Eltrombopag for Chronic ITP

Abstract & Commentary

By Andrew Artz, MD, MS, Division of Hematology/Oncology, University of Chicago, Chicago, IL; Dr. Artz reports no financial relationship to this field of study.

Synopsis: Recent studies have shown that thrombopoiesis stimulating molecules improve platelet counts in chronic refractory idiopathic thrombocytopenic purpura (ITP). Busser and colleagues performed a randomized dose escalating trial of eltrombopag, an oral thrombopoietin stimulating agent, vs placebo for chronic ITP. The three doses of 30 mg, 50 mg, and 75 mg daily that were investigated led to platelet counts above 50,000 per uL in 28%, 70% and 81% respectively. Toxicities were similar to placebo. Eltrombopag is an oral thrombomimetic with considerable activity in chronic ITP that warrants further clinical study.

Source: J. Bussel, et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl. J. Med. 2007. 357: 2237-2247.

Idiopathic (or immune) thrombocytopenic purpura (ITP) is an acquired platelet disorder diagnosed by exclusion.1 ITP has been classically described as a condition of platelet destruction. However, impaired megakaryopoiesis and/or reduced thrombopoietin levels (a platelet growth factor) have spurred interest in molecules that bind the thrombopoietin receptor, thereby enhancing megakaryopoiesis. Recent data employing AMG 531, a novel subcutaneously administered thrombopoiesis stimulating molecule showed considerable activity in chronic refractory ITP.2 In this study, Bussel and colleagues report on the activity of eltrombopag, an oral small molecule non-peptide thrombopoietin-receptor agonist, for refractory ITP in adults.

Investigators enrolled adults at 44 sites internationally with chronic refractory ITP and a platelet count < 30,000/uL. ITP considered secondary to another disease was excluded including HIV, systemic lupus erythematosus, and hepatitis C virus. Study drug was administered in a double-blind placebo fashion with random assignment to 30 mg, 50 mg, or 75 mg po daily of study drug or daily placebo for up to 6 weeks. A platelet count > 200,000/uL required discontinuation of study drug. The study was supported GlaxoSmithKline.

Among the 153 patients screened, 118 underwent randomization and 117 were treated over the 10 month period the study was open. The study design allotted for 272 patients with two planned interim analyses. The study was discontinued early when the efficacy endpoints were met early as per the pre-specified early stopping rules. The median age was 50 years, 62% were women, and 47% had undergone prior splenectomy. The primary endpoint of a platelet count of 50,000/uL or more by day 43 was achieved in 11% (3/27) of placebo patients, 28% (8/29) at 30 mg of drug, 70% (19/27) at 50 mg of drug, and 81% (21/26) at 75 mg of Eltrombopag. Significantly more patients in the 50 mg and 75 mg of eltrombopag reached the platelet count threshold compared to placebo (p < 0.002 and p <.001 respectively by day the second study visit of patients taking dose and mg had a platelet count> 50,000/uL. Finally, a platelet count > 200,000 /uL occurred in 4% of placebo patients and 15%, 37% and 50% at doses of 30, 50, and 75 mg. Adverse events were similar across study groups. One patient in the 50mg Eltrombopag died from cardiopulmonary failure. The patient had multiple cardiac risk factors.


In adults, ITP is often a recurrent clinical problem. Initial therapy involves glucocorticoids, IGIV and/or Anti-D (WinRho). A variety of interventions have been used for relapsed disease including agents used in upfront therapy, splenectomy, rituximab, and other immunosuppressive agents. Because of the chronic nature of ITP and cumulative toxicities of long-term therapy, a conservative approach has been advocated where treatment is generally reserved for a platelet count < 20,000-30,000/uL for asymptomatic individuals. More tolerable and effective treatments are clearly needed for chronic refractory ITP.

This study by Bussel and colleagues builds upon ongoing research into new ITP treatments based on stimulating megakaryopoiesis rather than immunosuppression. The initial enthusiasm using PEG-MGDF, a recombinant form of thrombopoietin, was erased when severe thrombocytopenia occurred related to thrombopoietin antibodies. A new generation of smaller, less immunogeneic molecules that are agonists for the thrombopoietin receptor but have a structure distinct from native thrombopoietin have been developed, reducing the risk of antibody formation. One year ago, promising results with the subcutaneously administered thrombopoiesis stimulating protein AMG 531 were reported. In this study, another thrombopoiesis stimulating protein, eltrombopag, showed highly promising activity with platelet counts exceeding 50,000/uL in 70% and 81% of the two higher study doses, compared to only 11% of placebo. Moreover, most of these responses had occurred by day 15 and almost half of the highest dose cohort achieved a platelet count of > 200,000 /uL.

As in early phase investigation, further study will be required. Long term follow-up will be needed to exclude antibody development, determine the results of re-exposure to drug, and dissect uncommon or late toxicities. Since studies using AMG-531 have shown marrow fibrosis, future trials would benefit from bone marrow evaluation. As an orally administered non-immunosuppressive drug, eltrombopag may have clinical advantages over further immunosuppression or subcutaneous preparations of thrombopoiesis stimulating molecules. Potentially even more interesting will be whether eltrombopag and other thrombopoiesis stimulating proteins are effective in thrombocytopenia from other conditions such as chemotherapy and hepatitis treatment.

In conclusion, daily doses of 50 mg and 75 mg orally of eltrombopag raise platelet counts in chronic refractory ITP and should be a high priority for future study.


1. Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med. 2002; 346:995-1008.

2. Bussel JB, et al. N Engl J Med. 2006;355:1672-1681.