1. Advances in the Treatment of Adult Immune Thrombocytopenia This activity is supported by an educational grant from Novartis. Keith McCrae, MD Director, Benign Hematology Departments of Hematology and Medical Oncology, and Cellular and Molecular Medicine Cleveland Clinic

2. Faculty Disclosure Keith McCrae, MD, has no real or apparent conflicts of interest to report.

3. About These Slides  Please feel free to use, update, and share some or all of these slides in your noncommercial presentations to colleagues or patients  When using our slides, please retain the source attribution:  These slides may not be published, posted online, or used in commercial presentations without permission. Please contact permissions@clinicaloptions.com for detailspermissions@clinicaloptions.com Slide credit: clinicaloptions.comclinicaloptions.com

4. Outline  Overview  Demographics  Insights on the Pathophysiology of ITP  Diagnosis of ITP  Clinical Manifestations  Management of ITP –Goals of therapy –First-line therapy –Selection of second-line therapies  Future directions Slide credit: clinicaloptions.comclinicaloptions.com

5. Overview

6. ITP Working Group Definitions  Primary ITP –Isolated thrombocytopenia (not caused by or associated with another disorder) –Platelet count <100,000/µl –Increased risk of bleeding  Diagnosis of exclusion –No firm clinical or laboratory guidelines establish this diagnosis with certainty  Best diagnostic parameter is response to therapy  Secondary ITP –All other immune-mediated thrombocytopenia –Infection-associated HCV, HIV, H pylori –Immunodeficiency –CVI, WAS –Autoimmune disorders –SLE, others –Lymphoproliferative –CLL, others –Drug-induced Rodeghiero F, et al. Blood. 2009;113:2386-2393. Slide credit: clinicaloptions.comclinicaloptions.com

7.  Accounts for estimated 20% of total ITP cases SLE 5% APS 2% CVID 1% CLL 2% Evan’s 2% ALPS, post-tx 1% HIV 1% HCV 2% H pylori 1% Postvaccine 1% Misc systemic infection 2% Primary 80% Cines DB, et al. Blood. 2009;113:6511-6521. Secondary ITP Fractionated by Form Slide credit: clinicaloptions.comclinicaloptions.com

8. Stages of ITP  Newly diagnosed ITP: ≤ 3 months from diagnosis  Persistent ITP: 3-12 months from diagnosis –Describes patients lacking spontaneous remission or complete response after treatment  Chronic ITP: lasting > 12 months  Severe ITP: Bleeding symptoms requiring treatment –Includes patients with new bleeding symptoms that warrant a dose escalation or treatment with a different platelet-enhancing agent Rodeghiero F, et al. Blood. 2009;113:2386-2393. Slide credit: clinicaloptions.comclinicaloptions.com

9. Incidence of ITP in Adults  Retrospective cohort analysis of adult pts in the UK Abrahamson PE, et al. Eur J Haematol. 2009;83:83-89. Slide credit: clinicaloptions.comclinicaloptions.com 12 10 8 6 4 2 0 18-1920-2930-3940-4950-5960-6970-7980-8990-99 Age, Yrs 3.6 1.6 4.9 0.6 3.5 1.3 3.0 1.8 4.2 3.0 5.5 3.9 6.4 10.5 9.2 9.3 10.8 8.1 Female Male Rate per 100,000 Person-Yrs

10.  Pts with ITP Prevalence of Primary ITP by Age/Sex Terrell DR, et al. Am J Hematol. 2012;87:848-852. 2003 2004 Age, Yrs Slide credit: clinicaloptions.comclinicaloptions.com 45 40 35 30 25 20 15 10 5 0 Prevalence (per 100,000) 0-9 10-1920-29 30-39 40-4950-59 60-69 70-7980+ 45 40 35 30 25 20 15 10 5 0 Prevalence (per 100,000) Age, Yrs 0-9 10-1920-29 30-39 40-4950-59 60-69 70-79 80+ Women Men

11. Insights on the Pathophysiology of ITP

12. Harrington’s Classic Experiment Harrington WJ, et al. J Lab Clin Med. 1951;38:1-10. Slide credit: clinicaloptions.comclinicaloptions.com 1000 800 600 400 200 123123456789 Platelets (Thousands) HrsDays

