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Immune thrombocytopenia (ITP) in adults: Second-line and subsequent therapies

James N George, MD
Donald M Arnold, MD, MSc
Section Editor
Lawrence LK Leung, MD
Deputy Editor
Jennifer S Tirnauer, MD


Therapy for immune thrombocytopenia (ITP) differs for different patients: some do not require any treatment; others have a spontaneous remission or respond to first-line therapy with glucocorticoids; and others continue to have severe thrombocytopenia with or without bleeding, necessitating additional therapy.

Here we discuss our approach to management of adults with ITP who require additional therapy beyond glucocorticoids (ie, second-line and subsequent therapies). The clinical manifestations, diagnosis, and initial treatment of adults and children presenting with ITP are discussed in detail separately.

(See "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis".)

(See "Immune thrombocytopenia (ITP) in adults: Initial treatment and prognosis".)

(See "Immune thrombocytopenia (ITP) in children: Initial management".)

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Literature review current through: Nov 2017. | This topic last updated: Nov 15, 2016.
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  1. Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood 2009; 113:2386.
  2. Ghanima W, Godeau B, Cines DB, Bussel JB. How I treat immune thrombocytopenia: the choice between splenectomy or a medical therapy as a second-line treatment. Blood 2012; 120:960.
  3. Toltl LJ, Arnold DM. Pathophysiology and management of chronic immune thrombocytopenia: focusing on what matters. Br J Haematol 2011; 152:52.
  4. Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood 2011; 117:4190.
  5. George JN, Woolf SH, Raskob GE, et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood 1996; 88:3.
  6. Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 2010; 115:168.
  7. British Committee for Standards in Haematology General Haematology Task Force. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Br J Haematol 2003; 120:574.
  8. Kojouri K, Vesely SK, Terrell DR, George JN. Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term platelet count responses, prediction of response, and surgical complications. Blood 2004; 104:2623.
  9. Patel VL, Mahévas M, Lee SY, et al. Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia. Blood 2012; 119:5989.
  10. Arnold DM, Dentali F, Crowther MA, et al. Systematic review: efficacy and safety of rituximab for adults with idiopathic thrombocytopenic purpura. Ann Intern Med 2007; 146:25.
  11. Aleem A, Alaskar AS, Algahtani F, et al. Rituximab in immune thrombocytopenia: transient responses, low rate of sustained remissions and poor response to further therapy in refractory patients. Int J Hematol 2010; 92:283.
  12. Ghanima W, Khelif A, Waage A, et al. Rituximab as second-line treatment for adult immune thrombocytopenia (the RITP trial): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2015; 385:1653.
  13. Arnold DM. Positioning new treatments in the management of immune thrombocytopenia. Pediatr Blood Cancer 2013; 60 Suppl 1:S19.
  14. Rodeghiero F, Ruggeri M. Is splenectomy still the gold standard for the treatment of chronic ITP? Am J Hematol 2008; 83:91.
  15. Cooper N, Evangelista ML, Amadori S, Stasi R. Should rituximab be used before or after splenectomy in patients with immune thrombocytopenic purpura? Curr Opin Hematol 2007; 14:642.
  16. Lu KH, George JN, Vesely SK, Terrell DR. Management of primary immune thrombocytopenia, 2012: a survey of oklahoma hematologists-oncologists. Am J Med Sci 2014; 347:190.
  17. Wang KK, Charles C, Heddle NM, et al. Understanding why patients with immune thrombocytopenia are deeply divided on splenectomy. Health Expect 2014; 17:809.
  18. Nazi I, Kelton JG, Larché M, et al. The effect of rituximab on vaccine responses in patients with immune thrombocytopenia. Blood 2013; 122:1946.
