Primary Immune Thrombocytopenia and Thrombopoietin Receptor Agonists: Feasibilities of Treatment Discontinuation upon Achieving Stable Complete Platelet Response

AUTOIMMUNE THROMBOCYTOPENIA

OYu Vinogradova1,2,3, MM Pankrashkina1, AL Neverova1, MV Chernikov1, LA Mukha1, DI Shikhbabaeva1, VV Ptushkin1,2,3,4

1 SP Botkin City Clinical Hospital, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284

2 Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology, 1 Samory Mashela ul., Moscow, Russian Federation, 117997

3 NI Pirogov Russian National Research Medical University, 1 Ostrovityanova ul., Moscow, Russian Federation, 117997

4 Russian Medical Academy of Postgraduate Education, 2/1 Barrikadnaya ul., Moscow, Russian Federation, 125993

For correspondence: Anna Leonidovna Neverova, PhD in Biology, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284; Tel.: +7(916)015-65-49; e-mail: anyuta6549@yandex.ru

For citation: Vinogradova OYu, Pankrashkina MM, Neverova AL, et al. Primary Immune Thrombocytopenia and Thrombopoietin Receptor Agonists: Feasibilities of Treatment Discontinuation upon Achieving Stable Complete Platelet Response. Clinical oncohematology. 2023;16(4):413–25. (In Russ).

DOI: 10.21320/2500-2139-2023-16-4-413-425

ABSTRACT

Aim. To assess the stability of clinical remission in patients with primary immune thrombocytopenia (ITP) after withdrawal of thrombopoietin receptor agonists (TPO-RAs).

Materials & Methods. The study enrolled 456 patients with primary ITP who received second- and subsequent-line TPO-RA treatment. Complete platelet response (PR) was achieved in 338 patients, the therapy was discontinued in 116 of them. The present prospective clinical study started in 2014 and focused on the data of these 116 patients. Among them, there were 27 (23 %) men and 89 (77 %) women. By the time of TPO-RA therapy onset, the median age of the patients was 60 years (range 13–87 years), on ITP diagnosis date it was 52 years (range 1–80 years).

Results. By the time of data analysis, 59 % of patients sustained PR after TPO-RA withdrawal. The median PR duration after TPO-RA withdrawal was 230 weeks. Romiplostim and eltrombopag recipients showed no significant differences in the survival rates without PR-loss after TPO-RA withdrawal. In the present study, the maximum PR duration achieved 9.5 years. The mid-term assessment of PR status was carried out in 3, 6, 12, 24, and 30 months after TPO-RA withdrawal and showed 99 %, 94 %, 83 %, 72 %, and 70 %, respectively. The number of previous therapy lines significantly affected the survival rates without PR-loss (p = 0.011). The age of patients, prior splenectomy, TPO-RA treatment duration, time to different PR levels on therapy, PR duration on TPO-RA therapy, and platelet count upon TPO-RA withdrawal showed no significant effect on this parameter. After PR-loss, TPO-RAs were administered again to 31 (27 %) patients. Repeated PR was achieved in 26 (84 %) of them.

Conclusion. TPO-RA administration yields multi-year off-treatment remission in some patients with primary ITP. Upon therapy discontinuation, 59 % of patients with complete PR sustained PR for 3 months to 9.5 years. Stable PR after TPO-RA withdrawal significantly correlated with only one of the studied prognostic parameters, i.e., the number of previous therapy lines.

Keywords: primary immune thrombocytopenia, ITP, thrombopoietin receptor agonists, romiplostim, eltrombopag.

Received: June 30, 2023

Accepted: September 15, 2023

Read in PDF

Статистика Plumx английский

REFERENCES

  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(11):2386–93. doi: 10.1182/blood-2008-07-162503.
  2. Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;115(2):168–86. doi: 10.1182/blood-2009-06-225565.
  3. Ионова Т.И., Виноградова О.Ю., Шелехова Т.В. и др. Изменения качества жизни у пациентов с хронической иммунной тромбоцитопенией в процессе терапии ромиплостимом, его эффективность и безопасность в условиях реальной клинической практики: результаты многоцентрового наблюдательного исследования. Клиническая онкогематология. 2023;16(2):154–65. doi: 10.21320/2500-2139-2023-16-2-154-165.
    [Ionova TI, Vinogradova OYu, Shelekhova TV, et al. Quality of Life Changes in Patients with Chronic Immune Thrombocytopenia in the Process of Romiplostim Therapy, its Efficacy and Safety in the Real-World Setting: Results of a Multi-Center Observational Study. Clinical oncohematology. 2023;16(2):154–65. doi: 10.21320/2500-2139-2023-16-2-154-165. (In Russ)]
  4. Perera M, Garrido T. Advances in the pathophysiology of primary immune thrombocytopenia Hematology. 2017;22(1):41–53. doi: 10.1080/10245332.2016.1219497.
  5. Ogawara H, Handa H, Morita K, et al. High Th1/Th2 ratio in patients with chronic idiopathic thrombocytopenic purpura. Eur J Haematol. 2003;71(4):283–8. doi: 10.1034/j.1600-0609.2003.00138.x.
  6. Houwerzijl EJ, Blom NR, van der Want JJ, et al. Ultrastructural study shows morphologic features of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura. Blood. 2004;103(2):500–6. doi: 10.1182/blood-2003-01-0275.
  7. Российские клинические рекомендации. Идиопатическая тромбоцитопеническая пурпура (ИТП) у взрослых (электронный документ). Доступно по: https://npngo.ru/uploads/media_document/631/4a7a26c4-0f1b-4588-b2db-4b99d54d72epdf. Ссылка активна на 30.06.2023.
    [Russian clinical guidelines. Idiopathic thrombocytopenic purpura (ITP) in adults. (Internet) Available from: https://npngo.ru/uploads/media_document/631/4a7a26c4-0f1b-4588-b2db-4b99d54d72e5.pdf. Accessed 30.06.2023. (In Russ)]
  8. Bussel J, Cooper N, Boccia R, et al. Immune thrombocytopenia. Expert Rev Hematol. 2021;14(11):1013–25. doi: 10.1080/17474086.2021.1995347.
  9. Kaushansky K, Drachman JG. The molecular and cellular biology of thrombopoietin: the primary regulator of platelet production. Oncogene. 2002;21(21):3359–67. doi: 10.1038/sj.onc.1205323.
  10. Kuter DJ. The biology of thrombopoietin and thrombopoietin receptor agonists. Int J Hematol. 2013;98(1):10–23. doi: 10.1007/s12185-013-1382-0.
  11. Emmons RV, Reid DM, Cohen RL, et al. Human thrombopoietin levels are high when thrombocytopenia is due to megakaryocyte deficiency and low when due to increased platelet destruction. Blood. 1996;87(10):4068–71.
  12. Ballem PJ, Segal GM, Stratton JR, et al. Mechanisms of thrombocytopenia in chronic autoimmune thrombocytopenic purpura. Evidence of both impaired platelet production and increased platelet clearance. J Clin Invest. 1987;80(1):33–40. doi: 10.1172/JCI113060.
  13. Wang B, Nichol JL, Sullivan JT. Pharmacodynamics and pharmacokinetics of AMG 531, a novel thrombopoietin receptor ligand. Clin Pharmacol Ther. 2004;76(6):628–38. doi: 10.1016/j.clpt.2004.08.010.
  14. 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):4639–45. doi: 10.1182/blood-2010-04-281717.
  15. 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(9610):395–403. doi: 10.1016/S0140-6736(08)60203-2.
  16. Kuter DJ. The structure, function, and clinical use of the thrombopoietin receptor agonist avatrombopag. Blood Rev. 2022;53:100909. doi: 10.1016/j.blre.2021.100909.
  17. Масчан А.А., Румянцев А.Г., Ковалева Л.Г. и др. Рекомендации российского совета экспертов по диагностике и лечению больных первичной иммунной тромбоцитопенией. Онкогематология. 2010;5(3):36–45.
    [Maschan AA, Rumyantsev AG, Kovaleva LG, et al. Recommendations of the Russian Expert Panel on diagnosis and treatment of primary immune Onkogematologiya. 2010;5(3):36–45. (In Russ)]
  18. Neunert C, Terrell DR, Arnold DM, et al. American society of hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019;3(23):3829–66. doi: 10.1182/bloodadvances.2019000966.
  19. Provan D, Arnold DM, Bussel JB, et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019;3(22):3780–817. doi: 10.1182/bloodadvances.2019000812.
  20. Wang L, Gao Z, Chen XP, et al. Efficacy and safety of thrombopoietin receptor agonists in patients with primary immune thrombocytopenia: A systematic review and meta-analysis. Sci Rep. 2016;6:39003. doi: 10.1038/srep39003.
  21. 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):183–95. doi: 10.1111/bjh.15090.
  22. Cheng G, Saleh MN, Marcher C, et al. Lancet. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet. 2011;377(9763):393–402. doi: 10.1016/S0140-6736(10)60959-2.
  23. 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(10):2161–71. doi: 10.1182/blood-2008-04-150078.
  24. Зотова И.И., Грицаев С.В., Шилова Е.Р. и др. Агонисты рецептора тромбопоэтина в лечении идиопатической тромбоцитопенической пурпуры (первичной иммунной тромбоцитопении): эффективность и безопасность в повседневной клинической практике. Клиническая онкогематология. 2017;10(1):93–100. doi: 10.21320/2500-2139-2017-10-1-93-100.
    [Zotova II, Gritsaev SV, Shilova ER, et al. Thrombopoietin Receptor Agonists in Treatment of Idiopathic Thrompocytopenic Purpura (Primary Immune Thrombocytopenia): Efficacy and Safety in Everyday Clinical Practice. Clinical oncohematology. 2017;10(1):93–100. doi: 10.21320/2500-2139-2017-10-1-93-100. (In Russ)]
  25. Птушкин В.В., Виноградова О.Ю., Панкрашкина М.М. и др. Агонисты рецептора тромбопоэтина в лечении хронической резистентной первичной иммунной тромбоцитопении: эффективность и безопасность в повседневной клинической практике. Терапевтический архив. 2018;90(7):70–6. doi: 10.26442/terarkh201890770-76.
    [Ptushkin VV, Vinogradova OY, Pankrashkina MM, et al. Thrombopoietin Receptor Agonists in the Treatment of Chronic Resistant Primary Immune Thrombocytopenia: Efficacy and Safety Data in Real Clinical Practice. Terapevticheskii arkhiv. 2018;90(7):70–6. doi: 10.26442/terarkh201890770-76. (In Russ)]
  26. Newland A, Bussel JM, Arnold DM, et al. Predictors of Remission in Adults with Immune Thrombocytopenia Treated with Romiplostim. Blood. 2018;132(Suppl 1):735. doi: 10.1182/blood-2018-99-109791.
  27. Lucchini E, Palandri F, Volpetti S, et al. Eltrombopag second-line therapy in adult patients with primary immune thrombocytopenia in an attempt to achieve sustained remission off-treatment: results of a phase II, multicentre, prospective study. Br J Haematol. 2021;193(2):386–96. doi: 10.1111/bjh.17334.
  28. Newland A, Cervinek L, Eggermann J, et al. Sustained hemostatic platelet counts in adult patients with primary immune thrombocytopenia (ITP) following cessation of romiplostim – four European case studies. Haematologica. 2011;96(Suppl 2):98, abstract 237.
  29. Bussel J, Rodeghiero F, Lyons R, et al. Sustained hemostatic platelet counts in adults with immune thrombocytopenia (ITP) following cessation of treatment with the TPO receptor agonist romoiplostim: report of 9 cases. Blood (ASH Annual Meeting Abstracts). 2011;118(21): Abstract 3281.
  30. Leven E, Miller A, Boulad N, et al. Successful Discontinuation of Eltrombopag Treatment in Patients with Chronic ITP. 2012;120(21):1085 doi: 10.1182/blood.V120.21.1085.1085.
  31. Bussel J, Wang X, Lopez A, Eisen M. Case study of remission in adults with immune thrombocytopenia following cessation of treatment with the thrombopoietin mimetic romiplostim. Hematology. 2016;21(4):257–62. doi: 10.1179/1607845415Y.0000000041.
  32. Stasi R, Newland A, Godeau B, et al. An interim analysis of a phase 2, single-arm study of platelet responses and remission rates in patients with immune thrombocytopenia (ITP) receiving romiplostim. Blood. 2013;122(21):1074.
  33. 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(3):537–45. doi: 10.1182/blood-2012-04-425512.
  34. Gonzalez-Lopez TJ, Gonzalez-Porras JR, Arefi M, et al. Sustained response after short-medium-term treatment with eltrombopag in patients with ITP. Blood. 2013;122(21):2323. doi: 10.1182/blood.V122.21.2323.2323.
  35. Ghadaki B, Nazi I, Kelton G, Donald MA. Sustained remissions of immune thrombocytopenia associated with the use of thrombopoetin receptor agonist. Transfusion. 2013;53(11):2807–12. doi: 10.1111/trf.12139.
  36. Gonzalez-Lopez TJ, Sanchez-Gonzalez B, Pascual C, et al. Sustained response after discontinuation of short-and medium-term treatment with eltrombopag in patients with immune thrombocytopenia. Platelets. 2015;26(1):83–6. doi: 10.3109/09537104.2013.870987.
  37. Gonzalez-Lopez TJ, Pascual C, Alvarez-Roman MT, et al. Successful discontinuation of eltrombopag after complete remission in patients with primary immune thrombocytopenia. Am J Hematol. 2015;90(3):E40–Е43. doi: 10.1002/ajh.23900.
  38. Mahevas 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):865–9. doi: 10.1111/bjh.12888.
  39. Cervinek L, Mayer J, Doubek M. Sustained remission of chronic immune thrombocytopenia after discontinuation of treatment with thrombopoietin-receptor agonists in adults. Int J Hematol. 2015;102(1):7–11. doi: 10.1007/s12185-015-1793-1.
  40. Provan D, Taylor L, Nandigham R, et al. Sustained responses following treatment with romiplostim in immune thrombocytopenia: a single-centre experience. J Hematol Thrombo Dis. 2014;2(4):147–9. doi: 10.4172/2329-8790.1000147.
  41. Newland A, Godeau B, Priego V, et al. Remission and platelet responses with romiplostim in primary immune thrombocytopenia: final results from a phase 2 study. Br J Haematol. 2016;172(2):262–73. doi: 10.1111/bjh.13827.
  42. Iino M, Sakamoto Y, Sato T. Treatment-free remission after thrombopoietin receptor agonist discontinuation in patients with newly diagnosed immune thrombocytopenia: an observational retrospective analysis in real-world clinical practice. Int J Hematol. 2020;112(2):159–68. doi: 10.1007/s12185-020-02893-y.
  43. Mahevas M, Guillet S, Viallard J-F, et al. Rate of Prolonged Response after Stopping Thrombopoietin-Receptor Agonists Treatment in Primary Immune Thrombocytopenia (ITP): Results from a Nationwide Prospective Multicenter Interventional Study (STOPAGO). 2021;138(Suppl 1):583. doi: 10.1182/blood-2021-152767.
  44. Doobaree IU, Newland A, McDonald V, et al. Primary immune thrombocytopenia (ITP) treated with romiplostim in routine clinical practice: retrospective study from the United Kingdom ITP Registry. Eur J Haematol. 2019;102(5):416–23. doi: 10.1111/ejh.13221.
  45. Forsythe A, Schneider J, Pham T, et al. Real-world evidence on clinical outcomes in immune thrombocytopenia treated with thrombopoietin receptor agonists. J Comp Eff Res. 2020;9(7):447–57. doi: 10.2217/cer-2019-0177.
  46. Виноградова О.Ю., Бобкова М.М., Черников М.В. и др. Сохранение ремиссии без лечения у больных иммунной тромбоцитопенией (ИТП) с полным стойким ответом на терапию агонистами тромбопоэтиновых рецепторов (аТПОр). Гематология и трансфузиология. 2020;65(S1):22.
    [Vinogradova OYu, Bobkova MM, Chernikov MV, et al. Sustaining off-treatment remission in immune thrombocytopenia (ITP) patients with complete stable response to thrombopoietin receptor agonists (TPO-RAs). Gematologiya i transfuziologiya. 2020;65(S1):22. (In Russ)]
  47. Barlassina A, Gonzalez-Lopez TJ, Cooper N, Zaja F. European Delphi panel to build consensus on tapering and discontinuing thrombopoietin receptor agonists in immune thrombocytopenia. Platelets. 2023:2170999. doi: 10.1080/09537104.2023.2170999. Epub ahead of print.