Emerging science of hydroxyurea therapy for pediatric sickle cell disease

Pediatric Research

Volumn 75, Issue 1-2, 2014, Pages 196-204

  Green, Nancy S ^a   Barral, Sandra ^b  

^a Division of Pediatric Hematology/Oncology/Stem Cell Transplantation Department of Pediatrics Columbia University ^*  (United States)

^b Vagelos College of Physicians and Surgeons   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

5 AZA 2' DEOXYCYTIDINE; AZACITIDINE; CYCLIC GMP; ERYTHROPOIETIN; HEMOGLOBIN BETA CHAIN; HEMOGLOBIN EPSILON CHAIN; HEMOGLOBIN F; HEMOGLOBIN GAMMA CHAIN; HEMOGLOBIN S; HISTONE DEACETYLASE INHIBITOR; HYDROXYUREA; PHOSPHODIESTERASE INHIBITOR;

ALLELE; CHILD; CHILDHOOD DISEASE; DRUG EFFICACY; DRUG MECHANISM; GENE EXPRESSION; GENETIC ANALYSIS; HUMAN; NONHUMAN; PRIORITY JOURNAL; REVIEW; SICKLE CELL; SICKLE CELL ANEMIA; SINGLE NUCLEOTIDE POLYMORPHISM; THERAPY EFFECT;

AGE FACTORS; ANEMIA, SICKLE CELL; ANIMALS; ANTISICKLING AGENTS; CHILD; CHILD, PRESCHOOL; FETAL HEMOGLOBIN; GENETIC MARKERS; GENETIC PREDISPOSITION TO DISEASE; HUMANS; HYDROXYUREA; INFANT; INFANT, NEWBORN; PHENOTYPE; POLYMORPHISM, SINGLE NUCLEOTIDE; RISK FACTORS; TREATMENT OUTCOME;

EID: 84900413237     PISSN: 00313998     EISSN: 15300447     Source Type: Journal    
DOI: 10.1038/pr.2013.227     Document Type: Review

References (82)