  19. Gonzalez-Porras JR, Escalante F, Pardal E, et al. Safety and efficacy of splenectomy in over 65-yrs-old patients with immune thrombocytopenia. Eur J Haematol 2013; 91:236.
  20. Wu JM, Lai IR, Yuan RH, Yu SC. Laparoscopic splenectomy for idiopathic thrombocytopenic purpura. Am J Surg 2004; 187:720.
  21. Fenaux P, Caulier MT, Hirschauer MC, et al. Reevaluation of the prognostic factors for splenectomy in chronic idiopathic thrombocytopenic purpura (ITP): a report on 181 cases. Eur J Haematol 1989; 42:259.
  22. Fabris F, Tassan T, Ramon R, et al. Age as the major predictive factor of long-term response to splenectomy in immune thrombocytopenic purpura. Br J Haematol 2001; 112:637.
  23. Keidar A, Feldman M, Szold A. Analysis of outcome of laparoscopic splenectomy for idiopathic thrombocytopenic purpura by platelet count. Am J Hematol 2005; 80:95.
  24. Thomsen RW, Schoonen WM, Farkas DK, et al. Risk for hospital contact with infection in patients with splenectomy: a population-based cohort study. Ann Intern Med 2009; 151:546.
  25. Schilling RF. Estimating the risk for sepsis after splenectomy in hereditary spherocytosis. Ann Intern Med 1995; 122:187.
  26. Bisharat N, Omari H, Lavi I, Raz R. Risk of infection and death among post-splenectomy patients. J Infect 2001; 43:182.
  27. Styrt B. Infection associated with asplenia: risks, mechanisms, and prevention. Am J Med 1990; 88:33N.
  28. Rubin LG, Schaffner W. Clinical practice. Care of the asplenic patient. N Engl J Med 2014; 371:349.
  29. Thomsen RW, Schoonen WM, Farkas DK, et al. Risk of venous thromboembolism in splenectomized patients compared with the general population and appendectomized patients: a 10-year nationwide cohort study. J Thromb Haemost 2010; 8:1413.
  30. Cragg MS, Walshe CA, Ivanov AO, Glennie MJ. The biology of CD20 and its potential as a target for mAb therapy. Curr Dir Autoimmun 2005; 8:140.
  31. Chugh S, Darvish-Kazem S, Lim W, et al. Rituximab plus standard of care for treatment of primary immune thrombocytopenia: a systematic review and meta-analysis. Lancet Haematol 2015; 2:e75.
  32. Auger S, Duny Y, Rossi JF, Quittet P. Rituximab before splenectomy in adults with primary idiopathic thrombocytopenic purpura: a meta-analysis. Br J Haematol 2012; 158:386.
  33. Zaja F, Vianelli N, Volpetti S, et al. Low-dose rituximab in adult patients with primary immune thrombocytopenia. Eur J Haematol 2010; 85:329.
  34. Zaja F, Volpetti S, Chiozzotto M, et al. Long-term follow-up analysis after rituximab salvage therapy in adult patients with immune thrombocytopenia. Am J Hematol 2012; 87:886.
  35. Tran H, Brighton T, Grigg A, et al. A multi-centre, single-arm, open-label study evaluating the safety and efficacy of fixed dose rituximab in patients with refractory, relapsed or chronic idiopathic thrombocytopenic purpura (R-ITP1000 study). Br J Haematol 2014; 167:243.
  36. Khellaf M, Charles-Nelson A, Fain O, et al. Safety and efficacy of rituximab in adult immune thrombocytopenia: results from a prospective registry including 248 patients. Blood 2014; 124:3228.
  37. Carson KR, Evens AM, Richey EA, et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood 2009; 113:4834.
  38. McCrae KR. Better late than never? Blood 2013; 122:1844.
  39. George JN, Terrell DR. Novel thrombopoietic agents: a new era for management of patients with thrombocytopenia. Haematologica 2008; 93:1445.
  40. Zeng Y, Duan X, Xu J, Ni X. TPO receptor agonist for chronic idiopathic thrombocytopenic purpura. Cochrane Database Syst Rev 2011; :CD008235.
  41. Kuter DJ. The biology of thrombopoietin and thrombopoietin receptor agonists. Int J Hematol 2013; 98:10.
  42. 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.
  43. Ghadaki B, Nazi I, Kelton JG, Arnold DM. Sustained remissions of immune thrombocytopenia associated with the use of thrombopoietin receptor agonists. Transfusion 2013; 53:2807.
  44. Nieto M, Calvo G, Hudson I, et al. The European Medicines Agency review of eltrombopag (Revolade) for the treatment of adult chronic immune (idiopathic) thrombocytopenic purpura: summary of the scientific assessment of the Committee for Medicinal Products for Human Use. Haematologica 2011; 96:e33.
