ITPNew and Old

Approaches to Management 11

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

Research Support/PIAmgen, 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

2

PP

PP

PP

PP

Macrophage

Thrombo-poietin

Peripheral blood

Bone marrow

PlateletMegakaryocyte

Pathophysiology of ITP

3

2010 ICR ITP Recommendations:

AbstractPreviously 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.

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. 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. 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

7

40 Cases of ICH in Children with ITP:40 Cases of ICH in Children with ITP:Psaila et al Blood 2009Psaila 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

9

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.

0.00.10.20.30.40.50.60.70.80.91.0

0 1 2 3 4 5 6 7 8 9 10 11 12

Time from Splenectomy (Years)

Re

mis

sio

n R

ate

(C

R+

PR

)

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

1515

17

Treg Activity in Patients on TPO Agents

Treg: Teffector 1:1 ratioOn treatment >3 mo

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)

20

rhTPO and PEG-rHUMGDF

NH2

Mpl-binding domain

rhTPOrhTPO• Glycosylated

• Full length

Polyethyleneglycol

COOHterminaldomain

NH2COOH

Mpl-binding domain

PEG-rHuMGDFPEG-rHuMGDF• Not glycosylated

• Truncated

• Additional polyethylene

glycol moiety

Kuter DJ, Begley CG, Blood 2002;100:3457.21

Platelet Production Is Platelet Production Is Suboptimal in ITP Patients 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

23

The approved TPO-R Agonists Have Multiple Names

• AMG531• Romiplostim• Nplate

• Eltrombopag• Promacta• Revolade

24

AMG 531

• Unique platform “peptibody”• Made in E. coli • Molecular weight = 60,000 D• 4 Mpl binding sites

Bussel JB et al. N Engl J Med. 2006;355:1672.

• No sequence homology with TPO• Cleared endothelial FcRn

Recycled• Cleared RES

Fc Carrier DomainTPO Agonist

PeptidesFc Carrier DomainTPO Agonist

Peptides

25

Cytoplasm of Megakaryocyte

STAT PP

RAS/RAF

MAPKK

p42/44

SOSSOS

GRB2

P P

JAK

SHC

Cell membrane

TPOreceptor

Inactive receptor Active receptor

TPO

Signal Transduction

Increased platelet production

TPO/AMG531: Mechanism of action

AKT

26

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

ThrombopoietinMW 64,000

EltrombopagMW 442

Eltrombopag: Oral Platelet Growth Factor

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Cytoplasm of Megakaryocyte

STAT PP

RAS/RAF

MAPKK

p42/44

SOSSOS

GRB2

P P

JAK

SHC

Cell membrane

Eltrombopag/AKR501:Mechanism of action

TPOReceptor

Inactive receptor Active receptor

Signal Transduction

Increased platelet production

Eltrombopag

Not via AKT ?

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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)

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

Efficacy of Romiplostim in Patients with Chronic Idiopathic Thrombocytopenic Purpura: A

Double-blind, Randomised Controlled Trial

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

Two parallel trials of 63 splenctomized and 62 non-splenectomized patients with ITP

Mean Platelet Count and Romiplostim Dose Over 204 Weeks

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.

0

50

100

150

200

250

300

4

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

Mean Dose

0

2

4

6

8

10

1 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 152 160 168 176 184 192 200Study Week

Mea

n (

SE

) P

late

let

Co

un

t x

109/L

Mea

n (

SD

) D

ose

(µ

g/k

g)

33

Weekly Platelet Count and Dose of AMG531 for Subject N-C

0

100

200

300

400

500

600

700

800

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43

Week

Pla

tele

ts (

K/u

L) Platelet

Countfor N-C

0

2

4

6

8

10

12

14

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43

Do

se (

mcg

/kg

)

WeeklyDose ofAMG531for N-C

36

Primary Endpoint 773A & B: Elevation of platelet counts

Res

po

nd

ers

(%)

– (≥

50G

i/L)

*1-sided P value. odds ratio (OR)eltrombopag / placebo

P = 0.07OR = 3.09

(0.69, 13.75)

P < 0.001*OR = 21.96

(4.72, 102.23)

P < 0.001*OR = 38.82

(7.62, 197.73)

11% 28% 70% 81% 16% 59%

**2-sided P value, OR, odds ratioeltrombopag / placebo

p < 0.001** OR = 9.61

(3.31, 27.86)

TRA100773A TRA100773B

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

Med

ian

Pla

tele

t C

ou

nt

(x 1

09/L

)

Cheng G, et al. Blood. 2008;112: Abstract 400.

150

125

100

75

50

25

0

BL Day8

Day15

Day22

Day29

Day36

Day43

Wk10

Wk14

Wk18

Wk22

Wk26

Wk1

Wk2

Wk4

PlaceboEltrombopag

During treatment Follow-up period

Eltrombopag was effective regardless of concomitant ITP therapy, splenectomy status or baseline platelet count

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

A

B

Platelet responses during the treatment period in all placebo- and romiplostim-treated patients and in patients by age cohort.

(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.

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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 ITP42

Diagnosis of ITP

Pred/Dex + IVIG or Anti-D

Splenectomy

Rituximab

???

Thrombopoietic Agents