Seminars in Hematology
Volume 47, Issue 3 , Pages 289-298 , July 2010

Toxicities of the Thrombopoietic Growth Factors

  • Adam Cuker

      Affiliations

    • Corresponding Author InformationAddress correspondence to Adam Cuker, MD, Penn Comprehensive Hemophilia and Thrombosis Program, Dulles 3, Hospital of the University of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104

References 

  1. Bussel JB, Kuter DJ, George JN, et al. AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP. N Engl J Med. 2006;355:1672–1681
  2. 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
  3. Kuter DJ, Rummel MJ, Boccia RV, et al. Comparison of splenectomy and treatment failure incidence in nonsplenectomized patients with immune thrombocytopenia (ITP) receiving romiplostim or medical standard of care: 1-year treatment and 6-month safety follow-up [abstract]. ASH Annual Meeting Abstracts. 2009;114:679
  4. Tomiyama Y, Miyakawa Y, Okamoto S, et al. Six month treatment of low dose eltrombopag is efficacious in Japanese patients with refractory chronic immune thrombocytopenic purpura (ITP) [abstract]. ASH Annual Meeting Abstracts. 2009;114:1324
  5. Bussel JB, Cheng G, Saleh MN, et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 2007;357:2237–2247
  6. Bussel JB, Provan D, Shamsi T, et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomized, double-blind, placebo-controlled trial. Lancet. 2009;373:641–648
  7. Cheng G, Saleh MN, Bussel JB, et al. Oral eltrombopag for the long-term treatment of patients with chronic idiopathic thrombocytopenic purpura: results of a phase III double-blind, placebo-controlled study (RAISE) [abstract]. ASH Annual Meeting Abstracts. 2008;112:400
  8. Bussel JB, Kuter DJ, Newland A, et al. Long-term efficacy and safety of romiplostim for the treatment of patients with chronic immune thrombocytopenia (ITP): 5-year update from an open-label extension study [abstract]. ASH Annual Meeting Abstracts. 2009;114:681
  9. Saleh MN, Bussel JB, Cheng G, et al. Long-term treatment of chronic immune thrombocytopenic purpura with oral eltrombopag: results from the EXTEND study [abstract]. ASH Annual Meeting Abstracts. 2009;114:682
  10. Kuter DJ, Bain B, Mufti G, Bagg A, Hasserjian RP. Bone marrow fibrosis: physiology and clinical significance of increased bone marrow stromal fibres. Br J Haematol. 2007;139:351–362
  11. Bauermeister DE. Quantitation of bone marrow reticulin—a normal change. Am J Clin Pathol. 1971;56:24–31
  12. Beckman EN, Brown AW. Normal reticulin level in iliac bone marrow. Arch Pathol Lab Med. 1990;114:1241–1243
  13. Mufti G, Hasserjian R, Bain B, Kuter D, Dreiling L, Nichol J. Bone marrow reticulin in patients with immune thrombocytopenic purpura [abstract]. ASH Annual Meeting Abstracts. 2006;108:3982
  14. Kimura A, Katoh O, Hyodo H, Kuramoto A. Transforming growth factor-beta regulates growth as well as collagen and fibronectin synthesis of human marrow fibroblasts. Br J Haematol. 1989;72:486–491
  15. Terui T, Niitsu Y, Mahara K, et al. The production of transforming growth factor-beta in acute megakaryoblastic leukemia and its possible implications in myelofibrosis. Blood. 1990;75:1540–1548
  16. Ulich TR, del Castillo J, Senaldi G, et al. Systemic hematologic effects of PEG-rHuMGDF-induced megakaryocyte hyperplasia in mice. Blood. 1996;87:5006–5015
  17. Yanagida M, Ide Y, Imai A, et al. The role of transforming growth factor-beta in PEG-rHuMGDF-induced reversible myelofibrosis in rats. Br J Haematol. 1997;99:739–745
  18. Kuter DJ, Mufti G, Bain BJ, Hasserjian R, Davis W, Rutstein M. Evaluation of bone marrow reticulin formation in chronic immune thrombocytopenia patients treated with romiplostim. Blood. 2009;114:3748–3756
  19. Yan XQ, Lacey D, Fletcher F, et al. Chronic exposure to retroviral vector encoded MGDF (mpl-ligand) induces lineage-specific growth and differentiation of megakaryocytes in mice. Blood. 1995;86:4025–4033
  20. 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;117:844–850
  21. Thiele J, Kvasnicka HM, Facchetti F, Franco V, van der Walt J, Orazi A. European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica. 2005;90:1128–1132
  22. Saleh MN, Bussel JB, Meyer O, et al. Results of bone marrow examinations in patients with chronic immune thrombocytopenic purpura treated with eltrombopag [abstract]. ASH Annual Meeting Abstracts. 2009;114:1326
  23. Cuker A, Chiang EY, Cines DB. Safety of the thrombopoiesis stimulating agents for the treatment of immune thrombocytopenia. Curr Drug Saf. 2010;5:171–181
  24. 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;76:205–213
  25. Bennett I, Forssen U, Enger C, Nelson J. Risk of thromboembolic events among patients with chronic idiopathic thrombocytopenic purpura (ITP) [abstract]. EHA Annual Meeting Abstracts. 2008;93(s1):307
  26. Hefer D, Jaloudi M. Thromboembolic events as an emerging adverse effect during high-dose intravenous immunoglobulin therapy in elderly patients: a case report and discussion of the relevant literature. Ann Hematol. 2005;84:411–415
  27. Mohren M, Markmann I, Dworschak U, et al. Thromboembolic complications after splenectomy for hematologic diseases. Am J Hematol. 2004;76:143–147
  28. Harker LA, Hunt P, Marzec UM, et al. Regulation of platelet production and function by megakaryocyte growth and development factor in nonhuman primates. Blood. 1996;87:1833–1844
  29. Harker LA, Marzec UM, Hunt P, et al. Dose-response effects of pegylated human megakaryocyte growth and development factor on platelet production and function in nonhuman primates. Blood. 1996;88:511–521
  30. Peng J, Friese P, Wolf RF, et al. Relative reactivity of platelets from thrombopoietin- and interleukin-6-treated dogs. Blood. 1996;87:4158–4163
  31. Erhardt JA, Erickson-Miller CL, Aivado M, Abboud M, Pillarisetti K, Toomey JR. Comparative analyses of the small molecule thrombopoietin receptor agonist eltrombopag and thrombopoietin on in vitro platelet function. Exp Hematol. 2009;37:1030–1037
  32. Vadhan-Raj S, Murray LJ, Bueso-Ramos C, et al. Stimulation of megakaryocyte and platelet production by a single dose of recombinant human thrombopoietin in patients with cancer. Ann Intern Med. 1997;126:673–681
  33. Fanucchi M, Glaspy J, Crawford J, et al. Effects of polyethylene glycol-conjugated recombinant human megakaryocyte growth and development factor on platelet counts after chemotherapy for lung cancer. N Engl J Med. 1997;336:404–409
  34. Basser RL, Underhill C, Davis I, et al. Enhancement of platelet recovery after myelosuppressive chemotherapy by recombinant human megakaryocyte growth and development factor in patients with advanced cancer. J Clin Oncol. 2000;18:2852–2861
  35. Liebman H, Henry D, Lefrere F, et al. Long-term safety profile of romiplostim in patients with chronic immune thrombocytopenia (ITP) [abstract]. ASH Annual Meeting Abstracts. 2008;112:3415
  36. Bussel JB, Cheng G, Saleh MN, Vasey S, Aivado M, Brainsky A. Thromboembolic events observed in eltrombopag clinical trials in chronic immune thrombocytopenic purpura [abstract]. ASH Annual Meeting Abstracts. 2009;114:2423
  37. Cheng G, Tarantino M, Gernsheimer T, Meyer O, Brainsky A, Stone NL. Platelet counts following eltrombopag discontinuation in patients with chronic immune thrombocytopenic purpura [abstract]. ASH Annual Meeting Abstracts. 2009;114:3517
