An overview of current treatment strategies for β-thalassemia

Introduction: At least 40,000 people per year worldwide are born with β-thalassemia. Patients with β-thalassemia major are reliant on regular red blood cell transfusions for survival from a young age. For those with β-thalassemia intermedia or hemoglobin (Hb) E/β-thalassemia, symptoms range from mild clinical presentation to a more severe phenotype and patients are not necessarily transfusion-dependent. Areas covered: Here, β-thalassemia treatment strategies including transfusion, splenectomy, fetal hemoglobin induction, hematopoietic stem-cell transplantation, in addition to potential future treatment options, are reviewed. Approaches for the monitoring and management of complications are also described. Expert opinion: The most important advances in the treatment of transfusion-dependent β-thalassemia major patients since the advent of iron chelation therapy are the introduction of oral iron chelators in addition to technologies for the direct measurement of iron in organs. For non-transfusion-dependent patients with β-thalassemia intermedia or HbE/β-thalassemia, recent studies have highlighted the significance of iron overload-related complications and the increase in incidence with advancing age, prompting the development of much-needed clinical treatment guidelines. Future research should focus on improving the treatment of β-thalassemia major patients to further extend survival and quality of life, and continued identification of β-thalassemia intermedia or HbE/β-thalassemia patients who may benefit from transfusion and iron chelation therapy.

[1]  L. Pierelli,et al.  Red blood cell alloimmunization in sickle cell disease and in thalassaemia: current status, future perspectives and potential role of molecular typing , 2014, Vox sanguinis.

[2]  D. Pennell,et al.  Deferasirox Compared With Deferoxamine For The Removal Of Cardiac Iron In Patients With β-Thalassemia Major: 2-Year Data From The Cordelia Extension , 2013 .

[3]  Matthew T. White,et al.  MRI-Guided Iron Assessment and Oral Chelator Use Improve Iron Status In Thalassemia Major Patients: a Six-Year Single Center Retrospective Cohort Study , 2013 .

[4]  R. Chopra,et al.  A Phase 2a, Open-Label, Dose-Finding Study To Determine The Safety and Tolerability Of Sotatercept (ACE-011) In Adults With Beta (β)-Thalassemia: Interim Results , 2013 .

[5]  S. Perrotta,et al.  Deferasirox–Deferoxamine Combination Therapy Reduces Cardiac Iron With Rapid Liver Iron Removal In Patients With Severe Transfusional Iron Overload (HYPERION) , 2013 .

[6]  G. Stamatoyannopoulos,et al.  Hematopoietic stem cell mobilization for gene therapy: superior mobilization by the combination of granulocyte-colony stimulating factor plus plerixafor in patients with β-thalassemia major. , 2013, Human gene therapy.

[7]  D. Pennell,et al.  Cardiovascular function and treatment in β-thalassemia major: a consensus statement from the American Heart Association. , 2013, Circulation.

[8]  M. Cappellini,et al.  Deferasirox effectively reduces iron overload in non-transfusion-dependent thalassemia (NTDT) patients: 1-year extension results from the THALASSA study , 2013, Annals of Hematology.

[9]  M. Cappellini,et al.  SERUM FERRITIN FOR PREDICTING CLINICALLY RELEVANT LIC THRESHOLDS TO GUIDE MANAGEMENT OF PATIENTS WITH NONTRANSFUSION-DEPENDENT THALASSEMIA TREATED WITH DEFERASIROX: THALASSA STUDY EXTENSION ANALYSIS , 2013 .

[10]  S. Rivella,et al.  Non-transfusion-dependent thalassemias , 2013, Haematologica.

[11]  Swee Lay Thein,et al.  The molecular basis of β-thalassemia. , 2013, Cold Spring Harbor perspectives in medicine.

[12]  M. Cappellini,et al.  Clinical experience with fetal hemoglobin induction therapy in patients with β-thalassemia. , 2013, Blood.

