THROMBOCYTOPENIA:
Treatment with 2^nd Generation Thrombopoietic Growth Factors
The speaker for this topic was Adrian Newland, FRCP from The Royal London Hospital in London, United Kingdom.

Thrombopoietin (TPO) is involved in all stages of thrombopoiesis from the stem cell to the mature megakaryocytes that release platelets into the circulation. Thrombopoietic growth factors may stimulate platelet production by promoting proliferation, survival, and differentiation of megakaryocyte precursors into mature megakaryocytes, and by platelet release. The 2^nd generation thrombopoietic growth factors include TPO nonpeptide mimetics (eltrombopag, AKR 501), TPO peptide mimetics (romiplostim, AMG 531), and TPO agonist antibodies.

Eltrombopag is an orally bioavailable small molecule TPO-R (receptor) agonist that interacts with TPO-R differently than endogenous TPO. It stimulates megakaryocyte proliferation and differentiation, but does not prime platelets for activation. Given daily, eltrombopag increases platelet counts in a dose-dependent manner. In an early phase I trial in which daily doses of the drug were given, the platelet count started to increase at 7-10 days and continued to rise as long as eltrombopag was given. However, if the drug was stopped within 2 to 3 weeks the platelet count would drop to less than 10,000. A phase II dose-response study in which chronic ITP patients received daily eltrombopag (30mg, 50mg, or 75mg) resulted in progressive increase in platelet production and a steady decrease in bleeding as long as the drug was given.

Romiplostim (AMG 531) is a novel thrombopoiesis-stimulating peptibody (TPO peptide mimetic) that is structurally unrelated to TPO. It targets and affects the TPO-R and increases platelet production in a dose-responsive manner. It is administered subcutaneously once weekly. The median time to first response is 3.1 weeks, therefore, it is not an ideal candidate for use in acute, severe bleeding. When the ultimate platelet response did occur, the platelet count reached 350,000 to 450,000 in 60-70% of patients in a phase II trial; in fact if counts exceed 400,000 to 450,000 AMG 531 should be held to avoid risk of thrombosis. In a phase III chronic ITP trial, platelet responses were durable with long-term (up to 2 years) platelet counts double the baseline value and ≥50,000 in >50% of patients. The overall platelet response in this trial was 83% (splenectomized patients 79%; non-splenectomized patients 88%). Repeated treatment with AMG 531 is well tolerated and no antibodies to the drug have currently developed.

Thrombocytopenia associated with other clinical conditions has been treated in clinical trials with these agents with the following results:

• Hepatitis C virus associated – eltrombopag is effective at higher doses; 100% of patients able to complete their anti-viral therapy because thrombocytopenia improved or corrected.
  
• Chemotherapy-induced – will see a small response that only decreases the number of thrombocytopoenic days by 2 or 3; cost-effective??
  
• Myeloablative therapy – see very little response at all.
  
• MDS – romiplostim (AMG 531) effective in low and intermediate-1 risk, 41% durable response (median duration of response 23 weeks). No antibodies occurred; 3 deaths not related to thrombocytopoenia or AMG 531 therapy.