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Semin Thromb Hemost 2015; 41(04): 395-404
DOI: 10.1055/s-0034-1544001
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Can Immune Thrombocytopenia Be Cured with Medical Therapy?

Adam Cuker
1   Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
2   Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
,
Eline T. Luning Prak
2   Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
,
Douglas B. Cines
1   Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
2   Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
› Author Affiliations
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Publication History

Publication Date:
20 March 2015 (online)

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Abstract

Primary immune thrombocytopenia (ITP) in adults often assumes a chronic course that requires persistent monitoring and treatment. Medical therapy has traditionally been viewed as a means of temporarily raising the platelet count with little or no potential to induce long-term platelet responses off treatment. However, several recent studies have tested the hypothesis that intensive medical therapy administered early in the disease course may ameliorate or even cure ITP. In this review, we propose a biological rationale for medical intervention that simultaneously targets the innate and adaptive immune responses administered early in the course of disease. We also critically examine data on long-term outcomes after single-agent and multi-agent medical therapy. Intensive regimens that target inflammation and adaptive immunity (e.g., combination high-dose dexamethasone and rituximab) appear to improve response rates at 6 to 12 months compared with standard first-line therapy (e.g., prednisone, high-dose dexamethasone alone) in newly diagnosed patients. Controlled trials with extended follow-up are needed to determine whether these intensive regimens induce more cures compared with standard treatment or merely delay relapse at the expense of potentially greater toxicity.