[13]  M. Angastiniotis,et al.  Cross-Talk between Available Guidelines for the Management of Patients with Beta-Thalassemia Major , 2013, Acta Haematologica.

[14]  M. Gadallah,et al.  Morbidities and Mortality in Transfusion-Dependent Beta-Thalassemia Patients (Single-Center Experience) , 2013, Pediatric hematology and oncology.

[15]  E. Leandros,et al.  Incidence, risk factors, and outcome of portal vein thrombosis after laparoscopic-assisted splenectomy in β-thalassemia patients: a prospective exploratory study. , 2013, Journal of laparoendoscopic & advanced surgical techniques. Part A.

[16]  M. Cappellini,et al.  Hepatocellular carcinoma in hepatitis-negative patients with thalassemia intermedia: a closer look at the role of siderosis. , 2013, Annals of hepatology.

[17]  R. Horne,et al.  Beliefs about chelation among thalassemia patients , 2012, Health and Quality of Life Outcomes.

[18]  S. Rivella,et al.  ACE-536 Improves Ineffective Erythropoiesis, Anemia and Co-Morbidities in β-Thalassemia , 2012 .

[19]  I. Boyd,et al.  ACE-536 Increases Hemoglobin in Healthy Postmenopausal Women: A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Multiple Ascending Dose Study , 2012 .

[20]  M. Mahdavi,et al.  Credibility of measurement of fructosamine and hemoglobin A1C in estimating blood glucose level of diabetic patients with thalassemia major , 2012 .

[21]  A. Thompson,et al.  Challenges of alloimmunization in patients with haemoglobinopathies , 2012, British journal of haematology.

[22]  Vip Viprakasit,et al.  Deferasirox reduces iron overload significantly in nontransfusion-dependent thalassemia: 1-year results from a prospective, randomized, double-blind, placebo-controlled study. , 2012, Blood.

[23]  Suthat Fucharoen,et al.  The hemoglobin E thalassemias. , 2012, Cold Spring Harbor perspectives in medicine.

[24]  F. Rodeghiero,et al.  Short‐ and long‐term risks of splenectomy for benign haematological disorders: should we revisit the indications? , 2012, British journal of haematology.

[25]  G. Lucarelli,et al.  Hematopoietic stem cell transplantation in thalassemia and sickle cell anemia. , 2012, Cold Spring Harbor perspectives in medicine.

[26]  M. Tsironi,et al.  A national registry of haemoglobinopathies in Greece: Deducted demographics, trends in mortality and affected births , 2012, Annals of Hematology.

[27]  N. Olivieri Treatment strategies for hemoglobin E beta-thalassemia. , 2012, Blood reviews.

[28]  M. Cappellini,et al.  Contemporary approaches to treatment of beta-thalassemia intermedia. , 2012, Blood reviews.

[29]  S. Rivella The role of ineffective erythropoiesis in non-transfusion-dependent thalassemia. , 2012, Blood reviews.

[30]  C. Leen,et al.  UK consensus guidelines for the use of the protease inhibitors boceprevir and telaprevir in genotype 1 chronic hepatitis C infected patients , 2012, Alimentary pharmacology & therapeutics.

[31]  J. Talwalkar,et al.  Recognizing and preventing death from compensated cirrhosis in the community , 2012, Liver international : official journal of the International Association for the Study of the Liver.

[32]  S. Rivella,et al.  β-thalassemia: a model for elucidating the dynamic regulation of ineffective erythropoiesis and iron metabolism. , 2011, Blood.

[33]  P. Brissot,et al.  Improvement in liver pathology of patients with β-thalassemia treated with deferasirox for at least 3 years. , 2011, Gastroenterology.

[34]  M. Cappellini,et al.  Changing patterns of splenectomy in transfusion‐dependent thalassemia patients , 2011, American journal of hematology.

[35]  C. Lobo,et al.  Retrospective epidemiological study of Latin American patients with transfusional hemosiderosis: the first Latin American epidemiological study in iron overload – the RELATH study , 2011, Hematology.

