Treatment of immune thrombocytopenic purpura: focus on eltrombopag

Abstract

Immune thrombocytopenic purpura (ITP) is a relatively common autoimmune disorder in which antibodies are produced to circulating platelets. Symptoms can be mild, but for most patients the risk of severe bleeding is unacceptable and treatment is required. Glucocorticoids followed by splenectomy had been the mainstays of therapy. High dose intravenous immunoglobulin and anti-RhD therapy are available for patients with severe illness, but produce only temporary benefit. Rituximab may provide more durable responses, danazol may be underutilized, and immunosuppressants and cytotoxic agents are less often required. Recently the pathophysiology of ITP has been more clearly elucidated, particularly the importance of decreased production of platelets in most patients and the very blunted rise that occurs in serum thrombopoietin (TPO). The isolation of TPO and better understanding of its role in thrombopoiesis has led to the development of new highly effective treatments. TPO analogs had some successes in treating highly refractory ITP patients but were taken out of development due to TPO-antibody induction. Two second-generation TPO-mimetics, romiplostim and the orally available eltrombopag, have recently been licensed in some territories for the treatment of ITP. Approval of eltrombopag was based on results from Phase II and III placebo-controlled clinical trials and a long-term extension study. About 80% of patients achieve significant increases in platelet count (11% of placebo patients), with reduced bleeding and reduced use of concomitant medications; responses are often durable with no tachyphylaxis. The side effects of eltrombopag are generally mild and not worse than placebo, although there are concerns about hepatic dysfunction, and the potentials for thromboses, marrow reticulin fibrosis, rebound thrombocytopenia and cataracts. This is an important new option for highly refractory patients, and its niche in earlier treatment (and for other thrombocytopenic disorders) is yet to be defined.

Monoclonal antibodies: indications, budget impact and use

“…Hospital physicians reported off‐label use of rituximab for idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, post‐transplant lymphoma, chronic graft versus host disease following allogeneic stem cell transplantation, and autoimmune haemolytic anemia. The literature also provided evidence about the use of rituximab for these conditions [19–24] . It should be noted that the use of rituximab for chronic lymphocytic leukaemia was considered to be off‐label use until the registration of rituximab was expanded to include this indication in August 2009.…”

“…The literature also provided evidence about the use of rituximab for these conditions. [19][20][21][22][23][24] It should be noted that the use of rituximab for chronic lymphocytic leukaemia was considered to be offlabel use until the registration of rituximab was expanded to include this indication in August 2009.…”

A review of immune thrombocytopenic purpura: focus on the novel thrombopoietin agonists

“…Researchers reviewed peptide libraries to find random, unrelated peptide and nonpeptide molecules that could stimulate TPO receptors without causing antibody production. 43 , 44 This strategy led to the development of two TPO mimetic drugs, romiplostim and eltrombopag, which have no sequence homology with endogenous thrombopoietin. 37 , 45 Both agents work by mimicking thrombopoietin and act by binding to or near the TPO receptor, stimulating megakaryopoiesis and platelet production.…”

“… 66 , 67 Phase I clinical studies in volunteers with normal platelet counts and in patients with thrombocytopenia secondary to hepatitis C infections, including a placebo-controlled clinical trial in adults assessing the platelet response and tolerability of eltrombopag, have been performed. 44 Seventy-three healthy men with similar demographics were randomized to receive oral eltrombopag over a 10 day period with doses ranging from 5 mg to 75 mg. The greatest result occurred in those receiving 50 mg and 75 mg daily, achieving platelet responses greater than 20% above baseline.…”

New advances in the treatment of adult chronic immune thrombocytopenic purpura: role of thrombopoietin receptor-stimulating agents

“…In all, seven of the 19 study subjects in the extension study were noted to have bone marrow reticulin formation, although two of these subjects had reticulin deposition at baseline. 121 Physicians are encouraged to evaluate the peripheral blood smear, with attention to erythrocyte morphology. After a stable dose has been achieved, regular examination of the peripheral smear and complete blood count is recommended.…”