A Short Review on Growth and Endocrine Long-term Complications in Children and Adolescents with β-Thalassemia Major: Conventional Treatment versus Hematopoietic Stem Cell Transplantation Growth and Endocrine Long-term Complications in thalassemia major after bone marrow transplantation

Main Article Content

Shayma Ahmed https://orcid.org/0000-0002-7044-2010
Ashraf Soliman https://orcid.org/0000-0002-7145-6561
Vincenzo De Sanctis
Nada Alaaraj https://orcid.org/0000-0001-9614-6511
Fawzia Alyafei https://orcid.org/0000-0001-6851-0654
Noor Hamed https://orcid.org/0000-0002-7012-5285
Mohamed Yassin https://orcid.org/0000-0002-1144-8076

Keywords

Allogeneic hematopoietic stem cell transplantation (HCT), β- thalassemia major, growth, endocrinopathies, fertility

Abstract

The conventional treatment of β-thalassemia (β-TM) patients is based on the correction of anemia through regular blood transfusions and iron chelation therapy. However, allogeneic hematopoietic stem cell transplantation (HSCT) remains the only currently available technique that has curative potential. Variable frequency and severity of long-term growth and endocrine changes after conventional treatment as well as after HSCT have been reported by different centers. The goal of this mini-review is to summarize and update knowledge about long-term growth and endocrine changes after HSCT in patients with β-TM in comparison to those occurring in β-TM patients on conventional treatment. Regular surveillance, early diagnosis, treatment, and follow-up in a multi-disciplinary specialized setting are suggested to optimize the patient's quality of life (www.actabiomedica.it).

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References

1. Thein SL. Genetic Basis and Genetic Modifiers of β-Thalassemia and Sickle Cell Disease. Adv Exp Med Biol 2017;1013:27-57.

2. Jaing TH, Chang TY, Chen SH, Lin CW, Wen YC, Chiu CC. Molecular genetics of β-thalassemia: A narrative review. Medicine (Baltimore) 2021;100(45):e27522.

3. Modell B, Darlison M. Global epidemiology of haemoglobin disorders and derived service indicators. Bull World Health Organ 2008;86:480–7

4. Viprakasit V, Ekwattanakit S. Clinical Classification, Screening and Diagnosis for Thalassemia. Hematol Oncol Clin North Am 2018;32:193-211.

5. Taher AT, Cappellini MD. How I manage medical complications of beta-thalassemia in adults. Blood 2018;132:1781–91.

6. Cappellini MD, Farmakis D, Porter J, Taher A. 2021 Guidelines for the Management of Non Transfusion Dependent Thalassaemia (NTDT). 4rd ed. Nicosia, Cyprus: Thalassaemia International Federation; 2021.

7. Vogiatzi MG, Macklin EA, Trachtenberg FL, et al. Differences in the prevalence of growth, endocrine and vitamin D abnormalities among the various thalassaemia syndromes in North America. Br J Haematol 2009; 146:546-56.

8. De Sanctis V, Elsedfy H, Soliman AT, et al . Endocrine profile of β-thalassemia major patients followed from childhood to advanced adulthood in a tertiary care center. Indian J Endocrinol Metab 2016;20:451-9.

9. Farmaki K, Tzoumari I, Pappa C, Chouliaras G, Berdoukas V. Normalisation of total body iron load with very intensive combined chelation reverses cardiac and endocrine complications of thalassaemia major. Br J Haematol 2010;148:466-75.

10. DivakarJose RR, Delhikumar CG, Ram Kumar G. Efficacy and Safety of Combined Oral Chelation with Deferiprone and Deferasirox on Iron Overload in Transfusion Dependent Children with Thalassemia - A Prospective Observational Study. Indian J Pediatr 2021;88:330-5.

11. Voskaridou E, Komninaka V, Karavas A, Terpos E, Akianidis V, Christoulas D. Combination therapy of deferasirox and deferoxamine shows significant improvements in markers of iron overload in a patient with β-thalassemia major and severe iron burden. Transfusion 2014;54:646-9.

