Skip to main content
SpringerLink
Log in

Thrombopoietin Receptor Agonists: Characteristics, Adverse Effects, and Indications

  • Chapter
  • First Online:
Antibody Therapy

  • 1178 Accesses

Abstract

While the most commonly utilized first-line therapeutics for the treatment of immune thrombocytopenia (ITP) target the peripheral destruction of platelets, a preponderant second-line therapeutic agent targeting increased megakaryopoiesis and/or platelet production has now emerged, in the form of thrombopoietin receptor agonists (TPO-RAs). These TPO-RAs, eltrombopag and romiplostim, have been proven safe and effective in treating ITP in both children and adults and have also been approved for use in severe aplastic anemia and chronic hepatitis, with ongoing investigation in the treatment of other clinical entities as well, including myelodysplastic syndrome and acute myelogenous leukemia, chemotherapy-induced thrombocytopenia, congenital thrombocytopenia, and other diseases. This chapter will detail TPO-RA use in all of these different clinical settings.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

References

  • Bartley TD, Bogenberger J, Hunt P, et al. Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor Mpl. Cell. 1994;77:1117–24.

    Article  CAS  PubMed  Google Scholar 

  • Biagiotti C, Carrai V, Bacchiarri F, et al. Persistent remission of chronic immune thrombocytopenia after thrombopoietin mimetics discontinuation. Haematologica. Conference Publication: (var.pagings). 2015;100:124.

    Article  Google Scholar 

  • Brynes RK, Orazi A, Theodore D, et al. Evaluation of bone marrow reticulin in patients with chronic immune thrombocytopenia treated with eltrombopag: data from the EXTEND study. Am J Hematol. 2015;90:598–601.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Bussel JB, 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.

    Article  CAS  PubMed  Google Scholar 

  • Bussel JB, Buchanan GR, Nugent DJ, et al. A randomized, double-blind study of romiplostim to determine its safety and efficacy in children with immune thrombocytopenia. Blood. 2011;118:28–36.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Bussel JB, de Miguel PG, Despotovic JM, et al. Eltrombopag for the treatment of children with persistent and chronic immune thrombocytopenia (PETIT): a randomised, multicentre, placebo-controlled study. Lancet Haematol. 2015a;2(8):e315–25.

    Article  PubMed  Google Scholar 

  • Bussel JB, Hsieh L, Buchanan GR, et al. Long-term use of the thrombopoietin-mimetic romiplostim in children with severe chronic immune thrombocytopenia (ITP). Pediatr Blood Cancer. 2015b;62:208–13.

    Article  CAS  PubMed  Google Scholar 

  • Bussel J, Shah KM, Brigstocke S, et al. Tapering eltrombopag in patients with chronic ITP: how successful is this and in whom does it work? Blood. 2015c;126:1054.

    Google Scholar 

  • Calmettes C, Vigouroux S, Tabrizi R, et al. Romiplostim (AMG531, Nplate) for secondary failure of platelet recovery after allo-SCT. Bone Marrow Transplant. 2011;46:1587–9.

    Article  CAS  PubMed  Google Scholar 

  • Carpenedo M, Cantoni S, Coccini V, et al. Response loss and development of neutralizing antibodies during long-term treatment with romiplostim in patients with immune thrombocytopenia: a case series. Eur J Haematol. 2016;97(1):101–3.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • de Sauvage FJ, Hass PE, Spencer SD, et al. Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand. Nature. 1994;369:533–8.

    Article  PubMed  Google Scholar 

  • Desmond R, Townsley D, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975–82.

    Article  CAS  PubMed  Google Scholar 

  • Ghadaki B, Nazi I, Kelton JG, et al. Sustained remissions of immune thrombocytopenia associated with the use of thrombopoietin receptor agonists. Transfusion. 2013;53:2807–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gill H, Leung G, Lopes D, et al. The thrombopoietin mimetics eltrombopag and romiplostim in the treatment of refractory aplastic anaemia. Br J Haematol. 2017;176(6):991–4.

