1. ADVANCES IN THE DIAGNOSIS AND TREATMENT OF THROMBOCYTOPENIA

3. Petechiae

4. Remove Antigen: Rx Inciting Agent = Fix “ITP” HIV Hepatitis C Helicobacter pylori

17. WHEN TO DO A BONE MARROW IN THE THROMBOCYTOPENIC PATIENT?

21. ITP: A SIMPLE DISEASE Patients make auto-antibodies directed against their own platelets These platelets are rapidly destroyed If the platelet count becomes low enough, bleeding symptoms may ensue Bleeding is rarely serious, ie an intracranial hemorrhage, even at very low counts

22. ITP: A COMPLICATED DISEASE Anti-platelet antibodies have not been able to be measured discriminatively: the diagnosis and prognosis (outcome, risk of bleeding) remain insecure Patients may not make platelets well Treatment is uncertain: who needs it, what to treat with and in which order

23. Pathophysiology of ITP Implications for Diagnosis and Treatment

24. Harrington WJ, et al. J. Lab Clin Med. 1951;38:1-10. 1000 800 600 400 200 1 2 3 1 2 3 4 5 6789 Effect on the Platelet Count of Plasma : ITP into Normal Hours Disease incidence (thousands) Days

25. ITP: what tests are helpful Complete CBC---not just the platelets Bone marrow---not in all/most cases Blood type & DAT-prognostic re hemolysis PT-PTT, Thyroid, Ig’s, lupus, SMA Anti-phospholipid antibodies Platelet turnover (estimates): platelet retics, thrombopoietin, large platelets

26. Who Needs Treatment with ITP? At What Platelet Count ? Needs to be individualized: job physical trauma ie sports access to care anxiety effect on fatigue

27. Acute Platelet Increase gold standard: IVIG at 1 gm/kg IV anti-D: as fast as IVIG at 75 mcg/kg Steroids: IV solumedrol 30/kg, high dose dexamethasone or Prednisone 2-4/kg Platelet transfusions Combinations including Steroids, IVIG, IV anti-D and/or vincristine

28. Advantages and Disadvantages of Treatment for Children with ITP Advantages Disadvantages Steroids: oral, continuous so much toxicity often works with any usage IVIG:rapid substantial blood product, platelet increase headache, 4-6hrs IV anti-D: 5-15 minute, at fever-chill, hemo- 75 mcg/kg=IVIG lysis, IVH, blood

29. ML18542 study Clinica Ematologica-Udine STUDY TREATMENTS days DD D RTX D:Dexamethasone 40 mg po daily x 4 D D DDD RTX 1 2 3 4 7 14 21 28 days ARM - A ARM - B RTX:Rituximab 375 mg/m 2 IV x 4

30. SPLENECTOMY

31. CONCLUSION: ITP IN CHILDHOOD Treatment is indicated for those at risk of (serious) bleeding Choice of treatment needs to be appropriate for the goal: acute vs cure New treatments will revolutionize care Understanding of pt pathophysiology may allow individualization of care

32. GUIDELINES FOR PLATELET TRANSFUSIONS “SAVE ‘EM TIL YOU REALLY NEED ‘EM” NEVER TRANSFUSE A NUMBER. ALWAYS TRANSFUSE A PATIENT!

33. Platelet Production Is Suboptimal in ITP Patients Autoantibodies inhibit Mk growth and promote apoptosis (Chang, McMillan) Autologous 111 In-platelet studies show platelet production < normal in 2/3 pts--- -same results with absolute platelet retics TPO levels normal in 75% of ITP patients (relative TPO deficiency) Damaged or Dysfunctional Mk in marrow (Houwerijl)

34. P P P P Macrophage Thrombo- poietin Peripheral blood Bone marrow Platelet Megakaryocyte Pathophysiology of ITP

35. TPO Agonists in Thrombocytopenic States: Focus on ITP Newer agents that will probably revolutionize our approach to thrombocytopenia in many conditions, not only ITP

36. rhTPO and PEG-rHUMGDF NH 2 Mpl-binding domain rhTPO Glycosylated Full length Polyethylene glycol COOH terminal domain NH 2 COOH Mpl-binding domain PEG-rHuMGDF Not glycosylated Truncated Additional polyethylene glycol moiety Kuter DJ, Begley CG, Blood 2002;100:3457.

