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Eltrombopag in Immune Thrombocytopenia, Aplastic Anemia, and Myelodysplastic Syndrome: From Megakaryopoiesis to Immunomodulation

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Abstract

Eltrombopag is an orally available thrombopoietin receptor agonist indicated for the treatment of immune thrombocytopenia (ITP). Beyond the effect on megakaryopoiesis, the drug also showed a stimulating effect on the hematopoietic stem cell with consistent clinical efficacy in aplastic anemia (AA) and myelodysplastic syndromes (MDS). Eltrombopag is highly effective in ITP and less so in AA and MDS. This observation underlines the importance of residual normal hematopoiesis, which is maximal in ITP, minimal/absent in AA, and dysregulated in MDS. In ITP, the drug at 50–75 mg daily induced up to 85% responses both in clinical trials and real-life studies, with the possibility of tapering and discontinuation. In AA, eltrombopag at 150 mg daily was effective in about 40% of cases relapsed/refractory to standard immunosuppression or ineligible for bone marrow transplant. In MDS, the drug seems less effective, with responses in about a quarter of patients at various schedules. The efficacy of eltrombopag in ITP, AA, and MDS suggests the existence of common immune-pathological mechanisms in these diseases, including autoimmunity against peripheral blood cells and bone marrow precursors, as well as a possible evolution of one condition into the other. Additional mechanisms of action emerging from the clinical use of eltrombopag include modulation of T-regulatory cells, restoration of Fc-γ receptor balance in phagocytes, and an iron-mobilizing effect. In this review, we analyzed the most recent literature on eltrombopag use and efficacy in patients with ITP, AA, and MDS, exploring the basis for different dosing, combined treatments, and discontinuation in each context.

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References

  1. Gonzalez-Porras JR, Bastida JM, et al. Eltrombopag in immune thrombocytopenia: efficacy review and update on drug safety. Ther Adv Drug Saf. 2018;9:263–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Gill H, Wong RSM, et al. From chronic immune thrombocytopenia to severe aplastic anemia: recent insights into the evolution of eltrombopag. Ther Adv Hematol. 2017;8:159–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Svensson T, Chowdhury O, et al. A pilot phase I dose finding safety study of the thrombopoietin-receptor agonist, eltrombopag, in patients with myelodysplastic syndrome treated with azacitidine. Eur J Haematol. 2014;93:439–45.

    CAS  PubMed  Google Scholar 

  4. Swaminathan M, Borthakur G, et al. A phase 2 clinical trial of eltrombopag for treatment of patients with myelodysplastic syndromes after hypomethylating-agent failure. Leuk Lymphoma. 2019;18:1–7.

    Google Scholar 

  5. Erickson-Miller CL, DeLorme E, Tian SS, et al. Discovery and characterization of a selective, nonpeptidyl thrombopoietin receptor agonist. Exp Hematol. 2005;33:85–93.

    CAS  PubMed  Google Scholar 

  6. Barcellini W. The relationship between idiopathic cytopenias/dysplasias of uncertain significance (ICUS/IDUS) and autoimmunity. Expert Rev Hematol. 2017;10:649–57.

    CAS  PubMed  Google Scholar 

  7. Barcellini W, Fattizzo B, et al. Clinical evolution of autoimmune cytopenias to idiopathic cytopenias/ dysplasias of uncertain significance (ICUS/IDUS) and bone marrow failure syndromes. Am J Hematol. 2017;92:E26–9.

    PubMed  Google Scholar 

  8. Olnes MJ, Scheinberg P, Calvo KR, et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med. 2012;367:11–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. US FDA. Promacta (eltrombopag) tablets: US prescribing information. 2014. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022291s012lbl.pdf. Accessed Jan 2019.

  10. Wire MB, Bruce J, Gauvin J, et al. A randomized, open-label, 5-period, balanced crossover study to evaluate the relative bioavailability of eltrombopag powder for oral suspension (PfOS) and tablet formulations and the effect of a high-calcium meal on eltrombopag pharmacokinetics when administered with or 2 hours before or after PfOS. Clin Ther. 2012;34:699–709.

    CAS  PubMed  Google Scholar 

  11. Deng Y, Madatian A, Wire MB, et al. Metabolism and disposition of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist, in healthy human subjects. Drug Metab Dispos. 2011;39:1734–46.

    CAS  PubMed  Google Scholar 

  12. Allred AJ, Bowen CJ, Park JW, et al. Eltrombopag increases plasma rosuvastatin exposure in healthy volunteers. Br J Clin Pharmacol. 2011;72:321–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Lambert MP, Gernsheimer TB. Clinical updates in adult immune thrombocytopenia. Blood. 2017;129:2829–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Nieswandt B, Bergmeier W, Rackebrandt K, et al. Identification of critical antigen-specific mechanisms in the development of immune thrombocytopenic purpura in mice. Blood. 2000;96:2520–7.

    CAS  PubMed  Google Scholar 

  15. Chang M, Nakagawa PA, Williams SA, et al. Immune thrombocytopenic purpura (ITP) plasma and purified ITP monoclonal autoantibodies inhibit megakaryocytopoiesis in vitro. Blood. 2003;102:887–95.

    CAS  Google Scholar 

  16. Leytin V, Mykhaylov S, Starkey AF, et al. Intravenous immunoglobulin inhibits antiglycoprotein IIb-induced platelet apoptosis in a murine model of immune thrombocytopenia. Br J Haematol. 2006;133:78–82.

    CAS  PubMed  Google Scholar 

  17. Sandler SG. Review: immune thrombocytopenic purpura: an update for immunohematologists. Immunohematology. 2004;20:112–7.

    CAS  PubMed  Google Scholar 

  18. Kuwana M, Okazaki Y, Ikeda Y. Splenic macrophages maintain the anti- platelet autoimmune response via uptake of opsonized platelets in patients with immune thrombocytopenic purpura. J Thromb Haemost. 2009;7:322–9.

    CAS  PubMed  Google Scholar 

  19. Qiu J, Liu X, Li X, et al. CD8(+) T cells induce platelet clearance in the liver via platelet desialylation in immune thrombocytopenia. Sci Rep. 2016;6:27445.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Mithoowani S, Gregory-Miller K, Goy J, et al. High-dose dexamethasone compared with prednisone for previously untreated primary immune thrombocytopenia: a systematic review and meta-analysis. Lancet Haematol. 2016;3:e489–96.

    PubMed  Google Scholar 

  21. Wei Y, Ji XB, Wang YW, et al. High-dose dexamethasone vs prednisone for treatment of adult immune thrombocytopenia: a prospective multicenter randomized trial. Blood. 2016;127:296–302.

    CAS  PubMed  Google Scholar 

  22. Bae SH, Ryoo H, Lee WS, Joo YD, Lee KH, Lee J, et al. High dose dexamethasone vs. conventional dose prednisolone for adults with immune thrombocytopenia: a prospective multicenter phase III trial. Blood. 2010;116:3687.

    Google Scholar 

  23. Godeau B, Caulier MT, Decuypere L, et al. Intravenous immunoglobulin for adults with autoimmune thrombocytopenic purpura: results of a randomized trial comparing 0.5 and 1 g/kg b.w. Br J Haematol. 1999;107:716–9.

    CAS  PubMed  Google Scholar 

  24. Zaja F, Baccarani M, Mazza P, et al. Dexamethasone plus rituximab yields higher sustained response rates than dexamethasone monotherapy in adults with primary immune thrombocytopenia. Blood. 2010;115:2755–62.

    CAS  PubMed  Google Scholar 

  25. Mikhael J, Northridge K, Lindquist K, et al. Short-term and long-term failure of laparoscopic splenectomy in adult immune thrombocytopenic purpura patients: a systematic review. Am J Hematol. 2009;84:743–8.

    PubMed  Google Scholar 

  26. Steurer M, Quittet P, Papadaki HA, et al. A large observational study of patients with primary immune thrombocytopenia receiving romiplostim in European clinical practice. Eur J Haematol. 2017;98:112–20.

    CAS  PubMed  Google Scholar 

  27. Gonzalez-Porras JR, Mingot-Castellano ME, Andrade MM, et al. Use of eltrombopag after romiplostim in primary immune thrombocytopenia. Br J Haematol. 2015;169:111–6.

    CAS  PubMed  Google Scholar 

  28. George JN, Mathias SD, Go RS, et al. Improved quality of life for romiplostim-treated patients with chronic immune thrombocytopenic purpura: results from two randomized, placebo-controlled trials. Br J Haematol. 2009;144:409–15.

    CAS  PubMed  Google Scholar 

  29. Bussel JB, Cheng G, Saleh MN, et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 2007;357:2237–47.

    CAS  PubMed  Google Scholar 

  30. Bussel J, Provan D, Shamsi T, et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;373:641–8.

    CAS  PubMed  Google Scholar 

  31. Cheng G, Saleh MN, Marcher C, et al. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet. 2011;377:393–402.

    CAS  PubMed  Google Scholar 

  32. Bussel JB, Saleh MN, Vasey SY, et al. Repeated short-term use of eltrombopag in patients with chronic immune thrombocytopenia (ITP). Br J Haematol. 2013;160:538–46.

    CAS  PubMed  Google Scholar 

  33. Saleh MN, Bussel JB, Cheng G, EXTEND Study Group, et al. Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study. Blood. 2013;121:537–45.

    CAS  PubMed  Google Scholar 

  34. Ghanima W, Cooper N, Rodeghiero F, Godeau B, Bussel JB. Thrombopoietin receptor agonists: ten years later. Haematologica. 2019;104:1112–23.

    PubMed  PubMed Central  Google Scholar 

  35. Wong RSM, Saleh MN, Khelif A, et al. Safety and efficacy of long-term treatment of chronic/persistent ITP with eltrombopag: final results of the EXTEND study. Blood. 2017;130:2527–36.

    CAS  PubMed  Google Scholar 

  36. Saleh MN, Bussel JB, Khelif A, et al. Improvements in patient health-related quality of life (HRQoL) with clinical efficacy in patients treated with eltrombopag: final results from the long-term, open-label extend study. Blood. 2016;128:3742.

    Google Scholar 

  37. Khelif A, Saleh MN, Salama A, et al. Changes in health-related quality of life with long-term eltrombopag treatment in adults with persistent/chronic immune thrombocytopenia: findings from the EXTEND study. Am J Hematol. 2019;94:200–8.

    CAS  PubMed  Google Scholar 

  38. Tripathi AK, Shukla A, Mishra S, et al. Eltrombopag therapy in newly diagnosed steroid non-responsive ITP patients. Int J Hematol. 2014;99:413–7.

    CAS  PubMed  Google Scholar 

  39. Gómez-Almaguer D, Herrera-Rojas MA, Jaime-Pérez JC, et al. Eltrombopag and high-dose dexamethasone as frontline treatment of newly diagnosed immune thrombocytopenia in adults. Blood. 2014;123:3906–8.

    PubMed  Google Scholar 

  40. Bussel J, De Miguel P, Despotovic J, et al. Eltrombopag for the treatment of children with Persistent and Chronic Immune Thrombocytopenia (PETIT): a randomised, multicentre, placebo-controlled study. Lancet Haematol. 2015;2:e315–25.

    PubMed  Google Scholar 

  41. Grainger JD, Locatelli F, Chotsampancharoen T, et al. Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial. Lancet. 2015;386:1649–58.

