Drug safety in thalassemia: lessons from the present and directions for the future

References

• Origa R. Beta-thalassemia. Genet Med. 2017 Jun;19(6):609–619.
   PubMed Web of Science ®Google Scholar
• De Sanctis V, Kattamis C, Canatan D, et al. Beta-thalassemia distribution in the old world: an ancient disease seen from a historical standpoint. Mediterr J Hematol Infect Dis. 2017 Feb 20;9(1):e2017018.
   PubMedGoogle Scholar
• Weatherall DJ. The inherited diseases of hemoglobin are an emerging global health burden. Blood. 2010 Jun 3;115(22):4331–4336.
   PubMed Web of Science ®Google Scholar
• Galanello R, Origa R. Beta-thalassemia. Orphanet J Rare Dis. 2010 May 21;5:11. 1172-5-11
   PubMed Web of Science ®Google Scholar
• Sleiman J, Tarhini A, Bou-Fakhredin R, et al. Non-transfusion-dependent thalassemia: an update on complications and management. Int J Mol Sci. 2018 Jan 8;19(1):182.
   PubMed Web of Science ®Google Scholar
• Galanello R, Melis MA, Ruggeri R, et al. Beta 0 thalassemia trait in sardinia. Hemoglobin. 1979;3(1):33–46.
   PubMed Web of Science ®Google Scholar
• Cappellini MD, Viprakasit V, Taher AT. An overview of current treatment strategies for β-thalassemia. Expert Opin Orphan Drugs. 2014;2(7):665–679.
   Web of Science ®Google Scholar
• Taher A, Vichinsky E, Mussallam K, et al. editors. Guidelines for the management of non transfusion dependent thalassaemia (NTDT). 3rd. Nicosia (Cyprus): Thalassaemia International Federation, 2013.
   Google Scholar
• Zurlo MG, De Stefano P, Borgna-Pignatti C, et al. Survival and causes of death in thalassaemia major. Lancet. 1989 Jul 1;2(8653):27–30.
   PubMed Web of Science ®Google Scholar
• Cappelini MD, Porter JB, El-Beshlawy A. Tailoring iron chelation by iron intake and serum ferritin: the prospective EPIC study of deferasirox in 1744 patients with transfusion-dependent anemias. Haematologica. 2010;95(4):557–566.
   PubMed Web of Science ®Google Scholar
• Angelucci E, Brittenham GM, McLaren CE, et al. Hepatic iron concentration and total body iron stores in thalassemia major. N Engl J Med. 2000 Aug 3;343(5):327–331.
   PubMed Web of Science ®Google Scholar
• Cappellini MD, Motta I. New therapeutic targets in transfusion-dependent and -independent thalassemia. Hematology Am Soc Hematol Educ Program. 2017 Dec 8;2017(1):278–283.
   PubMedGoogle Scholar
• Lee SJ, Klein JP, Barrett AJ, et al. Severity of chronic graft-versus-host disease: association with treatment-related mortality and relapse. Blood. 2002 Jul 15;100(2):406–414.
   PubMed Web of Science ®Google Scholar
• Lucarelli G, Isgro A, Sodani P, et al. Hematopoietic stem cell transplantation in thalassemia and sickle cell anemia. Cold Spring Harb Perspect Med. 2012 May;2(5):a011825.
   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 Feb;103(2):e46–9.
   PubMed Web of Science ®Google 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 Apr;20(4):408–414.
   PubMed Web of Science ®Google Scholar
• Verma A, Suragani RN, Aluri S, et al. Biological basis for efficacy of activin receptor ligand traps in myelodysplastic syndromes. J Clin Invest. 2020 Feb 3;130(2):582–589.
   PubMed Web of Science ®Google Scholar
• Casu C, Nemeth E, Rivella S. Hepcidin agonists as therapeutic tools. Blood. 2018 Apr 19;131(16):1790–1794.
   PubMed Web of Science ®Google Scholar
• Casu C, Chessa R, Liu A, et al. Minihepcidins improve ineffective erythropoiesis and splenomegaly in a new mouse model of adult beta-thalassemia major. Haematologica. 2020 Jul;105(7):1835–1844.
   PubMed Web of Science ®Google Scholar
• Rs SMITH. Iron excretion in thalassaemia major after administration of chelating agents. Br Med J. 1962 Dec 15;2(5319):1577–1580.
   PubMedGoogle Scholar
• Desferal® [Internet]. 2019 [ updated 3rd July; cited 2020 Oct 20th]. Available from: https://www.novartis.us/sites/www.novartis.us/files/desferal.pdf
   Google Scholar
• Porter J, Viprakasit V, Kattamis A. Iron overload and chelation. In: Cappellini MD, Cohen A, Porter J, et al., editors. Guidelines for the Management of Transfusion Dependent Thalassaemia (TDT). 3rd ed. Nicosia (CY): Thalassaemia International Federation; 2014.
   Google Scholar
• Brill PW, Winchester P, Giardina PJ, et al. Deferoxamine-induced bone dysplasia in patients with thalassemia major. AJR Am J Roentgenol. 1991 Mar;156(3):561–565.
   PubMed Web of Science ®Google Scholar
• Cohen A, Martin M, Mizanin J, et al. Vision and hearing during deferoxamine therapy. J Pediatr. 1990 Aug;117(2 Pt 1):326–330.
   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 Feb 15;95(4):1229–1236.
   PubMed Web of Science ®Google Scholar
• Warren JJ. Why deferoxamine therapy predisposes to Yersinia sepsis. Acta Haematol. 1987;77(3):191.
   PubMed Web of Science ®Google Scholar
• Green NS. Yersinia infections in patients with homozygous beta-thalassemia associated with iron overload and its treatment. Pediatr Hematol Oncol. 1992 Jul-Sep;9(3):247–254.
   PubMed Web of Science ®Google Scholar
• Ferriprox [Internet]. [ cited 2020 Oct 18]. Available from: https://www.ema.europa.eu/en/documents/product-information/ferriprox-epar-product-information_en.pdf
   Google Scholar
• Savulescu J. Thalassaemia major: the murky story of deferiprone. BMJ. 2004 Feb 14;328(7436):358–359.
   PubMedGoogle Scholar
• Ceci A, Baiardi P, Felisi M, et al. The safety and effectiveness of deferiprone in a large-scale, 3-year study in Italian patients. Br J Haematol. 2002 Jul;118(1):330–336.
   PubMed Web of Science ®Google Scholar
• Cohen AR, Galanello R, Piga A, et al. Safety and effectiveness of long-term therapy with the oral iron chelator deferiprone. Blood. 2003 Sep 1;102(5):1583–1587.
   PubMed Web of Science ®Google Scholar
• Hoffbrand AV, Cohen A, Hershko C. Role of deferiprone in chelation therapy for transfusional iron overload. Blood. 2003 Jul 1;102(1):17–24.
   PubMed Web of Science ®Google Scholar
• Anderson LJ, Wonke B, Prescott E, et al. Comparison of effects of oral deferiprone and subcutaneous desferrioxamine on myocardial iron concentrations and ventricular function in beta-thalassaemia. Lancet. 2002 Aug 17;360(9332):516–520.
   PubMed Web of Science ®Google Scholar
• Moukalled NM, Bou-Fakhredin R, Taher AT. Deferasirox: over a decade of experience in thalassemia. Mediterr J Hematol Infect Dis. 2018 Nov 1;10(1):e2018066.
   PubMedGoogle Scholar
• Origa R, Zappu A, Foschini ML, et al. Deferasirox and children: from clinical trials to the real world. Am J Hematol. 2016 Jun;91(6):E304–5.
   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 Mar 21;133(12):1279–1289.
   PubMed Web of Science ®Google Scholar
• Motta I, Bou-Fakhredin R, Taher AT, et al. Beta thalassemia: new therapeutic options beyond transfusion and iron chelation. Drugs. 2020 Jul;80(11):1053–1063.
   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 Mar 26;382(13):1219–1231.
   PubMed Web of Science ®Google Scholar
• Bradai M, Pissard S, Abad MT, et al. Decreased transfusion needs associated with hydroxyurea therapy in Algerian patients with thalassemia major or intermedia. Transfusion. 2007 Oct;47(10):1830–1836.
   PubMed Web of Science ®Google Scholar
• Taher A, Sheikh-Taha M. Hydroxyurea use in Lebanese patients with beta-thalassemia intermedia. J Pediatr Hematol Oncol. 2006 Feb;28(2):107.
   PubMed Web of Science ®Google Scholar
• Keikhaei B, Yousefi H, Bahadoram M. Clinical and haematological effects of hydroxyurea in beta-thalassemia intermedia patients. J Clin Diagn Res. 2015 Oct;9(10):OM01–3.
   PubMedGoogle Scholar
• Algiraigri AH, Wright NAM, Paolucci EO, et al. Hydroxyurea for nontransfusion-dependent beta-thalassemia: a systematic review and meta-analysis. Hematol Oncol Stem Cell Ther. 2017 Sep;10(3):116–125.
   PubMedGoogle Scholar
• Yassin AK. Promising response to thalidomide in symptomatic beta-thalassemia. Indian J Hematol Blood Transfus. 2020 Apr;36(2):337–341.
   PubMed Web of Science ®Google Scholar
• Yang K, Wu Y, Zhou Y, et al. Thalidomide for patients with beta-thalassemia: a multicenter experience. Mediterr J Hematol Infect Dis. 2020 May 1;12(1):e2020021.
   PubMedGoogle Scholar
• Ren Q, Zhou YL, Wang L, et al. Clinical trial on the effects of thalidomide on hemoglobin synthesis in patients with moderate thalassemia intermedia. Ann Hematol. 2018 Oct;97(10):1933–1939.
   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 Mar;104(3):477–484.
   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 Jan 11;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 Dec 9;130(1):491–506.
   PubMed Web of Science ®Google Scholar
• Richard F, Van Lier JJ, Roubert B, et al. Oral ferroportin inhibitor VIT-2763: first-in-human, phase 1 study in healthy volunteers. Am J Hematol. 2020 Jan;95(1):68–77.
   PubMed Web of Science ®Google Scholar
• Umscheid CA, Margolis D, Grossman CE. Key concepts of clinical trials: a narrative review. Postgrad Med. 2011;123(5):194–204.
   PubMed Web of Science ®Google Scholar
• Edwards IR, Biriell C. Harmonisation in pharmacovigilance. Drug Saf. 1994 Feb;10(2):93–102.
   PubMedGoogle Scholar
• Piga A, Galanello R, Forni GL, et al. Randomized phase II trial of deferasirox (exjade, ICL670), a once-daily, orally-administered iron chelator, in comparison to deferoxamine in thalassemia patients with transfusional iron overload. Haematologica. 2006 Jul;91(7):873–880.
   PubMed Web of Science ®Google Scholar
• Galanello R, Piga A, Forni GL, et al. Phase II clinical evaluation of deferasirox, a once-daily oral chelating agent, in pediatric patients with beta-thalassemia major. Haematologica. 2006 Oct;91(10):1343–1351.
   PubMed Web of Science ®Google Scholar
• Dee CM, Cheuk DK, Ha SY, et al. Incidence of deferasirox-associated renal tubular dysfunction in children and young adults with beta-thalassaemia. Br J Haematol. 2014 Nov;167(3):434–436.
   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 Jul 28;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 Dec;147(5):752–759.
   PubMed Web of Science ®Google Scholar
• Piga A, Roggero S, Salussolia I, et al. Deferiprone. Ann N Y Acad Sci. 2010 Aug;1202:75–78.
   PubMed Web of Science ®Google Scholar
• Cohen A, Galanello R, Piga A, et al. A multi-center safety trial of the oral iron chelator deferiprone. Ann N Y Acad Sci. 1998 Jun;30(850):223–226.
   Google Scholar
• Taher A, Sheikh-Taha M, Sharara A, et al. Safety and effectiveness of 100 mg/kg/day deferiprone in patients with thalassemia major: a two-year study. Acta Haematol. 2005;114(3):146–149.
   PubMed Web of Science ®Google Scholar
• Maggio A, Kattamis A, Felisi M, et al. Evaluation of the efficacy and safety of deferiprone compared with deferasirox in paediatric patients with transfusion-dependent haemoglobinopathies (DEEP-2): a multicentre, randomised, open-label, non-inferiority, phase 3 trial. Lancet Haematol. 2020 Jun;7(6):e469–78.
   PubMed Web of Science ®Google Scholar
• Hassan MA, Tolba OA. Iron chelation monotherapy in transfusion-dependent beta-thalassemia major patients: a comparative study of deferasirox and deferoxamine. Electron Physician. 2016 May 25;8(5):2425–2431.
   PubMedGoogle Scholar
• Phillips R, Hazell L, Sauzet O, et al. Analysis and reporting of adverse events in randomised controlled trials: a review. BMJ. 2019;9:e024537.
   PubMedGoogle Scholar
• Trifiro G, Gini R, Barone-Adesi F, et al. The role of European healthcare databases for post-marketing drug effectiveness, safety and value evaluation: where does Italy stand? Drug Saf. 2019 Mar;42(3):347–363.
   PubMed Web of Science ®Google Scholar
• Osborne V, Davies M, Layton D, et al. Utilisation and safety of deferasirox: results from an observational cohort study in england. Drug Saf. 2018 Mar;41(3):267–275.
   PubMed Web of Science ®Google Scholar
• Cassinerio E, Roghi A, Orofino N, et al. A 5-year follow-up in deferasirox treatment: improvement of cardiac and hepatic iron overload and amelioration in cardiac function in thalassemia major patients. Ann Hematol. 2015 Jun;94(6):939–945.
   PubMed Web of Science ®Google Scholar
• Vichinsky E, El-Beshlawy A, Al Zoebie A, et al. Long-term safety and efficacy of deferasirox in young pediatric patients with transfusional hemosiderosis: results from a 5-year observational study (ENTRUST). Pediatr Blood Cancer. 2017 Sep;64(9). Epub 2017 Mar 10. DOI:https://doi.org/10.1002/pbc.26507.
   Google Scholar
• Botzenhardt S, Felisi M, Bonifazi D, et al. Long-term safety of deferiprone treatment in children from the Mediterranean region with beta-thalassemia major: the DEEP-3 multi-center observational safety study. Haematologica. 2018 Jan;103(1):e1–4.
   PubMed Web of Science ®Google Scholar
• Nichols-Vinueza DX, White MT, Powell AJ, et al. MRI guided iron assessment and oral chelator use improve iron status in thalassemia major patients. Am J Hematol. 2014 Jul;89(7):684–688.
   PubMed Web of Science ®Google Scholar
• Parakh N, Chandra J, Sharma S, et al. Efficacy and safety of combined oral chelation with deferiprone and deferasirox in children with beta-thalassemia major: an experience from north india. J Pediatr Hematol Oncol. 2017 Apr;39(3):209–213.
   PubMed Web of Science ®Google Scholar
• Totadri S, Bansal D, Bhatia P, et al. The deferiprone and deferasirox combination is efficacious in iron overloaded patients with β-thalassemia major: a prospective, single center, open-label study. Pediatr Blood Cancer. 2015;62(9):1592–1596.
   PubMed Web of Science ®Google Scholar
• Antmen B, Karakas Z, Yesilipek MA, et al. Deferasirox in children with transfusion-dependent thalassemia or sickle cell anemia: a large cohort real-life experience from Turkey (REACH-THEM). Eur J Haematol. 2019 Feb;102(2):123–130.
   PubMed Web of Science ®Google Scholar
• Nolte F, Nuckel H, Schmidt B, et al. Tolerability and efficacy of deferasirox in patients with transfusional iron overload: results from a German 2-year non-interventional study. J Cancer Res Clin Oncol. 2018 Aug;144(8):1531–1538.
   PubMed Web of Science ®Google Scholar
• Olivieri NF, Sabouhanian A, Gallie BL. Single-center retrospective study of the effectiveness and toxicity of the oral iron chelating drugs deferiprone and deferasirox. PLoS One. 2019 Feb 27;14(2):e0211942.
   PubMed Web of Science ®Google Scholar
• Thakor DR, Desai CK, Kapadia JD, et al. Efficacy and safety of deferasirox in pediatric patients of thalassemia at a tertiary care teaching hospital. Indian J Med Paediatr Oncol. 2017 Apr-Jun;38(2):103–110.
   PubMed Web of Science ®Google Scholar
• Sultana J, Trifiro G. The potential role of big data in the detection of adverse drug reactions. Expert Rev Clin Pharmacol. 2020 Mar;13(3):201–204.
   PubMed Web of Science ®Google Scholar
• Sultana J, Azzopardi-Muscat N, Coleiro B, et al. Pharmacological therapy in a rare disease: challenges in the long-term management of granulomatosis with polyangiitis. Expert Opin Orphan Drugs. 2017;7(12):521–523.
   Web of Science ®Google Scholar
• Crisafulli S, Sultana J, Ingrasciotta Y, et al. Role of healthcare databases and registries for surveillance of orphan drugs in the real-world setting: the Italian case study. Expert Opin Drug Saf. 2019 Jun;18(6):497–509.
   PubMed Web of Science ®Google Scholar
• Gini R, Sturkenboom MCJ, Sultana J, et al. Working group 3 of ENCePP (inventory of EU data sources and methodological approaches for multisource studies) different strategies to execute multi-database studies for medicines surveillance in real-world setting: a reflection on the European model. Clin Pharmacol Ther. 2020;108(2):228–235.
   PubMedGoogle Scholar
• Scerri J, Churchill J, Banks D. ChurchillD - division of nursing, school of health sciences, Queen Margaret University, Edinburgh, Queen’s Nurse,(Scotland)., Banks D, Sultana J. Advocating a person-centered care approach to drug safety. Expert Opin Drug Saf. 2021 Mar;20(3):255–258.
   PubMed Web of Science ®Google Scholar
• 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 May;8(5):CD012349.
   Google Scholar
• Taher AT, Origa R, Perrotta S, et al. Influence of patient-reported outcomes on the treatment effect of deferasirox film-coated and dispersible tablet formulations in the ECLIPSE trial: a post hoc mediation analysis. Am J Hematol. 2019 Apr;94(4):E96–9.
   PubMed Web of Science ®Google Scholar