13. Epitope Spreading Leads to Diversity of Platelet Targets Cines DB, et al. N Eng J Med. 2002;346:995-1008. Slide credit: clinicaloptions.comclinicaloptions.com Glycoprotein IIb/IIIa autoantibody Glycoprotein Ib/IX Anti- glycoprotein Ib/IX Anti glycoprotein IIb/IIIa Glycoprotein Ib/IX B-cell clone 1 T-cell clone 1 Glycoprotein IIb/IIIa Glycoprotein Ib/IX Activated macrophage Glycoprotein IIb/IIIa Antibody-coated platelet Fcγ CD40 CD154 CD40 TCR CD154 B-cell clone 2 T-cell clone 2

14. Clearance of Antibody-Coated Platelets by Phagocyte Fcγ Receptors 1. Reprinted from The Lancet, Karpatkin S;349(9064):1531-1536, copyright (1997) with permission from Elsevier. 2. Republished with permission of American Society for Clinical Investigation from Psaila B, et al. J Clin Invest;118(8):2677-2681, copyright 2008; permission conveyed through Copyright Clearance Center, Inc. Antibody-Coated Platelet [1] Fcγ Family of Receptors [2] Slide credit: clinicaloptions.comclinicaloptions.com Activation ITIM inhibition Activation Low to medium Low to medium Low to medium Low to medium Low to medium HighAffinity for Fc Fragment Cell membrane FcγRIIIA FcγRIIIBFcγRIIC FcγRIIBFcγRIIAFcγRI

15. Production and Survival of Platelets in ITP 1. Harker LA. Br J Haematol. 1970;19:95-104. 2. Branehög I, et al. Br J Haematol. 1974; 27:127-143. 3. Stoll D, et al. Blood. 1985;65:584-588. 4. Ballem PJ, et al. J Clin Invest. 1987;80:33-40. Platelet Survival, Days StudyPlatelets Normal Subjects ITP Pts Turnover (x Normal) Harker 1970 [1] Allogeneic*9.90.344.9 Branehög 1974 [2] Allogeneic † 6.90.672.3 Stoll 1985 [3] Autologous8.02.90.9 Ballem 1987 [4] Autologous9.62.80.6 *Subjects with platelet counts > 25 x 10 9 /L received autologous platelets. † Subjects with platelet counts > 20 x 10 9 /L received autologous platelets. Slide credit: clinicaloptions.comclinicaloptions.com

16. 1. McMillan R, et al. Blood. 2004;103:1364-1369. 2. Republished with permission of American Society of Hematology, from Chang M, et al. Blood;102:887-895, copyright 2003; permission conveyed through Copyright Clearance Center, Inc. ITP Plasma Suppression of Megakaryocyte Production Slide credit: clinicaloptions.comclinicaloptions.com ITP-1ITP-2 ITP-3 ITP-4ITP-5ITP-6ITP-7 ITP-8 ITP-9 ITP-10 ITP-11 ITP-12 100 75 50 25 0 % Control Megakaryocytes

17. Cellular Immune Mechanisms in ITP  T cells –Proinflammatory response with increased Th1/Th2 activity [1] –Oligoclonal T-cell profiles [2] –Platelet-reactive T cells: GPIIb/IIIa target [3] –Cytotoxic T cells reactive with autologous platelets [4] –Resistance of CD4+ T cells to apoptosis [5] –Reduced number and function of CD4+CD25+ regulatory T cells [6]  Antigen presenting cells –Splenic macrophages take up opsonized platelets and stimulate T-cell proliferation without exogenous antigen [7] –Increased costimulatory activity on myeloid dendritic cells [8,9]  Mesenchymal stem cells –Decreased capacity to inhibit activated T-cell proliferation [10] 1. Zhou SF, et al. J Clin Immunol. 2013;33:938-946. 2. Ishiyama M, et al. Int J Hematol. 2006;83:147-151. 3. Kuwana M, et al. Blood. 2001;98:130-139. 4. Olsson B, et al. Nat Med. 2003;9:1123-1124. 5. c6.Liu B, et al. Eur J Haematol. 2007;78:139-143. 7. Kuwana M, et al. J Thromb Haemost. 2009;7:322-329. 8. Catani L, et al. Exp Hematol. 2006;34:879-887. 9. Zhou Z, et al. J Clin Immunol. 2010;30:814-822. 10. Zhang D, et al. Autoimmunity. 2014;47:519-529. Slide credit: clinicaloptions.comclinicaloptions.com

