broader use of hydroxyu...

  • from infancy to adolescence fifteen years of continuous treatment with Hydroxyurea in sickle cell anemia
    Medicine, 2014
    Co-Authors: Jane S. Hankins, Russell E. Ware, Matthew P Smeltzer, Courtney D Thornburg, Banu Aygun, Kerri Nottage, Winfred C. Wang
    Abstract:

    Despite documented laboratory and clinical benefits of Hydroxyurea for children with sickle cell anemia (SCA), the drug's long-term safety and efficacy remains poorly defined. The HUSOFT trial and extension study examined feasibility, toxicity, and hematological efficacy of Hydroxyurea in infants with SCA. This report describes HUSOFT participants who have continued Hydroxyurea therapy for 15 years. With IRB approval, medical records were reviewed for clinical, laboratory, and growth parameters. Twenty-eight infants enrolled in the original 2-year HUSOFT study received open-label liquid Hydroxyurea at 20 mg/kg/day; 17 completed the extension study with dose escalation to 30 mg/kg/day. Eight of these 17 (6 girls and 2 boys, all HbSS) have continued on daily Hydroxyurea for at least 15 years (median age at last follow-up 17.6 years) without interruption. All hematologic indices (Hb concentration, mean corpuscular volume (MCV), fetal hemoglobin) showed sustained effect after 15 years. The median maximum tolerated dose of Hydroxyurea has decreased from 30 to 26 mg/kg/day (range 19.5-31.2); neutropenia [absolute neutrophil count (ANC)<1.0×10⁹/L] prompting temporary drug discontinuation occurred a total of 10 times in 4 subjects and there was no severe neutropenia (ANC<0.5×10⁹/L). Growth rates over 15 years continued at the 50th percentile for both height and weight, and puberty occurred without delay (age range 10-14 years). There were 5.1 vaso-occlusive events (pain and acute chest syndrome)/100 patient years, 7.3 packed red blood cell transfusions/100 patient years. No malignancies, strokes, or deaths occurred. At last follow up, all subjects were at appropriate grade level (10-12 grade) with no history of repeated grades. A cohort of young teenagers with SCA who initiated treatment in infancy have had sustained and continued hematological benefits for a decade and a half. Growth and sexual development are normal and comparable to the general pediatric population. Continuous Hydroxyurea therapy since infancy appears safe and efficacious in SCA.

Winfred C. Wang - One of the best experts on this subject based on the ideXlab platform.

  • a clinically meaningful fetal hemoglobin threshold for children with sickle cell anemia during Hydroxyurea therapy
    American Journal of Hematology, 2017
    Co-Authors: Jeremie H Estepp, Russell E. Ware, Winfred C. Wang, Matthew P Smeltzer, Banu Aygun, Kerri Nottage, Guolian Kang, Christina M Abrams, Jane S. Hankins
    Abstract:

    Hydroxyurea has proven clinical benefits and is recommended to be offered to all children with sickle cell anemia (SCA), but the optimal dosing regimen remains controversial. Induction of red blood cell fetal hemoglobin (HbF) by Hydroxyurea appears to be dose-dependent. However, it is unknown whether maximizing HbF% improves clinical outcomes. HUSTLE (NCT00305175) is a prospective observational study with a primary goal of describing the long-term clinical effects of Hydroxyurea escalated to maximal tolerated dose (MTD) in children with SCA. In 230 children, providing 610 patient-years of follow up, the mean attained HbF% at MTD was >20% for up to 4 years of follow-up. When HbF% values were ≤20%, children had twice the odds of hospitalization for any reason (P  20% was associated with fewer hospitalizations without significant toxicity. These data support the use of Hydroxyurea in children, and suggest that the preferred dosing strategy is one that targets a HbF endpoint >20%.

  • from infancy to adolescence fifteen years of continuous treatment with Hydroxyurea in sickle cell anemia
    Medicine, 2014
    Co-Authors: Jane S. Hankins, Russell E. Ware, Matthew P Smeltzer, Courtney D Thornburg, Banu Aygun, Kerri Nottage, Winfred C. Wang
    Abstract:

