Clinical experience with fetal hemoglobin induction therapy in patients with β-thalassemia

Blood

Volumn 121, Issue 12, 2013, Pages 2199-2212

  Musallam, Khaled M ^a,b   Taher, Ali T ^b   Cappellini, Maria Domenica ^a   Sankaran, Vijay G ^c,d  

^a UNIVERSITY OF MILAN   (Italy)

^b AMERICAN UNIVERSITY OF BEIRUT   (Lebanon)

^c BOSTON CHILDREN S HOSPITAL   (United States)

^d WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AZACITIDINE; DNA; HEMOGLOBIN F; HYDROXYUREA; SHORT CHAIN FATTY ACID; ANTISICKLING AGENT;

BETA THALASSEMIA; CLINICAL OUTCOME; DNA METHYLATION; DNA SYNTHESIS INHIBITION; HUMAN; OUTCOME ASSESSMENT; PRIORITY JOURNAL; REVIEW; TREATMENT DURATION; BLOOD; DRUG EFFECT; EVALUATION; METABOLISM; PROFESSIONAL PRACTICE; SICKLE CELL ANEMIA; TREATMENT OUTCOME; UPREGULATION;

ANEMIA, SICKLE CELL; ANTISICKLING AGENTS; AZACITIDINE; BETA-THALASSEMIA; DNA METHYLATION; FETAL HEMOGLOBIN; HUMANS; HYDROXYUREA; PROFESSIONAL PRACTICE; TREATMENT OUTCOME; UP-REGULATION;

MLCS; MLOWN;

EID: 84877929461     PISSN: 00064971     EISSN: 15280020     Source Type: Journal    
DOI: 10.1182/blood-2012-10-408021     Document Type: Review

References (146)

1. Weatherall DJ, Clegg JB. The thalassaemia syndromes, 4th ed. Oxford: Blackwell Science; 2001.
2. Sankaran VG, Nathan DG. Thalassemia: An overview of 50 years of clinical research. Hematol Oncol Clin North Am. 2010;24(6):1005-1020.
3. Rund D, Rachmilewitz E. Betathalassemia. N Engl J Med. 2005;353(11): 1135-1146.
4. Musallam KM, Sankaran VG, Cappellini MD, et al. Fetal hemoglobin levels and morbidity in untransfused patients with b-thalassemia intermedia. Blood. 2012;119(2):364-367.
5. Nuinoon M, Makarasara W, Mushiroda T, et al. A genome-wide association identified the common genetic variants influence disease severity in beta0-thalassemia/hemoglobin E. Hum Genet. 2010;127(3):303-314.
6. Galanello R, Sanna S, Perseu L, et al. Amelioration of Sardinian beta0 thalassemia by genetic modifiers. Blood. 2009;114(18):3935-3937.
7. Danjou F, Anni F, Perseu L, et al. Genetic modifiers of b-thalassemia and clinical severity as assessed by age at first transfusion. Haematologica. 2012;97(7):989-993.
8. Badens C, Joly P, Agouti I, et al. Variants in genetic modifiers of b-thalassemia can help to predict the major or intermedia type of the disease. Haematologica. 2011;96(11): 1712-1714.
9. Uda M, Galanello R, Sanna S, et al. Genomewide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of betathalassemia. Proc Natl Acad Sci USA. 2008; 105(5):1620-1625.
10. Sankaran VG. Targeted therapeutic strategies for fetal hemoglobin induction. Hematology Am Soc Hematol Educ Program. 2011;2011:459-465.
11. Sankaran VG, Menne TF, Šćepanović D, et al. MicroRNA-15a and -16-1 act via MYB to elevate fetal hemoglobin expression in human trisomy 13. Proc Natl Acad Sci USA. 2011;108(4): 1519-1524.
12. Sankaran VG, Menne TF, Xu J, et al. Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Science. 2008;322(5909):1839-1842.
13. Jiang J, Best S, Menzel S, et al. cMYB is involved in the regulation of fetal hemoglobin production in adults. Blood. 2006;108(3): 1077-1083.
