2015 update on the pathogenesis and treatment of ITP Ming Hou Qilu Hospital, Shandong University.

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In the name of God Chronic ITP Debates & Dilemmas
Presentation transcript:

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

3 Background – The steroid response was significantly lower in ITP patients with anti- GPIbα antibodies or with antibodies against both GPIbα and GPIIbIIIa. Zeng Q, et al. Am J Hematol (2): – Anti-GPIb/IX also indicated poor response to IVIG in ITP. Peng J, et al. J Thromb Haemost (4): Anti-GPIb and platelet desialylation

4 Background -Sera from an ITP patient (anti-GPIb positive) led to platelet desialylation. Li J, et al. Haematologica. 2014;99(4): Oseltamivir phosphate was used to treat an adult ITP patient (anti- GPIb positive) successfully. Shao L, et al. Platelets. 2014:1-3.

5 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

6 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 non- responders to conventional first-line treatments and splenectomy. Anti-GPIb and platelet desialylation

7 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 PLT desialylation Neu1 translocation ?

8 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

9 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.

10 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

11 B cell depleting therapy and CD8 Tregs Results – B cell depletion upregulates CD8 + CD25 high Foxp3 + 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

12 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.

13 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.

14 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

15 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.

16 Treatment Review by Adam Cuker Prednisone vs Dexamethasone TRAs Tyrosine Kinase Inhibitor

High dose dex (single cycle and multiple cycles) Cuker A, et al, Sem Thromb Haemost, 2014, in press ReferencenInterventionDuration Response definition Response rate 6 mo Response rate 1 yr Single cycle Cheng NEJM Dex 40mg4 days>50 × 10 9 /L50%- Bae ASH Dex 40mg Pred 1mg/kg 4 days 4wk >30 × 10 9 /L 25% 36% Mashihadi Daru Dex 40mg Pred 1mg/kg vs Pred 1mg/kg 4 days d5-6 4wk ≥30 × 10 9 /L 90% 53% 90% 47% Mutiple cycles Horst Ann Hematol Dex 40mg d1-4 Q28d ≤6 cycles ≥50 × 10 9 /L67% Mazzucconi Blood Dex 40mg d1-4 Q28d 6 cycles ≥20 × 10 9 /L68% Mazzucconi Blood Dex 40mg d1-4 Q14d 4 cycles ≥30 × 10 9 /L60%

18 Summary of long-term response data Rx6 mo1 yr2 yr3 yr5 yr Prednisone~60%~40%~20-30% HDD × % HDD × 4-667%60-68% HDD + Ritux58-76%53% Rituximab~60%~40%~20% TRAs3-13% Splenectomy~80%~70%~65% Cuker A, et al, Sem Thromb Haemost, 2014, in press

19 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

20 Eltrombopag: a phase III study in China 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, chronic ITP patients Randomized (2:1) Eltrombopag group 104 patients Placebo group 51 patients Eltrombopag group Placebo group *Response rate (PLT> 50×10 9 /L) 57.7% (60/104)6% (3/50) Adverse events 63.5% (66/104) 66.7% (34/51) *P < Eltrombopag significantly increased platelet counts in Chinese adults with chronic ITP and was well-tolerated.

21 Discontinuation of eltrombopag Platelet response following eltrombopag cessation may be sustained in nearly half of adult patients with primary ITP after CR with eltrombopag. 260 ITP patients 77% (201/260) CR 80/201 Eltrombopag was discontinued 49 evaluble patients 45% (22/49) immediate relapse 12% (30/260) R 11% (29/260) NR 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

22 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

23 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

24 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.

25 Thank you!