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Targeted therapies for immune thrombocytopenic purpura: a meta-analysis of randomized controlled trials

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Abstract

Several targeted therapies have been approved in recent years for second-line treatment of immune thrombocytopenic purpura (ITP), providing an alternative to rituximab and splenectomy. The extent to which these drugs reduce bleeding risk has not been well defined. Targeted therapies recently approved for the treatment of ITP in adults were identified through a search of recently published professional guidelines. Randomized controlled trials (RCTs) supporting regulatory approval were identified through a search of drug labels on FDA@gov. Odds ratios (ORs) and associated 95% confidence intervals (CIs) were computed for pre-specified efficacy outcomes including platelet recovery to ≥ 50,000/µL, major and minor bleeding events, and survival. ORs for all adverse events were also computed. Four targeted therapies were identified, including three thrombopoietin receptor agonists and one tyrosine kinase inhibitor. Six RCTs, comprising 752 patients, were included in the meta-analysis. More patients treated with targeted therapies for ITP as compared to placebo achieved platelet counts over ≥ 50,000/µL (OR 8.29, 95% CI 5.59–12.29). Compared to placebo, targeted therapies for ITP were associated with significantly lower odds for major bleeding (OR 0.43, 95% CI 0.21–0.91), minor bleeding (OR 0.66, 95% CI 0.45–0.97), and with numerically lower mortality rates (OR 0.24, 95% CI 0.05–1.07). The odds for adverse events were comparable between the two arms (OR 1.43 95% CI 0.76–2.67). Compared to placebo, targeted therapies for ITP increase platelet counts, decrease bleeding events, and show a trend towards lower mortality, without increased toxicity. These findings support their use as a second-line ITP treatment.

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References

  1. Rodeghiero F, Stasi R, Gernsheimer T et al (2009) Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood 113(11):2386–2393

    Article  CAS  Google Scholar 

  2. Abrahamson PE, Hall SA, Feudjo-Tepie M, Mitrani-Gold FS, Logie J (2009) The incidence of idiopathic thrombocytopenic purpura among adults: a population-based study and literature review. Eur J Haematol 83(2):83–89

    Article  Google Scholar 

  3. Cohen YC, Djuibegovic B, Shamai-Lubovitz O, Mozes B (2000) The bleeding risk and natural history of idiopathic thrombocytopenic purpura in patients with persistent low platelet counts. Arch Intern Med 160(11):1630–1638

    Article  CAS  Google Scholar 

  4. Neunert C, Terrell DR, Arnold DM et al (2019) American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv 3(23):3829–3866

    Article  CAS  Google Scholar 

  5. Provan D, Arnold DM, Bussel JB et al (2019) Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv 3(22):3780–3817

    Article  Google Scholar 

  6. Kuter DJ, Bussel JB, Lyons RM et al (2008) Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet 371(9610):395–403

    Article  CAS  Google Scholar 

  7. Bussel JB, Provan D, Shamsi T et al (2009) Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet 373(9664):641–648

    Article  CAS  Google Scholar 

  8. Bussel JB, Cheng G, Saleh MN et al (2007) Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med 357(22):2237–2247

    Article  CAS  Google Scholar 

  9. Cheng G, Saleh MN, Marcher C et al (2011) Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet 377(9763):393–402

    Article  CAS  Google Scholar 

  10. Jurczak W, Chojnowski K, Mayer J et al (2018) Phase 3 randomised study of avatrombopag, a novel thrombopoietin receptor agonist for the treatment of chronic immune thrombocytopenia. Br J Haematol 183(3):479–490

    Article  CAS  Google Scholar 

  11. Bussel JB, Arnold DM, Grossbard E et al (2018) Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: results of two phase 3, randomized, placebo-controlled trials. Am J Hematol 93(7):921–930

    Article  CAS  Google Scholar 

  12. Bussel JB, Kuter DJ, Aledort LM et al (2014) A randomized trial of avatrombopag, an investigational thrombopoietin- receptor agonist, in persistent and chronic immune thrombocytopenia. Blood 123(25):3887–3894

    Article  CAS  Google Scholar 

  13. FDA Labels [Internet]. Available from: https://labels.fda.gov/. Accessed 10 Apr 2021

  14. Sweeting MJ, Sutton AJLP (2004) What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med 23(9):1351–1375

    Article  Google Scholar 

  15. Higgins JPT, Deeks JJ A, DG. Meta-analysis of rare events [Internet]. Cochrane Handb. Syst. Rev. Interv. Version 5.1.0 [updated March 2011]. 2011;Available from: http://www.cochrane-handbook.org

  16. Bussel JB, Kuter DJ, Pullarkat V et al (2009) Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP. Blood 113(19):4822

    Article  CAS  Google Scholar 

  17. Newland A, Godeau B, Priego V et al (2016) Remission and platelet responses with romiplostim in primary immune thrombocytopenia: final results from a phase 2 study. Br J Haematol 172(2):262–273

    Article  CAS  Google Scholar 

  18. Wong RSM, Saleh MN, Khelif A et al (2017) Safety and efficacy of long-term treatment of chronic/persistent ITP with eltrombopag: final results of the EXTEND study. Blood 130(23):2527–2536

    Article  CAS  Google Scholar 

  19. Miller AB, Hoogstraten B, Staquet M, Winkler A (1981) Reporting results of cancer treatment. Cancer 47(1):207–214

    Article  CAS  Google Scholar 

  20. Mithoowani S, Cervi A, Shah N et al (2020) Management of major bleeds in patients with immune thrombocytopenia. J Thromb Haemost 18(7):1783–1790

    Article  CAS  Google Scholar 

  21. Cooper N, Kruse A, Kruse C et al (2021) Immune thrombocytopenia (ITP) World Impact Survey (iWISh): patient and physician perceptions of diagnosis, signs and symptoms, and treatment. Am J Hematol 96(2):188–198

    Article  CAS  Google Scholar 

  22. Kistangari G, McCrae KR (2013) Immune thrombocytopenia. Hematol Oncol Clin N Am 27(3):495–520

    Article  Google Scholar 

  23. Kojouri K, Vesely SK, Terrell DR, George JN (2004) 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 104(9):2623–2634

    Article  CAS  Google Scholar 

  24. Rayaz, Ahmed Anup J., Devasia Auro, Viswabandya Kavitha M., Lakshmi Aby, Abraham Sampath, Karl John, Mathai Paul M., Jacob Deepak, Abraham Alok, Srivastava Vikram, Mathews Biju, George (2016) Long-term outcome following splenectomy for chronic and persistent immune thrombocytopenia (ITP) in adults and children. Ann Hematol 95(9):1429–1434. https://doi.org/10.1007/s00277-016-2738-3

  25. Khellaf M, Charles-Nelson A, Fain O et al (2014) Safety and efficacy of rituximab in adult immune thrombocytopenia: results from a prospective registry including 248 patients. Blood 124(22):3228–3236

    Article  CAS  Google Scholar 

  26. Ghanima W, Khelif A, Waage A et al (2015) Rituximab as second-line treatment for adult immune thrombocytopenia (the RITP trial): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 385(9978):1653–1661

    Article  CAS  Google Scholar 

  27. Moulis G, Sailler L, Sommet A, Lapeyre-Mestre M, Derumeaux H, Adoue D (2014) Rituximab versus splenectomy in persistent or chronic adult primary immune thrombocytopenia: an adjusted comparison of mortality and morbidity. Am J Hematol 89(1):41–46

    Article  CAS  Google Scholar 

  28. EtD framework for splenectomy compared with TPO-RAs.OU Sooner GRADE Team. https://guidelines.gradepro.org/profile/48EBDD57-1185-3054-9ADF-00ABE6EC1D18. Accessed 04/10/2021

  29. EtD framework for rituximab compared with TPO-RAs. OU Sooner GRADE Team. https://guidelines.gradepro.org/profile/F6795F46-991E-E43A-%0A99FA-95F588C70354%0A. Accessed 04/10/2021

  30. Birocchi S, Podda GM, Manzoni M, Casazza G, Cattaneo M (2020) Thrombopoietin receptor agonists for the treatment of primary immune thrombocytopenia: a meta-analysis and systematic review. Platelets 00(00):1–11

    Google Scholar 

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Authors and Affiliations

  1. Medicine T, Tel Aviv Sourasky Medical Center, Weizmann 6, 6423906, Tel Aviv, Israel

    Inbar Cohen & Ofer Isakov

  2. The Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, Tel Aviv, Israel

    Inbar Cohen, Ilya Kirgner, Avi Leader, Pia Raanani, Ofer Isakov & Daniel Shepshelovich

  3. Department of Medical Oncology, Shaare Zedek Medical Center, and the Faculty of Medicine, Hebrew University, Jerusalem, Israel

    Hadar Goldvaser

  4. Hematology Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Ilya Kirgner

  5. Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel

    Avi Leader & Pia Raanani

  6. Medicine D, Tel Aviv Sourasky Medical, Weizmann 6, 6423906, Tel Aviv, Israel

    Daniel Shepshelovich

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  1. Inbar Cohen
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Correspondence to Inbar Cohen.

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Cohen, I., Goldvaser, H., Kirgner, I. et al. Targeted therapies for immune thrombocytopenic purpura: a meta-analysis of randomized controlled trials. Ann Hematol 100, 2879–2887 (2021). https://doi.org/10.1007/s00277-021-04669-8

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  • DOI: https://doi.org/10.1007/s00277-021-04669-8

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