Refractory ITP

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Slide ประกอบการบรรยายเรื่อง refractory ITP โดย รศ.พลภัทร โรจน์นครินทร์ ในการประชุมกลางปี สมาคมโลหิตวิทยาแห่งประเทศไทย พฤศจิกายน 2552

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Refractory ITP

  1. 1. PONLAPAT ROJNUCKARIN, M.D. PH.D. CHULALONGKORN UNIVERSITY How do I treat refractory ITP
  2. 2. Time to responses to initial treatments Blood. 2009;113:2386
  3. 3. Definition of Refractory ITP BJH 2008; 143, 16
  4. 4. Conditions to be excluded <ul><li>Drugs: estrogen, valproic acid, quinine/quinidine </li></ul><ul><li>Infections: HIV, HCV, ? H. pyroli </li></ul><ul><li>Hereditary thrombocytopenia: May-Hegglin anomaly, Bernard-Soulier syndrome </li></ul><ul><li>Myelodysplastic syndrome </li></ul><ul><li>Thrombotic thrombocytopenic purpura </li></ul><ul><li>Lymphoma, CLL </li></ul><ul><li>Autoimmune diseases </li></ul>BJH 2008; 143, 16
  5. 5. May-Hegglin Anomaly
  6. 6. Bernard-Soulier syndrome
  7. 7. Aim of therapy <ul><li>Weight against the toxicity of therapy </li></ul><ul><li>Start treatment: Platelet < 30 x 10 9 /L or bleeding </li></ul><ul><li>Initial aim: Platelet > 100 x 10 9 /L </li></ul><ul><li>Poorly responsive or steroid-dependent ITP </li></ul><ul><ul><li>Platelet > 30 x 10 9 /L and No bleeding </li></ul></ul><ul><ul><li>Requires prednisolone < 10 mg/d </li></ul></ul><ul><li>Refractory </li></ul><ul><ul><li>? 10-20 x 10 9 /L </li></ul></ul><ul><ul><li>No clinical bleeding (Only bruises) irrespective of platelet count </li></ul></ul>
  8. 8. Initial treatment <ul><li>Prednisolone 1 mg/kg/d </li></ul><ul><li>Dexamethasone 40 mg/d x 4 days </li></ul><ul><ul><li>Every 4 weeks x 6 cycles </li></ul></ul><ul><ul><li>Followed by prednisolone 0.5 mg/kg/d </li></ul></ul><ul><li>Dexamethasone: lower steroid cumulative dose, but it is intolerable (Dizziness, insomnia, psychosis) in some patients. </li></ul>
  9. 9. P=.016 P=.046 Praituan, JTH 2009; 7: 1036
  10. 10. Prednisolone tapering <ul><li>Depending on plt response, Hx of relapse, steroid side effects </li></ul><ul><li>60 to 30 mg/d: 5 mg/wk </li></ul><ul><li>30 to 0 mg/d : very slowly, e.g. 6 months or more </li></ul><ul><li>Too rapid tapering may result in severe thrombocytopenia refractory to treatments </li></ul>
  11. 12. Splenectomy <ul><li>Complete Response (plt > 100 x10 9 ) 1731/2623 (66%) </li></ul><ul><li>Response in 3-4 days (within 10 days) </li></ul><ul><li>15% relapse (median of 33 months FU) </li></ul><ul><li>No reliable predictor of response (controversial) </li></ul><ul><ul><li>Young </li></ul></ul><ul><ul><li>Responsive to IVIg ( N Engl J Med 1997 ;336:1494 ) </li></ul></ul>Kojouri K et al, Blood 2004
  12. 13. Splenectomy <ul><li>Laparotomy </li></ul><ul><ul><li>12.9% complication (318/2465) </li></ul></ul><ul><ul><li>1% mortality (48/4955) </li></ul></ul><ul><li>Laparoscopy </li></ul><ul><ul><li>9.6% complication (88/921) </li></ul></ul><ul><ul><li>0.2% mortality (3/1301) </li></ul></ul><ul><li>Post-splenectomy sepsis 1/1500/yr </li></ul>Kojouri K et al, Blood 2004
  13. 14. Laparoscopic Splenectomy
  14. 15. Treatment of ITP
  15. 16. Refractory ITP denied splenectomy. <ul><li>19 patients </li></ul><ul><li>On Steroid/Danazol </li></ul><ul><li>All finally can stop therapy. </li></ul><ul><li>10: normal count (FU 7.7 (1-12) yr) </li></ul><ul><li>9: platelet increased (FU 10.3 (3-15) yr) </li></ul><ul><li>Spontaneous remissions are reported ( Ann Hematol. 2007; 86: 705 ). </li></ul>McMillan
  16. 17. Pulse Dexamethasone <ul><li>10 pt refractory ITP </li></ul><ul><li>Dexamethasone 40 mg/d X 4d every 28 days for 6 cycles </li></ul><ul><li>All have some responses </li></ul><ul><li>Later reports cannot reproduce this result. </li></ul>N Engl J Med 1994 ;330:1560-4
