4,677
Views
13
CrossRef citations to date
0
Altmetric
Thalassemia

Revisiting beta thalassemia intermedia: past, present, and future prospects

ORCID Icon, , &

References

  • Higgs DR, Engel JD, Stamatoyannopoulos G. Thalassaemia. Lancet. 2012;379(9813):373–383.
  • Musallam KM, Rivella S, Vichinsky E, et al. Non-transfusion-dependent thalassemias. Haematologica. 2013;98(6):833–844.
  • Rund D, Rachmilewitz E. Beta-thalassemia. N Engl J Med. 2005;353(11):1135–1146.
  • Haddad A, Tyan P, Radwan A, et al. beta-thalassemia intermedia: a bird’s-eye view. Turk J Haematol. 2014;31(1):5–16.
  • Weatherall DJ. The definition and epidemiology of non-transfusion-dependent thalassemia. Blood Rev. 2012;26(Suppl. 1):S3–S6.
  • Galanello R, Cao A. Relationship between genotype and phenotype – thalassemia intermedia. Cooleys Anemia. 1998;850:325–333.
  • Danjou F, Anni F, Galanello R. Beta-thalassemia: from genotype to phenotype. Haematol-Hematol J. 2011;96(11):1573–1575.
  • Taher A, Vichinsky E, Musallam K, et al. Guidelines for the management of non transfusion dependent thalassaemia (NTDT). Nicosia, Cyprus: Thalassaemia International Federation; 2013.
  • Weatherall DJ. Phenotype-genotype relationships in monogenic disease: lessons from the thalassaemias. Nat Rev Genet. 2001;2(4):245–255.
  • Camaschella C, Mazza U, Roetto A, et al. Genetic interactions in thalassemia-intermedia – analysis of beta-mutations, alpha-genotype, gamma-promoters, and beta-Lcr hypersensitive site-2 and site-4 in Italian patients. Am J Hematol. 1995;48(2):82–87.
  • Weatherall D. 2003 William Allan Award address – the thalassemias: the role of molecular genetics in an evolving global health problem. Am J Hum Genet. 2004;74(3):385–392.
  • Thein SL. Genetic insights into the clinical diversity of beta thalassaemia. Br J Haematol. 2004;124(3):264–274.
  • Musallam KM, Taher AT, Rachmilewitz EA. β-thalassemia intermedia: a clinical perspective. Csh Perspect Med. 2012;2(7): a013482.
  • Rivella S. The role of ineffective erythropoiesis in non-transfusion-dependent thalassemia. Blood Rev. 2012;26(Suppl. 1):S12–S15.
  • Ross P, Logan W. Roentgen findings in extramedullary hematopoiesis. Am J Roentgenol Radium Ther Nucl Med. 1969;106(3):604–613.
  • Aessopos A, Tassiopoulos S, Farmakis D, et al. Extramedullary hematopoiesis-related pleural effusion: the case of beta-thalassemia. Ann Thorac Surg. 2006;81(6):2037–2043.
  • Chuang CK, Chu SH, Fang JT, et al. Adrenal extramedullary hematopoietic tumor in a patient with beta-thalassemia. J Formos Med Assoc. 1998;97(6):431–433.
  • Kumar A, Aggarwal S, de Tilly LN. Case of the season. Thalassemia major with extramedullary hematopoiesis in the liver. Semin Roentgenol. 1995;30(2):99–101.
  • Thuret I. Current management of thalassemia intermedia. Transfus Clin Biol. 2014;21(4-5):143–149.
  • Taher A, Isma’eel H, Mehio G, et al. Prevalence of thromboembolic events among 8,860 patients with thalassaemia major and intermedia in the Mediterranean area and Iran. Thromb Haemost. 2006;96(4):488–491.
  • Taher AT, Otrock ZK, Uthman I, et al. Thalassemia and hypercoagulability. Blood Rev. 2008;22(5):283–292.
  • Taher AT, Musallam KM, Karimi M, et al. Splenectomy and thrombosis: the case of thalassemia intermedia. J Thromb Haemost. 2010;8(10):2152–2158.
  • Derchi G, Galanello R, Bina P, et al. Prevalence and risk factors for pulmonary arterial hypertension in a large group of beta-thalassemia patients using right heart catheterization: a Webthal study. Circulation. 2014;129(3):338–345.
  • Gladwin MT, Vichinsky E. Pulmonary complications of sickle cell disease. N Engl J Med. 2008;359(21):2254–2265.
  • Gladwin MT, Lancaster JR, Jr., Freeman BA, et al. Nitric oxide’s reactions with hemoglobin: a view through the SNO-storm. Nat Med. 2003;9(5):496–500.
  • 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.
  • Karimi M, Musallam KM, Cappellini MD, et al. Risk factors for pulmonary hypertension in patients with beta thalassemia intermedia. Eur J Intern Med. 2011;22(6):607–610.