    CAS  PubMed  Google Scholar 

  42. Kim TO, Despotovic J, Lambert MP. Eltrombopag for use in children with immune thrombocytopenia. Blood Adv. 2018;2:454–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Tumaini Massaro J, Chen Y, Ke Z. Efficacy and safety of thrombopoietin receptor agonists in children with chronic immune thrombocytopenic purpura: meta-analysis. Platelets. 2019;27:1–8.

    Google Scholar 

  44. González-López TJ, Alvarez-Román MT, Pascual C, et al. Eltrombopag safety and efficacy for primary chronic immune thrombocytopenia in clinical practice. Eur J Haematol. 2016;97:297–302.

    PubMed  Google Scholar 

  45. Depre F, Aboud N, Mayer B, et al. Efficacy and tolerability of old and new drugs used in the treatment of immune thrombocytopenia: results from a long-term observation in clinical practice. PLoS One. 2018;13:e0198184.

    PubMed  PubMed Central  Google Scholar 

  46. Mazza P, Minoia C, Melpignano A, et al. The use of thrombopoietin-receptor agonists (TPO-RAs) in immune thrombocytopenia (ITP): a “real life” retrospective multicenter experience of the Rete Ematologica Pugliese (REP). Ann Hematol. 2016;95:239–44.

    CAS  PubMed  Google Scholar 

  47. Eser A, Toptas T, Kara O, et al. Efficacy and safety of eltrombopag in treatment-refractory primary immune thrombocytopenia: a retrospective study. Blood Coagul Fibrinolysis. 2016;27:47–52.

    CAS  PubMed  Google Scholar 

  48. Mingot-Castellano ME, Caparrós IS, Fernández F, et al. Treatment characteristics, efficacy and safety of thrombopoietin analogues in routine management of primary immune thrombocytopenia. Blood Coagul Fibrinolysis. 2018;29:374–80.

    CAS  PubMed  Google Scholar 

  49. Arai Y, Matsui H, Jo T, et al. Comparison of treatments for persistent/chronic immune thrombocytopenia: a systematic review and network meta-analysis. Platelets. 2018;3:1–11.

    Google Scholar 

  50. González-López TJ, Pascual C, Álvarez-Román MT, et al. Successful discontinuation of eltrombopag after complete remission in patients with primary immune thrombocytopenia. Am J Hematol. 2015;90:E40–3.

    Google Scholar 

  51. Mahévas M, Fain O, Ebbo M, et al. The temporary use of thrombopoietin-receptor agonists may induce a prolonged remission in adult chronic immune thrombocytopenia. Results of a French observational study. Br J Haematol. 2014;165:865–9.

    PubMed  Google Scholar 

  52. Al-Samkari H, Kuter DJ. An alternative intermittent eltrombopag dosing protocol for the treatment of chronic immune thrombocytopenia. Br J Clin Pharmacol. 2018;84:2673–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. González-López TJ, Fernández-Fuertes F, Hernández-Rivas JA, et al. Efficacy and safety of eltrombopag in persistent and newly diagnosed ITP in clinical practice. Int J Hematol. 2017;106:508–16.

    PubMed  Google Scholar 

  54. Uto Y, Fujiwara S, Arai N, et al. Age and bone marrow cellularity are associated with response to eltrombopag in Japanese Adult Immune Thrombocytopenia patients: a retrospective single-center study. Rinsho Byori. 2015;63:548–56.

    CAS  PubMed  Google Scholar 

  55. Al-Samkari H, Kuter DJ, et al. Thrombopoietin level predicts response to treatment with eltrombopag and romiplostim in immune thrombocytopenia. Am J Hematol. 2018;93:1501–8.

    CAS  PubMed  Google Scholar 

  56. Fattizzo B, Pasquale R, Carpenedo M, et al. Bone marrow characteristics predict outcome in a multicenter cohort of primary immune thrombocytopenia patients treated with thrombopoietin analogues. Haematologica. 2019. https://doi.org/10.3324/haematol.2019.216804.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Bacigalupo A. How I treat acquired aplastic anemia. Blood. 2017;129:1428–36.