    Article  CAS  PubMed  Google Scholar 

  • 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(10004):1649–58.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Imbach P, Crowther M. Thrombopoietin-receptor agonists for primary immune thrombocytopenia. N Engl J Med. 2011;365:734–41. (Figure 1. Copyright © 2011 Massachusetts Medical Society. Reprinted with permission.)

    Article  CAS  PubMed  Google Scholar 

  • Kantarjian H, Giles F, List A, et al. The incidence and impact of thrombocytopenia in myelodysplastic syndromes. Cancer. 2007;109:170–1714.

    Article  Google Scholar 

  • Kantarjian H, Fenaux P, Sekeres MA, et al. Safety and efficacy of romiplostim in patients with lower-risk myelodysplastic syndrome and thrombocytopenia. J Clin Oncol. 2010a;28:437–44.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kantarjian HM, Mufti G, Fenaux P, et al. Romiplostim in thrombocytopenic patients with low-risk or intermediate-1-risk myelodysplastic syndrome results in reduced bleeding without impacting leukemic progression: updated follow-up results from a randomized, double-blind, placebo-controlled study. ASH Annu Meet Abstr Blood. 2015;126(23).

    Google Scholar 

  • Kato T, Ogami K, Shimada Y, et al. Purification and characterization of thrombopoietin. J Biochem (Tokyo). 1995;118:229–36.

    Article  CAS  Google Scholar 

  • Kellum A, Jagiello-Gruszfeld A, Bondarenko IN, et al. A randomized, double-blind, placebo-controlled, dose ranging study to assess the efficacy and safety of eltrombopag in patients receiving carboplatin/paclitaxel for advanced solid tumors. Curr Med Res Opin. 2010;26(10):2339–46.

    Article  CAS  PubMed  Google Scholar 

  • Kuter DJ. Milestones in understanding platelet production: a historical overview. Br J Haematol. 2014;165(2):248–58.

    Article  CAS  PubMed  Google Scholar 

  • Kuter DJ, Beeler DL, Rosenberg RD. The purification of megapoietin: a physiological regulator of megakaryocyte growth and platelet production. Proc Natl Acad Sci U S A. 1994;9(1):11104–8.

    Article  Google Scholar 

  • Kuter DJ, Bain B, Mufti G, et al. Bone marrow fibrosis: pathophysiology and clinical significance of increased bone marrow stromal fibres. Br J Haematol. 2007;139(3):351–62.

    Article  CAS  PubMed  Google Scholar 

  • Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008;371:395–403.

    Article  CAS  PubMed  Google Scholar 

  • Kuter DJ, Rummel M, Boccia R, et al. Romiplostim or standard of care in patients with immune thrombocytopenia. N Engl J Med. 2010;363(20):1889–99.

    Article  CAS  PubMed  Google Scholar 

  • Li J, Yang C, Xia Y, et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood. 2001;98:3241–8.

    Article  CAS  PubMed  Google Scholar 

  • Lok S, Kaushansky K, Holly RD, et al. Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production in vivo. Nature. 1994;369:565–8.

    Article  CAS  PubMed  Google Scholar 

  • Mittelman M, Platzbecker U, Afanasyev B, et al. Thrombopoietin receptor agonist eltrombopag for advanced MDS or AML and severe thrombocytopenia: 12-week, randomized, placebo-controlled, phase 2 ASPIRE study. Haematologica. 2016;101(s1):15–6.

    Google Scholar 

  • Neunert C, Despotovic J, Haley K, et al. Thrombopoietin receptor agonist use in children: data from the pediatric ITP consortium of North America ICON2 study. Pediatr Blood Cancer. 2016;63(8):1407–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Novartis PROMACTA [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2016.

    Google Scholar 

  • Oliva EN, Santini V, Alati C, et al. Eltrombopag for the treatment of low and intermediate-1 IPSS risk myelodysplastic syndromes: interim results on efficacy, safety and quality of life of an international, multicenter prospective, randomized, trial. ASH Annu Meet Abstr Blood. 2015;91.

