thrombopoietin receptor agonists and University of Washington January 13, 2012

Transcription

1 Tickle me eltrombopag: thrombopoietin receptor agonists and the regulation of platelet production Manoj Menon University of Washington January 13, 2012

2 Outline Clinical case Pathophysiology of ITP Therapeutic options Thrombopoietin Thrombopoietin agonists Immune modulation? Discussant Dr. Terry Gernsheimer

3 History of present illness 62 year old woman was in her usual state of health when she woke up with gingival bleeding Platelet count of 3,000 and admitted to OSH Treatment Platelets Methylprednisolone 500 mg Prednisone 60 mg Transient increase in platelets 19,000 10,000 Methylprednisolone 200 mg, Prednisone 80 mg and Rh o (D) Immune Globulin 50mcg 109,000

4 Clinical course Prednisone tapered platelet count decreased Prednisone increased platelet count increased Rituximab i 375 mg/m2 added d no response Referred to Dr. Gernsheimer; platelet count of 6,000 Admitted to UW

5 Platelet count Prednisone 50 QD, IVIG (.5 g/kg)

6 Platelet count Prednisone tapered

7 Platelet count Eltrombopag 50 mg QD added to Eltrombopag 50 mg QD added to prednisone

8 Platelet count Eltrombopag tapered

9 Platelet count Steroids discontinued

10 Platelet count Eltrombopag discontinued Eltrombopag discontinued, steroids discontinued

11 Platelet count

12 Pathophysiology of ITP O AP O Autoantibody Production Platelet Opsonization AP D D Platelet Destruction P Platelet Production P TC T-Cell Mediated Cytotoxicity TC Cines DB, Blanchette VS. N Engl J Med. 2002;346:

13 Therapeutic Approaches to ITP Reduce IgG production Corticosteroids Azathioprine Cyclophosphamide Rituximab Cyclosporine Remove splenic site of clearance Reduce Fc mediated clearance Corticosteroids IVIG Anti-D IgG Danazol Increase platelet production

14 Thrombopoietin Term first coined in 1958 to describe regulator of thrombopoiesis; i purified and cloned in 1994 Primarily produced in the liver, binds and activates receptors on hematopoietic stem cells, progenitor cells, and platelets l t Involved in nearly every step of y y p megakaryocyte development and regulation of platelet production

15 Thrombopoietin levels in ITP Healthy ITP AMT donors Mukai, et al.; Thromb Haemost 1996.

16 1 st generation TPO agonist Recombinant proteins based on the structure and function of TPO Autoantibodies formed against the recombinant agonist (pegylated) Neutralized endogenous TPO thrombocytopenia Kuter D J Blood 2007;109:

17 Search for the next generation TPO peptide mimetics TPO nonpeptide p mimetics TPO agonist antibodies

18 Romiplostim Synthetic fusion protein No sequence homology with TPO Binds to TPO receptor with high affinity

19 Eltrombopag Non-peptide small molecule Binds to the transmembrane region of the TPO receptor Activates intracellular signaling pathways Orally bioavailable Once daily dosing Kuter D J Blood 2007;109: Not immunogenic

20 Imbach & Crowther NEJM 2011; 365:

21 Eltrombopag platelet count > 50,000/mm3 on day 43 Bussel et al. NEJM 2007;357:

22 Eltrombopag Long Term Study: Median Platelet Count by Week Platelet Count (x10 3 /µl) Week n Saleh M, et al. ASH Abstract #

23 Sustained hemostatic platelet counts in adults with ITP following cessation of treatment with TPO agonist: ITP of various durations unresponsive to treatment ( 0.1 to 5.5 years) Multiple prior therapies (2 to 5) Treatment duration with TPO agonist 37 to 139 weeks TPO agonist discontinued Platelet count maintained for at least 6 months n = 9 Bussel, J, et al. ASH Abstract #

24 CD4 + regulatory T cells (Tregs) and ITP Critical role in maintenance of peripheral tolerance by both directly and indirectly suppressing activation and proliferation of many cell types Chong B H Blood 2010;116:

25 Circulating Treg-suppressive activity in patients before and on treatment with thrombopoietic agent Bao W et al. Blood 2010;116:

26 Platelet counts and TGF-β1 levels

27 Circulating TGF-β1 levels in patients before and on treatment with thrombopoietic agents. Bao W et al. Blood 2010;116:

28 scd40l levels in platelet-poor plasma of patient cohort Bao W et al. Blood 2010;116:

29 Immunologic profile of chronic ITP patients Treg suppresive activity improved in patients on treatment Levels of TGF-β1 correlated with degree of improvement in platelet counts Increase in total circulating TGF β1 in patients t on treatment t t Decrease in scd40l in patients on treatment

30 Immune modulation? Data suggest that TPO agents possess immunomodulatory activity Reduction in the overall inflammatory state Increase in platelet l t counts may play role in mediating the increase, via TGF β1, in Treg function in patients t on treatment

31 Further studies are needed d

32 Thanks! Karpatkin S. Autoimmune (idiopathic) thrombocytopenic purpura. Lancet. 1997;349: