Over 10 Years of Experience with TPO-RA in the Treatment of Immune Thrombocytopenia
Medications from the group of thrombopoietin receptor agonists (TPO-RA) have become an integral part of the therapy for patients with immune thrombocytopenia (ITP) over the past more than 10 years. Their administration represents a new approach compared to the previous, long-established treatment, and has significantly changed the prognosis of the disease in many patients.
Similar but Not Identical
The indication for TPO-RA is chronic ITP refractory to other treatment methods (i.e., corticosteroids, immunoglobulins, or possibly splenectomy). The goal of TPO-RA is to increase the number of platelets until the body is once again able to maintain an adequate amount in the blood. Long-term remission without the need for further treatment is achieved in about 10–30% of patients, so TPO-RA administration is usually long-term.
Both romiplostim and eltrombopag from the TPO-RA group bind to thrombopoietin (TPO) receptors, leading to a conformational change of the receptor, activation of the JAK2/STAT5 pathway, and increased proliferation of megakaryocytes and platelet production. Romiplostim binds directly and competitively to the extracellular binding site for TPO, while eltrombopag is a small molecule that binds to the transmembrane site.
Other differences lie in the activation of different signaling pathways in megakaryocytes, such as STAT3, ERK, or AKT. Romiplostim mainly stimulates mature precursors, while eltrombopag likely acts on earlier stages of development and stimulates megakaryocyte differentiation. These differences may explain why some patients respond to one drug and not the other.
TPO-RA may also have an immunomodulatory effect, primarily by supporting regulatory T lymphocytes. However, it is not yet known whether or to what extent these effects contribute to the induction and maintenance of the therapeutic response.
Clinical Response and Choice of Drug
The overall efficacy of both TPO-RAs is roughly comparable. In clinical trials, 40–60% of patients achieved a sustained response with platelet counts repeatedly > 50 × 109/l, without bleeding or the need for rescue medication. According to meta-analyses, TPO-RA reduces the risk of severe bleeding by 50% and similarly reduces the need for rescue medication.
Eltrombopag is administered orally, while romiplostim is given by subcutaneous injection. A disadvantage of eltrombopag is the need to take the tablets on an empty stomach, several hours apart from meals. If there are difficulties adhering to this rule or with elevated liver transaminases, romiplostim administration is more appropriate.
For clinical practice, it is important to note that if a patient does not respond to one drug, it is reasonable to try the other, which may be effective. In a study involving the switch of TPO-RA due to insufficient response, it was found that 80% of patients for whom eltrombopag was ineffective responded to romiplostim; conversely, 46% of those who did not respond to romiplostim responded to eltrombopag. Similarly, switching can be applied in case of adverse effects.
Conclusion
After more than 10 years of use, especially in patients with chronic ITP, TPO-RAs have proven to be an effective and safe modality even with long-term administration.
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Source: Ghanima W., Cooper N., Rodeghiero F. et al. Thrombopoietin receptor agonists: ten years later. Haematologica 2019; 104 (6): 1112–1123, doi: 10.3324/haematol.2018.212845.
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