ASH 2011 evidence-based practice guideline for ITP

1. ASH 2011 evidence-based practice guideline for ITP ITP in the adult Blood.2011;117(16):4190-4207 Presentor: 周益聖 Instructor: 蕭樑材 財團法人台灣癌症臨床研究發展基金會

2. Outline • Grade system of recommendation • IWG definition • Diagnosis • Course • Bleeding risk • Treatment of fresh case • IVIG vs High dose MTP + prednisolone vs placebo • HD dexamethasone • Treatment of refractory/relapase cases after initial steroid • Splenectomy • TPO agonists • Rituximab • Take home massage

3. Grade system of recommendation • 1A, 1B, 1C, 2A, 2B, 2C • Number: strength of recommendation • 1-we recommend.. • 2- we suggest.. • Alphabetical: quality of evidence • A- RCTs or exceptionally strong observation studies • B- RCTs with limitation or strong observation studies • C-RCTs with serious flaws , weaker observations or indirect evidence Blood.2011;117(16):4190-4207

4. International working group(IWG) definition • Newly diagnosed: diagnosis to 3 months • Persistent: 3 to 12 months from diagnosis • Chronic: more than 12 months Diagnosis 3 months 12 months Newly diagnosed Persistent Chronic Blood. 2009;113(11):2386-2393.

5. Diagnosis • Recommend • Check HCV and HIV (1B) • Suggest • Further investigation if abnormalities other than thrombocytopenia (including IDA) in the blood count or smear (2C) • Bone marrow examination not necessary irrespective of age with typical ITP(2C) • Insufficient evidence to recommend routine check anti-platelet Ab , APA, ANA, TPO levels Blood.2011;117(16):4190-4207

6. Causes of Secondary ITP • Antiphospholipid syndrome • Autoimmune thrombocytopenia(eg Evans syndrome) • Common variable immune deficiency • Drug administration side effect • Infection with CMV, Helicobacter pylori, HCV, HIV, varicella zoster • Lymphoproliferative disorder • Vaccination side effect • SLE Blood.2011;117(16):4190-4207

7. ITP & Anti-plateltAb Flow Cytometry using donor platelets as target cells detects detects autoAb in 70 %(31/44) in ITP SPRCA ( Solid phase red cell adherence assay)for plasma anti-platelet Ab Sensitivity: 50% (22/44), Specificty:100% J Chin Med Assoc 2006;69(12):569-574.

8. Treatment of fresh case • Suggest • Treat newly diagnosed patients with platelet count <30x10^9/L(2C) • Longer courses of steroid are preferred than short courses of steroid or IVIG as first-line treatment (2B) • IVIG combined with steroid if more rapid increase in platelet count desired(2B) • IVIG or anti-D as first line if steroid contraindicated(2C) • IVIG dose : 1g/Kg as one-time dose, repeated higher doses if necessary (2B) Br J Haematol 1999;107(4):716-719.(1.5g/Kg)

9. Treatment of fresh case • Suggest • Treat newly diagnosed patients with platelet count <30x10^9/L(2C) • Longer courses of steroid are preferred than short courses of steroid or IVIG as first-line treatment (2B) • IVIG combined with steroid if more rapid increase in platelet count desired(2B) • IVIG or anti-D as first line if steroid contraindicated(2C) • IVIG dose : 1g/Kg as one-time dose, repeated if necessary (2B) Blood.2011;117(16):4190-4207

10. Course of Severe ITP 72 pts : steroid only ( 1mg/ kg/ day) 9 pts: high dose IVIG (0.5-2g/kg) 28pts: combined both 5 pts: conservative CR:>100X10^9/L PR: 30X10^9/L ~ 100X10^9/L Haematologica 2006;91(8):1041-1045.

11. Course of Severe ITP without splenectomy Plt>30X10^9/L: 86% at 5 years CR:>100X10^9/L PR: 30X10^9/L ~ 100X10^9/L PR +CR:86% @ 5 yrs CR:61% @ 5 yrs Haematologica 2006;91(8):1041-1045.

12. ITP – persistent thrombocytopenia & fatal bleeding 47.8% in aged >60 yrs @ 5 yrs Plt<30x10^9/L Fatal bleeding 2.2% in aged <40 yrs @ 5 yrs 76% in aged >60 years at 2 years Non-fatal bleeding Arch Intern Med 2000;160(11):1630-1638.

13. Treatment of fresh case • Suggest • Treat newly diagnosed patients with platelet count <30x10^9/L(2C) • Longer courses of steroid are preferred than short courses of steroid or IVIG as first-line treatment (2B) • IVIG combined with steroid if more rapid increase in platelet count desired(2B) • IVIG or anti-D as first line if steroid contraindicated(2C) • IVIG dose : 1g/Kg as one-time dose, repeated if necessary (2B) Blood.2011;117(16):4190-4207

14. IVIG Vs. HDMP for ITP Plt<20x10^9/L HDMP 15mg/Kg/day D1-3 Daily dose<1g IVIG 0.7g/Kg/day D1-3 Prednisolone (10mg) 1mg/Kg/day D4-21 Lancet 2002;359(9300):23-29.

15. Longer time to loss of response Lancet 2002;359(9300):23-29.

16. Lancet 2002;359(9300):23-29.

17. High dose Dexamethasone for ITP Dex 40mg/day D1-4 -Dex 40mg/day D1-4 -Pred 15mg maintian N Engl J Med 2003;349(9):831-836.

18. -Plt at D10<90X10^9/L->70% relapse -36% required additional treatment -42% had plt >50X10^9/L at 6 months N Engl J Med 2003;349(9):831-836.

19. High dose Dexamethasone for ITP • Dexamasone 40mg IVA QD x4 days • Every 28 days for 6 cycles • Prednisone at 0.25 mg/kg/day PO • Plt < 20X10^9 /L • Bleeding symptoms related to thrombocytopenia • CR - >150X10^9/L • PR - 50X10^9/L ~ 150X10^9/L • MR( minimal response) • 20X10^9/L ~ 50X10^9/L (Monocenter: 1996 and June 2000 at the Haematology Department of the University La Sapienza of Rome,Hospital Policlinico Umberto I Italy) • 30X10^9/L ~ 50X10^9/L (GIMEMAmulticenter pilot study) • NR( no response) • <20X10^9/L (Monocenter) • <20X10^9/L (GIMEMAmulticenter pilot study) Blood 2007;109(4):1401-1407.

20. Monocenter trial RFS: 97% at 6 months 90% at 15 months 58% at 50 months RFS RFS: Cycle 6 : 94% at 15 months Cycle 3-4-5: 84% at 15 months RFS according to cycles Blood 2007;109(4):1401-1407.

21. Blood 2007;109(4):1401-1407.

22. GIMEMAmulticenter pilot study RFS: <18y/o: 96% at 15 ms >=18y/o: 60% at 15 ms RFS: CR : 87% at 15ms PR+MR:65% at 15ms Blood 2007;109(4):1401-1407.

23. Treatment of unresponsive or relapse cases after initial steroid • Recommend • Splenectomy for patients failing steroid (1B) • The only treatment for sustained remission off all treatment at 1 year and beyond in a high proportion of patients • Deferred for at least 6 months after diagnosis Blood. 2010;115(2):168-186. • Against further treatment in asymptomatic patients after splenectomy with platelet count >30x10^9/L (1C) Blood.2011;117(16):4190-4207

24. Chronic ITP post splenectomy Br J Haematol 2003;120(6):1079-1088.

25. Br J Haematol 2003;120(6):1079-1088.

26. Truly refractory cases post splenectomy : 5/183(2.7%) Br J Haematol 2003;120(6):1079-1088.

27. Br J Haematol 2003;120(6):1079-1088.

28. Chronic ITP after splenectomy failure Gooup 0: spontaneous remission Group 1: response to steroid,danazol,colchicine, vinblastin, rituximab,interferon Group 2:response to oral cyclophosphmide, azathioprine,cyclosproine Group 3: response to IV cyclophosphmide or C/T Blood 2004;104(4):956-960.

29. Blood 2004;104(4):956-960.

30. Blood 2004;104(4):956-960.

31. Laprascopic vs. open splenectomy • Both offer similar efficacy (1C) Blood 2004;104(9):2623-2634 Surg Endosc 2006;20(8):1208-1213. • 2010 CDC recommend • pneumococcal and meningococcal vaccination for elective splenectomy • One dose of H influenzae type b is not contraindicated before splenectomy Blood 2007;109(4):1401-1407.

32. Treatment of unresponsive or relapse cases after splenectomy • Recommend • TPO agonists for risk of bleeding who relapse after splenectomy or who have contraindication to splenectomy failing at least one other therapy (1B) • Suggest • TPO for risk of bleeding who failed one line of therapy (steroid or IVIG) and s/p no splenectomy (2C) • Rituximab for risk of bleeding who failed one line of therapy (steroid , IVIG or splenectomy) (2C)

33. Blood.2011;117(16):4190-4207

34. Eltrombopag & ITP 50 mg or placebo PO once daily for 6 weeks Increased from 50 mg to 75 mg after 3 weeks in patients with platelet counts less than 50 000 per μL Lancet 2009;373(9664):641-648.

35. Lancet 2009;373(9664): 641-648.

36. Lancet 2009;373(9664):641-648.

37. Romiplostim & ITP Lancet 2008;371(9610): 395-403. Splenectomised:3ug/Kg Non-splenectomised:2ug/Kg SC QW for 24 weeks To keep Plt 50×10⁹/L to 200×10⁹/L.

38. Lancet 2008;371(9610): 395-403.

39. Lancet 2008;371(9610): 395-403.

40. TPO agonists • US FDA approval: chronic ITP with insufficient response to steroid, IVIG , or splenectomy • Thrombocytopenia recurs or worsen if suddenly abrupted • Increased risk of portal venous thrombosis in chronic liver disease Hematol 2010;47(3):289-298. • Increased marrow reticulin fibrosis in 10/271 in the romiplostin trials Blood 2009;114(18):3748-3756.

41. Rituximab & ITP • Weekly infusion of 375mg/m2 for 4 weeksin 16/19 studies Ann Intern Med 2007;146(1):25-33.

42. Rituximab response • 30% at one year J Support Oncol 2007;5 4 suppl 2:82-84. 2007. • 9/26 (35%) had long-term response • median follow-up of 57 months (range 39–69) • 11/26 (42%) did not necessitate further therapy Eur J Haematol 2008;81(3):165-169.

43. Take home masage • Treat newly diagnosed patients with platelet count <30x10^9/L • Longer courses of steroid are preferred than short courses of steroid or IVIG as first-line treatment • Splenectomy for patients failing steroid • Against further treatment in asymptomatic patients after splenectomy with platelet count >30x10^9/L • TPO agonists for risk of bleeding who relpase after splenectomy or who have contraindication to splenectomy failing at least one other therapy • Rituximab for risk of bleeding who failed one line of therapy (steroid , IVIG or splenectomy)

44. Take home masage • Treat newly diagnosed patients with platelet count <30x10^9/L • Longer courses of steroid are preferred than short courses of steroid or IVIG as first-line treatment • Splenectomy for patients failing steroid • Against further treatment in asymptomatic patients after splenectomy with platelet count >30x10^9/L • TPO agonists for risk of bleeding who relpase after splenectomy or who have contraindication to splenectomy failing at least one other therapy • Rituximab for risk of bleeding who failed one line of therapy (steroid , IVIG or splenectomy)

45. Take home masage • Treat newly diagnosed patients with platelet count <30x10^9/L • Longer courses of steroid are preferred than short courses of steroid or IVIG as first-line treatment • Splenectomy for patients failing steroid • Against further treatment in asymptomatic patients after splenectomy with platelet count >30x10^9/L • TPO agonists for risk of bleeding who relpase after splenectomy or who have contraindication to splenectomy failing at least one other therapy • Rituximab for risk of bleeding who failed one line of therapy (steroid , IVIG or splenectomy)

46. Take home masage • Treat newly diagnosed patients with platelet count <30x10^9/L • Longer courses of steroid are preferred than short courses of steroid or IVIG as first-line treatment • Splenectomy for patients failing steroid • Against further treatment in asymptomatic patients after splenectomy with platelet count >30x10^9/L • TPO agonists for risk of bleeding who relpase after splenectomy or who have contraindication to splenectomy failing at least one other therapy • Rituximab for risk of bleeding who failed one line of therapy (steroid , IVIG or splenectomy)

47. Take home masage • Treat newly diagnosed patients with platelet count <30x10^9/L • Longer courses of steroid are preferred than short courses of steroid or IVIG as first-line treatment • Splenectomy for patients failing steroid • Against further treatment in asymptomatic patients after splenectomy with platelet count >30x10^9/L • TPO agonists for risk of bleeding who relpase after splenectomy or who have contraindication to splenectomy failing at least one other therapy • Rituximab for risk of bleeding who failed one line of therapy (steroid , IVIG or splenectomy)

48. Take home masage • Treat newly diagnosed patients with platelet count <30x10^9/L • Longer courses of steroid are preferred than short courses of steroid or IVIG as first-line treatment • Splenectomy for patients failing steroid • Against further treatment in asymptomatic patients after splenectomy with platelet count >30x10^9/L • TPO agonists for risk of bleeding who relpase after splenectomy or who have contraindication to splenectomy failing at least one other therapy • Rituximab for risk of bleeding who failed one line of therapy (steroid , IVIG or splenectomy)

49. Thanks for your attention!