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Idiophatic Thrombocytopenic
Purpura: Current Concepts In
Pathophysiology AndManagement
Dr. Roberto StasiS.C. di Oncologia ed Ematologia
Ospedale Regina Apostolorum
Albano Laziale
Italy
Slovenian Society of Hematology
Kranjska Gora, 3-4 October 2008
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Terminology adopted by the IWG on ITP
(Blood, in press)
ITP = Primary Immune Thrombocytopenia
Idiopathic thrombocytopenic purpura no
longer used
We know that ITPO is an autoimmune disorder
Not all patients with ITP have purpura
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ITP: Definition
1. Isolated thrombocytopenia with otherwise
normal CBC and peripheral smear
2.
No other conditions or factors that maycause thrombocytopenia
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Epidemiology: The incidence of ITP in
adults increases with age
Frederiksen and Schmidt. Blood 1999;94(3):909-913
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Role of B cells
Role of T cells
Role of dendrytic cells (?)
ITP: Pathophysiology
Stasi et al, Thromb Haemost 2008; 99: 413
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Harrington et al, J Lab Clin Med 38:1, 1951
1951 plasma
Carl V Moore
Passive transfer of ITP with ITP plasma
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Antibody production
Cytokine secretion (TNF alpha, chemokines)
Antigen presentation
Co-stimulatory signals for T cells
B cells in ITP
Stasi et al, Thromb Haemost 2008; 99: 413
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Oligoclonal T cells turn to polyclonal after
rituximab
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Cytokine secretion: (IFN-, IL-2, IL-10)
Co-stimulatory signals for B cells
Co-stimulatory signals for APC cells
Direct antiplatelet T-cell lysis
Preferential usage of TCR VB (oligoclonality)
Loss of appropriate T-cell apoptosis
Direct megakaryocyte damage (?)
Decreased Treg number and fuction
T cells in ITP
Stasi et al, Thromb Haemost 2008; 99: 413
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B cell
CD154 CD40CD40 CD154
Macrophage
(APC cell)MHC II
CD28CD80
Th cellTCR
IL-2IFN-
MegakaryocyteTc cell
Epitopespreading
Platelet
phagocytosis
X
XX
Platelet autoantibody production
Impaired megakaryocyte maturation
Reduced platelet production
CD28
CD80
Platelets
Tc cell-mediated
platelet destruction
Stasi et al, Thromb Haemost 2008; 99: 413
?
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Mechanism of Thrombocytopenia in ITP
Decreased platelet survival Impaired platelet production
No treatment
Prednisone
Post-splenectomy
No treatment
Prednisone
Post-splenectomy
Normal
range
Normal
range
Radiolabeled autologous platelets Production Platelet count / Platelet survival
Heterologous platelets
are cleared much faster
(minutes-hours)
Most patients have
inappropriately low or
normal rates of platelet
production
Ballem PJ et al. J Clin Invest. 1987;80:33-40
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Antibodies can also damage
megakaryocytes in the bone marrow
Electron micrographs,
showing normal
megakaryocytes (A) versus
the apoptotic damaged
megakaryocytes (B, C)
present in the bone marrowof patients with ITP
McMillan et al. Blood 2004;103:1364-1369
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TPO levels in ITP are not or only mildly
elevated
Kosugi et al. Br J Haematol1996;93:704706
Where it should be
Where it is
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Clinical presentation
Stasi & Provan. Mayo Clin Proc 2004;79:504522
Often diagnosed on the basis of routine labs
if thrombocytopenia is mild.
Signs/symptoms:
Easy bruising
Mucocutaneous bleeding
Life-threatening hemorrhages
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Impact of ITP on quality of life in relation to
other chronic conditions
All scores range from 0 to 100.