    Despite documented laboratory and clinical benefits of Hydroxyurea for children with sickle cell anemia (SCA), the drug's long-term safety and efficacy remains poorly defined. The HUSOFT trial and extension study examined feasibility, toxicity, and hematological efficacy of Hydroxyurea in infants with SCA. This report describes HUSOFT participants who have continued Hydroxyurea therapy for 15 years. With IRB approval, medical records were reviewed for clinical, laboratory, and growth parameters. Twenty-eight infants enrolled in the original 2-year HUSOFT study received open-label liquid Hydroxyurea at 20 mg/kg/day; 17 completed the extension study with dose escalation to 30 mg/kg/day. Eight of these 17 (6 girls and 2 boys, all HbSS) have continued on daily Hydroxyurea for at least 15 years (median age at last follow-up 17.6 years) without interruption. All hematologic indices (Hb concentration, mean corpuscular volume (MCV), fetal hemoglobin) showed sustained effect after 15 years. The median maximum tolerated dose of Hydroxyurea has decreased from 30 to 26 mg/kg/day (range 19.5-31.2); neutropenia [absolute neutrophil count (ANC)<1.0×10⁹/L] prompting temporary drug discontinuation occurred a total of 10 times in 4 subjects and there was no severe neutropenia (ANC<0.5×10⁹/L). Growth rates over 15 years continued at the 50th percentile for both height and weight, and puberty occurred without delay (age range 10-14 years). There were 5.1 vaso-occlusive events (pain and acute chest syndrome)/100 patient years, 7.3 packed red blood cell transfusions/100 patient years. No malignancies, strokes, or deaths occurred. At last follow up, all subjects were at appropriate grade level (10-12 grade) with no history of repeated grades. A cohort of young teenagers with SCA who initiated treatment in infancy have had sustained and continued hematological benefits for a decade and a half. Growth and sexual development are normal and comparable to the general pediatric population. Continuous Hydroxyurea therapy since infancy appears safe and efficacious in SCA.

  • immunologic effects of Hydroxyurea in sickle cell anemia
    Pediatrics, 2014
    Co-Authors: Howard M Lederman, Russell E. Ware, Winfred C. Wang, Lori Luchtmanjones, Myron A Waclawiw, Ram Kalpatthi, Margaret A Connolly, Jonathan C Goldsmith, Andrea J Swift, James F Casella
    Abstract:

    BACKGROUND AND OBJECTIVE: Susceptibility to encapsulated bacteria is well known in sickle cell disease (SCD). Hydroxyurea use is common in adults and children with SCD, but little is known about Hydroxyurea’s effects on immune function in SCD. Because Hydroxyurea inhibits ribonucleotide reductase, causing cell cycle arrest at the G1–S interface, we postulated that Hydroxyurea might delay transition from naive to memory T cells, with inhibition of immunologic maturation and vaccine responses. METHODS: T-cell subsets, naive and memory T cells, and antibody responses to pneumococcal and measles, mumps, and rubella vaccines were measured among participants in a multicenter, randomized, double-blind, placebo-controlled trial of Hydroxyurea in infants and young children with SCD (BABY HUG). RESULTS: Compared with placebo, Hydroxyurea treatment resulted in significantly lower total lymphocyte, CD4, and memory T-cell counts; however, these numbers were still within the range of historical healthy controls. Antibody responses to pneumococcal vaccination were not affected, but a delay in achieving protective measles antibody levels occurred in the Hydroxyurea group. Antibody levels to measles, mumps, and rubella showed no differences between groups at exit, indicating that effective immunization can be achieved despite Hydroxyurea use. CONCLUSIONS: Hydroxyurea does not appear to have significant deleterious effects on the immune function of infants and children with SCD. Additional assessments of lymphocyte parameters of Hydroxyurea-treated children may be warranted. No changes in current immunization schedules are recommended; however, for endemic disease or epidemics, adherence to accelerated immunization schedules for the measles, mumps, and rubella vaccine should be reinforced.

  • Hydroxyurea is associated with lower costs of care of young children with sickle cell anemia
    Pediatrics, 2013
    Co-Authors: Winfred C. Wang, Zhaoyu Luo, Scott T Miller, Bruce W Thompson, James F Casella, Suzette O Oyeku, Sheree L Boulet, Billie Fish, Scott D Grosse
    Abstract:

    BACKGROUND AND OBJECTIVE: In the BABY HUG trial, young children with sickle cell anemia randomized to receive Hydroxyurea had fewer episodes of pain, hospitalization, and transfusions. With anticipated broader use of Hydroxyurea in this population, we sought to estimate medical costs of care in treated versus untreated children. METHODS: The BABY HUG database was used to compare inpatient events in subjects receiving Hydroxyurea with those receiving placebo. Unit costs were estimated from the 2009 MarketScan Multi-state Medicaid Database for children with sickle cell disease, aged 1 to 3 years. Inpatient costs were based on length of hospital stay, modified by the occurrence of acute chest syndrome, splenic sequestration, or transfusion. Outpatient expenses were based on the schedule required for BABY HUG and a “standard” schedule for 1- to 3-year-olds with sickle cell anemia. RESULTS: There were 232 hospitalizations in the subjects receiving Hydroxyurea and 324 in those on placebo; length of hospital stay was similar in the 2 groups. Estimated outpatient expenses were greater in those receiving Hydroxyurea, but these were overshadowed by inpatient costs. The total estimated annual cost for those on Hydroxyurea ($11 072) was 21% less than the cost of those on placebo ($13 962; P = .038). CONCLUSIONS: Savings on inpatient care resulted in a significantly lower overall estimated medical care cost for young children with sickle cell anemia who were receiving Hydroxyurea compared with those receiving placebo. Because cost savings are likely to increase with age, these data provide additional support for broad use of Hydroxyurea treatment in this population.

  • Hydroxyurea treatment of children with hemoglobin sc disease
    Pediatric Blood & Cancer, 2013
    Co-Authors: Amber M Yates, Winfred C. Wang, Laurence Dedeken, Matthew P Smeltzer, Jeffrey D Lebensburger, Nancy Robitaille
    Abstract:

    The efficacy of Hydroxyurea in hemoglobin SC (HbSC) patients is not well documented. We describe the long-term response to Hydroxyurea in children with clinically severe HbSC. In 15 patients, Hydroxyurea resulted in a significant increase in mean corpuscular volume (MCV) and fetal hemoglobin (HbF) and a significant decrease in episodes of acute chest syndrome and hospitalization for pain; there was no effect on hemoglobin level. The most significant side effect was thrombocytopenia, which led to discontinuation of treatment in one patient. This study suggests that Hydroxyurea has efficacy and is safe for long-term therapy in patients with HbSC.

Alan N Schechter - One of the best experts on this subject based on the ideXlab platform.

  • Hydroxyurea nitrosylates and activates soluble guanylyl cyclase in human erythroid cells
    Blood, 2008
    Co-Authors: Vladan P Cokic, Constance Tom Noguchi, Silvana A Andric, Stanko S Stojilkovic, Alan N Schechter
    Abstract:

    Hydroxyurea, a drug widely used for treating myeloproliferative diseases, has also been approved for the treatment of sickle cell disease by raising fetal hemoglobin (HbF). We have shown that nitric oxide (NO) and the soluble guanylyl cyclase (sGC) pathways are involved in Hydroxyurea induction of HbF levels in erythroid progenitor cells (EPCs). We demonstrate now that during erythroid differentiation, endothelial NO synthase mRNA and protein levels decline steadily, as does the production of NO derivatives and cyclic adenosine monophosphate (cAMP) levels, but guanosine 3′,5′-cyclic monophosphate (cGMP) levels are stable. Hydroxyurea increased intracellular cGMP levels and cAMP levels in EPCs. The NO donor, DEANONOate, induced much higher cGMP levels, but reduced cAMP levels. Hydroxyurea (1 mM) induced production of approximately 45 pM cGMP/minute/ng of purified sGC, similar to induction by 1 μM DEANONOate. We found that Hydroxyurea and ProliNONOate produced iron-nitrosyl derivatives of sGC. Thus, we confirm that Hydroxyurea can directly interact with the deoxy-heme of sGC, presumably by a free-radical nitroxide pathway, and activate cGMP production. These data add to an expanding appreciation of the role of Hydroxyurea as an inducer of the NO/cGMP pathway in EPCs. These mechanisms may also be involved in the cytostatic effects of Hydroxyurea, as well as the induction of HbF.

  • Hydroxyurea induces fetal hemoglobin by the nitric oxide dependent activation of soluble guanylyl cyclase
    Journal of Clinical Investigation, 2003
    Co-Authors: Vladan P Cokic, Reginald Donovan Smith, Bojana B Beleslincokic, Joyce M Njoroge, Jeffery L Miller, Mark T Gladwin, Alan N Schechter
    Abstract:

    Hydroxyurea treatment of patients with sickle-cell disease increases fetal hemoglobin (HbF), which reduces hemoglobin S polymerization and clinical complications. Despite its use in the treatment of myeloproliferative diseases for over 30 years, its mechanism of action remains uncertain. Recent studies have demonstrated that Hydroxyurea generates the nitric oxide (NO) radical in vivo, and we therefore hypothesized that NO-donor properties might determine the hemoglobin phenotype. We treated both K562 erythroleukemic cells and human erythroid progenitor cells with S-nitrosocysteine (CysNO), an NO donor, and found similar dose- and time-dependent induction of γ-globin mRNA and HbF protein as we observed with Hydroxyurea. Both Hydroxyurea and CysNO increased cGMP levels, and the guanylyl cyclase inhibitors ODQ, NS 2028, and LY 83,538 abolished both the Hydroxyurea- and CysNO-induced γ-globin expression. These data provide strong evidence for an NO-derived mechanism for HbF induction by Hydroxyurea and suggest possibilities for therapies based on NO-releasing or -potentiating agents.

