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
27
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 ?
28
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.
41
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