Higher scores indicate better
health-related quality of life (HRQoL)
SF-36 scales
0
10
20
30
40
50
60
70
80
90
100
Physical
function
Physical
role
Bodily
pain
General
health
Social
function
Emotional
role
Vitality Mental
health
Healthy Arthritis Diabetes ITP
Adapted from: Bussel J et al. Presented at:
45th ASH Annual Meeting; Dec 69, 2003; San Diego, CA, USA
Data on file, Amgen
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The 3 categories of ITP patients
1. Those who must or should be treated. Active bleeding
OR
Platelet count 30 x 109/L
Stasi & Provan. Mayo Clin Proc 2004;79:504522
http://www.freefoto.com/preview.jsp?id=21-18-72http://www.freefoto.com/preview.jsp?id=21-18-73http://www.freefoto.com/preview.jsp?id=21-18-718/12/2019 Stasi R j08
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Management of the bleeding patient
How severe is bleeding?
Life-threatening (eg intracranial
haemorrhage, gastric haemorrhage
[melena]) see Emergency treatment
Not life-threatening
Severe (eg metrorrhagia, unstoppableepistaxis) see Emergency treatment
Mild to moderate (eg petechiae, ecchymoses,
gingival bleeding) see Standard treatment
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Emergency treatment
Intravenous immunoglobulin
1 g/kg, repeated the following day if the platelet
count remains
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If not bleeding, when should we treat
ITP patients?
Disease considerations
Patient considerations
Treatment considerations
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Lacey & Penner. Semin Thromb Hemost 1977;3:160174
0 = No bleeding
1 = Minimal bleeding after trauma
2 = Spontaneous but self-limited
bleeding
3 = Spontaneous bleeding requir ing
special attention
4 = Severe life-threatening bleeding
Disease considerations:
platelet count and bleeding in ITP
1401201008060402010 50
1
2
3
4
0
Ble
edingmanifestation
Platelet count x 10
3
/L
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Disease considerations:
natural history of chronic ITP in adults
Variable and unpredictable
Spontaneous remissions ~5-10%1
85% of patients achieve a platelet count
>30 x 109/L without any treatment2
Overall mortality risk relative to the general
population 4.2 in those with chronic severe ITP2
1. Stasi et al.Am J Med 1995;98:4364422. Portielje et al. Blood 2001;97:25492554
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Patient considerations
Risk of fatal haemorrhage greatest in older patients:1
0.4% per year in patients 60 years Energetic lifestyles require safer platelet counts
Platelet >2030 x 109/L Platelet >50 x 109/L Platelet >80 x 109/L
Cohen et al. Arch Intern Med 2000;160:16301638
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Only a few treatments are truly evidence based and
approved by EMEA
Long-term side effects for new agents are not
currently known
Treatment of ITP may be more dangerous than the
disease itself:1
6 patients out of 152 died
2 died from haemorrhage
4 died from infections probably treatment related
1. Portielje et al. Blood 2001;97:25492554
Treatment considerations
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Recommendation for safe platelet counts in
adults
Dentistry 10 x 109/L
Extractions 30 x 109/L
Regional dental block 30 x 109/L
Minor surgery 50 x 109/L
Major surgery 80 x 109/L
Obstetrics: Vaginal delivery 50 x 109/L
Caesarean section 80 x 109/L
BCSH Guidelines. Br J Haematol 2003;120:574596
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First-line therapy in newly-diagnosed ITP
Corticosteroids
Prednisone 12 mg/kg/day OR ~70%, sustained
responses ~15%1
High-dose dexamethasone 40 mg/day for 4 days ~85% OR, sustained responses >50%2
Early management for those unresponsive to steroids
IVIg 0.51 g/kg/day for 1 or 2 days OR ~80%(recommended for patients with critical bleeding)1
IV anti-D 5075 g/kg for 1 day OR ~70%1
1. Stasi et al. Thromb Haemost 2008;99:4132. Cheng et al. N Engl J Med 2003;349:831836
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Splenectomy in ITP
Indicated in case of:1
Severe thrombocytopenia (Plt
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Stasi et al, Am J Med 1995