  • nitric oxide donor properties of Hydroxyurea in patients with sickle cell disease
    British Journal of Haematology, 2002
    Co-Authors: Mark T Gladwin, James H Shelhamer, Frederick P Ognibene, Margaret E Peasefye, James S Nichols, Beth Link, Daksesh B Patel, Marcin A Jankowski, Lewis K Pannell, Alan N Schechter
    Abstract:

    Hydroxyurea therapy reduces the rates of vaso-occlusive crisis in patients with sickle cell anaemia and recent data suggest that Hydroxyurea treatment can generate nitric oxide (NO). Nitric oxide has been proposed as a novel therapy for sickle cell disease via a number of pathways. We therefore sought to determine whether Hydroxyurea has NO donor properties in patients with sickle cell anaemia and explore potential mechanisms by which NO production could be therapeutic. Venous blood was collected from 19 fasting sickle cell anaemia patients, on chronic Hydroxyurea therapy, at baseline and 2 and 4 h after a single morning dose of Hydroxyurea, as well as 10 patients not taking Hydroxyurea. The plasma and red cell NO reaction products nitrate, nitrite and nitrosylated- haemoglobin were measured using ozone-based chemiluminescent assays (using vanadium, KI and I3- reductants respectively). Consistent with NO release from Hydroxyurea, baseline levels of total nitrosylated haemoglobin increased from 300 nmol/l to 500 nmol/l (P = 0.01). Plasma nitrate and nitrite levels also significantly increased with peak levels observed at 2 h. Glutathionyl-haemoglobin levels were unchanged, while plasma secretory vascular cellular adhesion molecule-1 levels were reduced in patients taking Hydroxyurea (419 +/- 40 ng/ml) compared with control patients with sickle cell anaemia (653 +/- 55 ng/ml; P = 0.003), and were inversely correlated with fetal haemoglobin levels (r = -0.72; P = 0.002). These results demonstrate that Hydroxyurea therapy is associated with the intravascular and intraerythrocytic generation of NO. The role of NO in the induction of fetal haemoglobin and possible synergy between NO donor therapy and classic cytostatic and differentiating medications should be explored.

  • augmentation by erythropoietin of the fetal hemoglobin response to Hydroxyurea in sickle cell disease
    The New England Journal of Medicine, 1993
    Co-Authors: Griffin P Rodgers, Nobuhiro Uyesaka, Constance Tom Noguchi, George J Dover, Alan N Schechter, Arthur W. Nienhuis
    Abstract:

    Background Hydroxyurea increases the production of fetal hemoglobin in patients with sickle cell anemia, inhibiting the polymerization of hemoglobin S and potentially improving vaso-occlusive manifestations and hemolysis. Recombinant erythropoietin increases the number of reticulocytes containing fetal hemoglobin in laboratory animals and in humans. We studied whether Hydroxyurea and erythropoietin might have a potentiating effect on the production of fetal hemoglobin in patients with sickle cell disease. Methods We treated four patients who were receiving Hydroxyurea for sickle cell disease (three who were homozygous for sickle cell anemia and one with sickle β0-thalassemia) with escalating doses of intravenous erythropoietin for seven weeks, along with oral iron sulfate. Doses of Hydroxyurea on four consecutive days were alternated with doses of erythropoietin on three consecutive days. Results There was a 28 percent increase in the number of reticulocytes containing fetal hemoglobin and a 48 percent in...

Jane S. Hankins - One of the best experts on this subject based on the ideXlab platform.

