Real‐world evidence confirms thrombopoietin receptor agonists are safe and effective for all stages of immune thrombocytopenia
Authors: Drew Provan
Journal: American Journal of Hematology (2023)

The immune thrombocytopenia (ITP) landscape changed dramatically more than 10 years ago with the introduction of romiplostim shortly after eltrombopag. Before the development of these therapies, the management of ITP relied heavily on the use of off-label immunosuppressants and a number of other classes of therapy, none of which was particularly satisfactory in terms of responses or tolerability. The thrombopoietin receptor agonist (TPO-RA) class of therapy shifted the ITP management paradigm away from reducing the destruction of platelets toward boosting platelet production. Over the last decade or so, many adults and children with primary ITP have been treated with both romiplostim and eltrombopag successfully with a high efficacy rate and good tolerability. However, no treatment is ever perfect and one downside of romiplostim includes the fact that this is a subcutaneous injection, and for eltrombopag there are dietary restrictions which must be maintained in order to maximize bioavailability of the drug; in addition, liver function disturbance is seen in some patients.1, 2 Avatrombopag is a more recent addition to the TPO-RA class of treatments which, like eltrombopag, is a small molecule. However, there are distinct advantages of avatrombopag over eltrombopag. For example, avatrombopag requires no dietary restrictions and instead is recommended to be taken with food rather than having to avoid specific foodstuffs. In addition, avatrombopag has no effect on liver function unlike eltrombopag where transaminases are elevated in some patients. Over the last decade the licensing of the TPO-RAs has been confusing—partly because the TPO-RAs were developed at a time when chronic ITP was defined as 6 months or longer from diagnosis, patients with "chronic ITP" were enrolled in the registration studies for romiplostim and eltrombopag, and many of these had ITP for 6–12 months. The revised terminology consensus3 amended the definition of chronic ITP to 12 months or more from diagnosis, partly to avoid early splenectomy. Payers have tended to restrict TPO-RA usage based solely on the word "chronic" despite the fact that the goalposts (i.e., what defines "chronic ITP") had been changed. To further confuse matters, the license indications are not consistent between countries. When romiplostim and eltrombopag were first approved, the licensed indication was for adults with primary ITP who had chronic disease and had failed splenectomy or had a contraindication to splenectomy. This created a situation where clinicians and patients had to wait 1 year before being able to access the second-line therapy. This makes no sense since after failure of the first-line therapy there may be a period of 10 months during which the second-line TPO-RAs could not be accessed. However, real-world evidence, clinical studies, and clinical experience with these agents have confirmed the safety and efficacy of the TPO-RAs when used earlier than the license dictated.4, 5 Thankfully, over time the companies have been able to adjust their labels such that romiplostim and eltrombopag may be used without a requirement for splenectomy in addition to allowing use of the drug much earlier than chronic ITP (from 6 months for eltrombopag and after failure of the first-line therapy with romiplostim). Thus, a much wider group of patients with ITP have been able to access these treatments than when the drugs were first approved. Earlier access to TPO-RAs helps to avoid exposure to the older non-approved therapies. Avatrombopag has been licensed worldwide for adults with chronic primary immune thrombocytopenia. In this issue of the American Journal of Hematology, Virk and colleagues report on a multicenter observational study of the use of avatrombopag in two major groups of patients with ITP: those with early ITP and those with chronic ITP.6 The two groups compared in the study were (1) newly diagnosed (0–3 months) and persistent (3–12 months) and (2) patients with chronic ITP (12 months or later) to see any differences in treatment responses and outcomes that might exist in these two populations. The multicenter study included 75 patients of which 23 had newly diagnosed/persistent ITP and 52 patients had chronic ITP. In terms of response rates, the newly diagnosed/persistent group achieved a response, which was defined as a platelet count of 50 × 109/L or greater, in 91%, and in the chronic ITP group a response was obtained in 96%. Complete responses (platelets ≥100 × 109/L) were reported in 86% of the newly diagnosed/persistent ITP cohort with 81% complete responses in the chronic ITP group. The response durability between the two groups was similar. Analysis of the safety profile between the two groups showed no major bleeding events, thromboembolic events or requirement for discontinuation of avatrombopag in the newly diagnosed/persistent group, but there were four major bleeds reported in the chronic ITP group along with one thromboembolic event and two patients discontinued avatrombopag. The demographics were very similar between the two groups although the patients in the chronic ITP cohort were more heavily pretreated which is exactly what we would expect. Requirement for rescue therapy was similar between the two groups. Overall, similar to previously published data on the use of romiplostim and eltrombopag in early/late ITP, Virk and colleagues have shown that avatrombopag is equally safe and effective in both groups. Theoretically, avatrombopag should be available immediately after failure of the first-line therapy thereby avoiding unnecessary immunosuppression. However, the license is currently for adults with chronic ITP which severely limits its availability. One hopes the company will amend its license to allow early use which will give patients and healthcare professionals the freedom to choose between the three currently available TPO-RAs in early ITP. D.P. has received research support and honoraria from Amgen and Novartis and has acted as a consultant for UCB, MedImmune, Ono, SOBI and Argenx. Data sharing not applicable to this article.