J Yeungnam Med Sci.  2023 Jul;40(3):241-246. 10.12701/jyms.2022.00745.

Advances in management of pediatric chronic immune thrombocytopenia: a narrative review

• Lee JM

• KMID: 2544583
• DOI: http://doi.org/10.12701/jyms.2022.00745

Abstract

Immune thrombocytopenia (ITP) is a disease in which thrombocytopenia occurs because of immune-mediated platelet destruction and decreased platelet production. Although many pediatric patients with ITP experience spontaneous remission or reach remission within 12 months of first-line therapy, approximately 20% progress to chronic ITP. Patients who do not respond to first-line treatment or experience frequent relapses are of great concern to physicians. This review summarizes recent treatments for second-line treatment of pediatric chronic ITP.

Keyword

Dapsone; Immune thrombocytopenia; Rituximab; Splenectomy; Thrombopoietin

Reference

References

1. Lim JH, Kim YK, Min SH, Kim SW, Lee YH, Lee JM. Epidemiology and viral etiology of pediatric immune thrombocytopenia through Korean public health data analysis. J Clin Med. 2021; 10:1356.

2. Cooper N, Ghanima W. Immune thrombocytopenia. N Engl J Med. 2019; 381:945–55.

3. Bennett CM, Neunert C, Grace RF, Buchanan G, Imbach P, Vesely SK, et al. Predictors of remission in children with newly diagnosed immune thrombocytopenia: data from the Intercontinental Cooperative ITP Study Group Registry II participants. Pediatr Blood Cancer. 2018; 65:e26736.

4. Grainger JD, Rees JL, Reeves M, Bolton-Maggs PH. Changing trends in the UK management of childhood ITP. Arch Dis Child. 2012; 97:8–11.

5. Grimaldi-Bensouda L, Nordon C, Leblanc T, Abenhaim L, Allali S, Armari-Alla C, et al. Childhood immune thrombocytopenia: a nationwide cohort study on condition management and outcomes. Pediatr Blood Cancer. 2017; 64:e26389.

6. Kühne T, Imbach P, Bolton-Maggs PH, Berchtold W, Blanchette V, Buchanan GR, et al. Newly diagnosed idiopathic thrombocytopenic purpura in childhood: an observational study. Lancet. 2001; 358:2122–5.

7. Lilleyman JS. Intracranial haemorrhage in idiopathic thrombocytopenic purpura: Paediatric Haematology Forum of the British Society for Haematology. Arch Dis Child. 1994; 71:251–3.

8. Iyori H, Bessho F, Ookawa H, Konishi S, Shirahata A, Miyazaki S, et al. Intracranial hemorrhage in children with immune thrombocytopenic purpura. Ann Hematol. 2000; 79:691–5.

9. Neunert CE, Buchanan GR, Imbach P, Bolton-Maggs PH, Bennett CM, Neufeld EJ, et al. Severe hemorrhage in children with newly diagnosed immune thrombocytopenic purpura. Blood. 2008; 112:4003–8.

10. Neunert CE, Buchanan GR, Imbach P, Bolton-Maggs PH, Bennett CM, Neufeld E, et al. Bleeding manifestations and management of children with persistent and chronic immune thrombocytopenia: data from the Intercontinental Cooperative ITP Study Group (ICIS). Blood. 2013; 121:4457–62.

11. Choudhary DR, Naithani R, Mahapatra M, Kumar R, Mishra P, Saxena R. Intracranial hemorrhage in childhood immune thrombocytopenic purpura. Pediatr Blood Cancer. 2009; 52:529–31.

12. Psaila B, Petrovic A, Page LK, Menell J, Schonholz M, Bussel JB. Intracranial hemorrhage (ICH) in children with immune thrombocytopenia (ITP): study of 40 cases. Blood. 2009; 114:4777–83.

13. Elalfy M, Elbarbary N, Khaddah N, Abdelwahab M, El Rashidy F, Hassab H, et al. Intracranial hemorrhage in acute and chronic childhood immune thrombocytopenic purpura over a ten-year period: an Egyptian multicenter study. Acta Haematol. 2010; 123:59–63.

14. Jaime-Pérez JC, Ramos-Dávila EM, Meléndez-Flores JD, Gómez-De León A, Gómez-Almaguer D. Insights on chronic immune thrombocytopenia pathogenesis: a bench to bedside update. Blood Rev. 2021; 49:100827.

15. 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; 113:2386–93.

16. Kühne T, Berchtold W, Michaels LA, Wu R, Donato H, Espina B, et al. Newly diagnosed immune thrombocytopenia in children and adults: a comparative prospective observational registry of the Intercontinental Cooperative Immune Thrombocytopenia Study Group. Haematologica. 2011; 96:1831–7.

17. Schifferli A, Holbro A, Chitlur M, Coslovsky M, Imbach P, Donato H, et al. A comparative prospective observational study of children and adults with immune thrombocytopenia: 2-year follow-up. Am J Hematol. 2018; 93:751–9.

18. Jung JY, O AR, Kim JK, Park M. Clinical course and prognostic factors of childhood immune thrombocytopenia: single center experience of 10 years. Korean J Pediatr. 2016; 59:335–40.

19. Kim CY, Lee EH, Yoon HS. High remission rate of chronic immune thrombocytopenia in children: result of 20-year follow-up. Yonsei Med J. 2016; 57:127–31.

20. Shim YJ, Kim UH, Suh JK, Lee KS. Natural course of childhood chronic immune thrombocytopenia using the revised terminology and definitions of the international working group: a single center experience. Blood Res. 2014; 49:187–91.

21. Kim JY. Diagnostic approach of childhood immune thrombocytopenia. Clin Pediatr Hematol Oncol. 2018; 25:10–6.

22. Neunert C, Lim W, Crowther M, Cohen A, Solberg L Jr, Crowther MA, et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011; 117:4190–207.

23. 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; 3:3780–817.

24. Nomura S. Advances in diagnosis and treatments for immune thrombocytopenia. Clin Med Insights Blood Disord. 2016; 9:15–22.

25. Mitchell WB, Pinheiro MP, Boulad N, Kaplan D, Edison MN, Psaila B, et al. Effect of thrombopoietin receptor agonists on the apoptotic profile of platelets in patients with chronic immune thrombocytopenia. Am J Hematol. 2014; 89:E228–34.

26. 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; 3:3829–66.

27. Wire MB, Bruce J, Gauvin J, Pendry CJ, McGuire S, Qian Y, et al. A randomized, open-label, 5-period, balanced crossover study to evaluate the relative bioavailability of eltrombopag powder for oral suspension (PfOS) and tablet formulations and the effect of a high-calcium meal on eltrombopag pharmacokinetics when administered with or 2 hours before or after PfOS. Clin Ther. 2012; 34:699–709.

28. Deng Y, Madatian A, Wire MB, Bowen C, Park JW, Williams D, et al. Metabolism and disposition of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist, in healthy human subjects. Drug Metab Dispos. 2011; 39:1734–46.

29. Grainger JD, Locatelli F, Chotsampancharoen T, Donyush E, Pongtanakul B, Komvilaisak P, et al. Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial. Lancet. 2015; 386:1649–58.

30. Bussel JB, de Miguel PG, Despotovic JM, Grainger JD, Sevilla J, Blanchette VS, et al. Eltrombopag for the treatment of children with persistent and chronic immune thrombocytopenia (PETIT): a randomised, multicentre, placebo-controlled study. Lancet Haematol. 2015; 2:e315–25.

31. Giordano P, Lassandro G, Barone A, Cesaro S, Fotzi I, Giona F, et al. Use of eltrombopag in children with chronic immune thrombocytopenia (ITP): a real life retrospective multicenter experience of the Italian Association of Pediatric Hematology and Oncology (AIEOP). Front Med (Lausanne). 2020; 7:66.

32. Bussel JB, Buchanan GR, Nugent DJ, Gnarra DJ, Bomgaars LR, Blanchette VS, et al. A randomized, double-blind study of romiplostim to determine its safety and efficacy in children with immune thrombocytopenia. Blood. 2011; 118:28–36.

33. Bussel JB, Hsieh L, Buchanan GR, Stine K, Kalpatthi R, Gnarra DJ, et al. Long-term use of the thrombopoietin-mimetic romiplostim in children with severe chronic immune thrombocytopenia (ITP). Pediatr Blood Cancer. 2015; 62:208–13.

34. Tarantino MD, Bussel JB, Blanchette VS, Despotovic J, Bennett C, Raj A, et al. Romiplostim in children with immune thrombocytopenia: a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016; 388:45–54.

35. Neunert CE, Rose MJ. Romiplostim for the management of pediatric immune thrombocytopenia: drug development and current practice. Blood Adv. 2019; 3:1907–15.

36. Newland A, Godeau B, Priego V, Viallard JF, López Fernández MF, Orejudos A, et al. Remission and platelet responses with romiplostim in primary immune thrombocytopenia: final results from a phase 2 study. Br J Haematol. 2016; 172:262–73.

37. Kuter DJ, Newland A, Chong BH, Rodeghiero F, Romero MT, Pabinger I, et al. Romiplostim in adult patients with newly diagnosed or persistent immune thrombocytopenia (ITP) for up to 1 year and in those with chronic ITP for more than 1 year: a subgroup analysis of integrated data from completed romiplostim studies. Br J Haematol. 2019; 185:503–13.

38. Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Raab R, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood. 1994; 83:435–45.

39. Bennett CM, Rogers ZR, Kinnamon DD, Bussel JB, Mahoney DH, Abshire TC, et al. Prospective phase 1/2 study of rituximab in childhood and adolescent chronic immune thrombocytopenic purpura. Blood. 2006; 107:2639–42.

40. Parodi E, Rivetti E, Amendola G, Bisogno G, Calabrese R, Farruggia P, et al. Long-term follow-up analysis after rituximab therapy in children with refractory symptomatic ITP: identification of factors predictive of a sustained response. Br J Haematol. 2009; 144:552–8.

41. Tamminga RY, Bruin MC. Rituximab treatment for symptomatic chronic ITP. Pediatr Blood Cancer. 2006; 47(5 Suppl):714–6.

42. Wang J, Wiley JM, Luddy R, Greenberg J, Feuerstein MA, Bussel JB. Chronic immune thrombocytopenic purpura in children: assessment of rituximab treatment. J Pediatr. 2005; 146:217–21.

43. Kochhar M, Neunert C. Immune thrombocytopenia: a review of upfront treatment strategies. Blood Rev. 2021; 49:100822.

44. Patel VL, Mahévas M, Lee SY, Stasi R, Cunningham-Rundles S, Godeau B, et al. Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia. Blood. 2012; 119:5989–95.

45. Zaja F, Baccarani M, Mazza P, Bocchia M, Gugliotta L, Zaccaria A, et al. Dexamethasone plus rituximab yields higher sustained response rates than dexamethasone monotherapy in adults with primary immune thrombocytopenia. Blood. 2010; 115:2755–62.

46. Gudbrandsdottir S, Birgens HS, Frederiksen H, Jensen BA, Jensen MK, Kjeldsen L, et al. Rituximab and dexamethasone vs dexamethasone monotherapy in newly diagnosed patients with primary immune thrombocytopenia. Blood. 2013; 121:1976–81.

47. Wang J, Li Y, Wang C, Zhang Y, Gao C, Lang H, et al. Efficacy and safety of the combination treatment of rituximab and dexamethasone for adults with primary immune thrombocytopenia (ITP): a meta-analysis. Biomed Res Int. 2018; 2018:1316096.

48. Oved JH, Lee CS, Bussel JB. Treatment of children with persistent and chronic idiopathic thrombocytopenic purpura: 4 infusions of rituximab and three 4-day cycles of dexamethasone. J Pediatr. 2017; 191:225–31.

49. Moss C, Hamilton PJ. Thrombocytopenia in systemic lupus erythematosus responsive to dapsone. BMJ. 1988; 297:266.

50. Rodrigo C, Gooneratne L. Dapsone for primary immune thrombocytopenia in adults and children: an evidence-based review. J Thromb Haemost. 2013; 11:1946–53.

51. Godeau B, Durand JM, Roudot-Thoraval F, Tennezé A, Oksenhendler E, Kaplanski G, et al. Dapsone for chronic autoimmune thrombocytopenic purpura: a report of 66 cases. Br J Haematol. 1997; 97:336–9.

52. Khera S, Pramanik SK, Yanamandra U, Mishra K, Kapoor R, Das S. Dapsone: an old but effective therapy in pediatric refractory immune thrombocytopenia. Indian J Hematol Blood Transfus. 2020; 36:690–4.

53. Avila ML, Amiri N, Pullenayegum E, Blanchette V, Imbach P, Kühne T, et al. Long-term outcomes after splenectomy in children with immune thrombocytopenia: an update on the registry data from the Intercontinental Cooperative ITP Study Group. Haematologica. 2020; 105:2682–5.

54. Boyle S, White RH, Brunson A, Wun T. Splenectomy and the incidence of venous thromboembolism and sepsis in patients with immune thrombocytopenia. Blood. 2013; 121:4782–90.

55. El-Alfy MS, El-Tawil MM, Shahein N. 5- to 16-year follow-up following splenectomy in chronic immune thrombocytopenic purpura in children. Acta Haematol. 2003; 110:20–4.

56. Radaelli F, Faccini P, Goldaniga M, Guggiari E, Pozzoli E, Maiolo AT, et al. Factors predicting response to splenectomy in adult patients with idiopathic thrombocytopenic purpura. Haematologica. 2000; 85:1040–4.

57. Hemmila MR, Foley DS, Castle VP, Hirschl RB. The response to splenectomy in pediatric patients with idiopathic thrombocytopenic purpura who fail high-dose intravenous immune globulin. J Pediatr Surg. 2000; 35:967–72.

58. Law C, Marcaccio M, Tam P, Heddle N, Kelton JG. High-dose intravenous immune globulin and the response to splenectomy in patients with idiopathic thrombocytopenic purpura. N Engl J Med. 1997; 336:1494–8.

59. Holt D, Brown J, Terrill K, Goldsby R, Meyers RL, Heximer J, et al. Response to intravenous immunoglobulin predicts splenectomy response in children with immune thrombocytopenic purpura. Pediatrics. 2003; 111:87–90.

60. Grainger JD, Blanchette VS, Grotzinger KM, Roy A, Bussel JB. Health-related quality of life in children with chronic immune thrombocytopenia treated with eltrombopag in the PETIT study. Br J Haematol. 2019; 185:102–6.

61. Mathias SD, Li X, Eisen M, Carpenter N, Crosby RD, Blanchette VS. A phase 3, randomized, double-blind, placebo-controlled study to determine the effect of romiplostim on health-related quality of life in children with primary immune thrombocytopenia and associated burden in their parents. Pediatr Blood Cancer. 2016; 63:1232–7.

62. Klaassen RJ, Mathias SD, Buchanan G, Bussel J, Deuson R, Young NL, et al. Pilot study of the effect of romiplostim on child health-related quality of life (HRQoL) and parental burden in immune thrombocytopenia (ITP). Pediatr Blood Cancer. 2012; 58:395–8.