  • a clinically meaningful fetal hemoglobin threshold for children with sickle cell anemia during Hydroxyurea therapy
    American Journal of Hematology, 2017
    Co-Authors: Jeremie H Estepp, Russell E. Ware, Winfred C. Wang, Matthew P Smeltzer, Banu Aygun, Kerri Nottage, Guolian Kang, Christina M Abrams, Jane S. Hankins
    Abstract:

    Hydroxyurea has proven clinical benefits and is recommended to be offered to all children with sickle cell anemia (SCA), but the optimal dosing regimen remains controversial. Induction of red blood cell fetal hemoglobin (HbF) by Hydroxyurea appears to be dose-dependent. However, it is unknown whether maximizing HbF% improves clinical outcomes. HUSTLE (NCT00305175) is a prospective observational study with a primary goal of describing the long-term clinical effects of Hydroxyurea escalated to maximal tolerated dose (MTD) in children with SCA. In 230 children, providing 610 patient-years of follow up, the mean attained HbF% at MTD was >20% for up to 4 years of follow-up. When HbF% values were ≤20%, children had twice the odds of hospitalization for any reason (P  20% was associated with fewer hospitalizations without significant toxicity. These data support the use of Hydroxyurea in children, and suggest that the preferred dosing strategy is one that targets a HbF endpoint >20%.

  • prevention of conversion to abnormal transcranial doppler with Hydroxyurea in sickle cell anemia a phase iii international randomized clinical trial
    American Journal of Hematology, 2015
    Co-Authors: Jane S. Hankins, Mary Beth Mccarville, Angela Rankinemullings, Marvin Reid, Clarisse Lopes De Castro Lobo, Patricia Moura, Susanna Bortolusso Ali, Deanne Soares, Karen Aldred, Dennis W Jay
    Abstract:

    Children with sickle cell anemia (SCA) and conditional transcranial Doppler (TCD) ultrasound velocities (170-199 cm/sec) may develop stroke. However, with limited available clinical data, the current standard of care for conditional TCD velocities is observation. The efficacy of Hydroxyurea in preventing conversion from conditional to abnormal TCD (≥200 cm/sec), which confers a higher stroke risk, has not been studied prospectively in a randomized trial. Sparing Conversion to Abnormal TCD Elevation (SCATE #NCT01531387) was a National Heart, Lung, and Blood Institute-funded Phase III multicenter international clinical trial comparing alternative therapy (Hydroxyurea) to standard care (observation) to prevent conversion from conditional to abnormal TCD velocity in children with SCA. SCATE enrolled 38 children from the United States, Jamaica, and Brazil [HbSS (36), HbSβ(0) -thalassemia (1), and HbSD (1), median age = 5.4 years (range, 2.7-9.8)]. Because of the slow patient accrual and administrative delays, SCATE was terminated early. In an intention-to-treat analysis, the cumulative incidence of abnormal conversion was 9% (95% CI = 0-35%) in the Hydroxyurea arm and 47% (95% CI = 6-81%) in observation arm at 15 months (P = 0.16). In post hoc analysis according to treatment received, significantly fewer children on Hydroxyurea converted to abnormal TCD velocities when compared with observation (0% vs. 50%, P = 0.02). After a mean of 10.1 months, a significant change in mean TCD velocity was observed with Hydroxyurea treatment (-15.5 vs. +10.2 cm/sec, P = 0.02). No stroke events occurred in either arm. Hydroxyurea reduces TCD velocities in children with SCA and conditional velocities.

  • from infancy to adolescence fifteen years of continuous treatment with Hydroxyurea in sickle cell anemia
    Medicine, 2014
    Co-Authors: Jane S. Hankins, Russell E. Ware, Matthew P Smeltzer, Courtney D Thornburg, Banu Aygun, Kerri Nottage, Winfred C. Wang
    Abstract:

    Despite documented laboratory and clinical benefits of Hydroxyurea for children with sickle cell anemia (SCA), the drug's long-term safety and efficacy remains poorly defined. The HUSOFT trial and extension study examined feasibility, toxicity, and hematological efficacy of Hydroxyurea in infants with SCA. This report describes HUSOFT participants who have continued Hydroxyurea therapy for 15 years. With IRB approval, medical records were reviewed for clinical, laboratory, and growth parameters. Twenty-eight infants enrolled in the original 2-year HUSOFT study received open-label liquid Hydroxyurea at 20 mg/kg/day; 17 completed the extension study with dose escalation to 30 mg/kg/day. Eight of these 17 (6 girls and 2 boys, all HbSS) have continued on daily Hydroxyurea for at least 15 years (median age at last follow-up 17.6 years) without interruption. All hematologic indices (Hb concentration, mean corpuscular volume (MCV), fetal hemoglobin) showed sustained effect after 15 years. The median maximum tolerated dose of Hydroxyurea has decreased from 30 to 26 mg/kg/day (range 19.5-31.2); neutropenia [absolute neutrophil count (ANC)<1.0×10⁹/L] prompting temporary drug discontinuation occurred a total of 10 times in 4 subjects and there was no severe neutropenia (ANC<0.5×10⁹/L). Growth rates over 15 years continued at the 50th percentile for both height and weight, and puberty occurred without delay (age range 10-14 years). There were 5.1 vaso-occlusive events (pain and acute chest syndrome)/100 patient years, 7.3 packed red blood cell transfusions/100 patient years. No malignancies, strokes, or deaths occurred. At last follow up, all subjects were at appropriate grade level (10-12 grade) with no history of repeated grades. A cohort of young teenagers with SCA who initiated treatment in infancy have had sustained and continued hematological benefits for a decade and a half. Growth and sexual development are normal and comparable to the general pediatric population. Continuous Hydroxyurea therapy since infancy appears safe and efficacious in SCA.