12. Chai CAS, Nani Draman N, Yusoff SSM, et al. Non-compliance to iron chelation therapy in patients with transfusion-dependent thalassaemia. Ped Hematol Oncol J 2021;6:207-15

13. Fortin PM, Fisher SA, Madgwick KV, et al. Interventions for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia. Cochrane Database Syst Rev 2018;5: CD012349.

14. Wood JC, Ghugre N. Magnetic resonance imaging assessment of excess iron in thalassemia, sickle cell disease and other iron overload diseases. Hemoglobin 2008;32:85-96.

15. Baronciani D, Angelucci E, Potschger U, et al. Hemopoietic stem cell transplantation in thalassemia: a report from the European Society for Blood and Bone Marrow Transplantation Hemoglobinopathy Registry, 2000-2010. Bone Marrow Transplant 2016; 51:536-41.

16. Bhatia S. Long-term health impacts of hematopoietic stem cell transplantation inform recommendations for follow-up. Expert Rev Hematol 2011; 4: 437–54.

17. Cappellini MD, Motta I. New therapeutic targets in transfusion-dependent and -independent thalassemia. Hematology Am Soc Hematol Educ Program 2017;2017:278-83.

18. Thomas ED, Buckner CD, Sanders JE, et al. Marrow transplantation for Thalessemia. Lancet 1982; 2: 227-9.

19. Angelucci E, Baronciani D. Allogeneic stem cell transplantation for thalassemia major. Haematologica 2008;93:1780-4.

20. Jaing TH, Chang TY, Chen SH, Lin CW, Wen YC, Chiu CC. Molecular genetics of β-thalassemia: A narrative review. Medicine (Baltimore) 2021;100(45):e27522.

21. Mulas O, Mola B, Caocci G, La Nasa G. Conditioning Regimens in Patients with β-Thalassemia Who Underwent Hematopoietic Stem Cell Transplantation: A Scoping Review. J Clin Med 2022;11(4):907.

22. La Nasa G, Vacca A, Littera R,et al. What Unrelated Hematopoietic Stem Cell Transplantation in Thalassemia Taught us about Transplant Immunogenetics. Mediterr J Hematol Infect Dis 2016;8(1): e2016048.

23. Link-Rachner CS, Sockel K, Schuetz C. Established and Emerging Treatments of Skin GvHD. Front Immunol 2022;13:838494.

24. Sodani P, Gaziev D, Polchi P, et al. New approach for bone marrow transplantation in patients with class 3 thalassemia aged younger than 17 years. Blood 2004;104:1201-3.

25. Li C, Wu X, Feng X, et al. A novel conditioning regimen improves outcomes in beta-thalassemia major patients using unrelated donor peripheral blood stem cell transplantation. Blood 2012;120:3875-81.

26. Tan W, He Y, Feng X, et al. Thiotepa-Based Conditioning Regimen Compared to Non-Thiotepa Conditioning Regimen Prior to Allogeneic Stem Cell Transplantation in β Thalassemia Major: Impact on Survival. Blood 2018; 132 (Supplement 1): 2082.

27.King AA, Kamani N, Bunin N, Sahdev I,et al. Successful matched sibling donor marrow transplantation following reduced intensity conditioning in children with hemoglobinopathies. Am J Hematol 2015; 90: 1093–8.

28. Angelucci E, Matthes-Martin S, Baronciani D, et al. Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel. Haematologica 2014;99:811-20.

29. Khalil A, Zaidman I, Elhasid R, et al. Factors influencing outcome and incidence of late complications in children who underwent allogeneic hematopoietic stem cell transplantation for hemoglobinopathy. Pediatr Hematol Oncol 2012;29:694-703.

30. La Nasa G, Caocci G, Efficace F, et al. Longterm health-related quality of life evaluated more than 20 years after hematopoietic stem cell transplantation for thalassemia. Blood 2013;122:2262-70.

31. Angelucci E, Muretto P, Lucarelli G, et al. Phlebotomy to reduce iron overload in patients cured of thalassemia by bone marrow transplantation. Italian Cooperative Group for Phlebotomy Treatment of ransplanted Thalassemia Patients. Blood 1997;90:994-8.

32. Giardini C, Galimberti M, Lucarelli G, et al. Desferrioxamine therapy accelerates clearance of iron deposits after bone marrow transplantation for thalassaemia. Br J Haematol 1995;89:868-73.

33, Yesilipek MA, Karasu G, Kazik M, Uygun V, Ozturk Z. Posttransplant oral iron-chelating therapy in patients with beta-thalassemia major. Pediatr Hematol Oncol 2010; 27:374-9.

34. Dix SP, Yee GC. Pharmacologic and biologic agents. In: Whedon MK, Wujcik D, Edts . Blood and Marrow Stem Cell Transplantation: Principle, Practice and Nursing Insights. 2nd ed. Sudbury, MA: Jones and Barrlett Publishers; 1997; pp.100–150

35. Krivoy N, Hoffer E, Lurie Y, Bentur Y, Rowe JM. Busulfan use in hematopoietic stem cell transplantation: pharmacology, dose adjustment, safety and efficacy in adults and children. Curr Drug Saf 2008;3:60-6.

36. ten Brink MH, Zwaveling J, Swen JJ, Bredius RG, Lankester AC, Guchelaar HJ. Personalized busulfan and treosulfan conditioning for pediatric stem cell transplantation: the role of pharmacogenetics and pharmacokinetics. Drug Discov Today 2014;19:1572-86.

37. Slatter MA, Rao K, Abd Hamid IJ, et al . Treosulfan and Fludarabine Conditioning for Hematopoietic Stem Cell Transplantation in Children with Primary Immunodeficiency: UK Experience. Biol Blood Marrow Transplant 2018;24:529-36.

38.Slatter M, Boztug H, Pötschger U, et al. Treosulfan-based conditioning regimens for allogeneic haematopoietic stem cell transplantation in children with non-malignant diseases. Bone Marrow Transplant 2015;50:1536-41.

39. Jacobson PA, Green K, Birnbaum A, Remmel RP. Cytochrome P450 isozymes 3A4 and 2B6 are involved in the in vitro human metabolism of thiotepa to TEPA. Cancer Chemother Pharmacol 2002; 49:461–7.

40. Kondo E, Ikeda T, Goto H, et al. Pharmacokinetics of thiotepa in high-dose regimens for autologous hematopoietic stem cell transplant in Japanese patients with pediatric tumors or adult lymphoma. Cancer Chemother Pharmacol 2019;84:849-60.

41. Xian CJ, Cool JC, van Gangelen J, Foster BK, Howarth GS. Effects of etoposide and cyclophosphamide acute chemotherapy on growth plate and metaphyseal bone in rats. Cancer Biol Ther 2007;6:170-7.

42. Ponnapakkam T, Katikaneni R, Nichols T, et al. Prevention of chemotherapy-induced osteoporosis by cyclophosphamide with a long-acting form of parathyroid hormone. J Endocrinol Invest 2011;34:e392-7.

43. Zhao D, Wang C, Zhao Y, et al . Cyclophosphamide causes osteoporosis in C57BL/6 male mice: suppressive effects of cyclophosphamide on osteoblastogenesis and osteoclastogenesis. Oncotarget 2017; 8:98163-83.

44. Kim J, You S. Extended adverse effects of cyclophosphamide on mouse ovarian function. BMC Pharmacol Toxicol. 2021;22(1):3.

45. McGee EA, Hsueh AJ. Initial and cyclic recruitment of ovarian follicles. Endocr Rev 2000;21:200–14.

46. Drumond AL, Weng CC, Wang G, Chiarini-Garcia H, Eras-Garcia L, Meistrich ML. Effects of multiple doses of cyclophosphamide on mouse testes: accessing the germ cells lost, and the functional damage of stem cells. Reprod Toxicol 2011;32:395-406.
47. Kanno TYN., Sensiate L A, de Paula NA, Salles MJS. Toxic effects of different doses of cyclophosphamide on the reproductive parameters of male mice . Bras J Pharm Sc 2009; 45:313-9.

48. Niakani A, Farrokhi F, Hasanzadeh. Decapeptyl ameliorates cyclophosphamide-induced reproductive toxicity in male Balb/C mice: histomorphometric, stereologic and hormonal evidences. Iran J Reprod Med 2013;11:791-800.

49. Satoh K, Ohyama K, Nakagomi Y, et al. Effects of growth hormone on testicular dysfunction induced by cyclophosphamide (CP) in GH-deficient rats. Endocr J 2002; 49:611–9.

50. Bucci LR, Meistrich ML. Effects of busulfan on murine spermatogenesis: cytotoxicity, sterility, sperm abnormalities, and dominant lethal mutations. Mutat Res 1987;176:259-68.

51. Ma D, Han P, Song M, et al. β-carotene Rescues Busulfan Disrupted Spermatogenesis Through Elevation in Testicular Antioxidant Capability. Front Pharmacol 2021;12:593953.

52. Spears N, Lopes F, Stefansdottir A, et al. Ovarian damage from chemotherapy and current approaches to its protection. Hum Reprod Update 2019;25:673-93.

53. Rivkees SA, Crawford JD. The relationship of gonadal activity and chemotherapy-induced gonadal damage. JAMA1988;259:2123-5.

54. Bakker B, Oostdijk W, Bresters D, et al. Disturbances of growth and endocrine function after busulphan-based conditioning for haematopoietic stem cell transplantation during infancy and childhood. Bone Marrow Transplant 2004;33:1049-56.

55. Sanders JE, Hawley J, Levy W, et al. Pregnancies following high-dose cyclophosphamide with or without high-dose busulphan or total-body irradiation and bone marrow transplantation. Blood 1996; 87:3045–52.

56. Thibaud E, Rodriguez-Macias K, Trivin C, et al. Ovarian function after bone marrow transplantation during childhood. Bone Marrow Transplant 1998;21:287–90.

57. Teinturier C, Hartmann O, Valteau-Couanet D, Benhamou E, Bougneres PF. Ovarian function after autologous bone marrow transplantation in childhood: high-dose busulfan is a major cause of ovarian failure. Bone Marrow Transplant 1998;22:989-94.

58. Teinturier C, Hartmann O, Valteau-Couanet D, Benhamou E, Bougneres PF. Ovarian function after autologous bone marrow transplantation in childhood: high-dose busulfan is a major cause of ovarian failure. Bone Marrow Transplant 1998;22:989-94.

59. Levi M, Stemmer SM, Stein J, Shalgi R, Ben-Aharon I. Treosulfan induces distinctive gonadal toxicity compared with busulfan. Oncotarget 2018;9:19317-27.

60. Zini A, Phillips S, Lefebvre J, Baazeem A, Bissonnette F, Kadoch IJ, et al. Anti-sperm antibodies are not associated with sperm DNA damage: a prospective study of infertile men. J Reprod Immunol 2010;85:205–8

61. Soliman AT, De Sanctis V, Yassin M. Focus on prevalence of endocrinopathies in β-thalassemia major (TDT), intermedia (NTDT) and sickle cell disease (SCD). Riv Ital Med Adolesc (EndoThal) 2020; 18:104-8.

62. Arab-Zozani M, Kheyrandish S, Rastgar A, Miri-Moghaddam E. A Systematic Review and Meta-Analysis of Stature Growth Complications in β-thalassemia Major Patients. Ann Glob Health 2021;87:1-17.

63. He LN, Chen W, Yang Y, et al. Elevated prevalence of abnormal glucose metabolism and other endocrine disorders in patients with thalassemia major: a meta-analysis. Biomed Res Int. 2019; 2019: 6573497.
64. De Sanctis V, Eleftheriou A, Malaventura C; Thalassaemia International Federation Study Group on Growth and Endocrine Complications in Thalassaemia. Prevalence of endocrine complications and short stature in patients with thalassaemia major: a multicenter study by the Thalassaemia International Federation (TIF). Pediatr Endocrinol Rev 2004;2 Suppl 2:249-55.

65. Christoforidis A, Perifanis V, Athanassiou-Metaxa M. Combined chelation therapy improves glucose metabolism in patients with beta-thalassaemia major. Br J Haematol 2006;135:271– 2.

66. De Sanctis V, Soliman AT, Canatan D, et al. Thyroid Disorders in Homozygous β-Thalassemia: Current Knowledge, Emerging Issues and Open Problems. Mediterr J Hematol Infect Dis 2019;11(1):e2019029.

67. Farmaki K, Tzoumari I, Pappa C. Oral chelators in transfusion-dependent thalassemia major patients may prevent or reverse iron overload complications. Blood Cells Mol Dis 2011;47:33-40.

68. Sobhani S, Rahmani F, Rahmani M, Askari M, Kompani F. Serum ferritin levels and irregular use of iron chelators predict liver iron load in patients with major beta thalassemia: a cross-sectional study. Croat Med J 2019; 60:405–13.

69. Singer ST, Fischer R, Allen I, et al. Pituitary iron and factors predictive of fertility status in transfusion dependent thalassemia. Haematologica 2021;106:1740-4.

70. Ponte G, Ferrara M, Esposito L. Growth in homozygous beta-thalassemia after bone marrow transplantation. Bone Marrow Transplant 1991;8 Suppl 1:68-9.

71. De Sanctis V, Galimberti M, Lucarelli G, Polchi P, Ruggiero L, Vullo C. Gonadal function after allogenic bone marrow transplantation for thalassaemia. Arch Dis Child1 1991;66:517-20.

72. De Simone M, Olioso P, Di Bartolomeo P, et al. Growth and endocrine function following bone marrow transplantation for thalassemia. Bone Marrow Transplant 1995;15:227-33.

73. De Simone M, Verrotti A, Iughetti L, et al. Final height of thalassemic patients who underwent bone marrow transplantation during childhood. Bone Marrow Transplant 2001;28:201-5.

74. De Sanctis V. Growth and Puberty and Its Management in Thalassaemia. Horm Res. 2002;58 Suppl 1:72–9.

75. Li CK, Chik KW, Wong GW, Cheng PS, Lee V, Shing MM. Growth and endocrine function following bone marrow transplantation for thalassemia major. Pediatr Hematol Oncol 2004;21:411-9.

76. Vlachopapadopoulou E, Kitra V, Peristeri J, et al. Gonadal function of young patients with beta-thalassemia following bone marrow transplantation. J Pediatr Endocrinol Metab 2005;18:477-84.

77. Di Bartolomeo P, Santarone S, Di Bartolomeo E, et al. Long-Term Results of Survival in Patients with Thalassemia Major Treated with Bone Marrow Transplantation. Am J Hematol 2008;83:528-30.

78. Khalil A, Zaidman I, Elhasid R, Peretz-Nahum M, Futerman B, Ben-Arush M. Factors influencing outcome and incidence of late complications in children who underwent allogeneic hematopoietic stem cell transplantation for hemoglobinopathy. Pediatr Hematol Oncol 2012;29:694-703.

79. Poomthavorn P, Chawalitdamrong P, Hongeng S, et al. Gonadal function of beta-thalassemics following stem cell transplantation conditioned with myeloablative and reduced intensity regimens. J Pediatr Endocrinol Metab 2013;26:925-32.

80. La Nasa G, Caocci G, Efficace F, et al. Long- Term Health-Related Quality of Life Evaluated More than 20 Years after Hematopoietic Stem Cell Transplantation for Thalassemia. Blood 2013;122:2262-70.

81. Aldemir-Kocabaş B, Tezcan-Karasu G, Bircan I, Bircan O, Aktaş-Samur A, Yeşilipek MA. Evaluating the patients with thalassemia major for long-term endocrinological complications after bone marrow transplantation. Pediatr Hematol Oncol 2014;31:616-23.

82. Chaudhury S, Ayas M, Rosen C, et al. A Multicenter Retrospective Analysis Stressing the Importance of Long-Term Follow-Up after Hematopoietic Cell Transplantation for β-Thalassemia. Biol Blood Marrow Transplant 2017;23:1695-700.

83. Caocci G, Orofino MG, Vacca A, et al. Long-term survival of beta thalassemia major patients treated with hematopoietic stem cell transplantation compared with survival with conventional treatment. Am J Hematol 2017;92:1303-10.

84. Hamidieh AA, Mohseni F, Behfar M, et al. Short-term Assessment of HSCT Effects on the Hypothalamus-Pituitary Axis in Pediatric Thalassemic Patients. Arch Iran Med 2018;21:56-60.