1. Healthy People 2020. (http://healthypeople.gov/2020/topicsobjectives2020/ overview.aspxtopicid=4.) Accessed 6 September 2012.
2. Hassell KL. Population estimates of sickle cell disease in the U.S. Am J Prev Med 2010;38:Suppl:S512-21.
3. Hamideh D, Alvarez O. Sickle cell disease related mortality in the United States (1999-2009). Pediatr Blood Cancer 2013;60:1482-6.
4. Quinn CT, Rogers ZR, McCavit TL, Buchanan GR. Improved survival of children and adolescents with sickle cell disease. Blood 2010;115:3447-52.
5. Yanni E, Grosse SD, Yang Q, Olney RS. Trends in pediatric sickle cell disease-related mortality in the United States, 1983-2002. J Pediatr 2009;154:541-5.
6. Lanzkron S, Carroll CP, Haywood C Jr. Mortality rates and age at death from sickle cell disease: U.S., 1979-2005. Public Health Rep 2013;128:110-6.
7. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med 1995;332:1317-22.
8. Ferster A, Vermylen C, Cornu G, et al. Hydroxyurea for treatment of severe sickle cell anemia: a pediatric clinical trial. Blood 1996;88:1960-4.
9. McGann PT, Ware RE. Hydroxyurea for sickle cell anemia: what have we learned and what questions still remain Curr Opin Hematol 2011;18:158-65.
10. Strouse JJ, Heeney MM. Hydroxyurea for the treatment of sickle cell disease: efficacy, barriers, toxicity, and management in children. Pediatr Blood Cancer 2012;59:365-71.
11. Strouse JJ, Lanzkron S, Beach MC, et al. Hydroxyurea for sickle cell disease: a systematic review for efficacy and toxicity in children. Pediatrics 2008;122:1332-42.
12. Kinney TR, Helms RW, O'Branski EE, et al. Safety of hydroxyurea in children with sickle cell anemia: results of the HUG-KIDS study, a phase I/II trial. Pediatric Hydroxyurea Group. Blood 1999;94:1550-4.
13. Wang WC, Helms RW, Lynn HS, et al. Effect of hydroxyurea on growth in children with sickle cell anemia: results of the HUG-KIDS Study. J Pediatr 2002;140:225-9.
14. Ware RE, Eggleston B, Redding-Lallinger R, et al. Predictors of fetal hemoglobin response in children with sickle cell anemia receiving hydroxyurea therapy. Blood 2002;99:10-4.
15. Hankins JS, Ware RE, Rogers ZR, et al. Long-term hydroxyurea therapy for infants with sickle cell anemia: the HUSOFT extension study. Blood 2005;106:2269-75.
16. Thornburg CD, Dixon N, Burgett S, et al. A pilot study of hydroxyurea to prevent chronic organ damage in young children with sickle cell anemia. Pediatr Blood Cancer 2009;52:609-15.
17. Thornburg CD, Files BA, Luo Z, et al.; BABY HUG Investigators. Impact of hydroxyurea on clinical events in the BABY HUG trial. Blood 2012;120:4304-10; quiz 4448.
18. Wang WC, Ware RE, Miller ST, et al.; BABY HUG investigators. Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet 2011;377:1663-72.
19. Bernaudin F, Verlhac S, Arnaud C, et al. Impact of early transcranial Doppler screening and intensive therapy on cerebral vasculopathy outcome in a newborn sickle cell anemia cohort. Blood 2011;117:1130-40; quiz 1436.
20. de Montalembert M, Brousse V, Elie C, Bernaudin F, Shi J, Landais P; French Study Group on Sickle Cell Disease. Long-term hydroxyurea treatment in children with sickle cell disease: tolerance and clinical outcomes. Haematologica 2006;91:125-8.
21. Thornburg CD, Calatroni A, Panepinto JA. Differences in health-related quality of life in children with sickle cell disease receiving hydroxyurea. J Pediatr Hematol Oncol 2011;33:251-4.
22. Dampier C, Lieff S, LeBeau P, et al.; Comprehensive Sickle Cell Centers (CSCC) Clinical Trial Consortium (CTC). Health-related quality of life in children with sickle cell disease: a report from the Comprehensive Sickle Cell Centers Clinical Trial Consortium. Pediatr Blood Cancer 2010;55:485-94.
23. Zimmerman SA, Schultz WH, Davis JS, et al. Sustained long-term hematologic efficacy of hydroxyurea at maximum tolerated dose in children with sickle cell disease. Blood 2004;103:2039-45.
24. Aygun B, Mortier NA, Smeltzer MP, Shulkin BL, Hankins JS, Ware RE. Hydroxyurea treatment decreases glomerular hyperfiltration in children with sickle cell anemia. Am J Hematol 2013;88:116-9.
25. Alvarez O, Miller ST, Wang WC, et al.; BABY HUG Investigators. Effect of hydroxyurea treatment on renal function parameters: results from the multi-center placebo-controlled BABY HUG clinical trial for infants with sickle cell anemia. Pediatr Blood Cancer 2012;59:668-74.
26. Kratovil T, Bulas D, Driscoll MC, Speller-Brown B, McCarter R, Minniti CP. Hydroxyurea therapy lowers TCD velocities in children with sickle cell disease. Pediatr Blood Cancer 2006;47:894-900.
27. Zimmerman SA, Schultz WH, Burgett S, Mortier NA, Ware RE. Hydroxyurea therapy lowers transcranial Doppler flow velocities in children with sickle cell anemia. Blood 2007;110:1043-7.
28. Ware RE, Helms RW; SWiTCH Investigators. Stroke With Transfusions Changing to Hydroxyurea (SWiTCH). Blood 2012;119:3925-32.