  • Hydroxyurea treatment decreases glomerular hyperfiltration in children with sickle cell anemia
    American Journal of Hematology, 2013
    Co-Authors: Banu Aygun, Nicole A Mortier, Jane S. Hankins, Matthew P Smeltzer, Barry L Shulkin, Russell E. Ware
    Abstract:

    Glomerular hyperfiltration and microalbuminuria/proteinuria are early manifestations of sickle nephropathy. The effects of Hydroxyurea therapy on these renal manifestations of sickle cell anemia (SCA) are not well defined. Our objective was to investigate the effects of Hydroxyurea on glomerular filtration rate (GFR) measured by (99m)Tc-DTPA clearance, and on microalbuminuria/proteinuria in children with SCA. Hydroxyurea study of long-term effects (HUSTLE) is a prospective study (NCT00305175) with the goal of describing the long-term cellular, molecular, and clinical effects of Hydroxyurea therapy in SCA. Glomerular filtration rate, urine microalbumin, and serum cystatin C were measured before initiating Hydroxyurea therapy and then repeated after 3 years. Baseline and Year 3 values for HUSTLE subjects were compared using the Wilcoxon Signed Rank test. Associations between continuous variables were evaluated using Spearman correlation coefficient. Twenty-three children with SCA (median age 7.5 years, range, 2.5-14.0 years) received Hydroxyurea at maximum tolerated dose (MTD, 24.4 ± 4.5 mg/kg/day, range, 15.3-30.6 mg/kg/day). After 3 years of treatment, GFR measured by (99m)Tc-DTPA decreased significantly from 167 ± 46 mL/min/1.73 m² to 145 ± 27 mL/min/1.73 m² (P = 0.016). This decrease in GFR was significantly associated with increase in fetal hemoglobin (P = 0.042) and decrease in lactate dehydrogenase levels (P = 0.035). Urine microalbumin and cystatin C levels did not change significantly. Hydroxyurea at MTD is associated with a decrease in hyperfiltration in young children with SCA.

  • preservation of spleen and brain function in children with sickle cell anemia treated with Hydroxyurea
    Pediatric Blood & Cancer, 2008
    Co-Authors: Jane S. Hankins, Winfred C. Wang, Kathleen J Helton, Beth M Mccarville, Russell E. Ware
    Abstract:

    Introduction Chronic organ damage is an insidious process in patients with sickle cell anemia (SCA). Although Hydroxyurea prevents acute vaso-occlusive events, its effects on the preservation of organ function remain undefined. Patients and Methods We retrospectively reviewed our single institution experience with children with SCA treated with Hydroxyurea for clinical disease severity, who had optional radionuclide liver-spleen (LS) and brain magnetic resonance imaging (MRI)/with angiography (MRA) performed before and during therapy. Studies were reviewed by pediatric radiologists blinded to treatment status. Demographic and laboratory predictors were modeled using logistic regression. Results A total of 43 children had spleen function measured both at baseline and on therapy. After a median of 2.6 years (range, 0.2–8.6 years) of Hydroxyurea at maximum tolerated dose (MTD), six patients (14%) completely recovered splenic function and two (5%) had preserved splenic function. These eight children had a greater hemoglobin (Hb) concentration on Hydroxyurea therapy than those without splenic function (9.1 vs. 8.6 gm/dl, P = 0.01). Of 25 children with brain MRI/MRA studies performed before initiating Hydroxyurea and on therapy, 24 (96%) had no change in brain ischemic lesions compared with pre-treatment studies, after a median of 2.9 years of treatment. Conclusion These retrospective data suggest that Hydroxyurea at MTD possibly preserves spleen and brain function in children with SCA, and can even result in recovery of splenic function. Higher final Hb concentration during therapy is a significant laboratory predictor of improved splenic function. Pediatr Blood Cancer 2008;50:293–297. © 2007 Wiley-Liss, Inc.