[36]  A. Kattamis,et al.  Impact of magnetic resonance imaging on cardiac mortality in thalassemia major , 2011, Journal of magnetic resonance imaging : JMRI.

[37]  C. Borgna-Pignatti,et al.  Complications of thalassemia major and their treatment , 2011, Expert review of hematology.

[38]  A. Taher,et al.  Mediterranean Journal of Hematology and Infectious Diseases Thalassemia and Venous Thromboembolism , 2011 .

[39]  R. Storb,et al.  Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria. , 2011, Blood.

[40]  N. Siritanaratkul,et al.  Effectiveness of deferiprone in transfusion‐independent beta‐thalassemia/HbE patients , 2011, Hematology.

[41]  P. Strengers,et al.  Haemovigilance: an effective tool for improving transfusion practice , 2011, Vox sanguinis.

[42]  S. Manca-di-Villahermosa,et al.  Iron-chelating therapy for transfusional iron overload. , 2011, The New England journal of medicine.

[43]  E. Angelucci Hematopoietic stem cell transplantation in thalassemia. , 2010, Hematology. American Society of Hematology. Education Program.

[44]  R. Calzolari,et al.  Desensitization to hydroxycarbamide following long‐term treatment of thalassaemia intermedia as observed in vivo and in primary erythroid cultures from treated patients , 2010, British journal of haematology.

[45]  M. Karimi,et al.  Erratum: “Cerebrovascular accident in β‐thalassemia major (β‐TM) and β‐thalassemia intermedia (β‐TI)” by Karimi et al. Am J Hematol 83:77–79, 2008, DOI number 20938 , 2010 .

[46]  A T Taher,et al.  Splenectomy and thrombosis: the case of thalassemia intermedia , 2010, Journal of thrombosis and haemostasis : JTH.

[47]  Jérôme Larghero,et al.  Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia , 2010, Nature.

[48]  D. Guerrot,et al.  Acute renal failure and Fanconi syndrome due to deferasirox. , 2010, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[49]  D. Weatherall The inherited diseases of hemoglobin are an emerging global health burden. , 2010, Blood.

[50]  M. Falk,et al.  ACUTE INTERSTITIAL NEPHRITIS SECONDARY TO DEFERASIROX CAUSING ACUTE RENAL INJURY NEEDING SHORT‐TERM DIALYSIS , 2010, Nephrology.

[51]  M. Cappellini,et al.  Tailoring iron chelation by iron intake and serum ferritin: the prospective EPIC study of deferasirox in 1744 patients with transfusion-dependent anemias , 2010, Haematologica.

[52]  M. Cappellini,et al.  Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: the OPTIMAL CARE study. , 2010, Blood.

[53]  A. Taher,et al.  Paraspinal extramedullary hematopoiesis in patients with thalassemia intermedia , 2010, European Spine Journal.

[54]  Anita Nadkarni,et al.  Global burden, distribution and prevention of β-thalassemias and hemoglobin E disorders , 2010, Expert review of hematology.

[55]  K. Ghosh,et al.  Effect of hydroxyurea on the transfusion requirements in patients with severe HbE-β-thalassaemia: a genotypic and phenotypic study , 2010, Journal of Clinical Pathology.

[56]  Xiangmin Xu,et al.  The molecular basis of beta-thalassemia intermedia in southern China: genotypic heterogeneity and phenotypic diversity , 2010, BMC Medical Genetics.

[57]  J. Fernandes,et al.  Early cardiac iron overload in children with transfusion-dependent anemias , 2009, Haematologica.

[58]  S. Rivella Ineffective erythropoiesis and thalassemias , 2009, Current opinion in hematology.

[59]  M. Mallat,et al.  Treatment and Prevention of Hepatitis B and C in Thalassemia , 2009, Hemoglobin.

[60]  M. Cappellini,et al.  Correlation of liver iron concentration determined by R2 magnetic resonance imaging with serum ferritin in patients with thalassemia intermedia , 2008, Haematologica.

[61]  Matthew W. Darlison,et al.  Improved survival of thalassaemia major in the UK and relation to T2* cardiovascular magnetic resonance , 2008, Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance.

[62]  Matthew Darlison,et al.  Global epidemiology of haemoglobin disorders and derived service indicators. , 2008, Bulletin of the World Health Organization.

[63]  D. Weatherall,et al.  Studies in haemoglobin E beta‐thalassaemia , 2008, British journal of haematology.

[64]  Maria Domenica Cappellini,et al.  Italian Society of Hematology practice guidelines for the management of iron overload in thalassemia major and related disorders , 2008, Haematologica.

[65]  G. Lucarelli,et al.  Advances in the allogeneic transplantation for thalassemia. , 2008, Blood reviews.

[66]  D. Pennell,et al.  Journal of Cardiovascular Magnetic Resonance Open Access Combined Chelation Therapy in Thalassemia Major for the Treatment of Severe Myocardial Siderosis with Left Ventricular Dysfunction , 2008 .

[67]  M. Karimi,et al.  Cerebrovascular accident in β‐thalassemia major (β‐TM) and β‐thalassemia intermedia (β‐TI) , 2008 .

[68]  M. Karimi,et al.  Cerebrovascular accident in beta-thalassemia major (beta-TM) and beta-thalassemia intermedia (beta-TI). , 2008, American journal of hematology/oncology.

[69]  P. Landais,et al.  Decreased transfusion needs associated with hydroxyurea therapy in Algerian patients with thalassemia major or intermedia , 2007, Transfusion.

[70]  R. Ljung,et al.  The thalassaemia syndromes , 2007, Scandinavian journal of clinical and laboratory investigation.

[71]  M. Cappellini,et al.  Prevalence of thromboembolic events among 8,860 patients with thalassaemia major and intermedia in the Mediterranean area and Iran , 2006, Thrombosis and Haemostasis.

[72]  E. Vichinsky,et al.  Pulmonary hypertension in thalassemia: Association with platelet activation and hypercoagulable state , 2006, American journal of hematology.

[73]  E. Gotsis,et al.  Effect of enhanced iron chelation therapy on glucose metabolism in patients with β‐thalassaemia major , 2006, British journal of haematology.

[74]  M. Cappellini,et al.  Thalassemia intermedia: revisited. , 2006, Blood cells, molecules & diseases.

[75]  M. Sadelain Recent advances in globin gene transfer for the treatment of beta-thalassemia and sickle cell anemia , 2006, Current opinion in hematology.

[76]  S. Perrotta,et al.  A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia. , 2006, Blood.

[77]  Mark A Westwood,et al.  Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with asymptomatic myocardial siderosis. , 2006, Blood.

[78]  S. Vento,et al.  Infections and thalassaemia. , 2006, The Lancet. Infectious diseases.

[79]  A. Mancuso,et al.  Treatment with hydroxycarbamide for intermedia thalassaemia: decrease of efficacy in some patients during long‐term follow up , 2006, British journal of haematology.

[80]  R. Galanello,et al.  Osteoporosis in β‐Thalassemia: Clinical and Genetic Aspects , 2005 .

[81]  D. Weatherall,et al.  Fetal haemoglobin augmentation in E/β0 thalassaemia: clinical and haematological outcome , 2005, British journal of haematology.

[82]  Matthew W. Darlison,et al.  Standards for the Clinical Care of Children and Adults with Thalassaemia in the UK , 2005 .

[83]  D. Weatherall,et al.  Haemoglobin E beta thalassaemia in Sri Lanka. , 2005, Lancet.

[84]  R. Galanello,et al.  Osteoporosis in beta-thalassemia: Clinical and genetic aspects. , 2005, Annals of the New York Academy of Sciences.

[85]  M. Pillon,et al.  A prospective survey on incidence, risk factors and therapy of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation. , 2005, Haematologica.

[86]  V. De Sanctis,et al.  Effects of acarbose in beta-thalassaemia major patients with normal glucose tolerance and hyperinsulinism. , 2004, Pediatric endocrinology reviews : PER.

