Emerging therapies in β-thalassemia: toward a new era in management

References

• Marengo-Rowe AJ. The thalassemias and related disorders. Proc (Bayl Univ Med Cent). 2007;20(1):27–31.
   PubMedGoogle Scholar
• Weatherall DJ. The inherited diseases of hemoglobin are an emerging global health burden. Blood. 2010;115(22):4331–4336.
   PubMed Web of Science ®Google Scholar
• Modell B, Darlison M. Global epidemiology of haemoglobin disorders and derived service indicators. Bull World Health Organ. 2008;86(6):480–487.
   PubMed Web of Science ®Google Scholar
• Vichinsky E. Complexity of alpha thalassemia: growing health problem with new approaches to screening, diagnosis, and therapy. Ann N Y Acad Sci. 2010;1202:180–187.
   PubMed Web of Science ®Google Scholar
• Lorey F, Cunningham G, Vichinsky EP, et al. Universal newborn screening for Hb H disease in California. Genet Test. 2001;5(2):93–100.
   PubMedGoogle Scholar
• Lorey F. Asian immigration and public health in California: thalassemia in newborns in California. J Pediatr Hematol Oncol. 2000;22(6):564–566.
   PubMed Web of Science ®Google Scholar
• Michlitsch J, Azimi M, Hoppe C, et al. Newborn screening for hemoglobinopathies in California. Pediatr Blood Cancer. 2009;52(4):486–490.
   PubMed Web of Science ®Google Scholar
• Taher AT, Weatherall DJ, Cappellini MD. Thalassaemia. Lancet. 2018;391(10116):155–167.
   PubMed Web of Science ®Google Scholar
• Taher AT, Cappellini MD. How I manage medical complications of beta-thalassemia in adults. Blood. 2018;132(17):1781–1791.
   PubMed Web of Science ®Google Scholar
• Cazzola M, Finch CJH. Evaluation of erythroid marrow function in anemic patients. Haematologica. 1987;72(3):195.
   PubMed Web of Science ®Google Scholar
• Aivado M, Gattermann N, Bottomley S, et al. Erythroid marrow function in anemic patients. J Am Soc Hematol. 2001;97(12):4000–4002.
   Google Scholar
• Cazzola M, Stefano PD, Ponchio L, et al. Relationship between transfusion regimen and suppression of erythropoiesis in β‐thalassaemia major. Br J Haematol. 1995;89(3):473–478.
   PubMed Web of Science ®Google Scholar
• Borgna-Pignatti C, Rugolotto S, De Stefano P, et al. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica. 2004;89(10):1187–1193.
   PubMed Web of Science ®Google Scholar
• Modell B, Khan M, Darlison MJTL. Survival in β-thalassaemia major in the UK: data from the UK thalassaemia register. Lancet. 2000;355(9220):2051–2052.
   PubMed Web of Science ®Google Scholar
• Taher a, Vichinsky e, Musallam k, et al. For the management of non transfusion dependent thalassaemia (ntdt). 2013.
   Google Scholar
• Viprakasit V, Origa R, Fucharoen S. Genetic basis, pathophysiology and diagnosis. guidelines for the management of transfusion dependent thalassaemia (TDT) [Internet]. 3rd ed. Nicosia, Cyprus: Thalassaemia International Federation; 2014.
   Google Scholar
• Shah FT, Sayani F, Trompeter S, et al. Challenges of blood transfusions in beta-thalassemia. Blood Rev. 2019;37:100588.
   PubMed Web of Science ®Google Scholar
• Cappellini MD, Porter JB, Viprakasit V, et al. A paradigm shift on beta-thalassaemia treatment: how will we manage this old disease with new therapies? Blood rev. 2018;32(4):300–311.
   PubMed Web of Science ®Google Scholar
• Musallam KM, Taher AT, Karimi M, et al. Cerebral infarction in β-thalassemia intermedia: breaking the silence. Thrombosis research. 2012;130(5):695–702.
