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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 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 3 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. 4 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 5 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. 6 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 7 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 8 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. 9 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 10 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 11 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. 12 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. 13 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 14 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. 15 Treatment • Review by Adam Cuker • Prednisone vs Dexamethasone • TRAs • Tyrosine Kinase Inhibitor 16 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% 18 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 19 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 20 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 21 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 22 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 23 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. 24 Thank you! 25