14. Borg J, Papadopoulos P, Georgitsi M, et al. Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin. Nat Genet. 2010;42(9): 801-805.
15. Zhou D, Liu K, Sun CW, et al. KLF1 regulates BCL11A expression and gamma- to beta-globin gene switching. Nat Genet. 2010;42(9):742-744.
16. Bradner JE, Mak R, Tanguturi SK, et al. Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease. Proc Natl Acad Sci USA. 2010;107(28): 12617-12622.
17. van der Ploeg LH, Flavell RA. DNA methylation in the human gamma delta beta-globin locus in erythroid and nonerythroid tissues. Cell. 1980; 19(4):947-958.
18. Groudine M, Eisenman R, Weintraub H. Chromatin structure of endogenous retroviral genes and activation by an inhibitor of DNA methylation. Nature. 1981;292(5821):311-317.
19. Jones PA, Taylor SM. Cellular differentiation, cytidine analogs and DNA methylation. Cell. 1980;20(1):85-93.
20. DeSimone J, Heller P, Hall L, et al. 5-Azacytidine stimulates fetal hemoglobin synthesis in anemic baboons. Proc Natl Acad Sci USA. 1982;79(14): 4428-4431.
21. Ley TJ, DeSimone J, Anagnou NP, et al. 5-azacytidine selectively increases gammaglobin synthesis in a patient with beta1 thalassemia. N Engl J Med. 1982;307(24): 1469-1475.
22. Ley TJ, Anagnou NP, Young NS, et al. 5-azacytidine for beta thalassaemia?. Lancet. 1983;1(8322):467.
23. 5-azacytidine for beta-thalassaemia?. Lancet. 1983;1(8314-5):36-37.
24. Dunbar C, Travis W, Kan YW, et al. 5-Azacytidine treatment in a beta (0)-thalassaemic patient unable to be transfused due to multiple alloantibodies. Br J Haematol. 1989;72(3): 467-468.
25. Lowrey CH, Nienhuis AW. Brief report: Treatment with azacitidine of patients with end-stage betathalassemia. N Engl J Med. 1993;329(12): 845-848.
26. Dover GJ, Charache S, Boyer SH, et al. 5-Azacytidine increases HbF production and reduces anemia in sickle cell disease: Doseresponse analysis of subcutaneous and oral dosage regimens. Blood. 1985;66(3):527-532.
27. Charache S, Dover G, Smith K, et al. Treatment of sickle cell anemia with 5-azacytidine results in increased fetal hemoglobin production and is associated with nonrandom hypomethylation of DNA around the gamma-delta-beta-globin gene complex. Proc Natl Acad Sci USA. 1983;80(15): 4842-4846.
28. Dover GJ, Charache SH, Boyer SH, et al. 5-Azacytidine increases fetal hemoglobin production in a patient with sickle cell disease. Prog Clin Biol Res. 1983;134:475-488.
29. Ley TJ, DeSimone J, Noguchi CT, et al. 5-Azacytidine increases gamma-globin synthesis and reduces the proportion of dense cells in patients with sickle cell anemia. Blood. 1983; 62(2):370-380.
30. Mabaera R, Greene MR, Richardson CA, et al. Neither DNA hypomethylation nor changes in the kinetics of erythroid differentiation explain 5-azacytidine's ability to induce human fetal hemoglobin. Blood. 2008;111(1):411-420.
31. Saunthararajah Y, Hillery CA, Lavelle D, et al. Effects of 5-aza-29-deoxycytidine on fetal hemoglobin levels, red cell adhesion, and hematopoietic differentiation in patients with sickle cell disease. Blood. 2003;102(12): 3865-3870.
32. Koshy M, Dorn L, Bressler L, et al. 2-deoxy 5-azacytidine and fetal hemoglobin induction in sickle cell anemia. Blood. 2000;96(7): 2379-2384.
33. DeSimone J, Koshy M, Dorn L, et al. Maintenance of elevated fetal hemoglobin levels by decitabine during dose interval treatment of sickle cell anemia. Blood. 2002;99(11): 3905-3908.
