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Thrombopoietin receptor agonists in ITP
longer required. The TPO-RA were licensed in the US for the treatment of ITP in 2008, and, since then, their use has progressively increased around the world; they are cur- rently used in more than 100 countries. Their introduc- tion heralded a paradigm shift in the treatment of ITP. They are now widely used and many hematologists are well-acquainted with them. This is the 10-year anniver- sary of their licensure in the US for ITP and it seems appropriate to review the state of the art of these agents: what is known about their mechanism of effect, efficacy, and toxicity, and what remains to be learned, including an exploration of other clinical situations in which they might be useful.
Mechanism of action
Romiplostim and eltrombopag both bind to the throm- bopoietin (TPO) receptor, causing conformational change in the TPO receptor, activation of the JAK2/STAT5 path- way, and a resulting increased megakaryocyte progenitor proliferation and increased platelet production.4,5
However, there are some differences between the two agents (Figure 1). Romiplostim is a peptibody that binds directly and competitively at the TPO binding site, where- as eltrombopag is a small molecule which binds at a trans- membrane site. There are also differences in the activation of other signaling pathways in megakaryocytes (MK) such as STAT3, ERK and AKT (Table 1).6-8 Furthermore, romi- plostim mostly stimulates mature precursors, while eltrombopag appears to act earlier in the pathway, stimu- lating MK precursor cells and MK differentiation.4,6
In addition to differences in TPO-receptor activation, eltrombopag also has off-target effects. For example, eltrombopag chelates both extra- and intra-cellular calci- um and iron and can shuttle iron out of cells.9 The iron- chelating action of eltrombopag causes anti-proliferative effects on leukemic cells lines,10 and a TPO-independent effect on stimulating stem cells and MK precursors in vivo.
These differences may explain why some patients respond to one agent and not the other,11,12 and why treat- ment with both agents can be useful in very refractory patients.
Although the prime mechanism of action of the TPO-
Figure 1. Cellular mechanisms of action of thrombopoietin (TPO) and of thrombopoietin receptor agonists (TPO-RA). Binding of the ligand (TPO/TPO-RA) to the c- MPL receptor on the megakaryocyte causes conformational change in the receptor, resulting in downstream activation of the various signaling pathways including JAK2/STAT5, PI3K/AKT, ERK, ultimately resulting in increased platelet production. Various pathways can be activated by the different substances (see also Table 1). GRB2: growth factor receptor-binding protein 2; JAK: Janus kinase; MAPK: mitogen-activated protein kinase; P: phosphorylation; RAF: rapidly accelerated fibrosar- coma kinase; RAS: rat sarcoma GTPase; SHC: Src homology collagen protein; STAT: signal transducer and activator of transcription; PI3K: phosphatidylinositol 3- kinases; ERK: extracellular-signal-regulated kinase.
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