18. Molecular Mimicry in ITP Republished with permission of American Society of Hematology, from Molecular mimicry and immune thrombocytopenia, Aster RH, Blood;113:3887-3888, copyright 2009; permission conveyed through Copyright Clearance Center, Inc. Slide credit: clinicaloptions.comclinicaloptions.com

19. HCV Prevalence in Adult ITP StudyITP Pts, nHCV-Infected ITP Pts, n (%) Pawlotsky 1995 13914 (10) Pivetti 1996 3312 (36) Garcia-Suarez 2000 5113 (22) Sakuraya 2002 7911 (14) Zhang 2003 24733 (13) Rajan 2005 25076 (30) Total 799159 (20) Stasi R, et al. Hematol Oncol Clin North Am. 2009;23:1275-1297. Slide credit: clinicaloptions.comclinicaloptions.com

20. Diagnosis of ITP

21. Initial Diagnostic Evaluation of ITP in Children and Adults Provan D, et al. Blood. 2010;115:168-186. Basic Initial Evaluation  Patient history  Family history  Physical examination  Complete blood count  Reticulocyte count  Peripheral blood film  Quantitative immunoglobulins  Blood group (Rh)  Direct antiglobulin test  Helicobacter pylori  HIV  HCV  Bone marrow (in select patients) Assays of Potential Value  Platelet glycoprotein-specific antibodies  Antiphospholipid antibodies (including anticardiolipin and lupus anticoagulant)  Antithyroid antibodies and thyroid function  Pregnancy test in women of childbearing potential  Antinuclear antibodies  Viral PCR for parvovirus and CMV Assays of Unproven Benefit  Thrombopoietin  Reticulated platelets  Platelet-associated immunoglobulins  Platelet survival studies  Bleeding time  Serum complement Slide credit: clinicaloptions.comclinicaloptions.com

22. Clinical Manifestations

23. Adult ITP Presenting Symptoms by Platelet Count Neylon AJ, et al. Br J Haematol. 2003;122:966-974. Platelet Count Symptom, n (%) 0-9 x 10 9 /L (n = 114) 10-19 x 10 9 /L (n = 51) 20-29 x 10 9 /L (n = 26) 30-49 x 10 9 /L (n =54) Any (N = 245) Hemorrhage18 (16)6 (12)4 (15)2 (4)30 (12) Purpura75 (66)34 (67)12 (46)23 (43)144 (59) Asymptomatic21 (18)11 (22)10 (38)29 (54)71 (29) Slide credit: clinicaloptions.comclinicaloptions.com

24. Bleeding Manifestations in ITP 1. Helms AE, et al. Cutis. 2007:17:456-458. Image courtesy Stephen E. Helms, MD, University of Mississippi Medical Center, Jackson, MS 2. Kline A. Foot Ankle J. 2008;1:4. 3. Reproduced from Postgrad Med J, Awerbuch G, et al.;63:781-783, copyright 1987 with permission from BMJ Publishing Group Ltd. Slide credit: clinicaloptions.comclinicaloptions.com Hemorrhagic bullae [1] Ecchymoses and petechiae [2] CNS hemorrhage [3]

25. Estimated Annual Bleeding Incidence in ITP by Age Cohen YC, et al. Arch Intern Med. 2000;160:1630-1638. Fatal Hemorrhages Major Nonfatal Hemorrhages Age, Yrs Slide credit: clinicaloptions.comclinicaloptions.com 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0 < 4040-60> 60 0.130 0.012 0.004 Events per Pt-Yr 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0 Events per Pt-Yr Age, Yrs < 4040-60> 60 0.025 0.0725 0.719

26. Impact of ITP on Health-Related Quality of Life Mathias SD, et al. Health Qual Life Outcomes. 2008;6:13. HR-QoL Parameter, n (%) ITP Pts (N = 15) Signs and symptoms  Fatigue  Bleeding  Bruising  Other 14 (93) 8 (53) Treatment Effects  Steroids  Other treatments 13 (87) 8 (53) Emotional health  Fear, stress, anxiety  Relationships  Depression, isolation, loss of control  Mood, self- consciousness 11 (73) 7 (47) HR-QoL Parameter, n (%) ITP Pts (N = 15) Functional health  Daily activities  Sleep  Changes in lifestyle 13 (87) 11 (73) 9 (60) 7 (47) Work  Absences  Changes in attitudes  Career advancement  Productivity 13 (87) 10 (67) 5 (33) 3 (33) 4 (27) Slide credit: clinicaloptions.comclinicaloptions.com

27.  Mean 10.5-yr follow-up in primary ITP pts Portielje JE, et al. Blood. 2001;97:2549-2554. Morbidity and Mortality in Adults With ITP Adults With Primary ITP (N = 134) 85% (n = 114) had > 30 x 10 9 /L Off therapy Mortality risk mirroring the general population 6% (n = 8) had > 30 x 10 9 /L On maintenance therapy Increased number of hospitalizations but only minimal increase in mortality risk 9% (n = 12) had < 30 x 10 9 /L Refractory disease with severe thrombocytopenia Mortality risk of 4.2x (95% CI: 1.7-10.0) Slide credit: clinicaloptions.comclinicaloptions.com

28. Causes of Maternal Thrombocytopenia *Rare constitutional thrombocytopenias, infections, and hematologic malignancies. Palta A, et al. J Obstet Gynaecol. 2016;36:146-152. Burrows RF, et al. Am J Obstet Gynecol. 1990;162:731-734. Slide credit: clinicaloptions.comclinicaloptions.com 75% 15% to 20% 3% to 4% 1% to 2% Other* Benign ITP-immune Hypertension

29. Maternal Management of Pregnancy- Associated ITP  ITP responds in a similar fashion as in the nonpregnant patient  Corticosteroids increase risk for: –Hypertension/preeclampsia –Premature rupture of the fetal membranes –Osteoporosis  IVIg less toxic, at greater cost  Safe use of anti-D reported in a small number of patients  Splenectomy (if required) should be in early 2nd trimester  Thrombopoietic agents: class C Palta A, et al. J Obstet Gynaecol. 2015;[Epub ahead of print]. Slide credit: clinicaloptions.comclinicaloptions.com

30. Thrombocytopenia in Offspring of ITP Mothers  Incidence [1] –15% overall (platelets < 150 X 10 9 /L) –10% severe (platelets < 50 X 10 9 /L) –< 5% less than 20 X 10 9 /L  Pathogenesis [1] –transplacental transfer of pathogenic antibody –other factors  Cannot be predicted non- invasively [1,2] –No correlation with any maternal parameters –Best predictor is history of thrombocytopenia in prior offspring –Invasive testing (PUBS) can accurately predict the birth platelet count, but associated with a complication rate of 2- 3% –There is no evidence that mode of delivery affects incidence of ICH 1. Burrows RF, et al. Obstet Gynecol Surv. 1993;48:781-788. 2. Hachisuga K, et al. Blood Res. 2014;49:259-264. Slide credit: clinicaloptions.comclinicaloptions.com

31. Management of ITP

32. Goals of ITP Therapy  American Society of Hematology last published evidence-based guidance for ITP treatment in 2011 [1] –Updated recommendations are currently under development  Generally, clinicians should aim to: –Maintain a safe platelet count with minimal toxicity –Toxicity of therapy, particularly long-term steroid exposure, may be significant –Individualize therapy based on bleeding risk 1. Neunert C, et al. Blood. 2011;117:4190-4207. Slide credit: clinicaloptions.comclinicaloptions.com

33. Recommended “Safe” Platelet Ranges British Committee for Standards in Haematology General Haematology Task Force. Br J Haematol. 2003;120:574-596. Clinical SituationPlatelets General dentistry  Extractions  Regional dental block ≥ 10 x 10 9 /L ≥ 30 x 10 9 /L Surgery  Minor  Major ≥ 50 x 10 9 /L ≥ 80 x 10 9 /L Pregnancy  Vaginal delivery  Caesarean section  Spinal/epidural anesthesia > 50 x 10 9 /L > 80 x 10 9 /L Slide credit: clinicaloptions.comclinicaloptions.com

34. Therapy Options for ITP Provan D, et al. Blood. 2010;115:168-186. Clinical SituationTherapy Options First line (initial treatment for newly diagnosed ITP) Anti-D Corticosteroids: dexamethasone, methylprednisolone, prednis(ol)one IVIg Second line Azathioprine Cyclosporin A Cyclophosphamide Danazol Dapsone Mycophenolate mofetil Rituximab Splenectomy TPO receptor agonists (romiplostim and eltrombopag) Vinca alkaloids Treatment for patients failing first- and second-line therapies Category A*: TPO receptor agonists Category B † : campath-1 H, combination of first- and second- line therapies, combination chemotherapy, HSCT *Sufficient data to support recommendation. † Minimal data to support recommendation; potential for considerable toxicity. Slide credit: clinicaloptions.comclinicaloptions.com