    CAS  PubMed  Google Scholar 

  58. Camitta BM, Rappeport JM, Parkman R, et al. Selection of patients for bone marrow transplantation in severe aplastic anemia. Blood. 1975;45:355–63.

    CAS  PubMed  Google Scholar 

  59. Wang Y. Telomere length, expression of MRE11 and Ku80 in patients with aplastic anemia and their correlation with pathogenesis. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2017;25:503–9.

    PubMed  Google Scholar 

  60. Killick SB, Bown N, Cavenagh J, et al. British Society for Standards in Haematology. Guidelines for the diagnosis and management of adult aplastic anaemia. Br J Haematol. 2016;172:187–207.

    PubMed  Google Scholar 

  61. Scheinberg P, Nunez O, Weinstein B, et al. Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med. 2011;365:430–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Calado RT, Yewdell WT, Wilkerson KL, et al. Sex hormones, acting on the TERT gene, increase telomerase activity in human primary hematopoietic cells. Blood. 2009;114:2236–43.

    CAS  PubMed Central  Google Scholar 

  63. Townsley DM, Dumitriu B, Liu D, et al. Danazol treatment for telomere diseases. N Engl J Med. 2016;374:1922–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Bacigalupo A, Chaple M, Hows J, et al. Treatment of aplastic anemia (AA) with antilymphocyte globulin (ALG) and methylprednisolone (MPred) with or without androgens: a randomized trial from the EBMT SAA working party. Br J Haematol. 1993;83:145–51.

    CAS  PubMed  Google Scholar 

  65. Desmond R, Townsley DM, Dumitriu B, et al. Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Blood. 2014;123:1818–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Townsley DM, Scheinberg P, Winkler T, et al. Eltrombopag added to standard immunosuppression for aplastic anemia. N Engl J Med. 2017;376:1540–50.

    CAS  PubMed Central  Google Scholar 

  67. Winkler T, Fan X, Cooper J, et al. Treatment optimization and genomic outcomes in refractory severe aplastic anemia treated with eltrombopag. Blood. 2019;133(24):2575–85.

    CAS  PubMed  Google Scholar 

  68. Ecsedi M, Lengline É, Knol-Bout C, et al. Use of eltrombopag in aplastic anemia in Europe. Ann Hematol. 2019;98:1341–50.

    PubMed  Google Scholar 

  69. Hwang YY, Gill H, Chan TSY, et al. Eltrombopag in the management of aplastic anaemia: real-world experience in a non-trial setting. Hematology. 2018;23:399–404.

    CAS  PubMed  Google Scholar 

  70. Lengline E, Drenou B, Peterlin P, et al. Nationwide survey on the use of eltrombopag in patients with severe aplastic anemia: a report on behalf of the French Reference Center for Aplastic Anemia. Haematologica. 2018;103:212–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Fattizzo B, Kulasekararaj AG, et al. Clinical and morphologic predictors of outcome in older aplastic anemia patients treated with eltrombopag. Haematologica. 2019. https://doi.org/10.3324/haematol.2019.216374.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Mc Cormack PL. Eltrombopag: a review of its use in patients with severe aplastic anaemia. Drugs. 2015;75:525–31.

    CAS  Google Scholar 

  73. Vaht K, Göransson M, Carlson K, et al. Incidence and outcome of acquired aplastic anemia: real-world data from patients diagnosed in Sweden from 2000–2011. Haematologica. 2017;102:1683–90.

    PubMed  PubMed Central  Google Scholar 

  74. De Planque MM, Bacigalupo A, Wursch A, et al. Long term follow-up of severe aplastic anaemia patients treated with antithymocyte globulin. Br J Haematol. 1989;73:121–6.