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  • Hydroxyurea for children with sickle cell anemia in sub saharan africa
    The New England Journal of Medicine, 2019
    Co-Authors: Leon Tshilolo, Teresa Latham, Adam Lane, Banu Aygun, George Tomlinson, Thomas N Williams, Brigida Santos, Peter Olupotolupot, Susan E Stuber, Patrick T Mcgann
    Abstract:

    Abstract Background Hydroxyurea is an effective treatment for sickle cell anemia, but few studies have been conducted in sub-Saharan Africa, where the burden is greatest. Coexisting conditions such as malnutrition and malaria may affect the feasibility, safety, and benefits of Hydroxyurea in low-resource settings. Methods We enrolled children 1 to 10 years of age with sickle cell anemia in four sub-Saharan countries. Children received Hydroxyurea at a dose of 15 to 20 mg per kilogram of body weight per day for 6 months, followed by dose escalation. The end points assessed feasibility (enrollment, retention, and adherence), safety (dose levels, toxic effects, and malaria), and benefits (laboratory variables, sickle cell–related events, transfusions, and survival). Results A total of 635 children were fully enrolled; 606 children completed screening and began receiving Hydroxyurea at a mean (±SD) dose of 17.5±1.8 mg per kilogram per day. The retention rate was 94.2% at 3 years of treatment. Hydroxyurea ther...

  • a clinically meaningful fetal hemoglobin threshold for children with sickle cell anemia during Hydroxyurea therapy
    American Journal of Hematology, 2017
    Co-Authors: Jeremie H Estepp, Russell E. Ware, Winfred C. Wang, Matthew P Smeltzer, Banu Aygun, Kerri Nottage, Guolian Kang, Christina M Abrams, Jane S. Hankins
    Abstract:

    Hydroxyurea has proven clinical benefits and is recommended to be offered to all children with sickle cell anemia (SCA), but the optimal dosing regimen remains controversial. Induction of red blood cell fetal hemoglobin (HbF) by Hydroxyurea appears to be dose-dependent. However, it is unknown whether maximizing HbF% improves clinical outcomes. HUSTLE (NCT00305175) is a prospective observational study with a primary goal of describing the long-term clinical effects of Hydroxyurea escalated to maximal tolerated dose (MTD) in children with SCA. In 230 children, providing 610 patient-years of follow up, the mean attained HbF% at MTD was >20% for up to 4 years of follow-up. When HbF% values were ≤20%, children had twice the odds of hospitalization for any reason (P  20% was associated with fewer hospitalizations without significant toxicity. These data support the use of Hydroxyurea in children, and suggest that the preferred dosing strategy is one that targets a HbF endpoint >20%.

  • from infancy to adolescence fifteen years of continuous treatment with Hydroxyurea in sickle cell anemia
    Medicine, 2014
    Co-Authors: Jane S. Hankins, Russell E. Ware, Matthew P Smeltzer, Courtney D Thornburg, Banu Aygun, Kerri Nottage, Winfred C. Wang
    Abstract:

    Despite documented laboratory and clinical benefits of Hydroxyurea for children with sickle cell anemia (SCA), the drug's long-term safety and efficacy remains poorly defined. The HUSOFT trial and extension study examined feasibility, toxicity, and hematological efficacy of Hydroxyurea in infants with SCA. This report describes HUSOFT participants who have continued Hydroxyurea therapy for 15 years. With IRB approval, medical records were reviewed for clinical, laboratory, and growth parameters. Twenty-eight infants enrolled in the original 2-year HUSOFT study received open-label liquid Hydroxyurea at 20 mg/kg/day; 17 completed the extension study with dose escalation to 30 mg/kg/day. Eight of these 17 (6 girls and 2 boys, all HbSS) have continued on daily Hydroxyurea for at least 15 years (median age at last follow-up 17.6 years) without interruption. All hematologic indices (Hb concentration, mean corpuscular volume (MCV), fetal hemoglobin) showed sustained effect after 15 years. The median maximum tolerated dose of Hydroxyurea has decreased from 30 to 26 mg/kg/day (range 19.5-31.2); neutropenia [absolute neutrophil count (ANC)<1.0×10⁹/L] prompting temporary drug discontinuation occurred a total of 10 times in 4 subjects and there was no severe neutropenia (ANC<0.5×10⁹/L). Growth rates over 15 years continued at the 50th percentile for both height and weight, and puberty occurred without delay (age range 10-14 years). There were 5.1 vaso-occlusive events (pain and acute chest syndrome)/100 patient years, 7.3 packed red blood cell transfusions/100 patient years. No malignancies, strokes, or deaths occurred. At last follow up, all subjects were at appropriate grade level (10-12 grade) with no history of repeated grades. A cohort of young teenagers with SCA who initiated treatment in infancy have had sustained and continued hematological benefits for a decade and a half. Growth and sexual development are normal and comparable to the general pediatric population. Continuous Hydroxyurea therapy since infancy appears safe and efficacious in SCA.