85. Rahal I, Galambrun C, Bertrand Y, et al. Late effects after hematopoietic stem cell transplantation for β-thalassemia major: the French national experience. Haematologica 2018;103:1143-9.

86. See WQ, Tung JY, Cheuk DK, et al. Endocrine complications in patients with transfusiondependent
thalassaemia after haematopoietic stem cell transplantation. Bone Marrow Transplantat 2018;53:356-60.

87. Ntali G, Stella Roidi R, Stavroula Michala S, et al. Long-term endocrine sequelae of patients with beta-thalassemia following bone marrow transplantation in childhood/adolescence. Endocrine Abs 2018; 56;P678.

88. Rostami T, Mohammadifard MA, Ansari S, et al. Indicators of male fertility potential in adult patients with beta-thalassemia major: a comparative study between patients undergone allogeneic stem cell transplantation and transfusion-dependent patients. Fertil Res Pract 2020;6:4.

89. Cheuk DK, Mok AS, Lee AC, et al. Quality of life in patients with transfusion-dependent thalassemia after hematopoietic SCT. Bone Marrow Transplant 2008;42:319-27.

90. Uygun V, Tayfun F, Akcan M, et al . Quality of life assessment in hematopoietic stem cell transplantation performed on thalassemia major patients. Pediatr Hematol Oncol 2012;29:461-71.

91. Angelucci E. Hematopoietic stem cell transplantation in thalassemia. Hematology Am Soc Hematol Educ Program 2010;2010:456-62.

92.De Sanctis V, Soliman AT, Yassin MA, et al. Hypogonadism in male thalassemia major patients: pathophysiology, diagnosis and treatment. Acta Biomed 2018;89:6-15.

93. De Sanctis V, Elsedfy H, Soliman AT, et al. Acquired Hypogonadotropic Hypogonadism (AHH) in Thalassaemia Major Patients: An Underdiagnosed Condition? Mediterr J Hematol Infect Dis 2016;8(1): e2016001.

94. De Sanctis V, Soliman AT, El-Hakim I, et al . Marital status and paternity in patients with Transfusion- Dependent Thalassemia (TDT) and Non Transfusion-Dependent Thalassemia (NTDT): an ICET - A survey in different countries. Acta Biomed 2019;90:225-37.

95. De Sanctis V, Soliman AT, Elsedfy H, Di Maio S, Canatan D, Soliman N, Karimi M, Kattamis C. Gonadal dysfunction in adult male patients with thalassemia major: an update for clinicians caring for thalassemia. Expert Rev Hematol 2017;10:1095-1106.

96. Chen MJ, Peng SS, Lu MY, Yang YL, Jou ST, Chang HH, Chen SU, Lin DT, Lin KH. Effect of iron overload on impaired fertility in male patients with transfusion-dependent beta-thalassemia. Pediatr Res 2018;83:655-61.

97. Bajoria R, Chatterjee R. Hypogonadotrophic hypogonadism and diminished gonadal reserve accounts for dysfunctional gametogenesis in thalassaemia patients with iron overload presenting with infertility. Hemoglobin 2011;35:636-42.

98. Perera D, Pizzey A, Campbell A, Katz M, Porter J, Petrou M, Irvine DS, Chatterjee R. Sperm DNA damage in potentially fertile homozygous beta-thalassaemia patients with iron overload. Hum Reprod 2002;17:1820-5.

99. Picton HM, Wyns C, Anderson RA, et al.; ESHRE Task Force On Fertility Preservation In Severe Diseases. A European perspective on testicular tissue cryopreservation for fertility preservation in prepubertal and adolescent boys. Hum Reprod 2015;30:2463-75.

100. Brodigan K, Kapadia M, Frazier AL, et al. Safety of Surgical Fertility Preservation Procedures in Children Prior to Hematopoietic Stem Cell Transplant.Transplant Cell Ther 2021;27:696.e1-696.

101. Tichelli A, Rovó A. Fertility issues following hematopoietic stem cell transplantation. Expert Rev Hematol 2013;6:375-88.

102. ESHRE Guideline Group on Female Fertility Preservation, Anderson RA, Amant F, Braat D, et al. ESHRE guideline: female fertility preservation. Hum Reprod Open. 2020;2020(4),52.