    Google Scholar 

  75. Townsley DM, Dumitriu B, Young NS. Bone marrow failure and the telomeropathies. Blood. 2014;124:2775–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Lane AA, Odejide O, Kopp N, et al. Low frequency clonal mutations recoverable by deep sequencing in patients with aplastic anemia. Leukemia. 2013;27:968–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Yoshizato T, Dumitriu B, Hosokawa K, et al. Somatic mutations and clonal hematopoiesis in aplastic anemia. N Engl J Med. 2015;373:35–47.

    CAS  PubMed  Google Scholar 

  78. Kulasekararaj AG, Jiang J, Smith AE, et al. Somatic mutations identify a subgroup of aplastic anemia patients who progress to myelodysplastic syndrome. Blood. 2014;124:2698–704.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Young NS, Abkowitz JL, Luzzatto L. New insights into the pathophysiology of acquired cytopenias. Hematol Am Soc Hematol Educ Progr 2000;18–38.

    Google Scholar 

  80. Fattizzo B, Dunlop A, Ireland R, et al. Clinical significance of PNH clones in 3085 patients with cytopenia: a large single-center experience. Hematologica. 2018. Abstract PF304–215846.

  81. Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120:2454–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Sekeres MA. The epidemiology of myelodysplastic syndromes. Hematol Oncol Clin N Am. 2010;24:287–94.

    Google Scholar 

  83. Parmentier S, Schetelig J, Lorenz K, et al. Assessment of dysplastic hematopoiesis: lessons from healthy bone marrow donors. Haematologica. 2012;97:723–30.

    PubMed  PubMed Central  Google Scholar 

  84. Matsuda A, Germing U, Jinnai I, et al. Improvement of criteria for refractory cytopenia with multilineage dysplasia according to the WHO classification based on prognostic significance of morphological features in patients with refractory anemia according to the FAB classification. Leukemia. 2007;21:6782686.

    Google Scholar 

  85. Bennett JM, Orazi A, et al. Diagnostic criteria to distinguish hypocellular acute myeloid leukemia from hypocellular myelodysplastic sindrome and aplastic anemia: recommendations for a standardized approach. Haematologica. 2009;94:2642268.

    Google Scholar 

  86. Della Porta MG, Gallì A, Bacigalupo A, et al. Clinical effects of driver somatic mutations on the outcomes of patients with myelodysplastic syndromes treated with allogeneic hematopoietic stem-cell transplantation. J Clin Oncol. 2016;34:3627–37.

    PubMed  PubMed Central  Google Scholar 

  87. Santini V, Schemenau J, Levis A, et al. Can the revised IPSS predict response to erythropoietic-stimulating agents in patients with classical IPSS low or intermediate-1 MDS? Blood. 2013;122:2286–8.

    CAS  PubMed  Google Scholar 

  88. Alessandrino EP, Amadori S, Barosi G, et al. Evidence- and consensus-based practice guidelines for the therapy of primary myelodysplastic syndromes. A statement from the Italian Society of Hematology. Haematologica. 2002;87:1286–306.

    PubMed  Google Scholar 

  89. Li W, Morrone K, Kambhampati S, et al. Thrombocytopenia in MDS: epidemiology, mechanisms, clinical consequences and novel therapeutic strategies. Leukemia. 2016;30:536–44.

    CAS  PubMed  Google Scholar 

  90. Sekeres MA, Kantarjian H, Fenaux P, et al. Subcutaneous or intravenous administration of romiplostim in thrombocytopenic patients with lower risk myelodysplastic syndromes. Cancer. 2011;117:992–1000.

    CAS  PubMed  Google Scholar 

  91. Oliva EN, Santini V, Alati C, et al. Quality of life in patients with lower risk myelodysplastic syndromes with severe thrombocytopenia treated with eltrombopag: interim results of a randomized, placebo-controlled prospective trial [abstract]. Haematologica. 2015;100:575.

    Google Scholar 

  92. Kantarjian HM, Giles FJ, Greenberg PL, et al. Phase 2 study of romiplostim in patients with low- or intermediate-risk myelodys-plastic syndrome receiving azacitidine therapy. Blood. 2010;116:3163–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Greenberg PL, Garcia-Manero G, Moore M, et al. A randomized controlled trial of romiplostim in patients with low- or intermediate-risk myelodysplastic syndrome receiving decitabine. Leuk Lymphoma. 2013;54:321–8.

    CAS  PubMed  Google Scholar 

  94. Wang ES, Lyons RM, Larson RA, et al. A randomized, double-blind, placebo-controlled phase 2 study evaluating the efficacy and safety of romiplostim treatment of patients with low or intermediate-1 risk myelodysplastic syndrome receiving lenalidomide. J Hematol Oncol. 2012;5:71.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Mavroudi I, Pyrovolaki K, Pavlaki K, et al. Effect of the nonpeptide thrombopoietin receptor agonist eltrombopag on megakaryopoiesis of patients with lower risk myelodysplastic syndrome. Leuk Res. 2011;35:323–8.

    CAS  PubMed  Google Scholar 

  96. Oliva EN, Alati C, Santini V, et al. Eltrombopag versus placebo for low-risk myelodysplastic syndromes with thrombocytopenia (EQoL-MDS): phase 1 results of a single-blind, randomised, controlled, phase 2 superiority trial. Lancet Haematol. 2017;4:e127–36.

    PubMed  Google Scholar 

  97. Mittelman M, Platzbecker U, Afanasyev B, et al. Eltrombopag for advanced myelodysplastic syndromes or acute myeloid leukaemia and severe thrombocytopenia (ASPIRE): a randomised, placebo-controlled, phase 2 trial. Lancet Haematol. 2018;5:e34–43.

    PubMed  Google Scholar 

  98. Platzbecker U, Wong RS, Verma A, et al. Safety and tolerability of eltrombopag versus placebo for treatment of thrombocytopenia in patients with advanced myelodysplastic syndromes or acute myeloid leukaemia: a multicentre, randomised, placebo-controlled, double-blind, phase 1/2 trial. Lancet Haematol. 2015;2:e417–26.

    PubMed  Google Scholar 

  99. Dickinson M, Cherif H, et al. Azacitidine with or without eltrombopag for first-line treatment of intermediate- or high-risk MDS with thrombocytopenia. Blood. 2018;132:2629–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Sekeres MA, Giagounidis A, Kantarjian H, et al. Development and validation of a model to predict platelet response to romiplostim in patients with lower-risk myelodysplastic syndromes. Br J Haematol. 2014;167:337–45.

    CAS  PubMed  Google Scholar 

  101. Bao W, Bussel JB, Heck S, et al. Improved regulatory T-cell activity in patients with chronic immune thrombocytopenia treated with thrombopoietic agents. Blood. 2010;116:4639–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Liu XG, Liu S, Feng Q, et al. Thrombopoietin receptor agonists shift the balance of Fcγ receptors toward inhibitory receptor IIb on monocytes in ITP. Blood. 2016;128:852–61.

    CAS  Google Scholar 

  103. Roth M, Will B, Simkin G, et al. Eltrombopag inhibits the proliferation of leukemia cells via reduction of intracellular iron and induction of differentiation. Blood. 2012;120:386–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Lambert MP, Witmer CM, Kwiatkowski JL, et al. Therapy induced iron deficiency in children treated with eltrombopag for immune thrombocytopenia. Am J Hematol. 2017;92:E88–91.

    PubMed  Google Scholar 

  105. Bastian TW, Duck KA, Michalopoulos GC, et al. Eltrombopag, a thrombopoietin mimetic, crosses the blood–brain barrier and impairs iron-dependent hippocampal neuron dendrite development. J Thromb Haemost. 2017;15:565–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Pecci A, Gresele P, Klersy C, et al. Eltrombopag for the treatment of the inherited thrombocytopenia deriving from MYH9 mutations. Blood. 2010;116:5832–7.

    CAS  PubMed  Google Scholar 

  107. Fiore M, Saut N, Alessi MC, et al. Successful use of eltrombopag for surgical preparation in a patient with ANKRD26-related thrombocytopenia. Platelets. 2016;27:828–9.

    CAS  PubMed  Google Scholar 

  108. Gerrits AJ, Leven EA, Frelinger AL 3rd, et al. Effects of eltrombopag on platelet count and platelet activation in Wiskott–Aldrich syndrome/X-linked thrombocytopenia. Blood. 2015;126:1367–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Vlachodimitropoulou E, Chen YL, Garbowski M, et al. Eltrombopag: a powerful chelator of cellular or extracellular iron(III) alone or combined with a second chelator. Blood. 2017;130:1923–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Punzo F, Tortora C, Argenziano M, et al. Iron chelating properties of Eltrombopag: investigating its role in thalassemia-induced osteoporosis. PLoS One. 2018;13:e0208102.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Zhao Z, Sun Q, Sokoll LJ, et al. Eltrombopag mobilizes iron in patients with aplastic anemia. Blood. 2018;131:2399–402.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Fattizzo B, Cavallaro F, Milesi G, Barcellini W. Iron mobilization in a real life cohort of aplastic anemia patients treated with eltrombopag. Am J Hematol. 2019. https://doi.org/10.1002/ajh.25550[Epub ahead of print].

    Article  PubMed  Google Scholar 

  113. Caillon H, Peterlin P, Chevallier P, et al. Eltrombopag induces major non-toxic hypersiderraemia. Br J Haematol. 2019. https://doi.org/10.1111/bjh.15863[Epub ahead of print].

    Article  PubMed  Google Scholar 

  114. Kao JK, Wang SC, Ho LW, et al. Chronic iron overload results in impaired bacterial killing of THP-1 derived macrophage through the inhibition of lysosomal acidification. PLoS One. 2016;31(11):e0156713.

    Google Scholar 

  115. Weiss G. Iron and immunity: a double-edged sword. Eur J Clin Investig. 2002;32(Suppl 1):70–8.

    CAS  Google Scholar 

  116. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405.

    CAS  PubMed  Google Scholar 

  117. Malcovati L, Cazzola M. The shadowlands of MDS: idiopathic cytopenias of undetermined significance (ICUS) and clonal hematopoiesis of indeterminate potential (CHIP). Hematol Am Soc Hematol Educ Progr. 2015;2015:299–307.

    Google Scholar 

  118. Rafferty M, Leach M. Hypomegakaryocytic thrombocytopenia and increased number of PNH-phenotype cells—an emerging subgroup of myelodysplastic syndrome showing frequent response to immunosuppression. Br J Haematol. 2018;182:152–4.

    PubMed  Google Scholar 

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Authors and Affiliations

  1. UO Ematologia, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

    Bruno Fattizzo, Giorgia Levati, Ramona Cassin & Wilma Barcellini

  2. University of Milan, Milan, Italy

    Giorgia Levati

Authors
  1. Bruno Fattizzo
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  2. Giorgia Levati
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  3. Ramona Cassin
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  4. Wilma Barcellini
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Correspondence to Bruno Fattizzo.

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Bruno Fattizzo has received consulting honoraria from Apellis. Giorgia Levati and Ramona Cassin declare that they have no conflict of interest that might be relevant to the contents of this manuscript. Wilma Barcellini has received consulting fee or honoraria from Bioverativ, Apellis, Agios, Alexion, and Novartis, and has received speaker honoraria from Novartis.

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Fattizzo, B., Levati, G., Cassin, R. et al. Eltrombopag in Immune Thrombocytopenia, Aplastic Anemia, and Myelodysplastic Syndrome: From Megakaryopoiesis to Immunomodulation. Drugs 79, 1305–1319 (2019). https://doi.org/10.1007/s40265-019-01159-0

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