  45. Bussel JB, Kuter DJ, Aledort LM, et al. A randomized trial of avatrombopag, an investigational thrombopoietin-receptor agonist, in persistent and chronic immune thrombocytopenia. Blood 2014; 123:3887.
  46. Kuter DJ, Bussel JB, Newland A, et al. Long-term treatment with romiplostim in patients with chronic immune thrombocytopenia: safety and efficacy. Br J Haematol 2013; 161:411.
  47. Catalá-López F, Corrales I, de la Fuente-Honrubia C, et al. Risk of thromboembolism with thrombopoietin receptor agonists in adult patients with thrombocytopenia: Systematic review and meta-analysis of randomized controlled trials. Med Clin (Barc) 2015; 145:511.
  48. Cines DB, Gernsheimer T, Wasser J, et al. Integrated analysis of long-term safety in patients with chronic immune thrombocytopaenia (ITP) treated with the thrombopoietin (TPO) receptor agonist romiplostim. Int J Hematol 2015; 102:259.
  49. Broudy VC, Lin NL. AMG531 stimulates megakaryopoiesis in vitro by binding to Mpl. Cytokine 2004; 25:52.
  50. Newland A, Caulier MT, Kappers-Klunne M, et al. An open-label, unit dose-finding study of AMG 531, a novel thrombopoiesis-stimulating peptibody, in patients with immune thrombocytopenic purpura. Br J Haematol 2006; 135:547.
  51. Molineux G, Newland A. Development of romiplostim for the treatment of patients with chronic immune thrombocytopenia: from bench to bedside. Br J Haematol 2010; 150:9.
  52. Gernsheimer TB, George JN, Aledort LM, et al. Evaluation of bleeding and thrombotic events during long-term use of romiplostim in patients with chronic immune thrombocytopenia (ITP). J Thromb Haemost 2010; 8:1372.
  53. Kuter DJ, Rummel M, Boccia R, et al. Romiplostim or standard of care in patients with immune thrombocytopenia. N Engl J Med 2010; 363:1889.
  54. Bussel JB, Kuter DJ, George JN, et al. AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP. N Engl J Med 2006; 355:1672.
  55. 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.
  56. Khellaf M, Michel M, Quittet P, et al. Romiplostim safety and efficacy for immune thrombocytopenia in clinical practice: 2-year results of 72 adults in a romiplostim compassionate-use program. Blood 2011; 118:4338.
  57. Shirasugi Y, Ando K, Miyazaki K, et al. Romiplostim for the treatment of chronic immune thrombocytopenia in adult Japanese patients: a double-blind, randomized Phase III clinical trial. Int J Hematol 2011; 94:71.
  58. 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.
  59. Bussel JB, Kuter DJ, Pullarkat V, et al. Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP. Blood 2009; 113:2161.
  60. Janssens A, Rodeghiero F, Anderson D, et al. Changes in bone marrow morphology in adults receiving romiplostim for the treatment of thrombocytopenia associated with primary immune thrombocytopenia. Ann Hematol 2016; 95:1077.
  61. Tomiyama Y, Miyakawa Y, Okamoto S, et al. A lower starting dose of eltrombopag is efficacious in Japanese patients with previously treated chronic immune thrombocytopenia. J Thromb Haemost 2012; 10:799.
  62. 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.
  63. 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.
  64. 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.
  65. Sperati CJ, Streiff MB. Acute renal failure in a patient with antiphospholipid syndrome and immune thrombocytopenic purpura treated with eltrombopag. Am J Hematol 2010; 85:724.
  66. Jansen AJ, Swart RM, te Boekhorst PA. Thrombopoietin-receptor agonists for immune thrombocytopenia. N Engl J Med 2011; 365:2240.
  67. 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.
  68. Cheng G. Thrombopoietin Receptor Agonists for the treatment of ITP. Rinsho Ketsueki 2013; 54:1915.
  69. Ghanima W, Geyer JT, Lee CS, et al. Bone marrow fibrosis in 66 patients with immune thrombocytopenia treated with thrombopoietin-receptor agonists: a single-center, long-term follow-up. Haematologica 2014; 99:937.
