1. Home>
2. Specialties>
3. Oncology and Hematology>
4. Summary and Comment

Stimulating Platelet Production

New megakaryocyte-stimulating agents might allow patients with thrombocytopenia to avoid drug toxicity.

Three classes of agents that stimulate platelet production are being developed. These all bind to and stimulate the thrombopoietin (TPO) receptor: TPO peptide mimetics (e.g., AMG 531), TPO nonpeptide mimetics (e.g., AKR-501, eltrombopag), and TPO-agonist antibodies (genetically modified to create small bivalent fragments called minibodies; Blood 2007; 109:4607). All of the agents raise platelet counts in animal models; two, AMG 531 and eltrombopag, are currently in clinical development. AMG 531, when injected weekly for 6 weeks, significantly increased platelet counts in 12 of 16 patients with immune thrombocytopenic purpura (ITP; N Engl J Med 2006; 355:1672).

In a phase 1 dose-finding study of eltrombopag, conducted by industry employees, the drug (range, 5–75 mg) was given orally once daily for 10 days to 73 healthy men. Plasma samples were collected through day 28. Platelet counts increased by more than 20% above baseline in 6 of 9 men who received 30 mg, and in all 19 men who received 50 mg or 75 mg. The largest increase, 50% above baseline, was seen in men who received 75 mg daily. The platelet count began rising by day 8, peaked at day 16, and returned to baseline by day 22. The half-life of the drug was longer than 12 hours, and drug accumulated in the plasma at the higher dose levels. No consistent clinical or laboratory adverse effects were noted.

In a meeting abstract from a previous study of eltrombopag in patients with ITP, researchers reported that 86% of patients had increases in platelet counts to greater than 50,000/µL at a daily dose of 75 mg for 6 weeks. A trend toward less bleeding was seen, and no significant adverse effects manifested (Blood 2006; 108:abstract 475).

Comment: Most of the treatments that are recommended for patients with ITP (steroids, splenectomy, anti-D antibodies, cytotoxic agents, and, more recently, rituximab) are directed toward limiting the platelet destruction that occurs in this disease. However, although marrow megakaryocytes usually are increased in patients with ITP, they might not be producing platelets maximally. As demonstrated by these trials of megakaryocyte-stimulating agents, additional platelet production to raise platelet counts can be achieved in some of these patients. This new approach could allow patients to avoid some of the more toxic drugs that currently are prescribed for ITP. Furthermore, these agents could be useful in the management of thrombocytopenia that occurs in some patients with myelodysplasia, in whom megakaryocytes are present but platelet production is suboptimal. Some experts speculate that one or more of these new agents will be clinically available by the end of 2008. Whether these agents are indicated mainly for patients with refractory thrombocytopenia or also as a first-line therapy is still unclear.

— David Green, MD, PhD

Published in Journal Watch Oncology and Hematology June 25, 2007

Citation(s):

Jenkins JM et al. Phase 1 clinical study of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist. Blood 2007 Jun 1; 109:4739-41.

• Original article (Subscription may be required)
• Medline abstract (Free)