Advertisement

Romiplostim

  • David J. Kuter
Chapter
Part of the Cancer Treatment and Research book series (CTAR, volume 157)

Abstract

Thrombocytopenia is a common clinical problem associated with a wide range of medical conditions including immune thrombocytopenia (ITP), chemotherapy-induced thrombocytopenia (CIT), hepatitis C-related thrombocytopenia, and myelodysplastic syndromes (MDS). Until recently, the only treatments for thrombocytopenia were to alleviate the underlying cause or to provide platelet transfusions. With the discovery and recent clinical availability of thrombopoietin (TPO) mimetics, a new treatment option has emerged. Two TPO mimetics are currently clinically available for treating ITP: romiplostim (an injectable peptide TPO mimetic) and eltrombopag (a non-peptide, orally available TPO mimetic). This chapter reviews the development, biology, and clinical trials with romiplostim. With few adverse effects, romiplostim is effective in raising the platelet count in over 80% of ITP patients, allowing them to discontinue other therapies, reduce the need for splenectomy, and improve their quality of life. Long-term theoretical side effects of romiplostim treatment include reticulin formation, thromboembolism, and antibody formation to romiplostim. A practical way of using romiplostim is provided: a higher starting dose of 3 mg/kg is recommended along with efforts to avoid withholding the dose. Future studies will assess the utility of romiplostim in CIT, hepatitis-C related thrombocytopenia, and MDS.

