Tickle me eltrombopag: thrombopoietin receptor agonists and the regulation of platelet production Manoj Menon University of Washington January 13, 2012
Outline Clinical case Pathophysiology of ITP Therapeutic options Thrombopoietin Thrombopoietin agonists Immune modulation? Discussant Dr. Terry Gernsheimer
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
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
Platelet count Prednisone 50 QD, IVIG (.5 g/kg)
Platelet count Prednisone tapered
Platelet count Eltrombopag 50 mg QD added to Eltrombopag 50 mg QD added to prednisone
Platelet count Eltrombopag tapered
Platelet count Steroids discontinued
Platelet count Eltrombopag discontinued Eltrombopag discontinued, steroids discontinued
Platelet count
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;346:995-1008.
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
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
Thrombopoietin levels in ITP 250 25 200 20 150 15 100 10 50 5 0 0 Healthy ITP AMT donors Mukai, et al.; Thromb Haemost 1996.
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;109:4607-4616
Search for the next generation TPO peptide mimetics TPO nonpeptide p mimetics TPO agonist antibodies
Romiplostim Synthetic fusion protein No sequence homology with TPO Binds to TPO receptor with high affinity
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;109:4607-4616 Not immunogenic
Imbach & Crowther NEJM 2011; 365: 734-741
Eltrombopag platelet count > 50,000/mm3 on day 43 Bussel et al. NEJM 2007;357:2237-2247
Eltrombopag Long Term Study: Median Platelet Count by Week Platelet Count (x10 3 /µl) Week n 299 216 138 107 94 83 79 71 72 53 51 31 12 15 12 13 4 Saleh M, et al. ASH Abstract #67 2010
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 #18 2011
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;116:4388-4390
Circulating Treg-suppressive activity in patients before and on treatment with thrombopoietic agent Bao W et al. Blood 2010;116:4639-4645
Platelet counts and TGF-β1 levels
Circulating TGF-β1 levels in patients before and on treatment with thrombopoietic agents. Bao W et al. Blood 2010;116:4639-4645
scd40l levels in platelet-poor plasma of patient cohort Bao W et al. Blood 2010;116:4639-4645
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
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
Further studies are needed d
Thanks! Karpatkin S. Autoimmune (idiopathic) thrombocytopenic purpura. Lancet. 1997;349:1531-1536