  38. Söderberg KC, Jonsson F, Winqvist O, Hagmar L, Feychting M. Autoimmune diseases, asthma and risk of haematological malignancies: a nationwide case-control study in Sweden. Eur J Cancer. 2006;42:3028–3033
  39. Landgren O, Engels EA, Pfeiffer RM, et al. Autoimmunity and susceptibility to Hodgkin lymphoma: a population-based case-control study in Scandinavia. J Natl Cancer Inst. 2006;98:1321–1330
  40. Bennett I, Forssen U, Enger C, Nelson J. Risk of blood cancers among patients with chronic idiopathic thrombocytopenic purpura (ITP) [abstract]. EHA Annual Meeting Abstracts. 2008;93(s1):1449
  41. Erickson-Miller C, Kirchner J, Payne P, May E, Chadderton A. Eltrombopag does not enhance proliferation of non-megakaryocytic leukemia and lymphoma cell lines [abstract]. International Symposium of Myelodysplastic Syndrome Annual Meeting Abstracts. 2009;33(s1):P067
  42. Will B, Kawahara M, Luciano JP, et al. Effect of the nonpeptide thrombopoietin receptor agonist eltrombopag on bone marrow cells from patients with acute myeloid leukemia and myelodysplastic syndrome. Blood. 2009;114:3899–3908
  43. Archimbaud E, Ottoman OG, Yin JA, et al. A randomized, double-blind, placebo-controlled study with pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) as an adjunct to chemotherapy for adults with de novo acute myeloid leukemia. Blood. 1999;94:3694–3701
  44. 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. Epub 2009 December 14,10.1200/JCO.2009.24.7999. Available from: http://jco.ascopubs.org.
  45. Lyons RM, Larson RA, Kosmo MA, et al. Randomized phase II study evaluating the efficacy and safety of romiplostim treatment of patients with low or intermediate risk myelodysplastic syndrome (MDS) receiving lenalidomide [abstract]. ASH Annual Meeting Abstracts. 2009;114:1770
  46. Kantarjian H, Giles F, Greenberg P, et al. Effect of romiplostim in patients with low or intermediate risk myelodysplastic syndrome (MDS) receiving azacytidine [abstract]. ASH Annual Meeting Abstracts. 2008;112:224
  47. Greenberg PL, Garcia-Manero G, Moore MR, et al. Efficacy and safety of romiplostim in patients with low or intermediate-risk myelodysplastic syndrome (MDS) receiving decitabine [abstract]. ASH Annual Meeting Abstracts. 2009;114:1769
  48. Nomura S, Dan K, Hotta T, Fujimura K, Ikeda Y. Effects of pegylated recombinant human megakaryocyte growth and development factor in patients with idiopathic thrombocytopenic purpura. Blood. 2002;100:728–730
  49. Kuter DJ, Goodnough LT, Romo J, et al. Thrombopoietin therapy increases platelet yields in healthy platelet donors. Blood. 2001;98:1339–1345
  50. Li J, Yang C, Xia Y, et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood. 2001;98:3241–3248
  51. Maddrey WC, Cheng G, Khelif A, Wroblewski SL, Brainsky A. Evaluation of hepatobiliary parameters during eltrombopag treatment in patients with chronic immune thrombocytopenic purpura [abstract]. ASH Annual Meeting Abstracts. 2009;114:2410
  52. McHutchison JG, Dusheiko G, Shiffman ML, et al. Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C. N Engl J Med. 2007;357:2227–2236
  53. Portielje JE, Westendorp RG, Kluin-Nelemans HC, Brand A. Morbidity and mortality in adults with idiopathic thrombocytopenic purpura. Blood. 2001;97:2549–2554

 This work was supported in part by K12 HL087064-03 and a grant from the University of Pennsylvania Institute of Translational Medicine and Therapeutics.

PII: S0037-1963(10)00043-0

doi: 10.1053/j.seminhematol.2010.03.002

Seminars in Hematology
Volume 47, Issue 3 , Pages 289-298 , July 2010

Article Tools