Switching thrombopoietin receptor agonist treatments in patients with primary immune thrombocytopenia

Abstract

Primary immune thrombocytopenia (ITP) is a bleeding disorder that conventionally has been treated with steroids or other immunosuppressive treatments. The introduction of thrombopoietin receptor agonists (TPO-RAs), which increase platelet production, dramatically changed the treatment landscape for ITP by providing patients with well-tolerated, long-term treatment options. Two TPO-RAs, eltrombopag and romiplostim, have been approved in the United States and European Union for the treatment of ITP. Some patients do not benefit from the first TPO-RA they receive, so it is assumed that the alternate TPO-RA would have the same outcome. However, eltrombopag and romiplostim have distinct pharmacodynamic and pharmacokinetic properties and may have different tolerability and efficacy in individual patients with ITP. Published retrospective studies showed that >75% of patients who switched to the alternate TPO-RA maintained or achieved a response with the new treatment. Notably, most patients who switched due to lack of efficacy with the first TPO-RA responded to the alternate TPO-RA, which demonstrates an absence of cross-resistance between the two drugs. Therefore, switching to the alternate TPO-RA if the first TPO-RA fails to demonstrate a response should be considered before the use of a less-preferable option.

Keywords: eltrombopag; hemorrhage; immune thrombocytopenia; romiplostim; thrombopoietin.

Figure 1.

Thrombopoietin receptor (TPO-R) activation by TPO, romiplostim, and eltrombopag. TPO-Rs are found on the cell membranes of multiple cell types in the bone marrow, including multipotent hematopoietic stem cells, common myeloid progenitors, and megakaryocytes. (A) Upon binding to its receptor on the cell membrane, TPO activates the downstream STAT3/5, AKT, and ERK pathways, which may lead to increased megakaryocyte proliferation and increased platelet production. (B) Eltrombopag (EPAG) binds to the transmembrane domain of the TPO-R and strongly activates all TPO-R downstream pathways, leading to a robust increase in both megakaryocyte proliferation and platelet production.^, In addition, eltrombopag has TPO-R-independent activities, such as strong iron chelation, which may confer antileukemic effects;^, however, it is not known whether these activities have any important clinical implications for patients with ITP. (C) Romiplostim (ROM) competes with TPO for the extracellular TPO-R binding site, and it induces stronger activation of the AKT pathway than the STAT and ERK pathways, which favor megakaryocyte proliferation rather than platelet production.^,

Figure 2.

Switching considerations. In clinical practice, the decision to discontinue TPO-RA treatment could be made due to lack of efficacy, platelet fluctuations, safety and tolerability, or other factors. A trial with the alternate TPO-RA is often a plausible next step; however, a careful risk assessment and evaluation of non-TPO-RA options may be needed for patients who needed to discontinue the first TPO-RA due to adverse events related to the TPO-RA drug class. AC, anticoagulant; MF, bone marrow fibrosis; TEE, thromboembolic events; TPO-RA, thrombopoietin receptor agonist. *Immunosuppressive therapy with agents such as mycophenolate mofetil, cyclophosphamide, or azathioprine or other drugs, including danazol or vinca alkaloids. ^†Doses above 75 mg/day for eltrombopag and 10 μg/kg/week for romiplostim have not been approved for patients with immune thrombocytopenia. ^‡Data from reviewed studies were not sufficient to support the reduced platelet fluctuations associated with eltrombopag after switching to romiplostim. Nevertheless, a trial with romiplostim may be considered before switching to a non-TPO-RA option.