Transcript New advances in the pathogenesis and treatment of ITP 2014 ASH

2015 update on the pathogenesis
and treatment of ITP
Ming Hou
Qilu Hospital, Shandong University
Pathogenesis
• Platelet desialylation
– Anti-GPIb
– Cytotoxic T lymphocytes (CTLs)
• CD8 Tregs
– B cell depleting therapy
– Steroid therapy
Anti-GPIb and platelet desialylation
• Background
– The steroid response was significantly lower in ITP patients with antiGPIbα antibodies or with antibodies against both GPIbα and GPIIbIIIa.
Zeng Q, et al. Am J Hematol. 2012. 87(2): 206-8
– Anti-GPIb/IX also indicated poor response to IVIG in ITP.
Peng J, et al. J Thromb Haemost. 2014. 12(4): 497-504
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Anti-GPIb and platelet desialylation
• Background
- Sera from an ITP patient (anti-GPIb positive) led to platelet
desialylation. Li J, et al. Haematologica. 2014;99(4):61-63.
- Oseltamivir phosphate was used to treat an adult ITP patient (antiGPIb positive) successfully. Shao L, et al. Platelets. 2014:1-3.
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Anti-GPIb and platelet desialylation
• Results
- Anti-GPIbα antibodies induced significant platelet desialylation by
causing Neu1 translocation.
- Anti-GPIbα-opsonized platelets were cleared in the liver mediated by
the Ashwell-Morell receptor.
June Li, et al, Platelet Desialylation: A Novel Mechanism of Fc-independent Platelet Clearance and a
Potential Diagnostic Biomarker and Therapeutic Target in Immune Thrombocytopenia, 2014 ASH
abstract, 467
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Anti-GPIb and platelet desialylation
• Conclusion
– Anti-GPIbα antibodies cause platelet desialylation, leading to
Fc-independent platelet clearance in the liver.
– Patients with anti-GPIbα-mediated ITP who present with
significant platelet desialylation may be identified as likely nonresponders to conventional first-line treatments and
splenectomy.
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CTLs and platelet desialylation
• Background
- CTLs: direct lysis of platelets.
- The number of antigen-specific CTLs is
limited.
- Platelet lesion can lead to Neu1
translocation.
?
CTLs
PLT
lesion
Neu1
translocation
PLT
desialylation
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CTLs and platelet desialylation
• Results
- CTLs from ITP patients in cytotoxic group induced platelet desialylation
by causing Neu1 translocation.
- CTLs resulted in platelet clearance in the liver.
Jihua Qiu, et al, Platelet Desialylation Is Closely Associated with Cytotoxic T Lymphocyte-Mediated
Platelet Destruction in Immune Thrombocytopenia, 2014 ASH abstract, 463
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CTLs and platelet desialylation
• Conclusion
- CTLs may induce a secondary clearance of platelets in the
liver via platelet desialylation in addition to direct platelet
lysis in ITP.
- Our findings may help to explain how limited CTLs can
destruct the huge platelet mass in ITP.
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B cell depleting therapy and CD8 Tregs
• Background
– Antiplatelet antibody titer not necessarily decreases after response to
rituximab
– Response to rituximab in antiplatelet antibody negative ITP patients
Stasi et al, Blood, 2011;98:952
Cooper et al. Br J Haematol. 2012;158:539
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B cell depleting therapy and CD8 Tregs
• Results
– B cell depletion upregulates CD8+CD25highFoxp3+ T cells and
CD8+CD11c+ DC cells.
– B cell depletion downregulates CD8+ T cell proliferation.
– B cell depletion prevents cell-mediated ITP.
Li Guo, et al, CD20 B Cell Depleting Therapy Is Associated with up-Regulation of
CD8+CD25highFoxp3+ T Regulatory Cells in a Murine Model of Immune Thrombocytopenia (ITP),
2014 ASH abstract, 2785
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B cell depleting therapy and CD8 Tregs
• Conclusion
– This study indicates a significant immunomodulatory role
of B cells on antigen specific CD8+ T cell immune responses
via regulatory T cells and dendritic cells.
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Steroid therapy and CD8 Tregs
• Background
–CD8+ T cell depleted splenocytes (lacking in CTL cells)
engrafted mice have lower, but not higher, platelet counts.
–CD8+ T cells may play a protective role in attenuating
platelet clearance.
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Steroid therapy and CD8 Tregs
• Results
– Steroids injection is effective at rescuing platelet counts in both
passive and active ITP mouse model.
– CD8+ T cell depletion leads less responsiveness to DEX treatment.
– The CD8 Tregs populations ( CD8+CD25+Foxp3+, CD8+CD103+,
CD8+CD122+ and CD8+CD28-) are increased while CTL population
decreased following DEX treatment.