    Google Scholar 

  • Parameswaran R, Lunning M, Mantha S, et al. Romiplostim for management of chemotherapy-induced thrombocytopenia. Support Care Cancer. 2014;22(5):1217–22.

    Article  CAS  PubMed  Google Scholar 

  • 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(10):e417–26.

    Article  PubMed  Google Scholar 

  • Poon LM, Di Stasi A, Popat U, et al. Romiplostim for delayed platelet recovery and secondary thrombocytopenia following allogeneic stem cell transplantation. Am J Blood Res. 2013;3:260–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Popat U, Ray G, Basset R et al. Eltrombopag for post-transplant thrombocytopenia: results of phase II randomized double blind placebo controlled trial. ASH Annu Meet Abstr Blood 2015;738.

    Google Scholar 

  • Rizvi H, Butler T, Calaminici M, et al. United Kingdom immune thrombocytopenia registry: retrospective evaluation of bone marrow fibrosis in adult patients with primary immune thrombocytopenia and correlation with clinical findings. Br J Haematol. 2015;169(4):590–4.

    Article  PubMed  Google Scholar 

  • Rodeghiero F. Is ITP a thrombophilic disorder? Am J Hematol. 2016;91:423–36.

    Article  Google Scholar 

  • Rodeghiero F, Carli G. Beyond immune thrombocytopenia: the evolving role of thrombopoietin receptor agonists. Ann Hematol. 2017;96(9):1421–34. https://doi.org/10.1007/s00277-017-2953-6.

    Article  CAS  PubMed  Google Scholar 

  • Rodeghiero F, Stasi R, Giagounidis A, et al. Long-term safety and tolerability of romiplostim in patients with primary immune thrombocytopenia: a pooled analysis of 13 clinical trials. Eur J Haematol. 2013;91:423–36.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saleh MN, Bussel JB, Cheng G, 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.

    Article  CAS  PubMed  Google Scholar 

  • Tarantino MD, Bussel JB, Blanchette VS, et al. Romiplostim in children with immune thrombocytopenia: a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016;388(10039):45–54.

    Article  PubMed  Google Scholar 

  • Townsley D, Dumitriu B, Scheinberg P, et al. Eltrombopag added to standard immunosuppression for aplastic anemia accelerates count recovery and increases response rates. Blood. 2015;126:LBA-2.

    Article  Google Scholar 

  • Townsley DM, Scheinberg P, Winkler T, et al. Eltrombopag added to standard immunosuppression for aplastic anemia. N Engl J Med. 2017;376(16):1540–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • U.S. Food and Drug Administration. Eltrombopag. Available from www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&applno=022291. Accessed 22 May 2017a.

  • U.S. Food and Drug Administration. Romiplostim. Available from www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&applno=125268. Accessed 22 May 2017b.

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Winer ES, Safran H, Karaszewska B, et al. Eltrombopag with gemcitabine-based chemotherapy in patients with advanced solid tumors: a randomized phase I study. Cancer Med. 2015;4(1):16–26.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Zeigler FC, de Sauvage F, Widmer HR, et al. In vitro megakaryocytopoietic and thrombopoietic activity of c-mpl ligand (TPO) on purified murine hematopoietic stem cells. Blood. 1994;84(12):4045–52.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pediatric Hematology/Oncology, Baylor College of Medicine/Texas Children’s Hospital, 6701 Fannin Street, Houston, TX, 77030, USA

    Jenny Despotovic DO, MS & Amanda Grimes MD

Authors
  1. Jenny Despotovic DO, MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amanda Grimes MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Amanda Grimes MD .

Editor information

Editors and Affiliations

  1. Department of Pediatrics, Medical Faculty of the University of Basel, Basel, Switzerland

    Paul Imbach

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Cite this chapter

Despotovic, J., Grimes, A. (2018). Thrombopoietin Receptor Agonists: Characteristics, Adverse Effects, and Indications. In: Imbach, P. (eds) Antibody Therapy. Springer, Cham. https://doi.org/10.1007/978-3-319-68038-5_18

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-68038-5_18

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-68037-8

  • Online ISBN: 978-3-319-68038-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation