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ITP

ITP. New and Old Approaches to Management. Disclosures for James B. Bussel, MD. N/A = Not Applicable (no conflicts listed) Presentation includes discussion of the following off-label use of a drug or medical device: YES. Pathophysiology of ITP. Macrophage. P. Thrombo-poietin

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ITP

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  1. ITP New and Old Approaches to Management

  2. Disclosures for James B. Bussel, MD N/A = Not Applicable (no conflicts listed) Presentation includes discussion of the following off-label use of a drug or medical device: YES

  3. Pathophysiology of ITP Macrophage P Thrombo-poietin Peripheral blood P P Bone marrow P Platelet Megakaryocyte

  4. 2010 ICR ITP Recommendations:Abstract Previously published guidelines for the diagnosis and management of primary immune thrombocytopenia (ITP) require updating largely due to the introduction of new classes of therapeutic agents, and a greater understanding of the disease pathophysiology. However, treatment-related decisions still remain principally dependent on clinical expertise or patient preference rather than high-quality clinical trial evidence. This consensus document aims to report on new data and provide consensus-based recommendations relating to diagnosis and treatment of ITP in adults, in children, and during pregnancy. The inclusion of summary tables within this document, supported by information tables in the online appendices, is intended to aid in clinical decision making. Provan D, et al. Blood. 2010;115(2):168-186.

  5. 2011 ASH Guidelines:What is the Most Appropriate Next Therapy? • This section contains major changes vs. 1996 ASH Guidelines1,2 • Significant new treatments have been developed, including thrombopoietin receptor agonists (TPO-RAs) and rituximab • The Guidelines recommend: • Splenectomy for patients who have failed corticosteroid therapy (Grade 1B) (§4.4) • Splenectomy remains the only treatment that provides sustained remission off all treatments at one year and beyond in a high proportion of patients with ITP (§4.4) • TPO-RAs for patients at risk of bleeding who relapse after splenectomy or who have a contraindication to splenectomy and who have failed at least one other therapy (Grade 1B) (§4.4) 1. George JN, et al. Blood. 1996;88:3-40. 2. Neunert C, et al. Blood. Pre-published online, Feb 16, 2011.

  6. Eradicating or suppressing the infection will fix the ITP HIV Hepatitis C Helicobacter pylori CMV

  7. “Wet” Purpura

  8. 40 Cases of ICH in Children with ITP:Psaila et al Blood 2009 • Plt ct < 10k = 75% • Plt ct < 20k = 90% • 13 associated with head trauma • Compared to controls, all 9 with hematuria had an ICH-----bleeding beyond petechiae and ecchymoses • 10 died (25%) and 10 had major neurologic sequelae (25%)

  9. Acute Platelet Increase • gold standard: IVIG at 1 gm/kg • IV anti-D: as fast as IVIG at 75 mcg/kg • Steroids: IV solumedrol 30/kg, high dose dexamethasone or Prednisone 2-4/kg • Platelet transfusions • Combinations including Steroids, IVIG, IV anti-D and/or vincristine----especially in high risk or non-responding cases

  10. Therapies not Acutely Increasing the Platelet Count in ITP Thrombopoeitic agents Rituximab Azathioprine Mycophenolate mofetil (MMF) Cyclosporine Others

  11. New Approach to ITP in Adults Treat aggressively early in the course Prednisone increases the platelet count but results in long term improvement in only a handful of patients Giving dexamethasone (and anti-CD20) may be justified by preventing the development of chronic ITP Mazzucconi, MG et al. Blood. 2007;109:1401-1407; Zaja F, et al. Blood. 2010;115:2755-2762.

  12. Duration of Response to Rituximab Cooper N, et al. Br J Haematol. 2004;125:232-239.

  13. Long-term Effect of Rituximab • 32-40% achieve normal counts which persist for at least 1 year from initial treatment • Children with chronic ITP have similar response and relapse rate to adults • Indefinite response to anti-CD20 lasting more than 3-5 years: Children: 25% Adults: 20% Patel VL, et al. American Society of Hematology Annual Meeting 2010. Abstract 72.

  14. Splenectomy: Long-Term Outcome in 56 Adults With ITP • Early response rate ~80% • Responses usually rapid • 15% relapse rate in first year • Laparoscopic splenectomy results in less morbidity • Predictors of response controversial • Immunize with pneumococcal, Hib, meningococcal vaccine Schwartz J, et al. Am J Hematol.2003;72:94-98. Kojouri K, et al. Blood. 2004;104:2623-2634.

  15. Thrombopoietin and Thrombopoietic Agents

  16. Treg Activity in Patients on TPO Agents On treatment >3 mo Treg: Teffector 1:1 ratio

  17. Eltrombopag Improved Patient Health-related Quality of Life Physical role (P = 0.030) Vitality (P = 0.045) Emotional role (P = 0.023) Mental component summary (P = 0.030)

  18. rhTPO and PEG-rHUMGDF • rhTPO • Glycosylated • Full length • PEG-rHuMGDF • Not glycosylated • Truncated • Additional polyethylene • glycol moiety COOH terminal domain Polyethylene glycol COOH NH2 NH2 Mpl-binding domain Mpl-binding domain Kuter DJ, Begley CG, Blood 2002;100:3457.

  19. Platelet Production Is Suboptimal in ITP Patients Autoantibodies inhibit Mk growth and promote apoptosis (Chang, McMillan) Autologous 111In-platelet studies show platelet production < normal in 2/3 pts----same results with absolute platelet retics TPO levels normal in 75% of ITP patients (relative TPO deficiency) Damaged or Dysfunctional Mk in marrow (Houwerijl recapitulation of Minot and Dameshek)

  20. Status of Thrombopoietic Agonists in Active ITP Clinical Trial AMG531 --licensed in US August 2008 and approved in UK and multiple countries Eltrombopag--licensed in US November 2008 and approved in multiple countries AKR501 (EE501)----initial study in ITP completed LGB4665 --initial study in ITP completed S888 (Shionogi)--initial study in ITP completed 3SBIO---Studies in ITP completed in China

  21. AMG531 Romiplostim Nplate Eltrombopag Promacta Revolade The approved TPO-R Agonists Have Multiple Names

  22. TPO Agonist TPO Agonist Fc Fc Carrier Domain Carrier Domain Peptides Peptides AMG 531 • Unique platform “peptibody” • Made in E. coli • Molecular weight = 60,000 D • 4 Mpl binding sites • No sequence homology with TPO • Cleared endothelial FcRn • Recycled • Cleared RES Bussel JB et al. N Engl J Med. 2006;355:1672.

  23. TPO receptor TPO P P JAK Increased platelet production TPO/AMG531: Mechanism of action Inactive receptor Active receptor Cell membrane SHC GRB2 RAS/RAF SOS P STAT P Cytoplasm of Megakaryocyte MAPKK AKT p42/44 Signal Transduction

  24. Eltrombopag: Oral Platelet Growth Factor • Small molecule, non-peptide thrombopoietin receptor (TPO-R) agonist • Does not compete with TPO for binding to TPO-R • Low immunogenic potential • Active only in humans, chimps • Stimulates megakaryocyte proliferation and differentiation • Orally bioavailable • Increases platelet counts in normal volunteers Eltrombopag MW 442 Thrombopoietin MW 64,000

  25. TPO Receptor Eltrombopag P P JAK Increased platelet production Eltrombopag/AKR501:Mechanism of action Inactive receptor Active receptor Cell membrane SHC GRB2 RAS/RAF SOS P STAT P Cytoplasm of Megakaryocyte MAPKK Not via AKT ? p42/44 Signal Transduction

  26. Published Studies of Romiplostim (AMG531) and Eltrombopag Romiplostim: • Short term study • 6 month randomized placebo controlled • Study of avoidance of splenectomy • Pediatric pilot study • Long term extension study (up to 6 yrs) Eltrombopag: • Short term study • Confirmatory study • 6 month randomized placebo controlled • Repeat dosing study • Long term extension study (2 yrs) • (Hepatitis C study)

  27. Potential and Real Adverse Consequences of Thrombopoietic Growth Factors Thrombocytosis Thrombosis Stimulation of tumor growth Stimulation of leukemia cell growth (in MDS)-A Interactions with other cytokines Cataracts-E Abnormal LFTs-E Autoantibody formation-A Stem cell depletion Reduction in threshold for platelet activation Rebound worsening of thrombocytopenia Increased bone marrow reticulin Headache

  28. Efficacy of Romiplostim in Patients with Chronic Idiopathic Thrombocytopenic Purpura: A Double-blind, Randomised Controlled Trial Two parallel trials of 63 splenctomized and 62 non-splenectomized patients with ITP Kuter DJ, Bussel JB, et al. Lancet. 2008;371(9610):395-403.

  29. Mean Platelet Count and Romiplostim Dose Over 204 Weeks 300 250 Mean (SE) Platelet Count x 109/L 200 150 100 50 0 10 8 Mean (SD) Dose (µg/kg) 6 4 Mean Dose 2 0 1 4 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 152 160 168 176 184 192 200 Study Week n = 212 183 160 146 136 123 118 112 108 103 99 96 86 70 62 58 48 34 26 21 22 21 17 14 12 6 n is the number of patients with available platelet counts, excluding those who received rescue medications.Platelet counts within 8 weeks after receiving any rescue medications were excluded.

  30. Primary Endpoint 773A & B: Elevation of platelet counts TRA100773A TRA100773B P < 0.001* OR = 38.82 (7.62, 197.73) P < 0.001* OR = 21.96 (4.72, 102.23) p < 0.001** OR = 9.61 (3.31, 27.86) Responders (%) – (≥ 50Gi/L) P = 0.07 OR = 3.09 (0.69, 13.75) 59% 16% 70% 81% 28% 11% *1-sided P value. odds ratio (OR) eltrombopag / placebo **2-sided P value, OR, odds ratio eltrombopag / placebo Bussel JB, et al. N Engl J Med 2007;357:2237–47. Bussel JB, et al. Lancet 2009;373(9664):641–8.

  31. Eltrombopag: Phase III RAISE Study Platelet Response Placebo During treatment Follow-up period Eltrombopag 150 125 100 75 Median Platelet Count (x 109/L) 50 25 0 BL Day8 Day15 Day22 Day29 Day36 Day43 Wk10 Wk14 Wk18 Wk22 Wk26 Wk1 Wk2 Wk4 • Eltrombopag was effective regardless of concomitant ITP therapy, splenectomy status or baseline platelet count Cheng G, et al. Blood. 2008;112: Abstract 400.

  32. Twenty-two Patient Pediatric ITP Study With Romiplostim Responses in 15/17 romiplostim-treated children and 0/5 placebo 1st manuscript in Children in Blood

  33. Platelet responses during the treatment period in all placebo- and romiplostim-treated patients and in patients by age cohort. A (A) Percent of patients who had platelet counts of 50X109/L or greater for 2 consecutive weeks in the absence of rescue medication. (B) Percent of patients who had an increase in platelet counts of 20X109/L or more above baseline for 2 consecutive weeks in the absence of rescue medication. B

  34. Use of TPO-R Agents in ITP: Questions for the Present and the Future • How fast can one increase the count • What is the true rate of response • Do the different agents work equally in all patients • ***Do you give these agents indefinitely or may improvement be seen • Do TPO-R agonists work well with other treatments of ITP

  35. Diagnosis of ITP Pred/Dex + IVIG or Anti-D Rituximab Thrombopoietic Agents Splenectomy ???

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