  • whole exome sequencing identifies novel genes for fetal hemoglobin response to Hydroxyurea in children with sickle cell anemia
    PLOS ONE, 2014
    Co-Authors: Vivien A Sheehan, Nicole A Mortier, Thad A Howard, Banu Aygun, Jacy R Crosby, Aniko Sabo, Donna M Muzny, Shannon Duganperez, Kerri Nottage, Eric Boerwinkle
    Abstract:

    Hydroxyurea has proven efficacy in children and adults with sickle cell anemia (SCA), but with considerable inter-individual variability in the amount of fetal hemoglobin (HbF) produced. Sibling and twin studies indicate that some of that drug response variation is heritable. To test the hypothesis that genetic modifiers influence pharmacological induction of HbF, we investigated phenotype-genotype associations using whole exome sequencing of children with SCA treated prospectively with Hydroxyurea to maximum tolerated dose (MTD). We analyzed 171 unrelated patients enrolled in two prospective clinical trials, all treated with dose escalation to MTD. We examined two MTD drug response phenotypes: HbF (final %HbF minus baseline %HbF), and final %HbF. Analyzing individual genetic variants, we identified multiple low frequency and common variants associated with HbF induction by Hydroxyurea. A validation cohort of 130 pediatric sickle cell patients treated to MTD with Hydroxyurea was genotyped for 13 non-synonymous variants with the strongest association with HbF response to Hydroxyurea in the discovery cohort. A coding variant in Spalt-like transcription factor, or SALL2, was associated with higher final HbF in this second independent replication sample and SALL2 represents an outstanding novel candidate gene for further investigation. These findings may help focus future functional studies and provide new insights into the pharmacological HbF upregulation by Hydroxyurea in patients with SCA.

  • Hydroxyurea treatment decreases glomerular hyperfiltration in children with sickle cell anemia
    American Journal of Hematology, 2013
    Co-Authors: Banu Aygun, Nicole A Mortier, Jane S. Hankins, Matthew P Smeltzer, Barry L Shulkin, Russell E. Ware
    Abstract:

    Glomerular hyperfiltration and microalbuminuria/proteinuria are early manifestations of sickle nephropathy. The effects of Hydroxyurea therapy on these renal manifestations of sickle cell anemia (SCA) are not well defined. Our objective was to investigate the effects of Hydroxyurea on glomerular filtration rate (GFR) measured by (99m)Tc-DTPA clearance, and on microalbuminuria/proteinuria in children with SCA. Hydroxyurea study of long-term effects (HUSTLE) is a prospective study (NCT00305175) with the goal of describing the long-term cellular, molecular, and clinical effects of Hydroxyurea therapy in SCA. Glomerular filtration rate, urine microalbumin, and serum cystatin C were measured before initiating Hydroxyurea therapy and then repeated after 3 years. Baseline and Year 3 values for HUSTLE subjects were compared using the Wilcoxon Signed Rank test. Associations between continuous variables were evaluated using Spearman correlation coefficient. Twenty-three children with SCA (median age 7.5 years, range, 2.5-14.0 years) received Hydroxyurea at maximum tolerated dose (MTD, 24.4 ± 4.5 mg/kg/day, range, 15.3-30.6 mg/kg/day). After 3 years of treatment, GFR measured by (99m)Tc-DTPA decreased significantly from 167 ± 46 mL/min/1.73 m² to 145 ± 27 mL/min/1.73 m² (P = 0.016). This decrease in GFR was significantly associated with increase in fetal hemoglobin (P = 0.042) and decrease in lactate dehydrogenase levels (P = 0.035). Urine microalbumin and cystatin C levels did not change significantly. Hydroxyurea at MTD is associated with a decrease in hyperfiltration in young children with SCA.