thrombopoietin receptor agonists in immune thrombocytopenia

1. Kristen Sanfilippo M.D. Thrombopoietin Receptor Agonists in Immune Thrombocytopenia

2. Majority of Studies Use PLT < 150,000 for inclusion/exclusion criteria

3. ITP Treatment Treatment Goal: Prevention of bleeding events No clear data exists Severity of Bleeding Bleeding Risks (prior bleeding episodes, HTN, age) Activity Level Side Effects of Treatment ASH 2011 Guidelines: PLT < 30,000 (Grade 2C)

4. First Line Treatment Summary Longer course of corticosteroids are preferred over shorter courses of corticosteroids or IVIg as first line treatment (grade 2B) If IVIg is used, the dose should initially be 1g/kg as a onetime dose. This dosage may be repeated if necessary (Grade 2B) IVIg be used with corticosteroids when a more rapid increase in platelet count is required (Grade 2B) Either IVIg or anti-D (in appropriate patients) be used as a first line treatment if corticosteroids are contraindicated (Grade 2C)

5. Relapsed or Refractory ITP Refractory ITP: Severe ITP (ITP resulting in clinically relevant bleeding) that occurs after a splenectomy Relapsed ITP: Occurs after initial therapy, or with failure to achieve an adequate PLT response with initial therapy

6. Thrombopoietin (TPO) A glycoprotein hormone produced primarily by the liver Principal regulator of megakaryocyte development and platelet production Once released, platelets remain in circulation approximately 10 days TPO levels are either increased only slightly or abnormally normal in ITP Kuhne. Ann Hematol. 2010 Kosugi. Br J Haematol. 1996

9. Thrombopoietin Receptor Agonists Romiplostim (Nplate) Peptide Mimetic that binds to the TPO receptor in the same fashion as endogenous TPO1 Competitive Subcutaneous Injection Onset of action 5-14 days Eltrombopag (Promacta) Small molecule, synthetic non-peptide that binds to the TPO receptor at the transmembrane domain, thus acting distinct from TPO2 Additive Oral Onset of action 7-28 days Evangelista M. Curr Drug Discov Technol. 2007 Erickson-Miller CL. Stem Cells. 2009

10. Kuhne. Ann Hematol. 2010

11. Kuhne. Ann Hematol. 2010

12. Eltrombopag

13. Eltrombopag (Promacta)

14. Eltrombopag (Promacta): 773B

15. Eltrombopag (Promacta): 773B Primary End Point: 59% Eltrombopag vs. 16% Placebo (OR 9.61; 95% CI 3.31-27.86) (p < 0.0001) Dose Modification: 34 increased to 75mg 10 responded PLT returned to baseline at 2 weeks after treatment

16. Eltrombopag (Promacta): 773B Primary End Point: 59% Eltrombopag vs. 16% Placebo (OR 9.61; 95% CI 3.31-27.86) (p < 0.0001) Dose Modification: 34 increased to 75mg 10 responded PLT returned to baseline at 2 weeks after treatment

17. Eltrombopag (Promacta): 773B Prior Therapy Risk of Bleeding 61% vs. 79% OR 0.49 95% CI 0.26-0.89; p=0.021

18. Eltrombopag (Promacta): 773B Adverse Events: Overall no significant difference between Eltrombopag/Placebo 59% Eltrombopag vs. 37% Placebo N/V No thromboembolic events No increased incidence of marrow fibrosis

19. Eltrombopag (Promacta): RAISE

20. Eltrombopag (Promacta): RAISE Doses Required Eltrombopag = 25 mg = 21% 75 mg = 44% Placebo 75 mg = 93% Supportive Tx Decrease 59% Eltrombopag 32% Placebo

21. Eltrombopag (Promacta): RAISE OR 8.2 of responding to Eltrombopag over Placebo, 99% CI 3.59-18.73; p < 0.0001

22. Eltrombopag (Promacta): RAISE Clinically Significant Bleeding Events 33% Eltrombopag vs. 53% Placebo OR 0.35, 95% CI 0.19-0.64; p = 0.0008

23. Eltrombopag (Promacta): RAISE Nausea and Vomiting (5% more in Eltrombopag Goup) Venous Thromboembolism 3 patients on treatment with Eltrombopag Smoking, LAC Smoking, OCP New diagnosis of rectal ca, abdominal surgery Increased alanine aminotransferase and bilirubin No mention of increased marrow fibrosis

24. Romiplostim

25. Romiplostim (Nplate): Pivotal Trials

26. Romiplostim (Nplate): Dose Requirement

27. Romiplostim (Nplate): Outcomes Target PLT = 50,000 1 week: 25% of all Romiplostim patients 3 week: 50% of all Romiplostim patients PLT mean week 7-25 Splenectomized Patients Romiplostim 56,000-85,000 Placebo 13,000-21,000 Non-Splenectomized Romiplostim 63,000-96,000 Placebo 29,000-38,000

28. Romiplostim (Nplate): Response Overall PLT Response Rescue Therapy

29. Romiplostim (Nplate): Bleeding Significant Bleeding (severe, life threatening, fatal) Romiplostim: 6/84 (7%) 1 death from ICH Placebo: 5/41 (12%) 1 death from ICH

30. Romiplostim (Nplate): AEs Romiplostim 1 increase in marrow reticulin 2 VTE Placebo 1 fatal PE

31. Relapsed or Refractory ITP Splenectomy for patients who have failed corticosteroid therapy (Grade 1B) Thrombopoietin receptor antagonists for patients at risk of bleeding who relapse after splenectomy or who have a contraindication to splenectomy and who have failed at least one other therapy (Grade 1B) Eltrombopag and romiplostim may be considered for patients at risk of bleeding who have failed one line of therapy such as corticosteroids or IVIg and who have not had splenectomy (Grade 2C) Rituximab may be considered for patients at risk of bleeding who have failed one line of therapy such as corticosteroids, IVIg or splenectomy (Grade 2C)