Li Ma, et al, Unveiling the Regulatory Role of CD8+ T-Cells in the Pathogenesis and Effective Steroid
Treatment in ITP, 2014 ASH abstract, 576
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Steroid therapy and CD8 Tregs
• Conclusion
– These are the first reported animal models of effective
steroid treatment of ITP.
– These findings uncover a previously unidentified
regulatory role of CD8+ T cells in both ITP and steroid
treatment.
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Treatment
• Review by Adam Cuker
• Prednisone vs Dexamethasone
• TRAs
• Tyrosine Kinase Inhibitor
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High dose dex (single cycle and multiple cycles)
Reference
n
Intervention
Duration
Response
definition
Response rate
6 mo
Response rate
1 yr
125
Dex 40mg
4 days
>50 × 109/L
50%
-
Dex 40mg
4 days
Single cycle
Cheng NEJM
2003
>30 ×
Bae ASH 2010 151
Mashihadi
Daru 2012
60
25%
109/L
Pred 1mg/kg
4wk
36%
Dex 40mg
Pred 1mg/kg
vs
Pred 1mg/kg
4 days
d5-6
90%
90%
53%
47%
≥30 × 109/L
4wk
Mutiple cycles
Horst Ann
18
Hematol 2004
Dex 40mg d1-4
Q28d
≤6 cycles
≥50 × 109/L
Mazzucconi
Blood 2007
37
Dex 40mg d1-4
Q28d
6 cycles
≥20 × 109/L
68%
Mazzucconi
Blood 2007
48
Dex 40mg d1-4
Q14d
4 cycles
≥30 × 109/L
60%
Cuker A, et al, Sem Thromb Haemost, 2014, in press
67%
Summary of long-term response data
Rx
6 mo
1 yr
2 yr
Prednisone
~60%
~40%
~20-30%
HDD × 1
25-50%
HDD × 4-6
67%
60-68%
HDD + Ritux
58-76%
53%
Rituximab
~60%
TRAs
3-13%
Splenectomy
~80%
~40%
~70%
Cuker A, et al, Sem Thromb Haemost, 2014, in press
3 yr
5 yr
~20%
~65%
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Conventional prednisone vs high-dose dexamethasone
• One or two courses of HD-Dex demonstrated higher CR rate,
shorter time to response and less adverse events than PDN.
Yu Wei, et al, Conventional Oral Prednisone Versus High-Dose Dexamethasone for Management of
Adult Immune Thrombocytopenia: A Prospective Randomized Multicenter Clinical Trial, 2014 ASH
abstract, 1455
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Eltrombopag: a phase III study in China
• Eltrombopag significantly increased platelet counts in Chinese
adults with chronic ITP and was well-tolerated.
Eltrombopag Placebo
group
group
155 chronic ITP
patients
Randomized (2:1)
Eltrombopag
group
104 patients
Placebo
group
51 patients
*Response
rate (PLT>
50×109/L)
57.7% (60/104)
6% (3/50)
Adverse
events
63.5% (66/104)
66.7% (34/51)
*P < 0.001
Renchi Yang, et al, Effect of Eltrombopag on Platelet Response and Safety Results in Chinese Adults
with Chronic ITP-Primary Result of a Phase III Study, 2014 ASH abstract, 1464
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Discontinuation of eltrombopag
• Platelet response following eltrombopag
cessation may be sustained
in nearly half of
80/201
77% (201/260)
Eltrombopag
wasafter CR with
adult patients
with primary
ITP
CR
discontinued
45% (22/49)
eltrombopag.
immediate relapse
260 ITP
patients
12% (30/260)
R
11% (29/260)
NR
49
evaluble
patients
2% (1/49)
relapse at 10 mo
53% (26/49)
sustained response
Tomás José González-López, et al, Successful Discontinuation of Eltrombopag after Complete
Remission in Patients with Primary Immune Thrombocytopenia, 2014 ASH abstract, 1465
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Tyrosine Kinase Inhibitor- Dasatinib
• Dasatinib inhibits phosphorylation of Syk, inducing decreased
phagocytosis of platelets.
• Dasatinib might be effective in the treatment of ITP.
Tadashi Shimoyama, et al, Dasatinib Is Effective in the Treatment of Mice Models with Immune
Thrombocytopenia, 2014 ASH abstract, 1456
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Tyrosine Kinase Inhibitor- Fostamatinib
Another Syk inhibitor, fostamatinib,
shows a similar effect on improving the
thrombocytopenia in ITP.
Gulsum Emel Pamuk, et al, The Effects of the Spleen Tyrosine Kinase Inhibitor, Fostamatinib, on an
Immune Thrombocytopenia Mouse Model, 2014 ASH abstract, 2782
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Summary
• Platelet desialylation may contribute to the
pathogenesis of ITP.
• CD8 Tregs may play a predominantly protective role
in ITP.
• These clinical trials provide reliable bases and more
options for the treatment of ITP.
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Thank you!
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