34. Saunthararajah Y, Molokie R, Saraf S, et al. Clinical effectiveness of decitabine in severe sickle cell disease. Br J Haematol. 2008;141(1): 126-129.
35. Olivieri NF, Saunthararajah Y, Thayalasuthan V, et al; Thalassemia Clinical Research Network. A pilot study of subcutaneous decitabine in b-thalassemia intermedia. Blood. 2011;118(10): 2708-2711.
36. Campbell PJ, Green AR. The myeloproliferative disorders. N Engl J Med. 2006;355(23): 2452-2466.
37. Romanelli F, Hoven AD. Use of virostatics as a means of targeting human immunodeficiency virus infection. Curr Pharm Des. 2006;12(9): 1121-1127.
38. Platt OS, Orkin SH, Dover G, et al. Hydroxyurea enhances fetal hemoglobin production in sickle cell anemia. J Clin Invest. 1984;74(2):652-656.
39. Mabaera R, West RJ, Conine SJ, et al. A cell stress signaling model of fetal hemoglobin induction: what doesn't kill red blood cells may make them stronger. Exp Hematol. 2008;36(9): 1057-1072.
40. Cokic VP, Smith RD, Beleslin-Cokic BB, et al. Hydroxyurea induces fetal hemoglobin by the nitric oxide-dependent activation of soluble guanylyl cyclase. J Clin Invest. 2003;111(2): 231-239.
41. Cokic VP, Andric SA, Stojilkovic SS, et al. Hydroxyurea nitrosylates and activates soluble guanylyl cyclase in human erythroid cells. Blood. 2008;111(3):1117-1123.
42. Ikuta T, Ausenda S, Cappellini MD. Mechanism for fetal globin gene expression: Role of the soluble guanylate cyclase-cGMP-dependent protein kinase pathway. Proc Natl Acad Sci USA. 2001;98(4):1847-1852.
43. McGann PT, Ware RE. Hydroxyurea for sickle cell anemia: what have we learned and what questions still remain?. Curr Opin Hematol. 2011; 18(3):158-165.
44. Italia KY, Jijina FJ, Merchant R, et al. Response to hydroxyurea in beta thalassemia major and intermedia: Experience in western India. Clin Chim Acta. 2009;407(1-2):10-15.
45. Calzolari R, Pecoraro A, Borruso V, et al. Induction of gamma-globin gene transcription by hydroxycarbamide in primary erythroid cell cultures from Lepore patients. Br J Haematol. 2008;141(5):720-727.
46. Watanapokasin R, Sanmund D, Winichagoon P, et al. Hydroxyurea responses and fetal hemoglobin induction in beta-thalassemia/HbE patients' peripheral blood erythroid cell culture. Ann Hematol. 2006;85(3):164-169.
47. Watanapokasin Y, Chuncharunee S, Sanmund D, et al. In vivo and in vitro studies of fetal hemoglobin induction by hydroxyurea in betathalassemia/hemoglobin E patients. Exp Hematol. 2005;33(12):1486-1492.
48. Fibach E, Burke LP, Schechter AN, et al. Hydroxyurea increases fetal hemoglobin in cultured erythroid cells derived from normal individuals and patients with sickle cell anemia or beta-thalassemia. Blood. 1993;81(6):1630-1635.
49. Fucharoen S, Siritanaratkul N, Winichagoon P, et al. Hydroxyurea increases hemoglobin F levels and improves the effectiveness of erythropoiesis in beta-thalassemia/hemoglobin E disease. Blood. 1996;87(3):887-892.
50. Rigano P, Pecoraro A, Calzolari R, et al. Desensitization to hydroxycarbamide following long-term treatment of thalassaemia intermedia as observed in vivo and in primary erythroid cultures from treated patients. Br J Haematol. 2010;151(5):509-515.
51. Zeng YT, Huang SZ, Ren ZR, et al. Hydroxyurea therapy in beta-thalassaemia intermedia: Improvement in haematological parameters due to enhanced beta-globin synthesis. Br J Haematol. 1995;90(3):557-563.
52. Sauvage C, Rouyer-Fessard P, Beuzard Y. Improvement of mouse beta thalassaemia by hydroxyurea. Br J Haematol. 1993;84(3): 492-496.
53. Ware RE. How I use hydroxyurea to treat young patients with sickle cell anemia. Blood. 2010; 115(26):5300-5311.
54. Singer ST, Vichinsky EP, Larkin S, et al; E/beta Thalassemia Study Group. Hydroxycarbamideinduced changes in E/beta thalassemia red blood cells. Am J Hematol. 2008;83(11): 842-845.
55. Orringer EP, Blythe DS, Johnson AE, et al. Effects of hydroxyurea on hemoglobin F and water content in the red blood cells of dogs and of patients with sickle cell anemia. Blood. 1991; 78(1):212-216.
56. Ataga KI, Cappellini MD, Rachmilewitz EA. Betathalassaemia and sickle cell anaemia as paradigms of hypercoagulability. Br J Haematol. 2007;139(1):3-13.
57. Musallam KM, Taher AT. Thrombosis in thalassemia: why are we so concerned?. Hemoglobin. 2011;35(5-6):503-510.
58. Saxon BR, Rees D, Olivieri NF. Regression of extramedullary haemopoiesis and augmentation of fetal haemoglobin concentration during hydroxyurea therapy in beta thalassaemia. Br J Haematol. 1998;101(3):416-419.
59. Hajjar FM, Pearson HA. Pharmacologic treatment of thalassemia intermedia with hydroxyurea. J Pediatr. 1994;125(3):490-492.
60. Arruda VR, Lima CS, Saad ST, et al. Successful use of hydroxyurea in beta-thalassemia major. N Engl J Med. 1997;336(13):964.
61. Rigano P, Manfré L, La Galla R, et al. Clinical and hematological response to hydroxyurea in a patient with Hb Lepore/beta-thalassemia. Hemoglobin. 1997;21(3):219-226.
62. Styles L, Lewis B. Foote D, et al. Preliminary report: Hydroxyurea produces significant clinical response in thalassemia intermedia. Ann N Y Acad Sci. 1998;850:461-462.
63. Saxon BR, Waye JS, Olivieri NF. Increase in hemoglobin concentration during therapy with hydroxyurea in Cooley's anemia. Ann N Y Acad Sci. 1998;850:459-460.
64. Hoppe C, Vichinsky E, Lewis B, et al. Hydroxyurea and sodium phenylbutyrate therapy in thalassemia intermedia. Am J Hematol. 1999; 62(4):221-227.
65. Karimi M, Haghpanah S, Farhadi A, et al. Genotype-phenotype relationship of patients with b-thalassemia taking hydroxyurea: A 13-year experience in Iran. Int J Hematol. 2012; 95(1):51-56.
66. Amoozgar H, Farhani N, Khodadadi N, et al. Comparative study of pulmonary circulation and myocardial function in patients with b-thalassemia intermedia with and without hydroxyurea, a case-control study. Eur J Haematol. 2011;87(1):61-67.
67. Ansari SH, Shamsi TS, Ashraf M, et al. Efficacy of hydroxyurea in providing transfusion independence in b-thalassemia. J Pediatr Hematol Oncol. 2011;33(5):339-343.
68. Italia KY, Jijina FF, Merchant R, et al. Effect of hydroxyurea on the transfusion requirements in patients with severe HbE-beta-thalassaemia: A genotypic and phenotypic study. J Clin Pathol. 2010;63(2):147-150.
69. Karimi M, Cohan N, Mousavizadeh K, et al. Adverse effects of hydroxyurea in betathalassemia intermedia patients: 10 years' experience. Pediatr Hematol Oncol. 2010;27(3): 205-211.
70. Ehsani MA, Hedayati-Asl AA, Bagheri A, et al. Hydroxyurea-induced hematological response in transfusion-independent beta-thalassemia intermedia: Case series and review of literature [published correction appears in Pediatr Hematol Oncol. 2011;28(6):538]. Pediatr Hematol Oncol. 2009;26(8):560-565.
71. Zamani F, Shakeri R, Eslami SM, et al. Hydroxyurea therapy in 49 patients with major beta-thalassemia. Arch Iran Med. 2009;12(3): 295-297.
72. Koren A, Levin C, Dgany O, et al. Response to hydroxyurea therapy in beta-thalassemia. Am J Hematol. 2008;83(5):366-370.
73. Mtvarelidze Z, Kvezereli-Kopadze A, Kvezereli-Kopadze M, et al. Hematologic response to hydroxyurea therapy in children with betathalassemia major. Georgian Med News. 2008(156):91-94.
74. Ansari SH, Shamsi TS, Siddiqui FJ, et al. Efficacy of hydroxyurea (HU) in reduction of pack red cell (PRC) transfusion requirement among children having beta-thalassemia major: Karachi HU trial (KHUT). J Pediatr Hematol Oncol. 2007; 29(11):743-746.
75. Bradai M, Pissard S, Abad MT, et al. Decreased transfusion needs associated with hydroxyurea therapy in Algerian patients with thalassemia major or intermedia. Transfusion. 2007;47(10): 1830-1836.
76. Mancuso A, Maggio A, Renda D, et al. Treatment with hydroxycarbamide for intermedia thalassaemia: Decrease of efficacy in some patients during long-term follow up. Br J Haematol. 2006;133(1):105-106.
77. Dixit A, Chatterjee TC, Mishra P, et al. Hydroxyurea in thalassemia intermedia- a promising therapy. Ann Hematol. 2005;84(7): 441-446.
78. Karimi M, Darzi H, Yavarian M. Hematologic and clinical responses of thalassemia intermedia patients to hydroxyurea during 6 years of therapy in Iran. J Pediatr Hematol Oncol. 2005;27(7): 380-385.
79. Alebouyeh M, Moussavi F, Haddad-Deylami H, et al. Hydroxyurea in the treatment of major betathalassemia and importance of genetic screening. Ann Hematol. 2004;83(7):430-433.
80. Yavarian M, Karimi M, Bakker E, et al. Response to hydroxyurea treatment in Iranian transfusiondependent beta-thalassemia patients. Haematologica. 2004;89(10):1172-1178.
81. Bradai M, Abad MT, Pissard S, et al. Hydroxyurea can eliminate transfusion requirements in children with severe betathalassemia. Blood. 2003;102(4):1529-1530.
82. de Paula EV, Lima CS, Arruda VR, et al. Longterm hydroxyurea therapy in beta-thalassaemia patients. Eur J Haematol. 2003;70(3):151-155.
83. Choudhry VP, Lal A, Pati HP, et al. Hematological responses to hydroxyurea therapy in multitransfused thalassemic children. Indian J Pediatr. 1997;64(3):395-398.
84. Taher A, Sheikh-Taha M. Hydroxyurea use in Lebanese patients with beta-thalassemia intermedia. J Pediatr Hematol Oncol. 2006; 28(2):107.
85. Singer ST, Kuypers FA, Olivieri NF, et al; E/beta Thalassaemia Study Group. Fetal haemoglobin augmentation in E/beta(0) thalassaemia: Clinical and haematological outcome. Br J Haematol. 2005;131(3):378-388.
86. Amoyal I, Goldfarb A, Fibach E. Flow cytometric analysis of hydroxyurea effects on fetal hemoglobin production in cultures of betathalassemia erythroid precursors. Hemoglobin. 2003;27(2):77-87.
87. Taher AT, Musallam KM, Karimi M, et al. Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: The OPTIMAL CARE study. Blood. 2010;115(10): 1886-1892.
88. Musallam KM, Taher AT, Karimi M, et al. Cerebral infarction in b-thalassemia intermedia: Breaking the silence. Thromb Res. 2012;130(5): 695-702.
89. Ware RE, Helms RW. SWiTCH Investigators. Stroke With Transfusions Changing to Hydroxyurea (SWiTCH). Blood. 2012;119(17): 3925-3932.
90. Olivieri NF, Rees DC, Ginder GD, et al. Treatment of thalassaemia major with phenylbutyrate and hydroxyurea. Lancet. 1997; 350(9076):491-492.
91. Voskaridou E, Kalotychou V, Loukopoulos D. Clinical and laboratory effects of long-term administration of hydroxyurea to patients with sickle-cell/beta-thalassaemia. Br J Haematol. 1995;89(3):479-484.
92. Loukopoulos D, Voskaridou E, Kalotychou V, et al. Reduction of the clinical severity of sickle cell/beta-thalassemia with hydroxyurea: The experience of a single center in Greece. Blood Cells Mol Dis. 2000;26(5):453-466.
93. Bincoletto C, Perlingeiro RC, Saad ST, et al. Hydroxyurea promotes the reduction of spontaneous BFU-e to normal levels in SS and S/beta thalassemic patients. Hemoglobin. 2001; 25(1):1-7.
94. Rigano P, Rodgers GP, Renda D, et al. Clinical and hematological responses to hydroxyurea in Sicilian patients with Hb S/beta-thalassemia. Hemoglobin. 2001;25(1):9-17.
95. Koren A, Segal-Kupershmit D, Zalman L, et al. Effect of hydroxyurea in sickle cell anemia: A clinical trial in children and teenagers with severe sickle cell anemia and sickle cell betathalassemia. Pediatr Hematol Oncol. 1999;16(3): 221-232.
96. Panigrahi I, Dixit A, Arora S, et al. Do alpha deletions influence hydroxyurea response in thalassemia intermedia?. Hematology. 2005; 10(1):61-63.
97. Banan M, Bayat H, Azarkeivan A, et al. The XmnI and BCL11A single nucleotide polymorphisms may help predict hydroxyurea response in Iranian b-thalassemia patients. Hemoglobin. 2012;36(4):371-380.
98. Konstantinou E, Pashalidis I, Kolnagou A, et al. Interactions of hydroxycarbamide (hydroxyurea) with iron and copper: Implications on toxicity and therapeutic strategies. Hemoglobin. 2011;35(3): 237-246.
99. Karimi M, Borzouee M, Mehrabani A, et al. Echocardiographic finding in beta-thalassemia intermedia and major: Absence of pulmonary hypertension following hydroxyurea treatment in beta-thalassemia intermedia. Eur J Haematol. 2009;82(3):213-218.
100. Karimi M, Mohammadi F, Behmanesh F, et al. Effect of combination therapy of hydroxyurea with l-carnitine and magnesium chloride on hematologic parameters and cardiac function of patients with beta-thalassemia intermedia. Eur J Haematol. 2010;84(1):52-58.
101. Gamberini MR, Fortini M, De Sanctis V. Healing of leg ulcers with hydroxyurea in thalassaemia intermedia patients with associated endocrine complications. Pediatr Endocrinol Rev. 2004; 2 (suppl 2):319-322.
102. Haidar R, Mhaidli H, Taher AT. Paraspinal extramedullary hematopoiesis in patients with thalassemia intermedia. Eur Spine J. 2010; 19(6):871-878.
103. Felice AE, Borg J, Pizzuto M, et al. A review of cis-trans interplay between DNA sequences 59 to the (G)gamma- and beta-globin genes among Hb F-Malta-I heterozygotes/homozygotes and beta-thalassemia homozygotes/compound heterozygotes, and the effects of hydroxyurea on the Hb F/F-erythrocyte; the need for large multicenter trials. Hemoglobin. 2007;31(2): 279-288.
104. Zargari O, Kimyai-Asadi A, Jafroodi M. Cutaneous adverse reactions to hydroxyurea in patients with intermediate thalassemia. Pediatr Dermatol. 2004;21(6):633-635.
105. Karimi M, Zekavat OR, Haghpanah S, et al. Comparative study of hypogonadism in betathalassemia intermedia patients with and without hydroxyurea. Hematology. 2012;17(2):122-124.
106. Perrine SP, Greene MF, Faller DV. Delay in the fetal globin switch in infants of diabetic mothers. N Engl J Med. 1985;312(6):334-338.
107. Bard H, Prosmanne J. Relative rates of fetal hemoglobin and adult hemoglobin synthesis in cord blood of infants of insulin-dependent diabetic mothers. Pediatrics. 1985;75(6): 1143-1147.
108. Perrine SP, Rudolph A, Faller DV, et al. Butyrate infusions in the ovine fetus delay the biologic clock for globin gene switching. Proc Natl Acad Sci USA. 1988;85(22):8540-8542.
109. Perrine SP, Ginder GD, Faller DV, et al. A shortterm trial of butyrate to stimulate fetal-globingene expression in the beta-globin disorders. N Engl J Med. 1993;328(2):81-86.
110. Perrine SP, Olivieri NF, Faller DV, et al. Butyrate derivatives. New agents for stimulating fetal globin production in the beta-globin disorders. Am J Pediatr Hematol Oncol. 1994;16(1):67-71.
111. Sher GD, Ginder GD, Little J, et al. Extended therapy with intravenous arginine butyrate in patients with beta-hemoglobinopathies. N Engl J Med. 1995;332(24):1606-1610.
112. Atweh GF, Sutton M, Nassif I, et al. Sustained induction of fetal hemoglobin by pulse butyrate therapy in sickle cell disease. Blood. 1999;93(6): 1790-1797.
113. Collins AF, Pearson HA, Giardina P, et al. Oral sodium phenylbutyrate therapy in homozygous beta thalassemia: A clinical trial. Blood. 1995; 85(1):43-49.
114. Domenica Cappellini M, Graziadei G, Ciceri L, et al. Oral isobutyramide therapy in patients with thalassemia intermedia: Results of a phase II open study. Blood Cells Mol Dis. 2000;26(1): 105-111.
115. Reich S, Bührer C, Henze G, et al. Oral isobutyramide reduces transfusion requirements in some patients with homozygous betathalassemia. Blood. 2000;96(10):3357-3363.
116. Fathallah H, Taher A, Bazarbachi A, et al. Differences in response to fetal hemoglobin induction therapy in beta-thalassemia and sickle cell disease. Blood Cells Mol Dis. 2009;43(1): 58-62.
117. Kutlar A, Ataga K, Reid M, et al. A phase 1/2 trial of HQK-1001, an oral fetal globin inducer, in sickle cell disease. Am J Hematol. 2012;87(11): 1017-1021.
118. Singer ST, Vichinsky EP, Sweeters N, et al. Darbepoetin alfa for the treatment of anaemia in alpha- or beta- thalassaemia intermedia syndromes. Br J Haematol. 2011;154(2): 281-284.
119. Rachmilewitz EA, Aker M, Perry D, et al. Sustained increase in haemoglobin and RBC following long-term administration of recombinant human erythropoietin to patients with homozygous beta-thalassaemia. Br J Haematol. 1995;90(2):341-345.
120. Bourantas K, Economou G, Georgiou J. Administration of high doses of recombinant human erythropoietin to patients with betathalassemia intermedia: A preliminary trial. Eur J Haematol. 1997;58(1):22-25.
121. Nis li G, Kavakli K, Vergin C, et al. Recombinant human erythropoietin trial in thalassemia intermedia. J Trop Pediatr. 1996;42(6):330-334.
122. Nisli G, Kavakli K, Aydinok Y, et al. Recombinant erythropoietin trial in children with transfusiondependent homozygous beta-thalassemia. Acta Haematol. 1997;98(4):199-203.
123. Chaidos A, Makis A, Hatzimichael E, et al. Treatment of beta-thalassemia patients with recombinant human erythropoietin: Effect on transfusion requirements and soluble adhesion molecules. Acta Haematol. 2004;111(4): 189-195.
124. Galanello R, Barella S, Turco MP, et al. Serum erythropoietin and erythropoiesis in high- and low-fetal hemoglobin beta-thalassemia intermedia patients. Blood. 1994;83(2):561-565.
125. Rodgers GP, Dover GJ, Uyesaka N, et al. Augmentation by erythropoietin of the fetalhemoglobin response to hydroxyurea in sickle cell disease. N Engl J Med. 1993;328(2):73-80.
126. McDonagh KT, Dover GJ, Donahue RE, et al. Hydroxyurea-induced HbF production in anemic primates: Augmentation by erythropoietin, hematopoietic growth factors, and sodium butyrate. Exp Hematol. 1992;20(10):1156-1164.