  70. Vesely SK, Perdue JJ, Rizvi MA, et al. Management of adult patients with persistent idiopathic thrombocytopenic purpura following splenectomy: a systematic review. Ann Intern Med 2004; 140:112.
  71. Ahn YS, Rocha R, Mylvaganam R, et al. Long-term danazol therapy in autoimmune thrombocytopenia: unmaintained remission and age-dependent response in women. Ann Intern Med 1989; 111:723.
  72. Maloisel F, Andrès E, Zimmer J, et al. Danazol therapy in patients with chronic idiopathic thrombocytopenic purpura: long-term results. Am J Med 2004; 116:590.
  73. Andrès E, Zimmer J, Noel E, et al. Idiopathic thrombocytopenic purpura: a retrospective analysis in 139 patients of the influence of age on the response to corticosteroids, splenectomy and danazol. Drugs Aging 2003; 20:841.
  74. Stasi R, Provan D. Management of immune thrombocytopenic purpura in adults. Mayo Clin Proc 2004; 79:504.
  75. van Staa TP, Leufkens HG, Cooper C. The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporos Int 2002; 13:777.
  76. Guidry JA, George JN, Vesely SK, et al. Corticosteroid side-effects and risk for bleeding in immune thrombocytopenic purpura: patient and hematologist perspectives. Eur J Haematol 2009; 83:175.
  77. Zukerman E, Ingelfinger JR. Coping with Prednisone, St Martin's Press, New York 2007.
  78. Guidry JA, Watson S, George JN, et al. Addendum to corticosteroid side effects and risk for bleeding in immune thrombocytopenic purpura: patient perspectives. Eur J Haematol 2009; 83:497.
  79. Quiquandon I, Fenaux P, Caulier MT, et al. Re-evaluation of the role of azathioprine in the treatment of adult chronic idiopathic thrombocytopenic purpura: a report on 53 cases. Br J Haematol 1990; 74:223.
  80. Taylor A, Neave L, Solanki S, et al. Mycophenolate mofetil therapy for severe immune thrombocytopenia. Br J Haematol 2015; 171:625.
  81. Verlin M, Laros RK Jr, Penner JA. Treatment of refractory thrombocytopenic purpura with cyclophosphamine. Am J Hematol 1976; 1:97.
  82. Reiner A, Gernsheimer T, Slichter SJ. Pulse cyclophosphamide therapy for refractory autoimmune thrombocytopenic purpura. Blood 1995; 85:351.
  83. Zaja F, Marin L, Chiozzotto M, et al. Dapsone salvage therapy for adult patients with immune thrombocytopenia relapsed or refractory to steroid and rituximab. Am J Hematol 2012; 87:321.
  84. Rodrigo C, Gooneratne L. Dapsone for primary immune thrombocytopenia in adults and children: an evidence-based review. J Thromb Haemost 2013; 11:1946.
  85. Huhn RD, Fogarty PF, Nakamura R, et al. High-dose cyclophosphamide with autologous lymphocyte-depleted peripheral blood stem cell (PBSC) support for treatment of refractory chronic autoimmune thrombocytopenia. Blood 2003; 101:71.
  86. Passweg JR, Rabusin M, Musso M, et al. Haematopoetic stem cell transplantation for refractory autoimmune cytopenia. Br J Haematol 2004; 125:749.
  87. Zhou H, Xu M, Qin P, et al. A multicenter randomized open-label study of rituximab plus rhTPO vs rituximab in corticosteroid-resistant or relapsed ITP. Blood 2015; 125:1541.
  88. Choi PY, Roncolato F, Badoux X, et al. A novel triple therapy for ITP using high-dose dexamethasone, low-dose rituximab, and cyclosporine (TT4). Blood 2015; 126:500.
  89. Arnold DM, Nazi I, Santos A, et al. Combination immunosuppressant therapy for patients with chronic refractory immune thrombocytopenic purpura. Blood 2010; 115:29.
  90. Boruchov DM, Gururangan S, Driscoll MC, Bussel JB. Multiagent induction and maintenance therapy for patients with refractory immune thrombocytopenic purpura (ITP). Blood 2007; 110:3526.
  91. Figueroa M, Gehlsen J, Hammond D, et al. Combination chemotherapy in refractory immune thrombocytopenic purpura. N Engl J Med 1993; 328:1226.
  92. Gudbrandsdottir S, Birgens HS, Frederiksen H, et al. Rituximab and dexamethasone vs dexamethasone monotherapy in newly diagnosed patients with primary immune thrombocytopenia. Blood 2013; 121:1976.
  93. 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.