35. First-line Therapies

36. Corticosteroids  Prednisone –Dose: 1-2 mg/kg/day, then taper –Clinical responses in 65- 85% patients –Responses in 4-14 days; peak in 7-28 days [1] –Only 5-30% sustain response after discontinuation –Toxicity: glucose intolerance, psychosis, osteoporosis, Cushingoid habitus, weight gain  Dexamethasone –Dose: 40 mg daily x 4 days –1 or more cycles, every 2 wks –Higher incidence of sustained remissions? 1. Neunert C, et al. Blood. 2011;117:4190-4207. Slide credit: clinicaloptions.comclinicaloptions.com

37. GIMEMA: Dexamethasone in Previously Untreated ITP Mazzucconi MG, et al. Blood. 2007;109:1401-1407. Slide credit: clinicaloptions.comclinicaloptions.com 0510152025 1.00.75.50.25 0 CR: 87% (95% CI: 76.1% to 98.1%) at 15 mos PR + MR: 65% (95% CI: 39.4% to 91.0%) at 15 mos P =.050 Pts at risk CR: 58 Events: 5 Pts at risk PR + MR: 19 Events: 5 Mos Probability of Relapse-Free Survival

38. 80 High-Dose Dexamethasone vs Prednisone in Newly Diagnosed ITP Wei Y, et al. Blood. 2016;127:296-302. Slide credit: clinicaloptions.comclinicaloptions.com 100 60 40 20 0 061218243036 Mos 95 97 60 57 40 45 39 40 37 32 21 15 31 24 12 10 7474 Pts Responding (%) Pts at Risk, n High-dose dexamethasone Prednisone

39. Dexamethasone and Rituximab Bussel JB, et al. Haematologica. 2014;99:1264-1271. Slide credit: clinicaloptions.comclinicaloptions.com 100 80 60 40 20 0 100 80 60 40 20 0 100 80 60 40 20 0 100 80 60 40 20 0 7201224364860 7201224364860 7201224364860 7201224364860 59% 19% 17% 61% 47% 41% 69% 14% Mos of Response Responders: CR vs PRAll pts: children vs adults All pts: duration of ITPAll pts: females vs males Female (n = 37) Male (n = 30) Adults (n = 41) Children (n = 26) CR (n = 43) PR (n = 7) < 24 mos (n = 44) Duration of > 24 mos (n = 23) Continuing Response (%)

40. Intravenous Immunoglobulin (IVIg)  Dose: 0.5-2.0 g/kg over 2-5 days Efficacy  65% achieve platelet count > 100,000/µl, 85% > 50,000/µ  Most responses transient  30% become refractory Toxicity  Headache  Positive DAT  Anaphylaxis in IgA-deficient patients  Thrombosis  Renal Mechanisms  Modulation of Fc receptors  Attenuation of complement mediated damage  Induction of anti-inflammatory cytokines  Anti-cytokine antibodies  Neutralization of autoantibodies by anti-idiotypes  Modulation of T-cell activity  Inhibition of lymphocyte proliferation  FcRn Slide credit: clinicaloptions.comclinicaloptions.com

41. Intravenous Anti-Rh(D)  Creates RBC hemolysis and Fcγ receptor blockade  Initial dose: 50 µg/kg IV over 2- 5 minutes –Reduce if Hgb < 10 g/dL  > 70% responders; duration > 21 days in 50%  All patients drop Hgb (0.8 g/dL)  Recommended only for Rh- positive pts with no history of splenectomy  Rare but severe AE: intravascular hemolysis and disseminated intravascular coagulation [1]  Severe DIC in 1 in 20,232 infusions [2] 1. WinRho [package insert]. 2. Gaines AR. Blood. 2005;106:1532-1537.  Patients should be closely monitored in a health care setting for at least 8 hrs after administration  Dipstick urinalysis should be performed at baseline, 2 hrs, 4 hrs post administration and prior to end of monitoring period FDA Black Box Warning Slide credit: clinicaloptions.comclinicaloptions.com

