Cardiac Considerations in Hematopoietic Stem Cell Transplantation (HSCT) for Transfusion-Dependent Thalassemia: A Review
Abstract
Hematopoietic stem cell transplantation (HSCT) is considered a potentially curative treatment for several malignant and non-malignant hematologic disorders including transfusion-dependent thalassemia (TDT). However, HSCT is associated with short-term and long-term complications. One of the recognized causes of morbidity and mortality in TDT patients is heart-related complications. Additionally, cardiac involvement is likely to be more common in patients who proceed to HSCT. So the risks of cardiac complications should be carefully weighed against the advantages of the primary disease cure. This review aims to discuss the cardiac considerations that should be kept in mind in TDT patients going through the path of HSCT.
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2. Farmakis D, Porter J, Taher A, Cappellini MD, Angastiniotis M, Eleftheriou A. 2021 Thalassaemia international federation guidelines for the management of transfusion-dependent thalassemia. Hemasphere. 2022 Aug 1;6(8): e732.
3. Bhatia S. Long-term health impacts of hematopoietic stem cell transplantation inform recommendations for follow-up. Expert Rev Hematol. 2011; 4(4): 437–52.
4. Ohmoto A, Fuji S. Cardiac complications associated with hematopoietic stem-cell transplantation. Bone Marrow Transplant. 2021; 56(11): 2637–2643.
5. Kremastinos DT, Farmakis D, Aessopos A, et al. Beta-thalassemia cardiomyopathy: History, present considerations, and future perspectives. Circ Heart Fail. 2010; 3(3), 451–458.
6. Hershko C, Link G, Cabantchik I. Pathophysiology of iron overload. Ann NY Acad Sci. 1998; 850:191–201.
7. Nomani H, Bayat G, Sahebkar A, et al. Atrial fibrillation in β-thalassemia patients with a focus on the role of iron-overload and oxidative stress: A review. J Cell Physiol. 2019; 234(8): 12249–12266.
8. Rose RA, Sellan M, Simpson JA, et al. Iron overload decreases CaV1.3-dependent L-type Ca2+ currents leading to bradycardia, altered electrical conduction, and atrial fibrillation. Circ Arrhythm Electrophysiol. 2011; 4(5): 733–42.
9. Wood JC, Enriquez C, Ghugre N, et al. Physiology and pathophysiology of iron cardiomyopathy in thalassemia. Ann N Y Acad Sci. 2005; 1054: 386–95.
10. Russo V, Rago A, Pannone B, et al. Dispersion of repolarization and beta-thalassemia major: The prognostic role of QT and JT dispersion for identifying the high-risk patients for sudden death. Eur J Haematol. 2011; 86(4): 324–31.
11. Du ZD, Roguin N, Milgram E, et al. Pulmonary hypertension in patients with thalassemia major. Am Heart J. 1997; 134(3): 532-7.
12. Adjimani JP, Asare P. Antioxidant and free radical scavenging activity of iron chelators. Toxicol Rep. 2015; 2: 721–728.
13. Russo V, Melillo E, Papa AA, et al. Arrhythmias and Sudden Cardiac Death in Beta-Thalassemia Major
Patients: Noninvasive Diagnostic Tools and Early Markers. Cardiol Res Pract. 2019; 2019: 9319832.
14. Motta I, Mancarella M, Marcon A, et al. Management of age-associated medical complications in patients with beta-thalassemia. Expert Rev Hematol. 2020; 13(1): 85–94.
15. Ramazzotti A, Pepe A, Positano V, et al. Standardized T2* map of a normal human heart to correct T2* segmental artefacts; myocardial iron overload and fibrosis in thalassemia intermedia versus thalassemia major patients and electrocardiogram changes in thalassemia major patients. Hemoglobin. 2008; 32(1-2): 97–107.
16. Aydinok Y, Porter, JB, Piga A, et al. Prevalence and distribution of iron overload in patients with transfusion-dependent anemias differs across geographic regions: Results from the CORDELIA study. Eur J Haematol. 2015; 95(3): 244–253.
17. Matta B, Stow P. Sepsis-induced vasoparalysis does not involve the cerebral vasculature; indirect evidence from autoregulation and carbon dioxide reactivity studies. Br J Anaesth. 1996; 76(6): 790-4.
18. Coghlan JG, Handler CE, Kottaridis PD. Cardiac assessment of patients for haematopoietic stem cell transplantation. Best Practice & Research Clinical Haematology. 2007 Jun 1;20(2):247-63
19. Baker KS, Ness KK, Steinberger J, et al. Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a report from the bone marrow transplantation survivor study. Blood. 2005;106(11):699.
20. Tichelli A, Bucher C, Rovó A, et al. Premature cardiovascular disease after allogeneic hematopoietic stem-cell transplantation. Blood. 2007;110(9): 3463-3471.
21. Appelbaum F, Strauchen JA, Graw Jr RG, et al. Acute lethal carditis caused by high-dose combination chemotherapy. A unique clinical and pathological entity. Lancet. 1976; 1(7950): 58–62.
22. Gottdiener JS, Appelbaum FR, Ferrans VJ et al. Cardiotoxicity associated with high-dose cyclophosphamide therapy. Arch Intern Med 1981; 141: 758–763.
23. Pihkala J, Saarinen UM, Lundstrom U et al. Effects of bone marrow transplantation on myocardial function in children. Bone Marrow Transplant 1994; 13: 149–155.
24. Steinherz LJ, Steinherz PG, Mangiacasale D, O'Reilly R, Allen J, Sorell M, Miller DR. Cardiac changes with cyclophosphamide. Medical and Pediatric Oncology. 1981;9(5):417-22.
25. Hertenstein B, Stefanic M, Schmeiser T et al. Cardiac toxicity of bone marrow transplantation: predictive value of cardiologic evaluation before transplant. J Clin Oncol 1994; 12: 998–1004.
26. Dandoy CE, Davies SM, Hirsch R, et al. Abnormal echocardiography 7 days after stem cell transplantation may be an early indicator of thrombotic microangiopathy. Biol Blood Marrow Transplant. 2015;21:113–118.
27. Angelucci E, Mariotti E, Lucarelli G et al. Sudden cardiac tamponade after chemotherapy for marrow transplantation in thalassaemia. Lancet 1992; 339: 287–289.
28. Rhodes M, Lautz T, Kavanaugh-Mchugh A, Manes B, Calder C, Koyama T, Liske M, Parra D, Frangoul H. Pericardial effusion and cardiac tamponade in pediatric stem cell transplant recipients. Bone marrow transplantation. 2005;36(2):139-144.
29. Angelucci E, Mariotti E, Lucarelli G et al. Cardiac tamponade in thalassemia. Bone Marrow Transplant 1994; 13: 827–829.
30. Couriel D, Caldera H, Champlin R, et al. Acute graft-versus-host disease: Pathophysiology, clinical manifestations, and management. Cancer. 2004;101(9):1936–1946
31. Buja LM, Ferrans VJ, Graw RG. Cardiac pathologic findings in patients treated with bone marrow transplantation. Hum Pathol. 1976;7(1):17–45.
32. Roberts SS, Leeborg N, Loriaux M, et al. Acute graft‐versus‐host disease of the heart. Pediatric Blood Cancer. 2006;47(5):624-8.
33. Karakulska-Prystupiuk E, Basak G, Dwilewicz-Trojaczek J, et al. Pericarditis in patients with chronic graft-vs-host disease. Transplant Proc. 2018;50(7):2218-2222.
34. Rackley C, Schultz KR, Goldman FD, et al. Cardiac manifestations of graft versus-host disease. Biol Blood Marrow Transplant. 2005;11(10):773-80.
35. Kupari M, Volin L, Suokas A, et al. Cardiac involvement in bone marrow transplantation: electrocardiographic changes, arrhythmias, heart failure and autopsy findings. Bone Marrow Transplant. 1990; 5(2):91-8.
36. Seber A, Khan SP, Kersey JH. Unexplained effusions: association with allogeneic bone marrow transplantation and acute or chronic graft-versus-host disease. Bone Marrow Transplant. 1996; 17(2): 207–211.
37. Toren A, Nagler A. Massive pericardial effusion complicating the course of chronic graft-versus-host disease (cGVHD) in a child with acute lymphoblastic leukemia following allogeneic bone marrow transplantation. Bone Marrow Transplant. 1997; 20(9): 805–7.
38. Silberstein L, Davies A, Kelsey S, et al. Myositis, polyserositis with a large pericardial effusion and constrictive pericarditis as manifestations of chronic graft-versus-host disease after nonmyeloablative peripheral stem cell transplantation and subsequent donor lymphocyte infusion. Bone Marrow Transplant. 2001; 27(2): 231–3.
39. Cereda M, Trocino G, Pogliani EM, et al. A case of cardiac localization of graft-versus-host disease after allogenic bone marrow transplantation. Ital Heart J. 2003; 491): 60–3.
40. Armenian SH, Chemaitilly W, Chen M, et al. National Institutes of Health hematopoietic cell transplantation late effects initiative: the Cardiovascular Disease and Associated Risk Factors Working Group report. Biol Blood Marrow Transplant. 2017;23(2):201–210.
41. Armenian SH, Sun CL, Kawashima T, et al. Long-term health-related outcomes in survivors of childhood cancer treated with HSCT versus conventional therapy: a report from the bone marrow transplant survivor study (BMTSS) and Childhood Cancer Survivor Study (CCSS). Blood. 2011;118(5):1413–20.
42. Chow EJ, Anderson L, Baker KS, et al. Late effects surveillance recommendations among survivors of childhood hematopoietic cell transplantation: A Children’s Oncology Group Report. Biol Blood Marrow Transplant. 2016;22(5):782–95.
43. Ryan TD, Jefferies JL, Chin C, et al. Abnormal circumferential strain measured by echocardiography is present in patients with Shwachman–Diamond syndrome despite normal shortening fraction. Pediatr Blood Cancer. 2015;62(7):1228–31.
44. Niss O, Quinn CT, Lane A, et al. Cardiomyopathy with restrictive physiology in sickle cell disease. JACC Cardiovasc Imaging. 2016;9(3):243–52.
45. Braunlin EA, Stauffer NR, Peters CH, et al. Usefulness of bone marrow transplantation in the Hurler syndrome. Am J Cardiol. 2003;92(7):882–6.
46. Rotz SJ, Ryan TD, Hlavaty J, et al. Cardiotoxicity and cardiomyopathy in children and young adult survivors of hematopoietic stem cell transplant. Pediatric Blood Cancer. 2017;64(11):e26600.
2. Farmakis D, Porter J, Taher A, Cappellini MD, Angastiniotis M, Eleftheriou A. 2021 Thalassaemia international federation guidelines for the management of transfusion-dependent thalassemia. Hemasphere. 2022 Aug 1;6(8): e732.
3. Bhatia S. Long-term health impacts of hematopoietic stem cell transplantation inform recommendations for follow-up. Expert Rev Hematol. 2011; 4(4): 437–52.
4. Ohmoto A, Fuji S. Cardiac complications associated with hematopoietic stem-cell transplantation. Bone Marrow Transplant. 2021; 56(11): 2637–2643.
5. Kremastinos DT, Farmakis D, Aessopos A, et al. Beta-thalassemia cardiomyopathy: History, present considerations, and future perspectives. Circ Heart Fail. 2010; 3(3), 451–458.
6. Hershko C, Link G, Cabantchik I. Pathophysiology of iron overload. Ann NY Acad Sci. 1998; 850:191–201.
7. Nomani H, Bayat G, Sahebkar A, et al. Atrial fibrillation in β-thalassemia patients with a focus on the role of iron-overload and oxidative stress: A review. J Cell Physiol. 2019; 234(8): 12249–12266.
8. Rose RA, Sellan M, Simpson JA, et al. Iron overload decreases CaV1.3-dependent L-type Ca2+ currents leading to bradycardia, altered electrical conduction, and atrial fibrillation. Circ Arrhythm Electrophysiol. 2011; 4(5): 733–42.
9. Wood JC, Enriquez C, Ghugre N, et al. Physiology and pathophysiology of iron cardiomyopathy in thalassemia. Ann N Y Acad Sci. 2005; 1054: 386–95.
10. Russo V, Rago A, Pannone B, et al. Dispersion of repolarization and beta-thalassemia major: The prognostic role of QT and JT dispersion for identifying the high-risk patients for sudden death. Eur J Haematol. 2011; 86(4): 324–31.
11. Du ZD, Roguin N, Milgram E, et al. Pulmonary hypertension in patients with thalassemia major. Am Heart J. 1997; 134(3): 532-7.
12. Adjimani JP, Asare P. Antioxidant and free radical scavenging activity of iron chelators. Toxicol Rep. 2015; 2: 721–728.
13. Russo V, Melillo E, Papa AA, et al. Arrhythmias and Sudden Cardiac Death in Beta-Thalassemia Major
Patients: Noninvasive Diagnostic Tools and Early Markers. Cardiol Res Pract. 2019; 2019: 9319832.
14. Motta I, Mancarella M, Marcon A, et al. Management of age-associated medical complications in patients with beta-thalassemia. Expert Rev Hematol. 2020; 13(1): 85–94.
15. Ramazzotti A, Pepe A, Positano V, et al. Standardized T2* map of a normal human heart to correct T2* segmental artefacts; myocardial iron overload and fibrosis in thalassemia intermedia versus thalassemia major patients and electrocardiogram changes in thalassemia major patients. Hemoglobin. 2008; 32(1-2): 97–107.
16. Aydinok Y, Porter, JB, Piga A, et al. Prevalence and distribution of iron overload in patients with transfusion-dependent anemias differs across geographic regions: Results from the CORDELIA study. Eur J Haematol. 2015; 95(3): 244–253.
17. Matta B, Stow P. Sepsis-induced vasoparalysis does not involve the cerebral vasculature; indirect evidence from autoregulation and carbon dioxide reactivity studies. Br J Anaesth. 1996; 76(6): 790-4.
18. Coghlan JG, Handler CE, Kottaridis PD. Cardiac assessment of patients for haematopoietic stem cell transplantation. Best Practice & Research Clinical Haematology. 2007 Jun 1;20(2):247-63
19. Baker KS, Ness KK, Steinberger J, et al. Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a report from the bone marrow transplantation survivor study. Blood. 2005;106(11):699.
20. Tichelli A, Bucher C, Rovó A, et al. Premature cardiovascular disease after allogeneic hematopoietic stem-cell transplantation. Blood. 2007;110(9): 3463-3471.
21. Appelbaum F, Strauchen JA, Graw Jr RG, et al. Acute lethal carditis caused by high-dose combination chemotherapy. A unique clinical and pathological entity. Lancet. 1976; 1(7950): 58–62.
22. Gottdiener JS, Appelbaum FR, Ferrans VJ et al. Cardiotoxicity associated with high-dose cyclophosphamide therapy. Arch Intern Med 1981; 141: 758–763.
23. Pihkala J, Saarinen UM, Lundstrom U et al. Effects of bone marrow transplantation on myocardial function in children. Bone Marrow Transplant 1994; 13: 149–155.
24. Steinherz LJ, Steinherz PG, Mangiacasale D, O'Reilly R, Allen J, Sorell M, Miller DR. Cardiac changes with cyclophosphamide. Medical and Pediatric Oncology. 1981;9(5):417-22.
25. Hertenstein B, Stefanic M, Schmeiser T et al. Cardiac toxicity of bone marrow transplantation: predictive value of cardiologic evaluation before transplant. J Clin Oncol 1994; 12: 998–1004.
26. Dandoy CE, Davies SM, Hirsch R, et al. Abnormal echocardiography 7 days after stem cell transplantation may be an early indicator of thrombotic microangiopathy. Biol Blood Marrow Transplant. 2015;21:113–118.
27. Angelucci E, Mariotti E, Lucarelli G et al. Sudden cardiac tamponade after chemotherapy for marrow transplantation in thalassaemia. Lancet 1992; 339: 287–289.
28. Rhodes M, Lautz T, Kavanaugh-Mchugh A, Manes B, Calder C, Koyama T, Liske M, Parra D, Frangoul H. Pericardial effusion and cardiac tamponade in pediatric stem cell transplant recipients. Bone marrow transplantation. 2005;36(2):139-144.
29. Angelucci E, Mariotti E, Lucarelli G et al. Cardiac tamponade in thalassemia. Bone Marrow Transplant 1994; 13: 827–829.
30. Couriel D, Caldera H, Champlin R, et al. Acute graft-versus-host disease: Pathophysiology, clinical manifestations, and management. Cancer. 2004;101(9):1936–1946
31. Buja LM, Ferrans VJ, Graw RG. Cardiac pathologic findings in patients treated with bone marrow transplantation. Hum Pathol. 1976;7(1):17–45.
32. Roberts SS, Leeborg N, Loriaux M, et al. Acute graft‐versus‐host disease of the heart. Pediatric Blood Cancer. 2006;47(5):624-8.
33. Karakulska-Prystupiuk E, Basak G, Dwilewicz-Trojaczek J, et al. Pericarditis in patients with chronic graft-vs-host disease. Transplant Proc. 2018;50(7):2218-2222.
34. Rackley C, Schultz KR, Goldman FD, et al. Cardiac manifestations of graft versus-host disease. Biol Blood Marrow Transplant. 2005;11(10):773-80.
35. Kupari M, Volin L, Suokas A, et al. Cardiac involvement in bone marrow transplantation: electrocardiographic changes, arrhythmias, heart failure and autopsy findings. Bone Marrow Transplant. 1990; 5(2):91-8.
36. Seber A, Khan SP, Kersey JH. Unexplained effusions: association with allogeneic bone marrow transplantation and acute or chronic graft-versus-host disease. Bone Marrow Transplant. 1996; 17(2): 207–211.
37. Toren A, Nagler A. Massive pericardial effusion complicating the course of chronic graft-versus-host disease (cGVHD) in a child with acute lymphoblastic leukemia following allogeneic bone marrow transplantation. Bone Marrow Transplant. 1997; 20(9): 805–7.
38. Silberstein L, Davies A, Kelsey S, et al. Myositis, polyserositis with a large pericardial effusion and constrictive pericarditis as manifestations of chronic graft-versus-host disease after nonmyeloablative peripheral stem cell transplantation and subsequent donor lymphocyte infusion. Bone Marrow Transplant. 2001; 27(2): 231–3.
39. Cereda M, Trocino G, Pogliani EM, et al. A case of cardiac localization of graft-versus-host disease after allogenic bone marrow transplantation. Ital Heart J. 2003; 491): 60–3.
40. Armenian SH, Chemaitilly W, Chen M, et al. National Institutes of Health hematopoietic cell transplantation late effects initiative: the Cardiovascular Disease and Associated Risk Factors Working Group report. Biol Blood Marrow Transplant. 2017;23(2):201–210.
41. Armenian SH, Sun CL, Kawashima T, et al. Long-term health-related outcomes in survivors of childhood cancer treated with HSCT versus conventional therapy: a report from the bone marrow transplant survivor study (BMTSS) and Childhood Cancer Survivor Study (CCSS). Blood. 2011;118(5):1413–20.
42. Chow EJ, Anderson L, Baker KS, et al. Late effects surveillance recommendations among survivors of childhood hematopoietic cell transplantation: A Children’s Oncology Group Report. Biol Blood Marrow Transplant. 2016;22(5):782–95.
43. Ryan TD, Jefferies JL, Chin C, et al. Abnormal circumferential strain measured by echocardiography is present in patients with Shwachman–Diamond syndrome despite normal shortening fraction. Pediatr Blood Cancer. 2015;62(7):1228–31.
44. Niss O, Quinn CT, Lane A, et al. Cardiomyopathy with restrictive physiology in sickle cell disease. JACC Cardiovasc Imaging. 2016;9(3):243–52.
45. Braunlin EA, Stauffer NR, Peters CH, et al. Usefulness of bone marrow transplantation in the Hurler syndrome. Am J Cardiol. 2003;92(7):882–6.
46. Rotz SJ, Ryan TD, Hlavaty J, et al. Cardiotoxicity and cardiomyopathy in children and young adult survivors of hematopoietic stem cell transplant. Pediatric Blood Cancer. 2017;64(11):e26600.
| Files | ||
| Issue | Vol 19 No 1 (2025) | |
| Section | Review Article(s) | |
| DOI | https://doi.org/10.18502/ijhoscr.v19i1.17826 | |
| Keywords | ||
| Transfusion-dependent thalassemia; Hematopoietic stem cell transplant; Cardiotoxicity; Cardiomyopathy; Graft-versus-host disease | ||
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How to Cite
1.
Nateghi S, Rasooli A, Moadabshoar L, Panahi Z, Rostami M. Cardiac Considerations in Hematopoietic Stem Cell Transplantation (HSCT) for Transfusion-Dependent Thalassemia: A Review. Int J Hematol Oncol Stem Cell Res. 2023;19(1):69-74.
