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ITP Definition. Autoimmune disorder characterized by immunologic destruction and decreased production of otherwise normal platelets most commonly occurring in response to an unknown stimulus. PrimarySecondary (i.e. HIV, HCV, and antiphospholipid ab syndrome)PLT count of < 100,000 or 150,0007New (< 3 months) Persistent (3 to 12 months) Chronic (> 12 months).
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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)