   PubMed Web of Science ®Google Scholar
• 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. J Am Soc Hematol. 2010;115(10):1886–1892.
   Google Scholar
• Cappellini M-D, Cohen A, Porter J, et al. Guidelines for the management of transfusion dependent thalassaemia (TDT). Cyprus: Thalassaemia International Federation Nicosia; 2014.
   Google Scholar
• Taher A, Vichinsky E, Musallam K, et al. Guidelines for the management of non transfusion dependent thalassaemia (NTDT). Nicosia, Cyprus: Thalassaemia International Federation; 2013.
   Google Scholar
• Pennell DJ, Porter JB, Piga A, et al. A 1-year randomized controlled trial of deferasirox vs deferoxamine for myocardial iron removal in beta-thalassemia major (CORDELIA). Blood. 2014;123(10):1447–1454.
   PubMed Web of Science ®Google Scholar
• Davis BA, Porter JB. Long-term outcome of continuous 24-hour deferoxamine infusion via indwelling intravenous catheters in high-risk beta-thalassemia. Blood. 2000;95(4):1229–1236.
   PubMed Web of Science ®Google Scholar
• Pennell DJ, Berdoukas V, Karagiorga M, et al. Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with asymptomatic myocardial siderosis. Blood. 2006;107(9):3738–3744.
   PubMed Web of Science ®Google Scholar
• Tanner MA, Galanello R, Dessi C, et al. A randomized, placebo-controlled, double-blind trial of the effect of combined therapy with deferoxamine and deferiprone on myocardial iron in thalassemia major using cardiovascular magnetic resonance. Circulation. 2007;115(14):1876–1884.
   PubMed Web of Science ®Google Scholar
• Farmaki K, Tzoumari I, Pappa C, et al. Normalisation of total body iron load with very intensive combined chelation reverses cardiac and endocrine complications of thalassaemia major. Br J Haematol. 2010;148(3):466–475.
   PubMed Web of Science ®Google Scholar
• 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(1):33–40.
   PubMed Web of Science ®Google Scholar
• Pennell DJ, Porter JB, Cappellini MD, et al. Deferasirox for up to 3 years leads to continued improvement of myocardial T2* in patients with beta-thalassemia major. Haematologica. 2012;97(6):842–848.
   PubMed Web of Science ®Google Scholar
• Cappellini MD, Bejaoui M, Agaoglu L, et al. Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: efficacy and safety during 5 years’ follow-up. Blood. 2011;118(4):884–893.
   PubMed Web of Science ®Google Scholar
• Taher A, Cappellini MD, Vichinsky E, et al. Efficacy and safety of deferasirox doses of >30 mg/kg per d in patients with transfusion-dependent anaemia and iron overload. Br J Haematol. 2009;147(5):752–759.
   PubMed Web of Science ®Google Scholar
• Deugnier Y, Turlin B, Ropert M, et al. Improvement in liver pathology of patients with beta-thalassemia treated with deferasirox for at least 3 years. Gastroenterology. 2011;141(4):1202–11, 11 e1–3.
   PubMed Web of Science ®Google Scholar
• Pippard MJ, Weatherall DJ. Iron balance and the management of iron overload in beta-thalassemia intermedia. Birth Defects Orig Artic Ser. 1988;23(5B):29–33.
   PubMedGoogle Scholar
• Cossu P, Toccafondi C, Vardeu F, et al. Iron overload and desferrioxamine chelation therapy in beta-thalassemia intermedia. Eur J Pediatr. 1981;137(3):267–271.
   PubMed Web of Science ®Google Scholar
• Musallam KM, Taher AT, Cappellini MD, et al. Clinical experience with fetal hemoglobin induction therapy in patients with beta-thalassemia. Blood. 2013;121(12):2199–212; quiz 372.
   PubMed Web of Science ®Google Scholar
• 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. 1993.