Thrombocytopenia-free survival after
splenectomy
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Defining chronic refractory ITP
Stasi et al. Thromb Haemost 2008;99:413
The patient has failed to
respond to splenectomy
AND
The platelet count is
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Long-term outcomes in adults with chronic
ITP after splenectomy failure
105 patients with refractory ITP; median
follow-up 110 months
30% patients remained unresponsive
to treatment
16% died of ITP (bleeding, 11 patients; therapy
complications, 6 patients)
14% died of unrelated causes
McMillan & Durette. Blood 2004;104:956960
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Challenges facing clinicians in deciding on
treatments for chronic and refractory ITP
Treatment recommendations derive largely from
uncontrolled cohort studies and expert opinion
Criteria to define platelet count outcomes are not
standardized across studies making their results
difficult to compare
Important clinical outcomes, such as bleeding and
quality of life, are rarely reported in cl inical studies
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Management options in chronic refractory ITP
Simple measures
Interventional measures*
*Many of which are utilised in an off-label setting
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Simple measures
Look for accessory spleen1
Found in 12% of patients failing to respond
Look for H. pylori at presentation2
Variable reports of ITP response
post-eradication2
Tranexamic acid
Widely used (no robust evidence) Oral contraceptives
In young women
1. Stasi et al. Thromb Haemost 2008;99:4132. Stasi & Provan. Mayo Clin Proc 2004;79:504522
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Interventional measures: non-selective
therapies*
Oral/IV dexamethasone
IV methylprednisolone
Danazol
Dapsone
Azathioprine
Vinca alkaloids
IV cyclophosphamide
Cyclosporine
Combination chemotherapy Interferon-
Mycophenolate Mofetil
Osteoporosis, psychosis etc
Diabetes, fluid retention
Weight gain, hirsutism, LFTs abnormal
Haemolysis
Immunosuppression, LFTs abnormal
Neuropathy
Leukaemia, cytopenia, teratogenic
Nephrotoxic, immunosuppression
Leukaemia, myelosuppression Thrombocytopenia
Nausea, diarrhoea
BUT: No real evidence of which/when to use or in which order1
LFTs, liver function tests;Staph, staphylococcal 1. Stasi & Provan. Mayo Clin Proc 2004;79:504522*Many of which are utilised in an off-label setting
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Interventional measures: targeted therapies
Thrombopoietin receptor stimulators
Syk inhibitors
R788 (tamatinib fosdium)
Antibody therapies
Campath-1H (anti-CD52)
Anti-CD40 ligand (anti-CD154)
GMA161 (anti-CD16)
Rituximab
Staphylococcal protein A (PRYX-100)
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Rituximab systematic review: Efficacy
Arnold DM et al. Ann Intern Med. 2007;146:25-33
46,3
24,0
62,5
0,0
10,0
20,0
30,0
40,0
50,0
60,0
70,0
80,0
150 x 10E9/L 50-150 x 10E9/L >50 x 10E9/L
Pooledestimateforr
esponse(%)
19 reports for efficacy (n = 313)
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Rituximab in chronic ITP
No RCT. Long-term CR in 1520% of cases
Adverse events mild, but no long-term safety data
(>10 year data)
Deaths reported in 2.9% of ITP cases treated with
rituximab, but they could not be attr ibuted to the
study drug
Valuable option for patients at high risk for
splenectomy and for those not willing to undergo
surgery
Cooper et al. Curr Opin Hematol 2007;14:642646
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Autologous haematopoietic stem cell
transplantation
Only one phase I/II study reported
14 patients:
5 with Evans syndrome
6 durable complete responses (942 months)
2 durable partial responses No transplant-related death
Huhn et al. Blood 2003;101:7177
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Thrombopoietin receptor stimulators
Stimulate platelet production
Bind to and activate TPO-receptors (Mpl)
BUT no sequence homology to TPO
For two agents, romiplost im and eltrombopag, Phase
III studies are complete
Long-term side effects under investigation