  17. 18. Dapsone <ul><li>75-100 mg/d, inexpensive </li></ul><ul><li>Mild hemolysis: macrophage blocking </li></ul><ul><li>Response 33/66 </li></ul><ul><li>Usually relapse after stop the drug </li></ul><ul><li>SE: Hemolysis (G6PD def), Methemoglobinemia, agranulocytosis, liver toxicity </li></ul>Br J Haematol. 1997;97:336-9.
  18. 19. Colchicine <ul><li>Microtubule inhibitor in macrophage </li></ul><ul><li>1-2 mg/d </li></ul><ul><li>Effective 4/14 refractory case </li></ul><ul><li>SE: minimal, Nausea, Diarrhea </li></ul>Arch Intern Med. 1984; 144:2198
  19. 20. Danazol <ul><li>Attenuated androgen (600 mg/d, ฿ 60/d) </li></ul><ul><li>62.7% Good Response (may need 3-6 m.) </li></ul><ul><ul><li>82% Older women </li></ul></ul><ul><ul><li>18% Younger women </li></ul></ul><ul><li>71% of responses are long lasting. </li></ul><ul><li>Edema, Hirsutism, amenorrhea, liver toxicity </li></ul>Ahn YS. Acta Haematol. 1990;84: 122-9 Maloisel F. Am J Med. 2004; 116: 590-4
  20. 21. Rituximab <ul><li>Rituximab weekly X 4 (n= 79, pooled data) </li></ul><ul><li>55% OR, 28% sustained response </li></ul><ul><li>Effective even post splenectomy </li></ul><ul><li>Long duration of disease: poor response </li></ul><ul><li>CR: fewer relapses than PR </li></ul><ul><li>CR has lower B cell counts </li></ul>Br J Haematol. 2004 Apr;125(2):232-9.
  21. 22. Outcomes of Rituximab Blood. 2008;112:999
  22. 23. Immunosuppressive agents <ul><li>Cyclophosphamide 1 mg/kg/d CR 27% </li></ul><ul><li>Azathioprine 1mg/kg/d CR17% </li></ul><ul><li>but fewer side effects </li></ul><ul><li>Cyclosporin 2.5-3 mg/kg/d </li></ul><ul><li>MMF 1.5-2.0 g/d </li></ul>Ann Intern Med. 2004; 140: 112-20
  23. 24. Cyclophosphamide <ul><li>Cheap and effective </li></ul><ul><li>Long-term side effects: Sterility, MDS </li></ul><ul><li>Recommendation </li></ul><ul><li>Low dose: 50 mg/d </li></ul><ul><li>At 6 months: try tailing off </li></ul>
  24. 25. Azathioprine <ul><li>Active Metabolite: 6-MP </li></ul><ul><li>6-MP: metabolized by Xanthine Oxidase, Thiopurine methyltransferase (TPMT) </li></ul><ul><li>NOT with allopurinol </li></ul><ul><li>TPMT polymorphism: common in Thais,* may lead to prolonged & fatal pancytopenia, alopecia (early sign) </li></ul>*Br J Clin Pharm 2004; 58: 66
  25. 26. Combination chemotherapy <ul><li>10 refractory ITP </li></ul><ul><li>Cyclophosphamide, prednisolone  VCR, procarbazine, etoposide </li></ul><ul><li>6 CR but 2 relapses </li></ul><ul><li>2 PR but 1 relapse </li></ul><ul><li>2 No response </li></ul>N Engl J Med 1993;328:1226-9
  26. 27. Steroid refractory or dependence ITP Alternatives with Low side effect Pulse Dexamethasone Colchicine, Dapsone, Danazol, Rituximab, Combinations Splenectomy Second line: Cyclophosphamide, Azathioprine, MMF, CSP Third line: Combination chemotherapy, BMT, Experimental Rx
  27. 28. Control of TPO Levels NEJM 1998; 339: 746
  28. 29. Eltrombopag vs. placebo Lancet 2009; 373: 641
  29. 30. Romiplostim: Long-term response Blood 2009; 113: 2161
  30. 31. Thrombopoietic agents <ul><li>Limitations </li></ul><ul><li>Platelet counts will drop after stopping the drugs </li></ul><ul><li>? Long-term side effects: Myelofibrosis, cataracts (Eltrombopag), thrombosis, ? Leukemia </li></ul><ul><li>Cost </li></ul>
  31. 32. Patients with major bleeding <ul><li>Pulse steroid </li></ul><ul><li>Intravenous immuniglobulin </li></ul><ul><li>Vincristine </li></ul><ul><li>Platelet transfusion </li></ul>
  32. 33. Massive platelet transfusion (N=10) 3-7 Apheresis units Thromb Haemost 2008; 100: 762
  33. 34. Take home message <ul><li>There are several choices of therapy. </li></ul><ul><li>The doctors must consider toxicity, cost and patient preference. </li></ul><ul><li>Do not over-treat the patients. </li></ul>

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