Keywords

immune thrombocytopenia - treatment - cure - remission
 

  • References

  • 1 Cuker A, Cines DB. Immune thrombocytopenia. Hematology (Am Soc Hematol Educ Program) 2010; 2010: 377-384
    CrossrefPubMedGoogle Scholar
  • 2 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 (11) 2386-2393
    CrossrefPubMedGoogle Scholar
  • 3 Donato H, Picón A, Martinez M , et al. Demographic data, natural history, and prognostic factors of idiopathic thrombocytopenic purpura in children: a multicentered study from Argentina. Pediatr Blood Cancer 2009; 52 (4) 491-496
    CrossrefPubMedGoogle Scholar
  • 4 Liebman HA, Stasi R. Secondary immune thrombocytopenic purpura. Curr Opin Hematol 2007; 14 (5) 557-573
    CrossrefPubMedGoogle Scholar
  • 5 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 (9) 2623-2634
    CrossrefPubMedGoogle Scholar
  • 6 Rodeghiero F, Ruggeri M. Short- and long-term risks of splenectomy for benign haematological disorders: should we revisit the indications?. Br J Haematol 2012; 158 (1) 16-29
    CrossrefPubMedGoogle Scholar
  • 7 Hauber AB, Johnson FR, Grotzinger KM, Ozdemir S. Patients' benefit-risk preferences for chronic idiopathic thrombocytopenic purpura therapies. Ann Pharmacother 2010; 44 (3) 479-488
    CrossrefPubMedGoogle Scholar
  • 8 Bussel JB, Lee CS, Seery C , et al. Rituximab and three dexamethasone cycles provide responses similar to splenectomy in women and those with immune thrombocytopenia of less than two years duration. Haematologica 2014; 99 (7) 1264-1271
    CrossrefPubMedGoogle Scholar
  • 9 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 (14) 2755-2762
    CrossrefPubMedGoogle Scholar
  • 10 Stasi R, Stipa E, Masi M , et al. Long-term observation of 208 adults with chronic idiopathic thrombocytopenic purpura. Am J Med 1995; 98 (5) 436-442
    CrossrefPubMedGoogle Scholar
  • 11 Sailer T, Lechner K, Panzer S, Kyrle PA, Pabinger I. The course of severe autoimmune thrombocytopenia in patients not undergoing splenectomy. Haematologica 2006; 91 (8) 1041-1045
    PubMedGoogle Scholar
  • 12 Pizzuto J, Ambriz R. Therapeutic experience on 934 adults with idiopathic thrombocytopenic purpura: Multicentric Trial of the Cooperative Latin American group on Hemostasis and Thrombosis. Blood 1984; 64 (6) 1179-1183
    PubMedGoogle Scholar
  • 13 McHeyzer-Williams LJ, McHeyzer-Williams MG. Antigen-specific memory B cell development. Annu Rev Immunol 2005; 23: 487-513
    CrossrefPubMedGoogle Scholar
  • 14 Grimaldi D, Canouï-Poitrine F, Croisille L , et al. Antiplatelet antibodies detected by the MAIPA assay in newly diagnosed immune thrombocytopenia are associated with chronic outcome and higher risk of bleeding. Ann Hematol 2014; 93 (2) 309-315
    CrossrefPubMedGoogle Scholar
  • 15 McMillan R. The pathogenesis of chronic immune thrombocytopenic purpura. Semin Hematol 2007; 44 (4) (Suppl. 05) S3-S11
    CrossrefPubMedGoogle Scholar
  • 16 Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med 2002; 346 (13) 995-1008
    CrossrefPubMedGoogle Scholar
  • 17 Roark JH, Bussel JB, Cines DB, Siegel DL. Genetic analysis of autoantibodies in idiopathic thrombocytopenic purpura reveals evidence of clonal expansion and somatic mutation. Blood 2002; 100 (4) 1388-1398
    PubMedGoogle Scholar
  • 18 Jahn S, Niemann B, Winkler T, Kalden JR, von Baehr R. Expansion of a B-lymphocyte clone producing IgM auto-antibodies encoded by a somatically mutated VHI gene in the spleen of an autoimmune patient. Rheumatol Int 1994; 13 (5) 187-196
    CrossrefPubMedGoogle Scholar
  • 19 Shlomchik MJ, Craft JE, Mamula MJ. From T to B and back again: positive feedback in systemic autoimmune disease. Nat Rev Immunol 2001; 1 (2) 147-153
    CrossrefPubMedGoogle Scholar
  • 20 Cines DB, Cuker A, Semple JW. Pathogenesis of immune thrombocytopenia. Presse Med 2014; 43 (4, Pt 2) e49-e59
    CrossrefPubMedGoogle Scholar
  • 21 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 (3) 887-895
    CrossrefPubMedGoogle Scholar
  • 22 Tsubakio T, Tani P, Curd JG, McMillan R. Complement activation in vitro by antiplatelet antibodies in chronic immune thrombocytopenic purpura. Br J Haematol 1986; 63 (2) 293-300
    PubMedGoogle Scholar
  • 23 Horikawa K, Martin SW, Pogue SL , et al. Enhancement and suppression of signaling by the conserved tail of IgG memory-type B cell antigen receptors. J Exp Med 2007; 204 (4) 759-769
    CrossrefPubMedGoogle Scholar
  • 24 Martin SW, Goodnow CC. Burst-enhancing role of the IgG membrane tail as a molecular determinant of memory. Nat Immunol 2002; 3 (2) 182-188
    CrossrefPubMedGoogle Scholar
  • 25 Leandro MJ. B-cell subpopulations in humans and their differential susceptibility to depletion with anti-CD20 monoclonal antibodies. Arthritis Res Ther 2013; 15 (Suppl. 01) S3
    PubMedGoogle Scholar
  • 26 Eisenberg RA, Jawad AF, Boyer J , et al. Rituximab-treated patients have a poor response to influenza vaccination. J Clin Immunol 2013; 33 (2) 388-396
    CrossrefPubMedGoogle Scholar
  • 27 Mahévas M, Patin P, Huetz F , et al. B cell depletion in immune thrombocytopenia reveals splenic long-lived plasma cells. J Clin Invest 2013; 123 (1) 432-442
    CrossrefPubMedGoogle Scholar
  • 28 Liu YJ, Barthélémy C, de Bouteiller O, Arpin C, Durand I, Banchereau J. Memory B cells from human tonsils colonize mucosal epithelium and directly present antigen to T cells by rapid up-regulation of B7-1 and B7-2. Immunity 1995; 2 (3) 239-248
    CrossrefPubMedGoogle Scholar
  • 29 Kindler V, Zubler RH. Memory, but not naive, peripheral blood B lymphocytes differentiate into Ig-secreting cells after CD40 ligation and costimulation with IL-4 and the differentiation factors IL-2, IL-10, and IL-3. J Immunol 1997; 159 (5) 2085-2090
    PubMedGoogle Scholar
  • 30 Tangye SG, Avery DT, Hodgkin PD. A division-linked mechanism for the rapid generation of Ig-secreting cells from human memory B cells. J Immunol 2003; 170 (1) 261-269
    CrossrefPubMedGoogle Scholar
  • 31 Tangye SG, Liu YJ, Aversa G, Phillips JH, de Vries JE. Identification of functional human splenic memory B cells by expression of CD148 and CD27. J Exp Med 1998; 188 (9) 1691-1703
    CrossrefPubMedGoogle Scholar
  • 32 Mazzucconi MG, Francesconi M, Fidani P , et al. Treatment of idiopathic thrombocytopenic purpura (ITP): results of a multicentric protocol. Haematologica 1985; 70 (4) 329-336
    PubMedGoogle Scholar
  • 33 Bellucci S, Charpak Y, Chastang C, Tobelem G. Low doses v conventional doses of corticoids in immune thrombocytopenic purpura (ITP): results of a randomized clinical trial in 160 children, 223 adults. Blood 1988; 71 (4) 1165-1169
    PubMedGoogle Scholar
  • 34 Godeau B, Chevret S, Varet B , et al; French ATIP Study Group. Intravenous immunoglobulin or high-dose methylprednisolone, with or without oral prednisone, for adults with untreated severe autoimmune thrombocytopenic purpura: a randomised, multicentre trial. Lancet 2002; 359 (9300) 23-29
    CrossrefPubMedGoogle Scholar
  • 35 Newman GC, Novoa MV, Fodero EM, Lesser ML, Woloski BM, Bussel JB. A dose of 75 microg/kg/d of i.v. anti-D increases the platelet count more rapidly and for a longer period of time than 50 microg/kg/d in adults with immune thrombocytopenic purpura. Br J Haematol 2001; 112 (4) 1076-1078
    CrossrefPubMedGoogle Scholar
  • 36 Cooper N, Woloski BM, Fodero EM , et al. Does treatment with intermittent infusions of intravenous anti-D allow a proportion of adults with recently diagnosed immune thrombocytopenic purpura to avoid splenectomy?. Blood 2002; 99 (6) 1922-1927
    CrossrefPubMedGoogle Scholar
  • 37 Thompson RL, Moore RA, Hess CE, Wheby MS, Leavell BS. Idiopathic thrombocytopenic purpura. Long-term results of treatment and the prognostic significance of response to corticosteroids. Arch Intern Med 1972; 130 (5) 730-734
    CrossrefPubMedGoogle Scholar
  • 38 DiFino SM, Lachant NA, Kirshner JJ, Gottlieb AJ. Adult idiopathic thrombocytopenic purpura. Clinical findings and response to therapy. Am J Med 1980; 69 (3) 430-442
    CrossrefPubMedGoogle Scholar
  • 39 Portielje JE, Westendorp RG, Kluin-Nelemans HC, Brand A. Morbidity and mortality in adults with idiopathic thrombocytopenic purpura. Blood 2001; 97 (9) 2549-2554
    CrossrefPubMedGoogle Scholar
  • 40 Leung AY, Chim CS, Kwong YL, Lie AK, Au WY, Liang R. Clinicopathologic and prognostic features of chronic idiopathic thrombocytopenic purpura in adult Chinese patients: an analysis of 220 cases. Ann Hematol 2001; 80 (7) 384-386
    CrossrefPubMedGoogle Scholar
  • 41 Pamuk GE, Pamuk ON, Başlar Z , et al. Overview of 321 patients with idiopathic thrombocytopenic purpura. Retrospective analysis of the clinical features and response to therapy. Ann Hematol 2002; 81 (8) 436-440
    CrossrefPubMedGoogle Scholar
  • 42 McMillan R, Durette C. Long-term outcomes in adults with chronic ITP after splenectomy failure. Blood 2004; 104 (4) 956-960
    CrossrefPubMedGoogle Scholar
  • 43 Neylon AJ, Saunders PW, Howard MR, Proctor SJ, Taylor PR ; Northern Region Haematology Group. Clinically significant newly presenting autoimmune thrombocytopenic purpura in adults: a prospective study of a population-based cohort of 245 patients. Br J Haematol 2003; 122 (6) 966-974
    CrossrefPubMedGoogle Scholar
  • 44 Cheng Y, Wong RS, Soo YO , et al. Initial treatment of immune thrombocytopenic purpura with high-dose dexamethasone. N Engl J Med 2003; 349 (9) 831-836
    CrossrefPubMedGoogle Scholar
  • 45 Bae SH, Ryoo HM, Lee WS , et al. High dose dexamethasone vs. conventional dose prednisolone for adults with immune thrombocytopenia: a prospective multicenter phase III trial. Paper presented at: Annual Meeting of the American Society of Hematology; December 2010 ; Orlando, FL
    PubMedGoogle Scholar
  • 46 Mashhadi MA, Kaykhaei MA, Sepehri Z, Miri-Moghaddam E. Single course of high dose dexamethasone is more effective than conventional prednisolone therapy in the treatment of primary newly diagnosed immune thrombocytopenia. Daru 2012; 20 (1) 7
    CrossrefPubMedGoogle Scholar
  • 47 Borst F, Keuning JJ, van Hulsteijn H, Sinnige H, Vreugdenhil G. High-dose dexamethasone as a first- and second-line treatment of idiopathic thrombocytopenic purpura in adults. Ann Hematol 2004; 83 (12) 764-768
    CrossrefPubMedGoogle Scholar
  • 48 Mazzucconi MG, Fazi P, Bernasconi S , et al; Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) Thrombocytopenia Working Party. Therapy with high-dose dexamethasone (HD-DXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura: a GIMEMA experience. Blood 2007; 109 (4) 1401-1407
    CrossrefPubMedGoogle Scholar
  • 49 Zaja F, Vianelli N, Volpetti S , et al. Low-dose rituximab in adult patients with primary immune thrombocytopenia. Eur J Haematol 2010; 85 (4) 329-334
    CrossrefPubMedGoogle Scholar
  • 50 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 (1) 25-33
    CrossrefPubMedGoogle Scholar
  • 51 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 (3) 386-398
    CrossrefPubMedGoogle Scholar
  • 52 Arnold DM, Heddle NM, Carruthers J , et al. A pilot randomized trial of adjuvant rituximab or placebo for nonsplenectomized patients with immune thrombocytopenia. Blood 2012; 119 (6) 1356-1362
    CrossrefPubMedGoogle Scholar
  • 53 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 (25) 5989-5995
    CrossrefPubMedGoogle Scholar
  • 54 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 (3) 411-423
    CrossrefPubMedGoogle Scholar
  • 55 Saleh MN, Bussel JB, Cheng G , et al; EXTEND Study Group. Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study. Blood 2013; 121 (3) 537-545
    CrossrefPubMedGoogle Scholar
  • 56 Bussel JB, Rodeghiero F, Lyons RM , et al. Sustained hemostatic platelet counts in adults with immune thrombocytopenia (ITP) following cessation of treatment with the TPO receptor agonist romiplostim: report of 9 cases. Paper presented at: Annual Meeting of the American Society of Hematology; December 6, 2011; San Diego, CA
    PubMedGoogle Scholar
  • 57 Newland A, Cervinek L, Eggermann J, Lefrere F, Kreutzbauer G. Sustained hemostatic platelet counts in adult patients with primary immune thrombocytopenia (ITP) following cessation of romiplostim—four European case studies. Paper presented at: Annual Meeting of the European Society of Hematology; June 2011; London, United Kingdom
    PubMedGoogle Scholar
  • 58 Ghadaki B, Nazi I, Kelton JG, Arnold DM. Sustained remissions of immune thrombocytopenia associated with the use of thrombopoietin receptor agonists. Transfusion 2013; 53 (11) 2807-2812
    CrossrefPubMedGoogle Scholar
  • 59 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 (6) 865-869
    CrossrefPubMedGoogle Scholar
  • 60 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 (22) 4639-4645
    CrossrefPubMedGoogle Scholar
  • 61 Gómez-Almaguer D, Tarín-Arzaga L, Moreno-Jaime B , et al. High response rate to low-dose rituximab plus high-dose dexamethasone as frontline therapy in adult patients with primary immune thrombocytopenia. Eur J Haematol 2013; 90 (6) 494-500
    CrossrefPubMedGoogle Scholar
  • 62 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 (11) 1976-1981
    CrossrefPubMedGoogle Scholar
  • 63 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 (25) 3906-3908
    CrossrefPubMedGoogle Scholar
  • 64 Nazi I, Kelton JG, Larché M , et al. The effect of rituximab on vaccine responses in patients with immune thrombocytopenia. Blood 2013; 122 (11) 1946-1953
    CrossrefPubMedGoogle Scholar
  • 65 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 (20) 4834-4840
    CrossrefPubMedGoogle Scholar