  • Manfre L, Giarratano E, Maggio A, et al. MR imaging of the brain: findings in asymptomatic patients with thalassemia intermedia and sickle cell-thalassemia disease. AJR Am J Roentgenol. 1999;173(6):1477–1480.
  • Musallam KM, Taher AT, Karimi M, et al. Cerebral infarction in beta-thalassemia intermedia: breaking the silence. Thromb Res. 2012;130(5):695–702.
  • Karimi M, Haghpanah S, Bagheri MH, et al. Frequency and distribution of asymptomatic brain lesions in patients with beta-thalassemia intermedia. Ann Hematol. 2012;91(12):1833–1838.
  • Moukhadder HM, Halawi R, Cappellini MD, et al. Hepatocellular carcinoma as an emerging morbidity in the thalassemia syndromes: a comprehensive review. Cancer. 2017;123(5):751–758.
  • Borgna-Pignatti C, Vergine G, Lombardo T, et al. Hepatocellular carcinoma in the thalassaemia syndromes. Br J Haematol. 2004;124(1):114–117.
  • Restivo Pantalone G, Renda D, Valenza F, et al. Hepatocellular carcinoma in patients with thalassaemia syndromes: clinical characteristics and outcome in a long term single centre experience. Br J Haematol. 2010;150(2):245–247.
  • Fragatou S, Tsourveloudis I, Manesis G. Incidence of hepatocellular carcinoma in a thalassemia unit. Hemoglobin. 2010;34(3):221–226.
  • Kowdley KV. Iron, hemochromatosis, and hepatocellular carcinoma. Gastroenterology. 2004;127(5 Suppl. 1):S79–S86.
  • Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol. 2001;35(3):421–430.
  • Olivieri NF, Muraca GM, O’Donnell A, et al. Studies in haemoglobin E beta-thalassaemia. Br J Haematol. 2008;141(3):388–397.
  • Musallam KM, Cappellini MD, Daar S, et al. Serum ferritin levels and morbidity in beta-thalassemia intermedia: a 10-year Cohort study. Blood. 2012;120(21):1021.
  • Musallam KM, Taher AT, Duca L, et al. Levels of growth differentiation factor-15 are high and correlate with clinical severity in transfusion-independent patients with beta thalassemia intermedia. Blood Cells Mol Dis. 2011;47(4):232–234.
  • Matta BN, Abbas O, Maakaron JE, et al. Leg ulcers in patients with beta-thalassaemia intermedia: a single centre’s experience. J Eur Acad Dermatol Venereol. 2014;28(9):1245–1250.
  • Borgna-Pignatti C. Modern treatment of thalassaemia intermedia. Br J Haematol. 2007;138(3):291–304.
  • Sanctis VD, Tangerini A, Testa MR, et al. Final height and endocrine function in thalassaemia intermedia. J Pediatr Endocrinol Metab. 1998;11(Suppl. 3):965–971.
  • Inati A, Noureldine MA, Mansour A, et al. Endocrine and bone complications in beta-thalassemia intermedia: current understanding and treatment. Biomed Res Int. 2015;2015:813098.
  • Karamifar H, Shahriari M, Sadjadian N. Prevalence of endocrine complications in beta-thalassaemia major in the Islamic Republic of Iran. East Mediterr Health J. 2003;9(1–2):55–60.
  • Monge L, Pinach S, Caramellino L, et al. The possible role of autoimmunity in the pathogenesis of diabetes in B-thalassemia major. Diabetes Metab. 2001;27(2 Pt 1):149–154.
  • Argyropoulou MI, Kiortsis DN, Astrakas L, et al. Liver, bone marrow, pancreas and pituitary gland iron overload in young and adult thalassemic patients: a T2 relaxometry study. Eur Radiol. 2007;17(12):3025–3030.
  • Chern JP, Lin KH, Lu MY, et al. Abnormal glucose tolerance in transfusion-dependent beta-thalassemic patients. Diabetes Care. 2001;24(5):850–854.
  • Haidar R, Musallam KM, Taher AT. Bone disease and skeletal complications in patients with beta thalassemia major. Bone. 2011;48(3):425–432.
  • Skordis N, Christou S, Koliou M, et al. Fertility in female patients with thalassemia. J Pediatr Endocrinol Metab. 1998;11(Suppl. 3):935–943.
  • Nassar AH, Usta IM, Rechdan JB, et al. Pregnancy in patients with beta-thalassemia intermedia: outcome of mothers and newborns. Am J Hematol. 2006;81(7):499–502.
  • Nassar AH, Usta IM, Taher AM. Beta-thalassemia intermedia and pregnancy: should we anticoagulate? J Thromb Haemost. 2006;4(6):1413–1414.