42. Second-Line Therapies

43.  Rituximab  Splenectomy  Thrombopoietin receptor agonists –Romiplostim –Eltrobopag  Mycophenylate mofetil  Vinca alkaloids  Azathioprine  Cyclosporine A  Cyclophosphamide  Danazol  Dapsone Provan et al. Blood. 2010;115:168-186. Slide credit: clinicaloptions.comclinicaloptions.com

44. Splenectomy Vianella N, et al. Haematologica. 2013;98:875-880. Slide credit: clinicaloptions.comclinicaloptions.com 80 100 60 40 20 0 0120240360480600 Mos From Splenectomy Relapse-Free Survival (%) CR (n = 180) All pts (n = 206) R (n = 26) CR R = pts who responded

45. 120144168 VTE and Sepsis After Splenectomy in ITP Boyle S, et al. Blood. 2013;121:4782-4790. Slide credit: clinicaloptions.comclinicaloptions.com 0.25 0.20 0.15 0.10 0.05 0 024487296 Mos After Splenectomy Incidence of Sepsis 0.03 0.02 0.01 0 0 Mos After Splenectomy 24487296120 Incidence of Abdominal VTE Log-rank P =.0544 Splenectomized Nonsplenectomized 0 0.01 0.02 0.03 0.04 0.05 0.07 0.06 Log-rank P <.0001 Incidence of VTE 024487296120 Splenectomized Nonsplenectomized Splenectomized Nonsplenectomized Mos After Splenectomy

46. Rituximab Efficacy in Adult ITP: Systematic Analysis Arnold DM, et al. Ann Intern Med. 2007;146:25-33. Platelet Count Response, x 10 9 /L Pooled Estimate, % (95% CI) Contributing Reports, n Pts, n Overall response (> 50) 62.5 (52.6-72.5) 19313 CR (> 150) 46.3 (29.5-57.7) 13191 PR (50-150) 24.0 (15.2-32.7) 16284 Slide credit: clinicaloptions.comclinicaloptions.com

47.  At 5 yrs, 21% to 26% of adults and children demonstrate sustained response to rituximab Durable ITP Remissions After Rituximab Patel VL, et al. Blood. 2012;119:5989-5995. n = 38 n = 72 Slide credit: clinicaloptions.comclinicaloptions.com 100 80 60 40 20 0 100 80 60 40 20 0 350300250200150100500350300250200150100500 ChildrenAdults Wks From Initial Treatment Pts in Continuing Response (%) 26% 21%

48. RITP: Rituximab vs Placebo in ITP Relapse  Rituximab used as a second-line treatment in randomized, double- blind, multicenter, placebo-controlled trial Ghanima W, et al. Lancet. 2015;385:1653-1661. Slide credit: clinicaloptions.comclinicaloptions.com 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 020406080 020406080 Wks of CR Wks of Response Probability of an Event Log-rank P =.1951 Log-rank P =.0143 Placebo Rituximab

49.  Rituximab generally well tolerated with no grade 4 AEs reported RITP: Safety Data Ghanima W, et al. Lancet. 2015;385:1653-1661. AE, n (%) Rituximab (n = 55) Placebo (n = 54) Main safety outcomes  Death  Bleeding  Infections  VTE ‡ 0 21 (38)* 22 (40) † 2 (4) 1 (2) 27 (50)* 13 (24) † 0 Grade 3  Abdominal pain  Pneumonia  Appendicitis  Back pain  Ovarian cyst  Pelvic pain 0 1 (2) 0 2 (4) 1 (2) 0 1 (2) *Log-rank P = 0.08. † Log-rank P = 0.09. ‡ 1 pulmonary embolism, 1 deep venous thrombosis. AE, n (%) Rituximab (n = 55) Placebo (n = 54) Grade ≤ 2  Anemia  Pyrexia  Influenza  Bronchitis  URTI  Headache  Throat irritation  Cough  Rash  Abdominal pain  Back pain 2 (4) 4 (7) 8 (15) 4 (7) 3 (5) 5 (9) 8 (5) 1 (2) 3 (5) 2 (4) 0 3 (6) 2 (4) 4 (7) 2 (4) 1 (2) 3 (6) 2 (4) 1 (2) Slide credit: clinicaloptions.comclinicaloptions.com

50. TPO Receptor Agonists 1. Bussel JB, et al. N Engl J Med. 2006;355:1672-1781. 2. Bussel JB, et al. N Engl J Med. 2007;357:2237-2247. Slide credit: clinicaloptions.comclinicaloptions.com Fc Carrier Domain Peptide Receptor-Binding Domain Eltrombopag [2,3]  Peptidomimetic  PO bioavailable  Binds to transmembrane portion of TPO receptor Romiplostim [1]  Unique platform peptibody  Binds to ligand binding site of TPO receptor  SC injection H0 0 0 HN N N NCH 3 H3CH3C H3CH3C

