Eltrombopag in Aplastic Anemia

Abstract

The treatment of aplastic anemia is currently with immunosuppressive therapy (IST) with antithymocyte globulin and cyclosporine, to which two thirds of patients respond. However, a significant proportion of these responders relapse and many have persistent cytopenias. The management of these patients is challenging. Modifications to this standard approach using alternative immunosuppressive agents or adding hematopoietic cytokines such as G-CSF and erythropoietin have not improved outcome. A recent trial has shown that eltrombopag, a thrombopoeitin mimetic, is efficacious in the treatment of patients with severe aplastic anemia (SAA) refractory to IST. There is evidence that this drug works by directly stimulating marrow stem and progenitor cells thereby promoting hematopoietic recovery in patients with bone marrow failure. Several trials are ongoing in our institution using this very promising drug in combination therapy in the upfront treatment of SAA, in IST refractory SAA and in moderate disease.

An update on Acquired Aplastic Anemia

“…Additionally, when the drug was discontinued, these patients sustained their response. No increase in clonal evolution was observed with Eltrombopag compared to immune suppression [15]. Last year the results of a trial using Eltrombopag upfront in treatment-naive aplastic anemia patients were published; when Eltrombopag is used upfront with antithymocyte globulin and cyclosporine a response rate of 95% was observed [16].…”

iPSC modeling of severe aplastic anemia reveals impaired differentiation and telomere shortening in blood progenitors

“…Eltrombopag (EP) is a thrombopoietin (TPO) receptor agonist that promotes megakaryocyte maturation and platelet production without competing with endogenous TPO 35 . Beyond its role in megakaryopoiesis and platelet generation, TPO signaling has been also shown to be critical for HSC homeostasis and expansion in animal models and refractory SAA patients 36 – 38 .…”

Eltrombopag in severe aplastic anaemia: a guide to its use in the EU

“…Preliminary results also suggest that treatmentnaïve patients with severe aplastic anaemia also benefit with eltrombopag therapy. Patients with severe aplastic anaemia have bone marrow failure despite the presence of high levels of thrombopoietin, a key regulator of haematopoiesis [12,16]. Nonetheless, eltrombopag stimulates bone marrow stem and progenitor cells and may act by processes distinct from those of endogenous thrombopoietin [7,16].…”

“…Patients with severe aplastic anaemia have bone marrow failure despite the presence of high levels of thrombopoietin, a key regulator of haematopoiesis [12,16]. Nonetheless, eltrombopag stimulates bone marrow stem and progenitor cells and may act by processes distinct from those of endogenous thrombopoietin [7,16]. Full clarification of the drug's action has been hindered by the paucity of animal models, since it will only activate human and chimpanzee pathways.…”