TREATING ITP: What are the options in the era of new guidelines and new drugs?
Keywords:
ITP, splenectomy, romiplostim, eltrombopag, rituximab
Abstract
Primary immune thrombocytopenia (ITP) is an autoimmune disease characterised by isolated thrombocytopenia. Treating ITP may be challenging since different treatment modalities are available. While choosing the suitable option for every patient a physician should take into account both patient’s medical characteristics and wishes. The first line treatment options include: corticosteroids, intravenous immunoglobulins and intravenous anti-D immunoglobulin. Second line treatment options comprise medical (thrombopoietin receptor agonists, rituximab, fostamatinib, azathioprine, cyclophosphamide, cyclosporin A, hydroxychloroquine, mycophenolate mofetil, danazol, dapsone, vinca-alcaloids) and surgical (splenectomy) approach. However, there are some treatment gaps which remain uncovered with existing treatment modalities. Therefore, development of novel therapeutic strategies is required.
The aim of this review is to provide an illustrative overview of novel treatments for adult ITP.
References
Rodeghiero F, Stasi R, Gernsheimer T, Michel M, Provan D, Arnold DM, 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.
Terrell DR, Beebe LA, Vesely SK, Neas BR, Segal JB, George JN. The incidence of immune thrombocytopenic purpura in children and adults: A critical review of published reports. Am J Hematol. 2010;85(3):174-180.
Cooper N, Bussel J. The pathogenesis of immune thrombocytopaenic purpura. Br J Haematol. 2006;133(4):364-374.
Audia S, Mahévas M, Samson M, Godeau B, Bonnotte B. Pathogenesis of immune thrombocytopenia. Autoimmun Rev. 2017;16(6):620-632.
Provan D, Arnold DM, Bussel JB, Chong BH, Cooper N, Gernsheimer T, et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019;3(22):3780-3817.
Piel-Julian ML, Mahévas M, Germain J, Languille L, Comont T, Lapeyre-Mestre M, et al. Risk factors for bleeding, including platelet count threshold, in newly diagnosed immune thrombocytopenia adults. J Thromb Haemost. 2018;16(9):1830-1842.
Khellaf M, Michel M, Schaeffer A, Bierling P, Godeau B. Assessment of a therapeutic strategy for adults with severe autoimmune thrombocytopenic purpura based on a bleeding score rather than platelet count. Haematologica. 2005;90(6):829-832.
Matzdorff A, Meyer O, Ostermann H, Kiefel V, Eberl W, Kühne T, et al. Immune Thrombocytopenia - Current Diagnostics and Therapy: Recommendations of a Joint Working Group of DGHO, ÖGHO, SGH, GPOH, and DGTI. Oncol Res Treat. 2018;41 Suppl 5:1-30.
Kitchens CS. Amelioration of endothelial abnormalities by prednisone in experimental thrombocytopenia in the rabbit. J Clin Invest. 1977;60(5):1129-1134.
Cooper N. State of the art - how I manage immune thrombocytopenia. Br J Haematol. 2017;177(1):39-54.
Mithoowani S, Gregory-Miller K, Goy J, Miller MC, Wang G, Noroozi N, et al. High-dose dexamethasone compared with prednisone for previously untreated primary immune thrombocytopenia: a systematic review and meta-analysis. Lancet Haematol. 2016;3(10):e489-e496.
Essilini A, Comont T, Germain J, Brun N, Dingremont C, Castel B, et al. Pretreatment with standard-dose intravenous methylprednisolone does not improve outcomes in newly diagnosed immune thrombocytopenia (ITP). Eur J Haematol. 2018;100(5):412-418.
Godeau B, Chevret S, Varet B, Lefrere F, Zini MF, Bassompierre F, et al. 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.
Neunert C, Terrell DR, Arnold DM, Buchanan G, Cines DB, Cooper N, et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019;3(23):3829-3866
Rice JB, White AG, Scarpati LM, Wan G, Nelson WW. Long-term Systemic Corticosteroid Exposure: A Systematic Literature Review. Clin Ther. 2017;39(11):2216-2229.
Bierling P, Godeau B. Intravenous immunoglobulin for autoimmune thrombocytopenic purpura. Hum Immunol. 2005;66(4):387-394.
Orbach H, Katz U, Sherer Y, Shoenfeld Y. Intravenous immunoglobulin: adverse effects and safe administration. Clin Rev Allergy Immunol. 2005;29(3):173-184.
Scaradavou A, Woo B, Woloski BM, Cunningham-Rundles S, Ettineger LJ, Aledort LM, et al. Intravenous anti-D treatment of immune thrombocytopenic purpura: experience in 272 patients. Blood. 1997;89(8):2689-2700.
Despotovic JM, Lambert MP, Herman JH, Gernsheimer TB, McCrae KR, Tarantino MD, et al. RhIG for the treatment of immune thrombocytopenia: consensus and controversy (CME). Transfusion. 2012;52(5):1126-1125.
Wong RSM, Saleh MN, Khelif A, Salama A, Portella MSO, Burgess P, et al. Safety and efficacy of long-term treatment of chronic/persistent ITP with eltrombopag: final results of the EXTEND study. Blood. 2017;130 (23):2527–2536.
Cines DB, Wasser J, Rodeghiero F, Chong BH, Steurer M, Provan D, et al. Safety and efficacy of romiplostim in splenectomized and nonsplenectomized patients with primary immune thrombocytopenia. Haematologica. 2017;102(8):1342-1351.
Ghanima W, Cooper N, Rodeghiero F, Godeau B, Bussel JB. Thrombopoietin receptor agonists: ten years later. Haematologica. 2019;104(6):1112-1123.
González-Porras JR, Godeau B, Carpenedo M. Switching thrombopoietin receptor agonist treatments in patients with primary immune thrombocytopenia. Ther Adv Hematol. 2019;10:2040620719837906. Published 2019 May 9.
Bussel, J.B. Avatrombopag. Br J Haematol. 2018;183(3): 342-343.
Xie C, Zhao H, Bao X, Fu H, Lou L. Pharmacological characterization of hetrombopag, a novel orally active human thrombopoietin receptor agonist. J Cell Mol Med. 2018;22(11):5367-5377.
Shirley M, McCafferty EH, Blair HA. Lusutrombopag: A Review in Thrombocytopenia in Patients with Chronic Liver Disease Prior to a Scheduled Procedure. Drugs. 2019;79(15):1689-1695.
Zaja F, Carpenedo M, Baratè C, Borchiellini A, Chiurazzi F, Finazzi G, et al. Tapering and discontinuation of thrombopoietin receptor agonists in immune thrombocytopenia: Real-world recommendations. Blood Rev. 2020;41:100647.
Chugh S, Darvish-Kazem S, Lim W, Crowther MA, Ghanima W, Wang G, et al. Rituximab plus standard of care for treatment of primary immune thrombocytopenia: a systematic review and meta-analysis. Lancet Haematol. 2015;2(2):e75-e81.
Stasi R, Stipa E, Forte V, Meo P, Amadori S. Variable patterns of response to rituximab treatment in adults with chronic idiopathic thrombocytopenic purpura. Blood. 2002;99(10):3872-3873.
Li Y, Shi Y, He Z, Chen Q, Liu Z, Yu L, et al. The efficacy and safety of low-dose rituximab in immune thrombocytopenia: a systematic review and meta-analysis. Platelets. 2019;30(6):690-697.
Marangon M, Vianelli N, Palandri F, Mazzucconi MG, Santoro C, Barcellini W, et al. Rituximab in immune thrombocytopenia: gender, age, and response as predictors of long-term response. Eur J Haematol. 2017;98(4):371-377.
Bussel J, Arnold DM, Grossbard E, Mayer J, Trelinski J, Homenda W, et al. Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: Results of two phase 3, randomized, placebo-controlled trials. Am J Hematol. 2018;93(7):921-930.
Lambert MP. Immunomodulatory Second-Line Therapies for Immune Thrombocytopenia. Hamostaseologie. 2019;39(3):266-271.
Chang H, Tang TC, Hung YS, Li PL, Kuo MC, Wu JH, et al. Immune thrombocytopenia: Effectiveness of frontline steroids and comparison of azathioprine, splenectomy, and rituximab as second-line treatment. Eur J Haematol. 2018;101(4):549-555.
Verlin M, Laros RK Jr, Penner JA. Treatment of refractory thrombocytopenic purpura with cyclophosphamine. Am J Hematol. 1976;1(1):97-104.
Emilia G, Morselli M, Luppi M, Longo G, Marasca R, Gandini G, et al. Long-term salvage therapy with cyclosporin A in refractory idiopathic thrombocytopenic purpura. Blood. 2002;99(4):1482-1485.
Mohammadpour F, Kargar M, Hadjibabaie M. The Role of Hydroxychloroquine as a Steroid-sparing Agent in the Treatment of Immune Thrombocytopenia: A Review of the Literature. J Res Pharm Pract. 2018;7(1):4-12.
Provan D, Moss AJ, Newland AC, Bussel JB. Efficacy of mycophenolate mofetil as single-agent therapy for refractory immune thrombocytopenic purpura. Am J Hematol. 2006;81(1):19-25.
Weber E, Reynaud Q, Fort R, Durupt S, Cathebras P, Durieu I, et al. Immunomodulatory treatments for persistent and chronic immune thrombocytopenic purpura: A PRISMA-compliant systematic review and meta-analysis of 28 studies. Medicine (Baltimore). 2017;96(37):e7534.
Park YH, Yi HG, Lee MH, Kim CS, Lim JH. Clinical efficacy and tolerability of vincristine in splenectomized patients with refractory or relapsed immune thrombocytopenia: a retrospective single-center study. Int J Hematol. 2016;103(2):180-188.
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.
Chaturvedi S, Arnold DM, McCrae KR. Splenectomy for immune thrombocytopenia: down but not out. Blood. 2018;131(11):1172-1182.
Rodeghiero F. A critical appraisal of the evidence for the role of splenectomy in adults and children with ITP. Br J Haematol. 2018;181(2):183-195.
Bartholomew JR, Salgia R, Bell WR. Control of Bleeding in Patients With Immune and Nonimmune Thrombocytopenia With Aminocaproic Acid. Arch Intern Med. 1989;149(9):1959–1961.
Mayer B, Salama A. Successful treatment of bleeding with tranexamic acid in a series of 12 patients with immune thrombocytopenia. Vox Sang. 2017;112(8):767-772.
Rodeghiero F, Marranconi E. Management of immune thrombocytopenia in women: current standards and special considerations. Expert Rev Hematol. 2020;13(2):175-185.
Terrell DR, Beebe LA, Vesely SK, Neas BR, Segal JB, George JN. The incidence of immune thrombocytopenic purpura in children and adults: A critical review of published reports. Am J Hematol. 2010;85(3):174-180.
Cooper N, Bussel J. The pathogenesis of immune thrombocytopaenic purpura. Br J Haematol. 2006;133(4):364-374.
Audia S, Mahévas M, Samson M, Godeau B, Bonnotte B. Pathogenesis of immune thrombocytopenia. Autoimmun Rev. 2017;16(6):620-632.
Provan D, Arnold DM, Bussel JB, Chong BH, Cooper N, Gernsheimer T, et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019;3(22):3780-3817.
Piel-Julian ML, Mahévas M, Germain J, Languille L, Comont T, Lapeyre-Mestre M, et al. Risk factors for bleeding, including platelet count threshold, in newly diagnosed immune thrombocytopenia adults. J Thromb Haemost. 2018;16(9):1830-1842.
Khellaf M, Michel M, Schaeffer A, Bierling P, Godeau B. Assessment of a therapeutic strategy for adults with severe autoimmune thrombocytopenic purpura based on a bleeding score rather than platelet count. Haematologica. 2005;90(6):829-832.
Matzdorff A, Meyer O, Ostermann H, Kiefel V, Eberl W, Kühne T, et al. Immune Thrombocytopenia - Current Diagnostics and Therapy: Recommendations of a Joint Working Group of DGHO, ÖGHO, SGH, GPOH, and DGTI. Oncol Res Treat. 2018;41 Suppl 5:1-30.
Kitchens CS. Amelioration of endothelial abnormalities by prednisone in experimental thrombocytopenia in the rabbit. J Clin Invest. 1977;60(5):1129-1134.
Cooper N. State of the art - how I manage immune thrombocytopenia. Br J Haematol. 2017;177(1):39-54.
Mithoowani S, Gregory-Miller K, Goy J, Miller MC, Wang G, Noroozi N, et al. High-dose dexamethasone compared with prednisone for previously untreated primary immune thrombocytopenia: a systematic review and meta-analysis. Lancet Haematol. 2016;3(10):e489-e496.
Essilini A, Comont T, Germain J, Brun N, Dingremont C, Castel B, et al. Pretreatment with standard-dose intravenous methylprednisolone does not improve outcomes in newly diagnosed immune thrombocytopenia (ITP). Eur J Haematol. 2018;100(5):412-418.
Godeau B, Chevret S, Varet B, Lefrere F, Zini MF, Bassompierre F, et al. 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.
Neunert C, Terrell DR, Arnold DM, Buchanan G, Cines DB, Cooper N, et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019;3(23):3829-3866
Rice JB, White AG, Scarpati LM, Wan G, Nelson WW. Long-term Systemic Corticosteroid Exposure: A Systematic Literature Review. Clin Ther. 2017;39(11):2216-2229.
Bierling P, Godeau B. Intravenous immunoglobulin for autoimmune thrombocytopenic purpura. Hum Immunol. 2005;66(4):387-394.
Orbach H, Katz U, Sherer Y, Shoenfeld Y. Intravenous immunoglobulin: adverse effects and safe administration. Clin Rev Allergy Immunol. 2005;29(3):173-184.
Scaradavou A, Woo B, Woloski BM, Cunningham-Rundles S, Ettineger LJ, Aledort LM, et al. Intravenous anti-D treatment of immune thrombocytopenic purpura: experience in 272 patients. Blood. 1997;89(8):2689-2700.
Despotovic JM, Lambert MP, Herman JH, Gernsheimer TB, McCrae KR, Tarantino MD, et al. RhIG for the treatment of immune thrombocytopenia: consensus and controversy (CME). Transfusion. 2012;52(5):1126-1125.
Wong RSM, Saleh MN, Khelif A, Salama A, Portella MSO, Burgess P, et al. Safety and efficacy of long-term treatment of chronic/persistent ITP with eltrombopag: final results of the EXTEND study. Blood. 2017;130 (23):2527–2536.
Cines DB, Wasser J, Rodeghiero F, Chong BH, Steurer M, Provan D, et al. Safety and efficacy of romiplostim in splenectomized and nonsplenectomized patients with primary immune thrombocytopenia. Haematologica. 2017;102(8):1342-1351.
Ghanima W, Cooper N, Rodeghiero F, Godeau B, Bussel JB. Thrombopoietin receptor agonists: ten years later. Haematologica. 2019;104(6):1112-1123.
González-Porras JR, Godeau B, Carpenedo M. Switching thrombopoietin receptor agonist treatments in patients with primary immune thrombocytopenia. Ther Adv Hematol. 2019;10:2040620719837906. Published 2019 May 9.
Bussel, J.B. Avatrombopag. Br J Haematol. 2018;183(3): 342-343.
Xie C, Zhao H, Bao X, Fu H, Lou L. Pharmacological characterization of hetrombopag, a novel orally active human thrombopoietin receptor agonist. J Cell Mol Med. 2018;22(11):5367-5377.
Shirley M, McCafferty EH, Blair HA. Lusutrombopag: A Review in Thrombocytopenia in Patients with Chronic Liver Disease Prior to a Scheduled Procedure. Drugs. 2019;79(15):1689-1695.
Zaja F, Carpenedo M, Baratè C, Borchiellini A, Chiurazzi F, Finazzi G, et al. Tapering and discontinuation of thrombopoietin receptor agonists in immune thrombocytopenia: Real-world recommendations. Blood Rev. 2020;41:100647.
Chugh S, Darvish-Kazem S, Lim W, Crowther MA, Ghanima W, Wang G, et al. Rituximab plus standard of care for treatment of primary immune thrombocytopenia: a systematic review and meta-analysis. Lancet Haematol. 2015;2(2):e75-e81.
Stasi R, Stipa E, Forte V, Meo P, Amadori S. Variable patterns of response to rituximab treatment in adults with chronic idiopathic thrombocytopenic purpura. Blood. 2002;99(10):3872-3873.
Li Y, Shi Y, He Z, Chen Q, Liu Z, Yu L, et al. The efficacy and safety of low-dose rituximab in immune thrombocytopenia: a systematic review and meta-analysis. Platelets. 2019;30(6):690-697.
Marangon M, Vianelli N, Palandri F, Mazzucconi MG, Santoro C, Barcellini W, et al. Rituximab in immune thrombocytopenia: gender, age, and response as predictors of long-term response. Eur J Haematol. 2017;98(4):371-377.
Bussel J, Arnold DM, Grossbard E, Mayer J, Trelinski J, Homenda W, et al. Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: Results of two phase 3, randomized, placebo-controlled trials. Am J Hematol. 2018;93(7):921-930.
Lambert MP. Immunomodulatory Second-Line Therapies for Immune Thrombocytopenia. Hamostaseologie. 2019;39(3):266-271.
Chang H, Tang TC, Hung YS, Li PL, Kuo MC, Wu JH, et al. Immune thrombocytopenia: Effectiveness of frontline steroids and comparison of azathioprine, splenectomy, and rituximab as second-line treatment. Eur J Haematol. 2018;101(4):549-555.
Verlin M, Laros RK Jr, Penner JA. Treatment of refractory thrombocytopenic purpura with cyclophosphamine. Am J Hematol. 1976;1(1):97-104.
Emilia G, Morselli M, Luppi M, Longo G, Marasca R, Gandini G, et al. Long-term salvage therapy with cyclosporin A in refractory idiopathic thrombocytopenic purpura. Blood. 2002;99(4):1482-1485.
Mohammadpour F, Kargar M, Hadjibabaie M. The Role of Hydroxychloroquine as a Steroid-sparing Agent in the Treatment of Immune Thrombocytopenia: A Review of the Literature. J Res Pharm Pract. 2018;7(1):4-12.
Provan D, Moss AJ, Newland AC, Bussel JB. Efficacy of mycophenolate mofetil as single-agent therapy for refractory immune thrombocytopenic purpura. Am J Hematol. 2006;81(1):19-25.
Weber E, Reynaud Q, Fort R, Durupt S, Cathebras P, Durieu I, et al. Immunomodulatory treatments for persistent and chronic immune thrombocytopenic purpura: A PRISMA-compliant systematic review and meta-analysis of 28 studies. Medicine (Baltimore). 2017;96(37):e7534.
Park YH, Yi HG, Lee MH, Kim CS, Lim JH. Clinical efficacy and tolerability of vincristine in splenectomized patients with refractory or relapsed immune thrombocytopenia: a retrospective single-center study. Int J Hematol. 2016;103(2):180-188.
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.
Chaturvedi S, Arnold DM, McCrae KR. Splenectomy for immune thrombocytopenia: down but not out. Blood. 2018;131(11):1172-1182.
Rodeghiero F. A critical appraisal of the evidence for the role of splenectomy in adults and children with ITP. Br J Haematol. 2018;181(2):183-195.
Bartholomew JR, Salgia R, Bell WR. Control of Bleeding in Patients With Immune and Nonimmune Thrombocytopenia With Aminocaproic Acid. Arch Intern Med. 1989;149(9):1959–1961.
Mayer B, Salama A. Successful treatment of bleeding with tranexamic acid in a series of 12 patients with immune thrombocytopenia. Vox Sang. 2017;112(8):767-772.
Rodeghiero F, Marranconi E. Management of immune thrombocytopenia in women: current standards and special considerations. Expert Rev Hematol. 2020;13(2):175-185.