51. Romiplostim in Chronic ITP 0 38.1 (P =.0013) Durable Platelet Response (%) 0 20 40 60 80 100 4.8 61.0 (P <.0001) SplenectomizedNon- splenectomized 0 78.6 Overall Platelet Response (%) 14.3 87.8 PlaceboRomiplostim Kuter DJ, et al. Lancet. 2008;371:395-403. Overall Platelet Response Slide credit: clinicaloptions.comclinicaloptions.com 0 20 40 60 80 100 (P <.0001) SplenectomizedNon- splenectomized Durable Platelet Response

52. Long-term Romiplostim: Efficacy Kuter DJ, et al. Br J Haematol. 2013;161:411-423. 12 10 8 6 4 2 0 Mean Dose (μg/kg) 272181624324048566472808896104112120128136144152160168176184192200208216224232240248256264 n = 2919279272262254244230227206162136118111108103100979589878378685851412822 2321191615 350 300 250 200 150 100 0 Median (Q1, Q3) Platelet Count x 10 9 /L 272081624324048566472808896104112120128136144152160168176184192200208216224232240248256264 n = 29111257242233227228210 194156129110100959285838182807574675745413126222319171314 Study Wk 50 Slide credit: clinicaloptions.comclinicaloptions.com

53. Long-Term Romiplostim: Safety Data Cines DB, et al. Int J Hematol. 2015;102:259-270. Slide credit: clinicaloptions.comclinicaloptions.com

54. RAISE: Eltrombopag in Chronic ITP Cheng G, et al. Lancet. 2011;377:393-402. Placebo Eltrombopag Placebo, splenectomized Placebo, not splenectomized Eltrombopag, splenectomized Eltrombopag, not splenectomized Pts at Risk, n Placebo Eltrombopag 61 135 60 134 59 131 58 129 59 123 59 128 58 128 43 96 44 95 43 91 53 110 54 110 55 118 58 119 46 101 Median Platelet Count per μL (x10 3 ) 140 120 100 80 60 40 20 0 On treatmentPost- treatment Pts at Risk, n Placebo Eltrombopag 61 135 61 134 60 133 59 133 60 131 60 134 59 134 47 108 48 112 47 113 58 132 54 110 55 118 58 119 50 114 Pts Responding to treatment (%) 60 50 40 30 20 10 0 On treatment Post- treatment Study Wk Median Platelet Count per μL (x10 2 ) 140 120 100 80 60 40 20 0 On treatment Post- treatment 160 02612345610141822124 Slide credit: clinicaloptions.comclinicaloptions.com Placebo Eltrombopag

55. EXTEND: Eltrombopag in Chronic ITP Saleh MN, et al. Blood. 2013;121:537-545. 200 150 100 50 0 Median Platelet Count (x 10 9 /L) 156BL123481624324048566472808896104112120128136144152 Pts at Risk, n Wks n = 253n = 218n = 147 n = 32 10290285272 2431661281079468777871726150433112 151211299 60 50 40 30 0 Pts (%) 156BL123481624324048566472808896104112120128136144152 Pts at Risk, n Wks 9290284270 238160121998963737868 5950413112 151211299 20 10 Grades 1-4 Grades 2-4 Slide credit: clinicaloptions.comclinicaloptions.com

56. EXTEND: Adverse Events Leading to Withdrawal from Study Saleh MN, et al. Blood. 2013;121:537-545. AE, n (%)N = 299 Any38 (13) Tromboembolic11 (4) Hepatobiliary6 (2) Cataract4 (1) Headache2 (<1) Angina pectoris1 (<1) Death NOS1 (<1) Ectopic pregnancy1 (<1) Epistaxis1 (<1) Fatigue1 (<1) Hypertension1 (<1) Lung neoplasm1 (<1) Lymphoma1 (<1) AE, n (%)N = 299 Mouth hemorrhage1 (<1) Multi-organ failure1 (<1) Muscle spasms1 (<1) Myelofibrosis1 (<1) Optic neuritis1 (<1) Palpitations1 (<1) Petechiae1 (<1) Pneumonia1 (<1) Renal failure1 (<1) Retinal pigment epitheliopathy1 (<1) Road traffic accident1 (<1) Subarachnoid hemorrhage1 (<1) Toxic neuropathy1 (<1) Slide credit: clinicaloptions.comclinicaloptions.com

57. TPO Receptor Agonists CharacteristicRomiplostimEltrombopag ClassificationPeptibodyNon-peptide small molecule IndicationsChronic ITP Severe aplastic anemia Hepatitis C-associated thrombocytopenia Pediatric chronic ITP > 6 yrs of age Delivery/dosingSC, weeklyPO, daily TPO-R binding siteLigand-binding domainTransmembrane domain Rebound thrombocytopenia 4-10% Elevated transaminases--3-7% Myalgias10%5% Marrow fibrosis MF2: 10-70%, MF3: 1-3%. Rare collagen MF2: 10-70%, MF3: 1-3%. Rare collagen Kuter DJ. Semin Hematol. 2010;47:243-248. Slide credit: clinicaloptions.comclinicaloptions.com

58. Choosing Second-line Therapy in ITP Republished with permission of American Society of Hematology, from Ghanima W, et al. Blood;120:960-969, copyright 2012; permission conveyed through Copyright Clearance Center, Inc. Slide credit: clinicaloptions.comclinicaloptions.com ITP unresponsive or relapsed after first-line therapy Choose a second-line treatment based on the following factors Restrictions on use of TPO receptor agonist/rituximab by health funding authorities 1. Contraindication to splenectomy, eg, comorbidity 2. No restrictions on use of TPO receptor agonist/rituximab Other factors: 1. Old age (> 60-70 yrs depending on physical condition) 2. Mixed/hepatic platelet sequestration on radioisotope study 3. Newly diagnosed (0-3 mos) or persistent (3-12 mos) ITP 4. Exposure to malaria, babesia, or other infections cleared by the spleen Other factors: 1.Chronic ITP (> 1 yr) 2.Pt prefers Tx with high cure rate and/or no maintenance therapy 3.Wish to become pregnant 1.Pt refuses splenectomy but prefers Tx with curative intent 2.High risk of thrombosis 3.Anticipated poor compliance 4.Inability to meet dietary restrictions (eltrombopag) Pt/physician seeks Tx with high response rate SplenectomyRituximabTPO-RA

59. Future Directions: Current Phase III Trials TrialNCT# rhTPO Combining Cyclosporin A vs Cyclosporin A in Steroid- Resistant/Relapsed ITP NCT02203422 2 Cycles Rituximab vs Standard Regimen in Management of Steroid-Resistant/Relapsed ITP NCT02137681 Multicenter Open-Labeled Pilot Study on rhTPO in Management of ITP in Pregnancy NCT02391272 Efficacy and Safety of Different Doses and Frequencies of rhTPO in Primary ITP NCT02139501 Study of Fostamatinib Disodium in the Treatment of Persistent/Chronic ITP NCT02076412 Safety and Efficacy of Eltrombopag at Escalated Doses Up to 150 mg in Patients With Persistent and Chronic ITP Not Responsive to 75 mg NCT01880047 ClinicalTrials.gov Slide credit: clinicaloptions.comclinicaloptions.com

60. Conclusions  ITP is a common hematologic disorder with a complex pathogenesis involving accelerated platelet destruction, impaired platelet production, and humoral/cellular immunity abnormalities  Viral and other pathogens play important roles in development of secondary ITP  Multiple therapeutic strategies exist for the treatment of ITP and should be individualized for each patient –First-line –Corticosteroids: effective, but usually do not provide long-term responses –Second-line –Splenectomy: remains an effective long-term therapy –Rituximab: may potentially provide long-term remissions in a subset of patients –Thrombopoietic agents: provide an important new treatment option  The role of aggressive management in newly-diagnosed ITP is uncertain  The choice of a second line therapy depends on patient characteristics and desired outcomes Slide credit: clinicaloptions.comclinicaloptions.com

61. Win a $100 Gift Card Use anywhere Debit MasterCards are accepted Millions of locations worldwide Enter your email and complete the survey using the link below Check out the related CME-certified module and claim your credit: Advances in the Treatment of Adult Immune Thrombocytopenia Keith R. McCrae, MD Enter now: clinicaloptions.com/itpdrawing clinicaloptions.com/itpdrawing Note: Drawing ends April 5, 2016