1. 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.  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.  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.  Newly diagnosed: diagnosis to 3 months  Persistent: 3 to 12 months from diagnosis  Chronic: more than 12 months 3 months 12 months Diagnosis Newly diagnosed PersistentChronic Blood. 2009;113(11):2386-2393.

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

11. Plt> 30X10^9/L: 86% at 5 years CR:>100X10^9/L PR: 30X10^9/L ~ 100X10^9/L CR:61% @ 5 yrs PR +CR:86% @ 5 yrs Haematologica 2006;91(8):1041-1045.

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

13.  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 0.7g/Kg/day D1-3 Plt<20x10^9/L HDMP 15mg/Kg/day D1-3 Daily dose<1g Prednisolone (10mg) 1mg/Kg/day D4-21 Lancet 2002;359(9300):23-29.

15. Longer time to loss of response

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

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

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

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

26. Truly refractory cases post splenectomy : 5/183(2.7%)

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

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

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

31.  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.  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. Lancet 2009;373(9664): 641-648. 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 μ L

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

37. Lancet 2008;371(9610): 395-403. SC QW for 24 weeks To keep Plt 50×10 ⁹ /L to 200×10 ⁹ /L. Splenectomised:3ug/Kg Non- splenectomised:2ug/Kg

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

40.  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.  Weekly infusion of 375mg/m 2 for 4 weeks in 16/19 studies Ann Intern Med 2007;146(1):25-33.

42.  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.  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.  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.  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.  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.  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.  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!