[87]  E. Neufeld,et al.  Complications of beta-thalassemia major in North America. , 2004, Blood.

[88]  G. Sanna,et al.  Iron overload and desferrioxamine chelation therapy in β-thalassemia intermedia , 1981, European Journal of Pediatrics.

[89]  A. Cnaan,et al.  Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. , 2004, Haematologica.

[90]  R. Galanello,et al.  Safety and effectiveness of long-term therapy with the oral iron chelator deferiprone. , 2003, Blood.

[91]  A. Hoffbrand,et al.  Role of deferiprone in chelation therapy for transfusional iron overload. , 2003, Blood.

[92]  John P Klein,et al.  Severity of chronic graft-versus-host disease: association with treatment-related mortality and relapse. , 2002, Blood.

[93]  M. Cappellini,et al.  The safety and effectiveness of deferiprone in a large‐scale, 3‐year study in Italian patients , 2002, British journal of haematology.

[94]  W. Wanachiwanawin Infections in E-β thalassemia. , 2000 .

[95]  M. Cappellini,et al.  Venous thromboembolism and hypercoagulability in splenectomized patients with thalassaemia intermedia. , 2000, British journal of haematology.

[96]  C. McLaren,et al.  Hepatic iron concentration and total body iron stores in thalassemia major. , 2000, The New England journal of medicine.

[97]  K. Konstantopoulos,et al.  Chelation therapy in patients with thalassemia using the orally active iron chelator deferiprone (L1). , 2000, Haematologica.

[98]  S. Musumeci,et al.  Thromboembolic Events in Beta Thalassemia Major: An Italian Multicenter Study , 1998, Acta Haematologica.

[99]  G. Koren,et al.  Iron-chelation therapy with oral deferiprone in patients with thalassemia major. , 1995, The New England journal of medicine.

[100]  J. H. MacMillan,et al.  Survival in Medically Treated Patients with Homozygous β-Thalassemia , 1994 .

[101]  R. Lifeso,et al.  Combined radiotherapeutic and surgical management of a spinal cord compression by extramedullary hematopoiesis in a patient with hemoglobin E beta-thalassemia. , 1994, Acta haematologica.

[102]  J. H. MacMillan,et al.  Survival in medically treated patients with homozygous beta-thalassemia. , 1994, The New England journal of medicine.

[103]  Y. Schneider,et al.  Mucormycosis during deferoxamine therapy is a siderophore-mediated infection. In vitro and in vivo animal studies. , 1993, The Journal of clinical investigation.

[104]  G. Papa,et al.  Incidence and clinical study of ectopic erythropoiesis in adult patients with thalassemia intermedia. , 1992, Annali italiani di medicina interna : organo ufficiale della Societa italiana di medicina interna.

[105]  G. Koren,et al.  Reduction of tissue iron stores and normalization of serum ferritin during treatment with the oral iron chelator L1 in thalassemia intermedia. , 1992, Blood.

[106]  P. Giardina,et al.  Deferoxamine-induced bone dysplasia in patients with thalassemia major. , 1991, AJR. American journal of roentgenology.

[107]  A. Piga,et al.  SURVIVAL AND CAUSES OF DEATH IN THALASSAEMIA MAJOR , 1989, The Lancet.

[108]  MARROW TRANSPLANTATION FOR THALASSAEMIA , 1987, The Lancet.

[109]  M. Cazzola,et al.  Evaluation of erythroid marrow function in anemic patients. , 1987, Haematologica.

[110]  M. Cazzola,et al.  Erythroid marrow function in anemic patients. , 1987, Blood.

[111]  S. De Virgiliis,et al.  Iron overload and desferrioxamine chelation therapy in beta-thalassemia intermedia. , 1981, European journal of pediatrics.

[112]  Classification and Diagnosis of Diabetes Mellitus and Other Categories of Glucose Intolerance , 1979, Diabetes.