New and Old Approaches to Management

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New and Old Approaches to Management ITP New and Old Approaches to Management

Disclosures for James B. Bussel, MD Research Support/PI Amgen, GlaxoSmithKline, Eisai, Sysmex, Cangene, Shionogi, IgG America, Employee N/A Consultant/Scientific Advisory Board Amgen, GlaxoSmithKline, Ligand, Shionogi, Eisai, Cangene Stockholder Amgen, GlaxoSmithKline Speakers’ Bureau 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 Peripheral blood P P Bone marrow P Platelet Megakaryocyte

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.

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.

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

“Wet” Purpura

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%)

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

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

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.

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

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.

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.

Thrombopoietin and Thrombopoietic Agents

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

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) HRQoL physical and mental components were impaired slightly at baseline The physical component summary includes all domains, but physical function, physical role, bodily pain, and general health contribute proportionately the most to the aggregate scores. The mental component summary includes all domains, but vitality, social function, emotional role, and mental health contribute proportionately the most to the aggregate scores. Three additional domains (not listed above) were investigated—physical function (P = 0.154), general health (P = 0.243), and mental health (P = 0.154); eltrombopag treatment resulted in non-significant increases in all 3 component scores compared with placebo. In addition, there were strong statistically significant correlations between improvements in HRQoL and both elevations in platelet counts and reductions in bleeding symptoms (P <0.05 for all 8 domain scores and both component summary scores). 20

rhTPO and PEG-rHUMGDF rhTPO PEG-rHuMGDF Glycosylated Not glycosylated Full length PEG-rHuMGDF Not glycosylated Truncated Additional polyethylene glycol moiety COOH terminal domain Polyethylene glycol Fact Check: Fig 3 NH2 COOH NH2 Mpl-binding domain Mpl-binding domain 21 Kuter DJ, Begley CG, Blood 2002;100:3457.

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)

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 AKR501---no abstracts Ligand---normal volunteer poster 23

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

AMG 531 Fc Carrier Domain TPO Agonist Peptides Fact Check: figure 1 of article 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.

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

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

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

Published Studies of Romiplostim (AMG531) and Eltrombopag 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)

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 30

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 32 Kuter DJ, Bussel JB, et al. Lancet. 2008;371(9610):395-403.

Mean Platelet Count and Romiplostim Dose Over 204 Weeks 300 250 Mean (SE) Platelet Count x 109/L 200 150 100 50 10 8 Mean (SD) Dose (µg/kg) 6 4 Mean Dose 2 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.

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) This slide shows the main efficacy result for the dose-finding phase II study. It is evident that the proportion of responders increases with the higher Promacta doses – only 11% of subjects in placebo achieved the primary endpoint, compared to 28, 70 and 81% in the Promacta arm. The difference between placebo and the 50 and 75 mg Promacta arm was highly statistically significant. WHAT IS THE IMPLICATION OF 1 vs 2 SIDED p VALUE? Responders (%) – (≥ 50Gi/L) P = 0.07 OR = 3.09 (0.69, 13.75) 11% 28% 70% 81% 16% 59% *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.

Eltrombopag: Phase III RAISE Study Platelet Response Placebo During treatment Follow-up period Eltrombopag 150 125 100 75 If plt count rose to over 50,000, considered a responder Median Platelet Count (x 109/L) 50 25 BL Day 8 Day 15 Day 22 Day 29 Day 36 Day 43 Wk 10 Wk 14 Wk 18 Wk 22 Wk 26 Wk 1 Wk 2 Wk 4 Eltrombopag was effective regardless of concomitant ITP therapy, splenectomy status or baseline platelet count Cheng G, et al. Blood. 2008;112: Abstract 400.

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

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 (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.

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

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