1. New and Old Approaches to Management
ITP
New and Old Approaches to Management

2. 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

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):

5. 2011 ASH Guidelines: What is the Most Appropriate Next Therapy?
This section contains major changes vs 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: 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: ;
Zaja F, et al. Blood. 2010;115:

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

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 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:

15. Thrombopoietin and Thrombopoietic Agents

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

20. 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

21. 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.

22. 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)

23. 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
LGB 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

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

25. 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.

26. 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

27. 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

28. 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

29. 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)

30. 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

32. 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):

33. 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.

37. Primary Endpoint 773A & B: Elevation of platelet counts
TRA100773A
TRA100773B
P < 0.001*
OR = 38.82
(7.62, )
P < 0.001*
OR = 21.96
(4.72, )
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.

38. 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.

39. 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

40. 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.

42. 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

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