Romiplostim approved by FDA
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P
P
P
JAK2 JAK2
TPO
TPO-R
CRH-1
LATENT STAT
MONOMERS
Recruitment and
phosphorilation
P P
JAK2 JAK2
TPO-R TPO-R
P
P P
P P
TPO
Dimerization
Into nucleus: binds DNA
and activates
transcription
SHCGRB2
SOSRAS/RAF
MAPK
P42/44
Cell membraneCRH-2
Histidine 499
TPO acts through c-Mpl (TPO-receptor)
Stasi et al. Drugs 2008
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No sequence similarity to natural TPO
Therefore, does not elicit anti-TPO antibodies
Romiplostim (nPLate)
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Romiplostim in Chronic ITP
Randomized,
double-blind,
Phase 3 trial
(n = 125)
Splenectomy
(n = 63)
Non-splenectomized
(n = 62)
Placebo
(n = 21)
Romiplostim 1 mcg/kg
SQ q wk, target
Plt 50200x109/L
(n = 42)
Placebo
(n = 21)
Romiplosti m 1 mcg/kg
SQ q wk, target
Plt 50200x109/L
(n = 41)
Weekly, s.c. romiplostim in slowly escalating doses (1 g/kg up to15 g/kg) for 24 weeks
Dose adjusted to achieve a platelet count of 50,000-200,000
Inclusion criteria: Age 18; ITP with platelet count
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Target platelet count 50,000-200,000
SEMSplenectomised
Non-splenectomised
Kuter et al. Lancet. 2008;371:395-403
Dose Adjustments
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Range = middle 2 quart ilesSplenectomised
Non-splenectomised
Platelet Counts
Kuter et al. Lancet. 2008;371:395-403
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Kuter et al. Lancet. 2008;371:395-403
Definition of durable response rate
Platelets 50,000/L forat least 6 of the last 8
weeks of treatment
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Romiplostim efficacy
Kuter et al. Lancet. 2008;371:395-403
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Placebo Romiplostim
Severe or life-
threatening
bleeding
5/41 (12%) 6/84 (7%)
Thrombosis 1 1 popliteal art.
thrombosis
1 CVA
Death 1 ICH
1 PE
1 ICH after
starting aspirin to
treat thrombosis
Increased bone
marrow reticulin
1 (reversible)
Adverse Events
Kuter et al. Lancet. 2008;371:395-403
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Eltrombopagc-Mpl
Kuter DJ. Blood 2007;109:4607
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Eltrombopag for Chronic ITP
Randomized
Double-blind
Phase 2 Trial
(n = 118)
Placebo
(n = 29)
Eltrombopag30 mg PO
once daily
(n = 30)
Eltrombopag50 mg PO
once daily
(n = 30)
Eltrombopag75 mg PO
once daily
(n = 28)
Bussel et al. N Engl J Med. 2007;357:2237-2247
Primary end point: Platelet count 50,000/mcl by day 43
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Bussel et al. N Engl J Med. 2007;357:2237-2247
Platelet count 50,000/mcl
by day 43Bleeding
Eltrombopag efficacy
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Eltrombopag was effective regardless of concurrent
ITP therapy, splenectomy or baseline platelet count
Bussel et al. N Engl J Med. 2007;357:2237-2247
Response to eltrombopag by randomization strata
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Adverse Events
Mild-moderate headache in all groups including placebo (10-20%)
One 66-yo with COPD and NSCLC died of sepsis after receiving50 mg eltrombopag for 21 days
No thrombosis reported
Conclusions
Eltrombopag 50-75 mg PO QD is effective for short-term
treatment of chronic ITP (50,000 platelets in ~80% of patients)
The drug is well tolerated
Significant improvement in bleeding symptoms and quality of life
were not well documented in this study
Would a higher dose increase the response rate to 100%?
Bussel et al. N Engl J Med. 2007;357:2237-2247
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*
*
*
Long-term Safety and Efficacy of
Thrombopoietic Agents are Unknown
Kuter DJ. Blood 2007;109:4607
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ITP: Conclusions
Both B-cells and T-cell are deranged
Thrombocytopenia is due both to increased platelet
destruction and impaired platelet production
High-dose DXM probably better than PDN as front-
line therapy
Great efficacy of new thrombopoietic agents in
chronic ITP, but long-term safety data are lacking
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