127. Lavelle D, Molokie R, Ducksworth J, et al. Effects of hydroxurea, stem cell factor, and erythropoietin in combination on fetal hemoglobin in the baboon. Exp Hematol. 2001; 29(2):156-162.
128. Loukopoulos D, Voskaridou E, Stamoulakatou A, et al. Hydroxyurea therapy in thalassemia. Ann N Y Acad Sci. 1998;850:120-128.
129. Kumar M, Fallon RJ, Hill JS, et al. Esthesioneuroblastoma in children. J Pediatr Hematol Oncol. 2002;24(6):482-487.
130. Aerbajinai W, Zhu J, Gao Z, et al. Thalidomide induces gamma-globin gene expression through increased reactive oxygen species-mediated p38 MAPK signaling and histone H4 acetylation in adult erythropoiesis. Blood. 2007;110(8): 2864-2871.
131. Aguilar-Lopez LB, Delgado-Lamas JL, Rubio-Jurado B, et al. Thalidomide therapy in a patient with thalassemia major. Blood Cells Mol Dis. 2008;41(1):136-137.
132. Masera N, Tavecchia L, Capra M, et al. Optimal response to thalidomide in a patient with thalassaemia major resistant to conventional therapy. Blood Transfus. 2010;8(1):63-65.
133. Moutouh-de Parseval LA, Verhelle D, Glezer E, et al. Pomalidomide and lenalidomide regulate erythropoiesis and fetal hemoglobin production in human CD341 cells. J Clin Invest. 2008; 118(1):248-258.
134. Meiler SE, Wade M, Kutlar F, et al. Pomalidomide augments fetal hemoglobin production without the myelosuppressive effects of hydroxyurea in transgenic sickle cell mice. Blood. 2011;118(4):1109-1112.
135. Steinberg MH, Forget BG, Higgs DR, et al. Disorders of hemoglobin: Genetics, pathophysiology, and clinical management, 2nd ed. New York: Cambridge University Press; 2009.
136. Weatherall DJ. The definition and epidemiology of non-transfusion-dependent thalassemia. Blood Rev. 2012;26 (suppl 1):S3-S6.
137. Taher AT, Musallam KM, Karimi M, et al. Contemporary approaches to treatment of betathalassemia intermedia. Blood Rev. 2012;26 (suppl 1):S24-S27.
138. Vichinsky E. Advances in the treatment of alpha-thalassemia. Blood Rev. 2012;26 (suppl 1):S31-S34.
139. Olivieri NF. Treatment strategies for hemoglobin E beta-thalassemia. Blood Rev. 2012;26 (suppl 1):S28-S30.
140. Musallam KM, Taher AT, Rachmilewitz EA. b-Thalassemia Intermedia: A Clinical Perspective. Cold Spring Harb Perspect Med. 2012;2(7):a013482.
141. Cazzola M, De Stefano P, Ponchio L, et al. Relationship between transfusion regimen and suppression of erythropoiesis in betathalassaemia major. Br J Haematol. 1995;89(3): 473-478.
142. Cappellini MD, Cohen A, Eleftheriou A, et al. Guidelines for the clinical management of thalassemia, ed 2nd rev. Nicosia, Cyprus: Thalassaemia International Federation; 2009
143. O'Donnell A, Premawardhena A, Arambepola M, et al. Age-related changes in adaptation to severe anemia in childhood in developing countries. Proc Natl Acad Sci USA. 2007; 104(22):9440-9444.
144. Allen A, Fisher C, Premawardhena A, et al. Adaptation to anemia in hemoglobin E-ß thalassemia. Blood. 2010;116(24): 5368-5370.
145. Sripichai O, Makarasara W, Munkongdee T, et al. A scoring system for the classification of beta-thalassemia/Hb E disease severity. Am J Hematol. 2008;83(6):482-484.
146. Taher AT, Musallam KM, El-Beshlawy A, et al. Age-related complications in treatment-naïve patients with thalassaemia intermedia. Br J Haematol. 2010;150(4): 486-489.