29. Alvarez O, Yovetich NA, Scott JP, et al.; Investigators of the Stroke With Transfusions Changing to Hydroxyurea Clinical Trial (SWiTCH). Pain and other non-neurological adverse events in children with sickle cell anemia and previous stroke who received hydroxyurea and phlebotomy or chronic transfusions and chelation: results from the SWiTCH clinical trial. Am J Hematol 2013;88:932-8.
30. Steinberg MH, McCarthy WF, Castro O, et al.; Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia and MSH Patients' Follow-Up. The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: a 17.5 year follow-up. Am J Hematol 2010;85:403-8.
31. Voskaridou E, Christoulas D, Bilalis A, et al. The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS). Blood 2010;115:2354-63.
32. Lobo CL, Pinto JF, Nascimento EM, Moura PG, Cardoso GP, Hankins JS. The effect of hydroxcarbamide therapy on survival of children with sickle cell disease. Br J Haematol 2013;161:852-60.
33. Ware RE, Despotovic JM, Mortier NA, et al. Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia. Blood 2011;118:4985-91.
34. Platt OS. Hydroxyurea for the treatment of sickle cell anemia. N Engl J Med 2008;358:1362-9.
35. Bunn HF. Subunit assembly of hemoglobin: an important determinant of hematologic phenotype. Blood 1987;69:1-6.
36. Powars DR, Weiss JN, Chan LS, Schroeder WA. Is there a threshold level of fetal hemoglobin that ameliorates morbidity in sickle cell anemia Blood 1984;63:921-6.
37. Green NS, Fabry ME, Kaptue-Noche L, Nagel RL. Senegal haplotype is associated with higher HbF than Benin and Cameroon haplotypes in African children with sickle cell anemia. Am J Hematol 1993;44:145-6.
38. Makani J, Menzel S, Nkya S, et al. Genetics of fetal hemoglobin in Tanzanian and British patients with sickle cell anemia. Blood 2011;117:1390-2.
39. Nagel RL, Erlingsson S, Fabry ME, et al. The Senegal DNA haplotype is associated with the amelioration of anemia in African-American sickle cell anemia patients. Blood 1991;77:1371-5.
40. Solovieff N, Hartley SW, Baldwin CT, et al. Ancestry of African Americans with sickle cell disease. Blood Cells Mol Dis 2011;47:41-5.
41. Fathallah H, Atweh GF. Induction of fetal hemoglobin in the treatment of sickle cell disease. Hematology Am Soc Hematol Educ Program 2006;1:58-62.
42. Lebensburger JD, Pestina TI, Ware RE, Boyd KL, Persons DA. Hydroxyurea therapy requires HbF induction for clinical benefit in a sickle cell mouse model. Haematologica 2010;95:1599-603.
43. Gambero S, Canalli AA, Traina F, et al. Therapy with hydroxyurea is associated with reduced adhesion molecule gene and protein expression in sickle red cells with a concomitant reduction in adhesive properties. Eur J Haematol 2007;78:144-51.
44. Tsai M, Kita A, Leach J, et al. In vitro modeling of the microvascular occlusion and thrombosis that occur in hematologic diseases using microfluidic technology. J Clin Invest 2012;122:408-18.
45. Nébor D, Romana M, Santiago R, et al. Fetal hemoglobin and hydroxycarbamide moduate both plasma concentration and cellular origin of circulating microparticles in sickle cell anemia children. Haematologica 2013;98:862-7.
46. Lebensburger JD, Howard T, Hu Y, et al. Hydroxyurea therapy of a murine model of sickle cell anemia inhibits the progression of pneumococcal disease by down-modulating E-selectin. Blood 2012;119:1915-21.
47. Lou TF, Singh M, Mackie A, Li W, Pace BS. Hydroxyurea generates nitric oxide in human erythroid cells: mechanisms for gamma-globin gene activation. Exp Biol Med (Maywood) 2009;234:1374-82.
48. Kato GJ, Hebbel RP, Steinberg MH, Gladwin MT. Vasculopathy in sickle cell disease: biology, pathophysiology, genetics, translational medicine, and new research directions. Am J Hematol 2009;84:618-25.
49. King SB. Nitric oxide production from hydroxyurea. Free Radic Biol Med 2004;37:737-44.
50. Bunn HF, Nathan DG, Dover GJ, et al. Pulmonary hypertension and nitric oxide depletion in sickle cell disease. Blood 2010;116:687-92.
51. Green NS, Ender KL, Pashankar F, et al. Candidate sequence variants and fetal hemoglobin in children with sickle cell disease treated with hydroxyurea. PLoS ONE 2013;8:e55709.
52. Meier ER, Byrnes C, Weissman M, Noel P, Luban NL, Miller JL. Expression patterns of fetal hemoglobin in sickle cell erythrocytes are both patient-and treatment-specific during childhood. Pediatr Blood Cancer 2011;56:103-9.
53. Italia K, Jain D, Gattani S, et al. Hydroxyurea in sickle cell disease-a study of clinico-pharmacological efficacy in the Indian haplotype. Blood Cells Mol Dis 2009;42:25-31.
54. Ma Q, Wyszynski DF, Farrell JJ, et al. Fetal hemoglobin in sickle cell anemia: genetic determinants of response to hydroxyurea. Pharmacogenomics J 2007;7:386-94.
55. Steinberg MH, Voskaridou E, Kutlar A, et al. Concordant fetal hemoglobin response to hydroxyurea in siblings with sickle cell disease. Am J Hematol 2003;72:121-6.
56. Thein SL, Menzel S. Discovering the genetics underlying foetal haemoglobin production in adults. Br J Haematol 2009;145:455-67.
57. Garner C, Tatu T, Reittie JE, et al. Genetic influences on F cells and other hematologic variables: a twin heritability study. Blood 2000;95:342-6.
58. Bae HT, Baldwin CT, Sebastiani P, et al. Meta-analysis of 2040 sickle cell anemia patients: BCL11A and HBS1L-MYB are the major modifiers of HbF in African Americans. Blood 2012;120:1961-2.
59. Bhatnagar P, Purvis S, Barron-Casella E, et al. Genome-wide association study identifies genetic variants influencing F-cell levels in sickle-cell patients. J Hum Genet 2011;56:316-23.
60. Galarneau G, Palmer CD, Sankaran VG, Orkin SH, Hirschhorn JN, Lettre G. Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation. Nat Genet 2010;42:1049-51.
61. Lettre G, Sankaran VG, Bezerra MA, et al. DNA polymorphisms at the BCL11A, HBS1L-MYB, and beta-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease. Proc Natl Acad Sci USA 2008;105:11869-74.
62. Sebastiani P, Solovieff N, Hartley SW, et al. Genetic modifiers of the severity of sickle cell anemia identified through a genome-wide association study. Am J Hematol 2010;85:29-35.
63. Sedgewick AE, Timofeev N, Sebastiani P, et al. BCL11A is a major HbF quantitative trait locus in three different populations with beta-hemoglobinopathies. Blood Cells Mol Dis 2008;41:255-8.
64. Kumkhaek C, Taylor JG 6th, Zhu J, Hoppe C, Kato GJ, Rodgers GP. Fetal haemoglobin response to hydroxycarbamide treatment and sar1a promoter polymorphisms in sickle cell anaemia. Br J Haematol 2008;141:254-9.
65. Solovieff N, Milton JN, Hartley SW, et al. Fetal hemoglobin in sickle cell anemia: genome-wide association studies suggest a regulatory region in the 5' olfactory receptor gene cluster. Blood 2010;115:1815-22.
66. Flanagan JM, Steward S, Howard TA, et al. Hydroxycarbamide alters erythroid gene expression in children with sickle cell anaemia. Br J Haematol 2012;157:240-8.
67. Bauer DE, Orkin SH. Update on fetal hemoglobin gene regulation in hemoglobinopathies. Curr Opin Pediatr 2011;23:1-8.
68. Yang YM, Pace B. Pharmacologic induction of fetal hemoglobin synthesis: cellular and molecular mechanisms. Pediatr Pathol Mol Med 2001;20:87-106.
69. Bollenbach T, Quan S, Chait R, Kishony R. Nonoptimal microbial response to antibiotics underlies suppressive drug interactions. Cell 2009;139:707-18.
70. Costa FC, da Cunha AF, Fattori A, et al. Gene expression profiles of erythroid precursors characterise several mechanisms of the action of hydroxycarbamide in sickle cell anaemia. Br J Haematol 2007;136:333-42.
71. Almeida CB, Scheiermann C, Jang JE, et al. Hydroxyurea and a cGMPamplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice. Blood 2012;120:2879-88.
72. Cokic VP, Andric SA, Stojilkovic SS, Noguchi CT, Schechter AN. Hydroxyurea nitrosylates and activates soluble guanylyl cyclase in human erythroid cells. Blood 2008;111:1117-23.
73. Tang DC, Zhu J, Liu W, et al. The hydroxyurea-induced small GTP-binding protein SAR modulates gamma-globin gene expression in human erythroid cells. Blood 2005;106:3256-63.
74. Walker AL, Steward S, Howard TA, et al. Epigenetic and molecular profiles of erythroid cells after hydroxyurea treatment in sickle cell anemia. Blood 2011;118:5664-70.
75. Lanzkron S, Strouse JJ, Wilson R, et al. Systematic review: hydroxyurea for the treatment of adults with sickle cell disease. Ann Intern Med 2008;148:939-55.
76. Flanagan JM, Howard TA, Mortier N, et al. Assessment of genotoxicity associated with hydroxyurea therapy in children with sickle cell anemia. Mutat Res 2010;698:38-42.
77. Kaul DK, Fabry ME, Suzuka SM, Zhang X. Antisickling fetal hemoglobin reduces hypoxia-inducible factor-1a expression in normoxic sickle mice: microvascular implications. Am J Physiol Heart Circ Physiol 2013;304:H42-50.
78. Candrilli SD, O'Brien SH, Ware RE, Nahata MC, Seiber EE, Balkrishnan R. Hydroxyurea adherence and associated outcomes among Medicaid enrollees with sickle cell disease. Am J Hematol 2011;86:273-7.
79. Thornburg CD, Rogers ZR, Jeng MR, et al.; BABY HUG Investigators. Adherence to study medication and visits: data from the BABY HUG trial. Pediatr Blood Cancer 2010;54:260-4.
80. Haywood C Jr, Beach MC, Lanzkron S, et al. A systematic review of barriers and interventions to improve appropriate use of therapies for sickle cell disease. J Natl Med Assoc 2009;101:1022-33.
81. Oyeku SO, Driscoll MC, Cohen HW, et al. Parental and other factors associated with hydroxyurea use for pediatric sickle cell disease. Pediatr Blood Cancer 2013;60:653-8.
82. Roth M, Krystal J, Manwani D, Driscoll C, Ricafort R. Stem cell transplant for children with sickle cell anemia: parent and patient interest. Biol Blood Marrow Transplant 2012;18:1709-15.