  • Nassar AH, Naja M, Cesaretti C, et al. Pregnancy outcome in patients with beta-thalassemia intermedia at two tertiary care centers, in Beirut and Milan. Haematologica. 2008;93(10):1586–1587.
  • Taher AT, Musallam KM, Cappellini MD, et al. Optimal management of beta thalassaemia intermedia. Br J Haematol. 2011;152(5):512–523.
  • Tuck SM, Jensen CE, Wonke B, et al. Pregnancy management and outcomes in women with thalassaemia major. J Pediatr Endocrinol Metab. 1998;11(Suppl. 3):923–928.
  • Mojtahedzadeh F, Kosaryan M, Mahdavi MR, et al. The effect of folic acid supplementation in beta-thalassemia major: a randomized placebo-controlled clinical trial. Arch Iran Med. 2006;9(3):266–268.
  • Puliyel M, Sposto R, Berdoukas VA, et al. Ferritin trends do not predict changes in total body iron in patients with transfusional iron overload. Am J Hematol. 2014;89(4):391–394.
  • Musallam KM, Cappellini MD, Daar S, et al. Serum ferritin level and morbidity risk in transfusion-independent patients with beta-thalassemia intermedia: the ORIENT study. Haematologica. 2014;99(11):e218–e221.
  • Taher A, El Rassi F, Isma’eel H, et al. Correlation of liver iron concentration determined by R2 magnetic resonance imaging with serum ferritin in patients with thalassemia intermedia. Haematologica. 2008;93(10):1584–1586.
  • Pakbaz Z, Fischer R, Fung E, et al. Serum ferritin underestimates liver iron concentration in transfusion independent thalassemia patients as compared to regularly transfused thalassemia and sickle cell patients. Pediatr Blood Cancer. 2007;49(3):329–332.
  • Angelucci E, Brittenham GM, McLaren CE, et al. Hepatic iron concentration and total body iron stores in thalassemia major. N Engl J Med. 2000;343(5):327–331.
  • Musallam KM, Cappellini MD, Taher AT. Evaluation of the 5 mg/g liver iron concentration threshold and its association with morbidity in patients with beta-thalassemia intermedia. Blood Cells Mol Dis. 2013;51(1):35–38.
  • Taher A, Musallam KM, El Rassi F, et al. Levels of non-transferrin-bound iron as an index of iron overload in patients with thalassaemia intermedia. Br J Haematol. 2009;146(5):569–572.
  • Vichinsky E. Non-transfusion-dependent thalassemia and thalassemia intermedia: epidemiology, complications, and management. Curr Med Res Opin. 2016;32(1):191–204.
  • Cappellini MD, Cohen A, Piga A, et al. A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia. Blood. 2006;107(9):3455–3462.
  • Cappellini MD, Cohen A, Porter J, et al. Guidelines for the management of transfusion dependent thalassaemia (TDT). TIF publication. 2014 (20).
  • Musallam KM, Angastiniotis M, Eleftheriou A, et al. Cross-talk between available guidelines for the management of patients with beta-thalassemia major. Acta Haematol-Basel. 2013;130(2):64–73.
  • Taher AT, Porter JB, Viprakasit V, et al. Deferasirox effectively reduces iron overload in non-transfusion-dependent thalassemia (NTDT) patients: 1-year extension results from the THALASSA study. Ann Hematol. 2013;92(11):1485–1493.
  • Taher AT, Cappellini MD, Aydinok Y, et al. Optimising iron chelation therapy with deferasirox for non-transfusion-dependent thalassaemia patients: 1-year results from the THETIS study. Blood Cells Mol Dis. 2016;57:23–29.
  • Taher AT, Origa R, Perrotta S, et al. New film-coated tablet formulation of deferasirox is well tolerated in patients with thalassemia or lower-risk MDS: results of the randomized, phase II ECLIPSE study. Am J Hematol. 2017;92(5):420–428.
  • Saliba AN, Taher AT. Morbidities in non-transfusion-dependent thalassemia. Ann N Y Acad Sci. 2016;1368(1):82–94.
  • Musallam KM, Taher AT, Cappellini MD, et al. Clinical experience with fetal hemoglobin induction therapy in patients with beta-thalassemia. Blood. 2013;121(12):2199–2212. quiz 372.
  • Preza GC, Ruchala P, Pinon R, et al. Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload. J Clin Invest. 2011;121(12):4880–4888.
  • Casu C, Goldberg A, Nemeth E, et al. Treatment with minihepcidin peptide improves anemia and iron overload in a mouse model of thalassemia intermedia. Blood. 2013;122(21):431.
  • Casu C, Oikonomidau R, Shah Y, et al. Concurrent treatment with minhepcidin and deferiprone improves anemia and enhances reduction of spleen iron in a mouse model of non-transfusion dependent thalassemia. Blood. 2014;124(21):748.
  • Gardenghi S, Ramos P, Roy CN, et al. Hepcidin as a therapeutic tool to limit iron overload and improve anemia in beta-thalassemia. Blood. 2010;116(21):443–444.
  • Ramos E, Ruchala P, Goodnough JB, et al. Minihepcidins prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis. Blood. 2012;120(18):3829–3836.
  • Sankaran VG, Weiss MJ. Anemia: progress in molecular mechanisms and therapies. Nat Med. 2015;21(3):221–230.
  • Nai A, Pagani A, Mandelli G, et al. Deletion of TMPRSS6 attenuates the phenotype in a mouse model of beta-thalassemia. Blood. 2012;119(21):5021–5029.
  • Guo S, Casu C, Gardenghi S, et al. Reducing TMPRSS6 ameliorates hemochromatosis and beta-thalassemia in mice. J Clin Invest. 2013;123(4):1531–1541.
  • Schmidt PJ, Toudjarska I, Sendamarai AK, et al. An RNAi therapeutic targeting Tmprss6 decreases iron overload in Hfe(-/-) mice and ameliorates anemia and iron overload in murine beta-thalassemia intermedia. Blood. 2013;121(7):1200–1208.
  • Casu C, Aghajan M, Oikonomidou PR, et al. Combination of Tmprss6- ASO and the iron chelator deferiprone improves erythropoiesis and reduces iron overload in a mouse model of beta-thalassemia intermedia. Haematologica. 2016;101(1):e8–e11.
  • Libani IV, Guy EC, Melchiori L, et al. Decreased differentiation of erythroid cells exacerbates ineffective erythropoiesis in beta-thalassemia. Blood. 2008;112(3):875–885.
  • Taher A, Hussain I, Cappellini MD. Thalassemia intermedia: revisited. Blood Cell Mol Dis. 2006;37(1):12–20.
  • Aydinok Y, Karakas Z, Cassinerio E, et al. Efficacy and safety of ruxolitinib in regularly transfused patients with thalassemia: results from single-arm, multicenter, phase 2a truth study. Blood. 2016;128(22):852.
  • Melchiori L, Gardenghi S, Guy EC, et al. Use of Jak2 inhibitors to limit ineffective erythropoiesis and iron absorption in mice affected by beta-thalassemia and other disorders of red cell production. Blood. 2009;114(22):798.
  • Li HH, Rybicki AC, Suzuka SM, et al. Transferrin therapy ameliorates disease in beta-thalassemic mice. Nat Med. 2010;16(2):177–182.
  • Ruckle J, Jacobs M, Kramer W, et al. Single-dose, randomized, double-blind, placebo-controlled study of ACE-011 (ActRIIA-IgG1) in postmenopausal women. J Bone Miner Res. 2009;24(4):744–752.
  • Cappellini MD, Porter J, Origa R, et al. A phase 2a, open-label, dose-finding study to determine the safety and tolerability of sotatercept (ACE-011) in adults with beta (beta)-thalassemia: interim results. Blood. 2013;122(21):3448.
  • Taher AT, Cappellini MD. Management of non-transfusion-dependent thalassemia: a practical guide. Drugs. 2014;74(15):1719–1729.
  • 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, 2000-20. Bone Marrow Transpl. 2016;51(4):536–541.
  • King A, Shenoy S. Evidence-based focused review of the status of hematopoietic stem cell transplantation as treatment of sickle cell disease and thalassemia. Blood. 2014;123(20):3089–3094.
  • Locatelli F, Kabbara N, Ruggeri A, et al. Outcome of patients with hemoglobinopathies given either cord blood or bone marrow transplantation from an HLA-identical sibling. Blood. 2013;122(6):1072–1078.
  • Lucarelli G, Galimberti M, Polchi P, et al. Marrow transplantation in patients with thalassemia responsive to iron chelation-therapy. New Engl J Med. 1993;329(12):840–844.
  • 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(5):811–820.
  • Bank A, Dorazio R, Leboulch P. A phase I/II clinical trial of beta-globin gene therapy for beta-thalassemia. Ann NY Acad Sci. 2005;1054:308–316.
  • Raja JV, Rachchh MA, Gokani RH. Recent advances in gene therapy for thalassemia. J Pharm Bioallied Sci. 2012;4(3):194–201.
  • Rai P, Malik P. Gene therapy for hemoglobin disorders – a mini-review. J Rare Dis Res Treat. 2016;1(2):25–31.
  • Cox DB, Platt RJ, Zhang F. Therapeutic genome editing: prospects and challenges. Nat Med. 2015;21(2):121–131.
  • Cappellini MD, Porter JB, Musallam KM, et al. Development of a new disease severity scoring system for patients with non-transfusion-dependent thalassemia. Eur J Intern Med. 2016;28:91–96.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.