37. Why Are We Not Using the 1st Generation Thrombopoietins? Initial use of MGDF (and also rhuTPO) resulted in the development of antibodies to exogenous (administered) 1st generation TPO’s that cross-reacted with endogenous TPO (native eTPO): a number of multiply- dosed recipients developed a lasting thrombocytopenia.

38. AMG 531 Unique platform “peptibody” Made in E. coli Molecular weight = 60,000 D 4 Mpl binding sites Bussel JB et al. N Engl J Med. 2006;355:1672. No sequence homology with TPO Cleared endothelial FcRn  Recycled Cleared RES FcCarrier Domain TPO Agonist PeptidesFcCarrier Domain TPO Agonist Peptides

39. Romiplostim: 38% Durable Response, 79% Overall Response Durable Response Overall Response Number of Weeks Platelet Response Platelet response: platelet count ≥ 50 x 10 9 /L Durable platelet response: platelet response for ≥ 6 weeks of final 8 weeks, in the absence of rescue medications during 24 week trial Overall response: either durable or transient platelet response (≥ 4 weekly platelet responses) Error bars represent standard deviation of the mean 0.0 38.1 (P = 0.0013) 0.0 78.6 0 20 40 60 80 100 (P < 0.0001) Durable Platelet Response (%) Overall Platelet Response (%) Mean (SE) Number of Weeks With Platelet Response 0.2 (0.1) 12.3 (1.2) 0 5 10 15 20 (P < 0.0001) 0 20 40 60 80 100 Placebo Romiplostim

40. Romiplostim (AMG 531): Summary In splenectomized patients: 38% durable response, 79% overall response Increased and maintained platelet counts over 24 weeks Significantly decreased the use of rescue medications All romiplostim patients discontinued or reduced concurrent ITP therapy (corticosteroids, azathioprine, danazol) Romiplostim appeared to be well tolerated

41. Romiplostim: Summary of Long-term Dosing Efficacy Data Summary The majority of patients achieved long-term platelet counts > 50 x 10 9 /L and double the baseline value –Mean platelet count maintained between 50 and 250 x 10 9 /L over 2 years Use of concomitant and rescue medications was substantially reduced over time No trend in this study for adverse events to increase in frequency with longer drug exposure One patient had neutralizing antibodies to AMG 531; negative on retesting

42.  Small molecule, non-peptide thrombopoietin receptor (TPO-R) agonist  Does not compete with TPO for binding to TPO-R  Low immunogenic potential  Active only in humans, chimps  Stimulates megakaryocyte proliferation and differentiation  Orally bioavailable  Increases platelet counts in normal volunteers Thrombopoietin MW 64,000 Eltrombopag MW 442 Eltrombopag: Oral Platelet Growth Factor

43. Primary Endpoint: Percentage of Patients With Platelets ≥50,000/µL at Day 43 Visit † Responders (%) Placebo § Eltrombopag P <0.001 ‡ OR = 9.61 (3.31, 27.86) † Last observation carried forward. ‡ Indicates significance at 5% (2-sided) level of significance. § 1 patient received IVIg on Day 1. Logistic regression analysis adjusted for randomization stratification variables.

44. Median Platelet Counts (25th and 75th Percentiles) Baseline to Week 20 1Baseline2364587119101312161415181719 20 0 50 100 150 200 250 300 350 Week 1061071069990979276836567625160395548424339 33 Number of subjects: Platelet count (Gi/L) Splenectomized pts respond as well as non-splenectomized pts

45. Conclusions The EXTEND data suggest that oral eltrombopag was well tolerated and safe Eltrombopag up to 75 mg/day increased and sustained platelet counts >50,000/ μ L in the majority of patients Eltrombopag reduced the incidence and severity of bleeding

46. HCV Phase II Study 0 50 100 150 200 250 014284256708498112 Study Day Median Platelet Count Placebo 30 mg 50 mg 75 mg INITIATIONMAINTENANCE McHutchison, NEJM 2007