Keywords

Thrombopoietin Romiplostim ITP Thrombocytopenia Platelets 

References

  1. 1.
    Kelemen E, Cserhati I, Tanos B. Demonstration and some properties of human thrombopoietin in thrombocythaemic sera. Acta Haematol. 1958;20:350–5.CrossRefPubMedGoogle Scholar
  2. 2.
    Lok S, Foster DC. The structure, biology and potential therapeutic applications of recombinant thrombopoietin. Stem Cells. 1994;12:586–98.CrossRefPubMedGoogle Scholar
  3. 3.
    Kuter DJ, Beeler DL, Rosenberg RD. The purification of megapoietin: a physiological regulator of megakaryocyte growth and platelet production. Proc Natl Acad Sci USA. 1994;91:11104–8.CrossRefPubMedGoogle Scholar
  4. 4.
    de Sauvage FJ, Hass PE, Spencer SD, Malloy BE, Gurney AL, Spencer SA, Darbonne WC, Henzel WJ, Wong SC, Kuang WJ. Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand. Nature. 1994;369:533–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Bartley TD, Bogenberger J, Hunt P, Li YS, Lu HS, Martin F, Chang MS, Samal B, Nichol JL, Swift S, Johnson MJ, Hsu RY, Parker VP, Suggs S, Skrine JD, Merewether LA, Clogston C, Hsu E, Hokom MM, Hornkohl A, Choi E, Pangelinan M, Sun Y, Mar V, McNinch J, Simonet L, Jacobsen F, Xie C, Shutter J, Chute H, Basu R, Selander L, Trollinger D, Sieu L, Padilla D, Trail G, Elliott G, Izumi R, Covey T, Crouse J, Garcia A, Xu W, Del Castillo J, Biron J, Cole S, Hu MCT, Pacifici R, Ponting I, Saris C, Wen D, Yung YP, Lin H, Bosselman RA. Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor Mpl. Cell. 1994;77:1117–24.CrossRefPubMedGoogle Scholar
  6. 6.
    Kato T, Ogami K, Shimada Y, Iwamatsu A, Sohma Y, Akahori H, Horie K, Kokubo A, Kudo Y, Maeda E. Purification and characterization of thrombopoietin. J Biochem. 1995;118:229–36.PubMedGoogle Scholar
  7. 7.
    Wendling F, Tambourin P. The oncogene V-MPL, a putative truncated cytokine receptor which immortalized hemtopoietic progenitors. Nouv Rev Fr Hematol. 1991;33:145–6.PubMedGoogle Scholar
  8. 8.
    Li J, Yang C, Xia Y, Bertino A, Glaspy J, Roberts M, Kuter DJ. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood. 2001;98:3241–8.CrossRefPubMedGoogle Scholar
  9. 9.
    Kuter DJ. Thrombopoietin and thrombopoietin mimetics in the treatment of thrombocytopenia. Annu Rev Med. 2009;60:193–206.CrossRefPubMedGoogle Scholar
  10. 10.
    Kuter DJ. New drugs for familiar therapeutic targets: thrombopoietin receptor agonists and immune thrombocytopenic purpura. Eur J Haematol Suppl. 2008;69:9–18.CrossRefPubMedGoogle Scholar
  11. 11.
    Kuter DJ. New thrombopoietic growth factors. Blood. 2007;109:4607–16.CrossRefPubMedGoogle Scholar
  12. 12.
    Cwirla SE, Balasubramanian P, Duffin DJ, Wagstrom CR, Gates CM, Singer SC, Davis AM, Tansik RL, Mattheakis LC, Boytos CM, Schatz PJ, Baccanari DP, Wrighton NC, Barrett RW, Dower WJ. Peptide agonist of the thrombopoietin receptor as potent as the natural cytokine. Science. 1997;276:1696–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Cerneus D, Brown K, Harris R, End D, Molloy C, Yurkow E, Koblish H, Franks C, Moolenaar M, Burggraaf K. Stimulation of platelet production in healthy volunteers by a novel pegylated peptide-based thrombopoietin (TPO) receptor agonist. Blood. 2005;106:363a–4a.Google Scholar
  14. 14.
    Frederickson S, Renshaw MW, Lin B, Smith LM, Calveley P, Springhorn JP, Johnson K, Wang Y, Su X, Shen Y, Bowdish KS. A rationally designed agonist antibody fragment that functionally mimics thrombopoietin. Proc Natl Acad Sci USA. 2006;103:14307–12.CrossRefPubMedGoogle Scholar
  15. 15.
    Bussel JB, Kuter DJ, George JN, McMillan R, Aledort LM, Conklin GT, Lichtin AE, Lyons RM, Nieva J, Wasser JS, Wiznitzer I, Kelly R, Chen CF, Nichol JL. AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP. N Engl J Med. 2006;355:1672–81.CrossRefPubMedGoogle Scholar
  16. 16.
    Wang B, Nichol JL, Sullivan JT. Pharmacodynamics and pharmacokinetics of AMG 531, a novel thrombopoietin receptor ligand. Clin Pharmacol Ther. 2004;76:628–38.CrossRefPubMedGoogle Scholar
  17. 17.
    Sabath DF, Kaushansky K, Broudy VC. Deletion of the extracellular membrane-distal cytokine receptor homology module of Mpl results in constitutive cell growth and loss of thrombopoietin binding. Blood. 1999;94:365–7.PubMedGoogle Scholar
  18. 18.
    Kuter DJ, Begley CG. Recombinant human thrombopoietin: basic biology and evaluation of clinical studies. Blood. 2002;100:3457–69.CrossRefPubMedGoogle Scholar
  19. 19.
    Kaushansky K. Thrombopoietin. N Engl J Med. 1998;339:746–54CrossRefPubMedGoogle Scholar
  20. 20.
    Broudy VC, Lin NL. AMG531 stimulates megakaryopoiesis in vitro by binding to Mpl. Cytokine. 2004;25:52–60.CrossRefPubMedGoogle Scholar
  21. 21.
    Kuter DJ, Bussel J, Newland A, de Wolf JT, Guthrie TH, Jr, Wasser JS, Gehl L, Nie K, Berger D. Long-term treatment with romiplostim in patients with chronic immune thrombocytopenic purpura (ITP): 3-year update from an open-label extension study. Blood. 2008;112:154a.Google Scholar
  22. 22.
    Harker LA, Finch CA. Thrombokinetics in man. J Clin Invest. 1969;48:963–74.CrossRefPubMedGoogle Scholar
  23. 23.
    Ballem PJ, Segal GM, Stratton JR, Gernsheimer T, Adamson JW, Slichter SJ. Mechanisms of thrombocytopenia in chronic autoimmune thrombocytopenic purpura. Evidence of both impaired platelet production and increased platelet clearance. J Clin Invest. 1987;80:33–40.CrossRefPubMedGoogle Scholar
  24. 24.
    McMillan R, Wang L, Tomer A, Nichol J, Pistillo J. Suppression of in vitro megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic ITP. Blood. 2004;103:1364–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Houwerzijl EJ, Blom NR, van der Want JJ, Esselink MT, Koornstra JJ, Smit JW, Louwes H, Vellenga E, de Wolf JT. Ultrastructural study shows morphologic features of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura. Blood. 2004;103:500–6.CrossRefPubMedGoogle Scholar
  26. 26.
    Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, Senecal FM, Aledort LM, George JN, Kessler CM, Sanz MA, Liebman HA, Slovick FT, de Wolf JT, Bourgeois E, Guthrie TH, Jr, Newland A, Wasser JS, Hamburg SI, Grande C, Lefrere F, Lichtin AE, Tarantino MD, Terebelo HR, Viallard JF, Cuevas FJ, Go RS, Henry DH, Redner RL, Rice L, Schipperus MR, Guo DM, Nichol JL. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008;371:395–403.CrossRefPubMedGoogle Scholar
  27. 27.
    Rummel M, Boccia R, Macik G, Pabinger I, Selleslag D, Gehl L, Wang X, Berger DP, Kuter DJ. Efficacy and safety of romiplostim versus standard of care as chronic therapy for nonsplenectomized patients with immune thrombocytopenia (ITP). Haematologica. 2009;94(Supp 2):425 abs 1059.Google Scholar
  28. 28.
    Bussel J, Kuter DJ, Pullarkat V, Lyons RM, Guo M, Nichol JL. Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with ITP. Blood. 2009;113:2161–71.CrossRefPubMedGoogle Scholar
  29. 29.
    George JN, Raskob GE. Idiopathic thrombocytopenic purpura: a concise summary of the pathophysiology and diagnosis in children and adults. Semin Hematol. 1998;35:5–8.PubMedGoogle Scholar
  30. 30.
    George JN. Treatment options for chronic idiopathic (immune) thrombocytopenic purpura. Semin Hematol. 2000;37:31–4.CrossRefPubMedGoogle Scholar
  31. 31.
    Komatsu N, Okamoto T, Yoshida T, Nakeo S, Urabe A, Nagasawa T, Yonemura Y, Takeshita A, Ikeda Y, Sawada K, Hotta T, Kanamaru A, Bessho M, Minami N, Okamura T, Jinnai I, Kanakura Y, Mizoguchi H. Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) increased platelet counts (plt) in patients with aplastic anemia (AA) and myelodysplastic syndrome (MDS). Blood. 2000;96:296a.Google Scholar
  32. 32.
    Kantarjian H, Giles F, Fenaux P, Becker P, Boruchov A, Bowen D, Hellstrom-Lindberg E, Larson R, Lyons R, Muus P. Evaluating safety and efficacy of AMG 531 for the treatment of thrombocytopenic patients with myelodysplastic syndrome (MDS): preliminary results of a phase 1/2 study. J Clin Oncol. 2007;25:365a.Google Scholar
  33. 33.
    Kantarjian H, Fenaux P, Sekeres MA, Becker P, Boruchov A, Bowen D, Larson R, Lyons R, Muus P, Shammo J, Ehrman M, Hu K, Nichol J. Phase 1/2 study of AMG 531 in thrombocytopenic patients (pts) with low-risk myelodysplastic syndrome (MDS): update including extended treatment. Blood. 2007;110:81a.Google Scholar
  34. 34.
    Kantarjian H, Giles F, Greenberg P, Paquette RL, Wang E, Gabrilove JL, Garcia-Manero G, Gray J, Hu K, Franklin, J. Effect of romiplostim in patients (pts) with low or intermediate risk myelodysplastic syndrome (MDS) receiving azacytidine. Blood. 2008;112:89a.Google Scholar
  35. 35.
    Rajan SK, Espina BM, Liebman HA. Hepatitis C virus-related thrombocytopenia: clinical and laboratory characteristics compared with chronic immune thrombocytopenic purpura. Br J Haematol. 2005;129:818–24.CrossRefPubMedGoogle Scholar
  36. 36.
    McHutchison JG, Dusheiko G, Shiffman ML, Rodriguez-Torres M, Sigal S, Bourliere M, Berg T, Gordon SC, Campbell FM, Theodore D, Blackman N, Jenkins J, Afdhal NH. Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C. N Engl J Med. 2007;357:2227–36.CrossRefPubMedGoogle Scholar
  37. 37.
    Aledort LM, Hayward CP, Chen MG, Nichol JL, Bussel J. Prospective screening of 205 patients with ITP, including diagnosis, serological markers, and the relationship between platelet counts, endogenous thrombopoietin, and circulating antithrombopoietin antibodies. Am J Hematol. 2004;76:205–13.CrossRefPubMedGoogle Scholar
  38. 38.
    Kuter DJ, Bain B, Mufti G, Bagg A, Hasserjian RP. Bone marrow fibrosis: pathophysiology and clinical significance of increased bone marrow stromal fibres. Br J Haematol. 2007;139:351–62.CrossRefPubMedGoogle Scholar
  39. 39.
    Douglas VK, Tallman MS, Cripe LD, Peterson LC. Thrombopoietin administered during induction chemotherapy to patients with acute myeloid leukemia induces transient morphologic changes that may resemble chronic myeloproliferative disorders. Am J Clin Pathol. 2002;117:844–50.CrossRefPubMedGoogle Scholar
  40. 40.
    ODAC Meeting Briefing Document. 2008. http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4345b1-02-AMGEN.pdf. Amgen, Inc.

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Hematology DivisionMassachusetts General HospitalBostonUSA

Personalised recommendations