   Google Scholar
• Watanapokasin R, Sanmund D, Winichagoon P, et al. Hydroxyurea responses and fetal hemoglobin induction in β-thalassemia/HbE patients’ peripheral blood erythroid cell culture. Ann Hematol. 2006;85(3):164–169.
   PubMed Web of Science ®Google Scholar
• Watanapokasin Y, Chuncharunee S, Sanmund D, et al. In vivo and in vitro studies of fetal hemoglobin induction by hydroxyurea in β-thalassemia/hemoglobin E patients. Exp Hematol. 2005;33(12):1486–1492.
   PubMed Web of Science ®Google Scholar
• 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 Hematol. 2008;141(5):720–727.
   PubMed Web of Science ®Google Scholar
• Italia KY, Jijina FJ, Merchant R, et al. Response to hydroxyurea in β thalassemia major and intermedia: experience in western India. Clin Chim Acta. 2009;407(1–2):10–15.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Goodman MA, Malik P. The potential of gene therapy approaches for the treatment of hemoglobinopathies: achievements and challenges. Ther Adv Hematol. 2016;7(5):302–315.
   PubMed Web of Science ®Google Scholar
• Rivella S. beta-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies. Haematologica. 2015;100(4):418–430.
   PubMed Web of Science ®Google Scholar
• Breda L, Casu C, Gardenghi S, et al. Therapeutic hemoglobin levels after gene transfer in beta-thalassemia mice and in hematopoietic cells of beta-thalassemia and sickle cells disease patients. PLoS One. 2012;7(3):e32345.
   PubMed Web of Science ®Google Scholar
• May C, Rivella S, Callegari J, et al. Therapeutic haemoglobin synthesis in beta-thalassaemic mice expressing lentivirus-encoded human beta-globin. Nature. 2000;406(6791):82–86.
   PubMed Web of Science ®Google Scholar
• May C, Rivella S, Chadburn A, et al. Successful treatment of murine beta-thalassemia intermedia by transfer of the human beta-globin gene. Blood. 2002;99(6):1902–1908.
   PubMed Web of Science ®Google Scholar
• Rivella S, May C, Chadburn A, et al. A novel murine model of Cooley anemia and its rescue by lentiviral-mediated human beta-globin gene transfer. Blood. 2003;101(8):2932–2939.
   PubMed Web of Science ®Google Scholar
• Cavazzana-Calvo M, Payen E, Negre O, et al. Transfusion independence and HMGA2 activation after gene therapy of human beta-thalassaemia. Nature. 2010;467(7313):318–322.
   PubMed Web of Science ®Google Scholar
• Negre O, Eggimann AV, Beuzard Y, et al. Gene Therapy of the beta-hemoglobinopathies by lentiviral transfer of the beta(A(T87Q))-globin gene. Hum Gene Ther. 2016;27(2):148–165.
   PubMed Web of Science ®Google Scholar
• Negre O, Bartholomae C, Beuzard Y, et al. Preclinical evaluation of efficacy and safety of an improved lentiviral vector for the treatment of beta-thalassemia and sickle cell disease. Curr Gene Ther. 2015;15(1):64–81.
   PubMed Web of Science ®Google Scholar
• Boulad F, Mansilla-Soto J, Cabriolu A, et al. Gene therapy and genome editing. Hematol Oncol Clin North Am. 2018;32(2):329–342.
   PubMed Web of Science ®Google Scholar
• Thompson AA, Walters MC, Kwiatkowski J, et al., Gene therapy in patients with transfusion-dependent beta-thalassemia. N Engl J Med. 2018;378(16):1479–1493.
   PubMed Web of Science ®Google Scholar
• Marktel S, Scaramuzza S, Cicalese MP, et al. Intrabone hematopoietic stem cell gene therapy for adult and pediatric patients affected by transfusion-dependent ss-thalassemia. Nat Med. 2019;25(2):234–241.
   PubMed Web of Science ®Google Scholar
• Bauer DE, Kamran SC, Lessard S, et al. An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level. Science. 2013;342(6155):253–257.
   PubMed Web of Science ®Google Scholar
• Costa FC, Fedosyuk H, Neades R, et al. Induction of fetal hemoglobin in vivo mediated by a synthetic gamma-globin zinc finger activator. Anemia. 2012;2012:507894.
   PubMedGoogle Scholar
• Guda S, Brendel C, Renella R, et al. miRNA-embedded shRNAs for lineage-specific BCL11A knockdown and hemoglobin F induction. Mol Ther. 2015;23(9):1465–1474.
   PubMed Web of Science ®Google Scholar
• Mishra B, Chou S, Lin MI, et al. Crispr/Cas9-Mediated Genome Editing of Human CD34+ Cells Upregulate Fetal Hemoglobin to Clinically Relevant Levels in Single Cell-Derived Erythroid Colonies. Blood. 2016;128(22):3623.
   Google Scholar
• Basak A, Hancarova M, Ulirsch JC, et al. BCL11A deletions result in fetal hemoglobin persistence and neurodevelopmental alterations. J Clin Invest. 2015;125(6):2363–2368.
   PubMed Web of Science ®Google Scholar
• Giani FC, Fiorini C, Wakabayashi A, et al. Targeted application of human genetic variation can improve red blood cell production from stem cells. Cell Stem Cell. 2016;18(1):73–78.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Brendel C, Guda S, Renella R, et al. Lineage-specific BCL11A knockdown circumvents toxicities and reverses sickle phenotype. J Clin Invest. 2016;126(10):3868–3878.
   PubMed Web of Science ®Google Scholar
• Bjurstrom CF, Mojadidi M, Phillips J, et al. Reactivating fetal hemoglobin expression in human adult erythroblasts through BCL11A knockdown using targeted endonucleases. Mol Ther Nucleic Acids. 2016;5:e351.
   PubMedGoogle Scholar
• Cavazzana M, Antoniani C, Miccio A. Gene therapy for beta-hemoglobinopathies. Mol Ther. 2017;25(5):1142–1154.
   PubMedGoogle Scholar
• Makis A, Hatzimichael E, Papassotiriou I, et al. 2017 Clinical trials update in new treatments of beta-thalassemia. Am J Hematol. 2016;91(11):1135–1145.
   PubMed Web of Science ®Google Scholar
• Genovese P, Schiroli G, Escobar G, et al. Targeted genome editing in human repopulating haematopoietic stem cells. Nature. 2014;510(7504):235–240.
   PubMed Web of Science ®Google Scholar
• Xu P, Tong Y, Liu X-Z, et al. Both TALENs and CRISPR/Cas9 directly target the HBB IVS2–654 (C> T) mutation in β-thalassemia-derived iPSCs. Sci Rep. 2015;5:12065.
   PubMed Web of Science ®Google Scholar
• Finotti A, Borgatti M, Gambari R. Ground state naive pluripotent stem cells and CRISPR/Cas9 gene correction for beta-thalassemia. Stem Cell Investig. 2016;3:66.
   PubMedGoogle Scholar
• Chattong S, Ruangwattanasuk O, Yindeedej W, et al. CD34+ cells from dental pulp stem cells with a ZFN-mediated and homology-driven repair-mediated locus-specific knock-in of an artificial beta-globin gene. Gene Ther. 2017;24(7):425–432.
   PubMed Web of Science ®Google Scholar
• DeWitt MA, Magis W, Bray NL, et al. Selection-free genome editing of the sickle mutation in human adult hematopoietic stem/progenitor cells. Sci Transl Med. 2016;8(360):360ra134.
   PubMed Web of Science ®Google Scholar
• Mettananda S, Fisher CA, Hay D, et al. Editing an alpha-globin enhancer in primary human hematopoietic stem cells as a treatment for beta-thalassemia. Nat Commun. 2017;8(1):424.
   PubMedGoogle Scholar
• Mettananda S, Fisher CA, Sloane-Stanley JA, et al. Selective silencing of alpha-globin by the histone demethylase inhibitor IOX1: a potentially new pathway for treatment of beta-thalassemia. Haematologica. 2017;102(3):e80–e4.
   PubMed Web of Science ®Google Scholar
• Mettananda S, Yasara N, Fisher CA, et al. Synergistic silencing of alpha-globin and induction of gamma-globin by histone deacetylase inhibitor, vorinostat as a potential therapy for beta-thalassaemia. Sci Rep. 2019;9(1):11649.
   PubMedGoogle Scholar
• Suragani RN, Cadena SM, Cawley SM, et al. Transforming growth factor-beta superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis. Nat Med. 2014;20(4):408–414.
   PubMed Web of Science ®Google Scholar
• Cappellini MD, Porter J, Origa R, et al. Sotatercept, a novel transforming growth factor beta ligand trap, improves anemia in beta-thalassemia: a phase II, open-label, dose-finding study. Haematologica. 2019;104(3):477–484.
   PubMed Web of Science ®Google Scholar
• Dussiot M, Maciel TT, Fricot A, et al. An activin receptor IIA ligand trap corrects ineffective erythropoiesis in beta-thalassemia. Nat Med. 2014;20(4):398–407.
   PubMed Web of Science ®Google Scholar
• El-Beshlawy A, El-Ghamrawy M. Recent trends in treatment of thalassemia. Blood Cells Mol Dis. 2019;76:53–58.
   PubMed Web of Science ®Google Scholar
• Martinez PA, Suragani RN, Bhasin M, et al. RAP-536 (murine ACE-536/luspatercept) inhibits Smad2/3 signaling and promotes erythroid differentiation by restoring GATA-1 function in murine b-thalassemia. Am Soc Hematol. 2015;126:751.
   Google Scholar
• Guerra A, Musallam KM, Taher AT, et al. Emerging Therapies. Hematol Oncol Clin North Am. 2018;32(2):343–352.
   PubMed Web of Science ®Google Scholar
• Attie KM, Allison MJ, McClure T, et al. A phase 1 study of ACE-536, a regulator of erythroid differentiation, in healthy volunteers. Am J Hematol. 2014;89(7):766–770.
   PubMed Web of Science ®Google Scholar
• Piga A, Perrotta S, Gamberini MR, et al. Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with beta-thalassemia. Blood. 2019;133(12):1279–1289.
   PubMed Web of Science ®Google Scholar
• Cappellini MD, Viprakasit V, Taher AT, et al., A phase 3 trial of luspatercept in patients with transfusion-dependent beta-thalassemia. N Engl J Med. 2020;382(13):1219–1231.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Casu C, Presti VL, Oikonomidou PR, et al. Short-term administration of JAK2 inhibitors reduces splenomegaly in mouse models of beta-thalassemia intermedia and major. Haematologica. 2018;103(2):e46–e9.
   PubMed Web of Science ®Google Scholar
• Taher AT, Karakas Z, Cassinerio E, et al. Efficacy and safety of ruxolitinib in regularly transfused patients with thalassemia: results from a phase 2a study. Blood. 2018;131(2):263–265.
   PubMed Web of Science ®Google Scholar
• Manolova V, Nyffenegger N, Flace A, et al. Oral ferroportin inhibitor ameliorates ineffective erythropoiesis in a model of beta-thalassemia. J Clin Invest. 2019; 130(1). DOI:10.1172/JCI129382
   PubMed Web of Science ®Google Scholar
• Casu C, Oikonomidou PR, Chen H, et al. Minihepcidin peptides as disease modifiers in mice affected by beta-thalassemia and polycythemia vera. Blood. 2016;128(2):265–276.
   PubMed Web of Science ®Google Scholar
• Finberg KEJTJoci. Striking the target in iron overload disorders. J. Clin. Invest. 2013;123(4):1424–1427.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar