Introduction
Primary immune thrombocytopenia (ITP) is an autoimmune disease characterized by a transient or persistent decrease in platelet counts (< 100 × 10
9/l) [
1,
2]. ITP is a rare condition affecting individuals of all ages with an estimated yearly incidence of approximately 1.9–6.4 per 100,000 in children [
3,
4]. Pediatric ITP is more likely to be short-lived and resolves spontaneously than adult disease [
5]. However, there is a subset of children for whom this is not the case, and it is clear that a high level of heterogeneity exists within the pediatric population, in terms of clinical presentation, treatment responses, and remission rates [
5].
The most common symptom of ITP is increased bleeding tendency, which frequently presents as bruising and petechiae [
6,
7]. Severe mucosal bleeding episodes can occur in some children; these are preferably managed in hospital [
8]. Severe bleeding has been reported in up to 20% of cases (depending on the definition of severe bleeding) [
9,
10], while life-threatening intracranial hemorrhage is very rare, occurring in < 1% of cases [
9,
11,
12]. ITP can have a profound negative impact on the health-related quality of life (HRQoL) of children [
13‐
15].
Historically, an arbitrary distinction with no biological basis has been made between “acute” and “chronic” ITP, with the latter typically defined as a disease duration of ≥ 6 months [
6]. In 2009, an international working group proposed that ITP should instead be considered to have three phases, defined as newly diagnosed (≤ 3 months after diagnosis), persistent (> 3–12 months after diagnosis), and chronic (> 12 months after diagnosis) [
1]. These definitions were created because of the reduced likelihood of spontaneous remission with increased duration of ITP (highlighting to clinicians that irreversible treatments such as splenectomy should be avoided for patients who could still achieve remission) [
5,
6,
16]. The change in the definition has posed many challenges in clinical practice, such as how to best treat children within the new framework when original drug indications and clinical trial data were based on the old definition.
Various management options have been used for children with newly diagnosed or persistent ITP. In children requiring intervention, the standard first-line therapy has generally been corticosteroids with the addition of intravenous immunoglobulin (IVIg) or anti-D to manage acute bleeding episodes; however, long-term corticosteroid use is associated with a number of serious adverse events, and so its duration of use should be limited [
6,
7,
17]. A range of subsequent therapies are in clinical use, with thrombopoietin receptor agonists (TPO-RAs), which stimulate platelet production via activation of the c-Mpl receptor [
18], being key second-line agents recommended by recent international and national guidelines [
6,
7,
17].
Romiplostim is a TPO-RA that is approved in Europe for the treatment of chronic ITP in children ≥ 1 year of age who are refractory to other treatments (e.g., corticosteroids and immunoglobulins) [
19]. Notably, the European label of romiplostim in adult patients has recently been updated to remove the chronic disease restriction; romiplostim is approved for all adults with primary ITP who are refractory to other treatments [
19]. In the USA, romiplostim is approved for children ≥ 1 year of age with ITP for ≥ 6 months who have had insufficient response to corticosteroids, immunoglobulins, or splenectomy [
20]. Numerous studies have demonstrated the efficacy of romiplostim in increasing platelet counts, together with its low toxicity and high tolerability in children with chronic ITP [
21‐
28]. Additionally, romiplostim may induce sustained treatment-free responses in a subset of children with chronic ITP [
25,
27].
The labels of romiplostim in Europe and the USA were granted based on clinical trials that were mainly performed using the historical definition of chronic ITP (≥ 6 months after diagnosis). However, under the current definitions for ITP phases [
1], some of the children in the pivotal trials of romiplostim who had ITP for ≥ 6 months but < 1 year and were previously classed as having chronic ITP would now be classified as having persistent ITP. Ideally, the labels should reflect the populations of the trials on which the approvals were based. Furthermore, while romiplostim is approved for treating children with chronic ITP in Europe, a growing number of real-world studies suggest that romiplostim is being used in clinical practice to treat newly diagnosed or persistent ITP in children who do not respond to first-line therapies. The aim of this narrative review is to collate and evaluate all the available evidence from randomized clinical trials, real-world studies, and case reports on the use of romiplostim for treating children with newly diagnosed or persistent ITP.
Reflection on the role of romiplostim for children with newly diagnosed or persistent ITP and future perspectives
Randomized clinical trial data for romiplostim are lacking particularly for children with newly diagnosed ITP, and there a number of important research topics to be considered (Table
3). These include efficacy and safety of TPO-RAs in this patient population, as well as the optimal timing of treatment with respect to TPO-RAs versus other approaches. While limited pharmacoeconomic data are available (see Cost-effectiveness section), further studies are required to understand the cost–benefit of early TPO-RA use versus other approaches. Additionally, other important questions include whether there is distinct subgroup of children who will benefit from early TPO-RA use, if there are markers to identify this subgroup, and if there is a clinical advantage to the early use of TPO-RAs versus corticosteroids and “watch and wait.”
Table 3
Key remaining questions on the role of romiplostim for children with newly diagnosed or persistent ITP
Biological/clinical questions | • Is there a subgroup of children who benefit most from the early use of TPO-RAs? |
• Is the early use of TPO-RAs associated with a changed incidence of chronic ITP or altered course of ITP? |
Questions to be answered in interventional trials | • What is the efficacy of TPO-RAs in children with newly diagnosed ITP? |
• In children with newly diagnosed ITP, should a first attempt with corticosteroids be undertaken before using TPO-RAs in those who do not respond or who respond inadequately? |
• Can corticosteroids be omitted if TPO-RAs are used in children with newly diagnosed ITP? Could this strategy lead to a reduction in the overuse of corticosteroids? Conversely, could it lead to an overuse of TPO-RAs? |
• What are the relative benefits of TPO-RAs versus “watch and wait”? |
• How should children who do not respond to TPO-RAs be managed? |
• What is the safety profile associated with the early use of TPO-RAs in children? |
Pharmacoeconomic questions | • Is there a pharmacoeconomic benefit or otherwise to the early use of TPO-RAs in children? |
Despite the lack of randomized clinical trial data and remaining questions, the collective body of evidence, which includes real-world studies and case reports, supports the early use of romiplostim in children who have received prior corticosteroid or IVIg treatment. Overall, the available efficacy data indicate that a high proportion of children with newly diagnosed and persistent ITP achieve platelet responses, with responses appearing similar to those reported for chronic ITP [
29,
35,
36]. Furthermore, the available safety and tolerability data from studies that included children with newly diagnosed or persistent ITP identified no major concerns, thus supporting the well-characterized safety profile in children with chronic ITP. However, while the available efficacy and safety evidence support the use of romiplostim earlier in the course of ITP, it is important to note that its use for the treatment of children with newly diagnosed or persistent ITP is currently off-label in Europe (as is its first-line use in these populations) and so may not be reimbursed.
Importantly, there is some evidence that patients with newly diagnosed or persistent ITP develop treatment-free durable platelet responses or lasting remission after treatment with romiplostim [
31,
35,
36]. While spontaneous remission is common in children at this stage of disease, it has been speculated that the various biological actions of romiplostim may positively affect remission rates [
18,
37]. It has been postulated that romiplostim could restore immune tolerance by increasing exposure to platelet antigens, thereby reducing platelet antibodies [
37,
38]. Additionally, some information suggests that increased presence of platelets following romiplostim and other TPO-RA treatments may lead to an increase in the serum levels of TGF-β, which could improve regulatory T cell function and immune tolerance [
18,
39]. The molecular mechanisms by which romiplostim mediates its effects on the immune system are not fully understood, but its Fc fragment might play a role. Fc fragments of other immunogenic drugs have been reported to confer tolerogenic effects, although it should be noted that the importance of the Fc fragment of romiplostim has not yet been fully investigated [
18]. Overall, further studies are required to investigate the extent to which romiplostim can lead to long-term treatment-free responses in children with newly diagnosed or persistent ITP and the mechanisms behind this effect.
First-line treatment of children with newly diagnosed or persistent ITP
Several first-line management options have been used for children with newly diagnosed or persistent ITP. Observation (“watch and wait”) is recommended in children with newly diagnosed ITP with mild-to-moderate bleeding if it has a minimal impact on HRQoL [
7,
17]; however, observation is less validated in children with persistent ITP, as it is based on the expectation of spontaneous future improvement [
7]. When treatment is required for children with newly diagnosed ITP, corticosteroids have been used as the standard first-line therapy due to their effectiveness in increasing platelet counts in the short term [
6,
7,
17]. However, long-term corticosteroids have been associated with a range of serious adverse effects including hypertension, hyperglycemia, gastritis, and mood changes [
40]. Furthermore, corticosteroids can cause a range of less serious side effects that could negatively affect HRQoL [
41], which may be a particular concern in children. As a result, corticosteroids should be used for as short a time as possible in children, with the ASH guidelines recommending against courses longer than 7 days [
17], the International Consensus Report recommending stopping by 3 weeks including taper [
7], and the joint working group of European hematology societies in Germany, Austria, and Switzerland guidelines recommending no longer than 2 weeks [
6]. Other first-line treatments for children with severe bleeding include IVIg and anti-D, which have the benefit of rapidly increasing platelet counts but frequently demonstrate only transient responses [
40]. Furthermore, these treatments are associated with serious, albeit transient, side effects, including infusion reactions, headaches, aseptic meningitis, and hemolysis [
40].
Overall, first-line treatment for patients with diagnosed or persistent ITP should be personalized and prevent severe bleeding episodes (by maintaining target platelet levels > 20–30 × 10
9/l) while having minimal toxicity and improving HRQoL [
7]. Current clinical management strategies of ITP are associated with a substantial healthcare burden and an effect on the HRQoL of children [
13,
42], and there is an overreliance on corticosteroids in clinical practice [
7]. It is possible that TPO-RAs such as romiplostim may help children avoid side effects associated with long-term corticosteroid use and treatment with IVIg and anti-D during acute bleeding episodes. Furthermore, the earlier use of TPO-RAs may represent a more efficient use of healthcare resources than the current standard practice [
42], although no specific studies have examined this in children.
An aim of first-line therapy for patients with newly diagnosed or persistent ITP should be the prevention of long-term chronic disease where possible; however, this is not achieved in most patients using corticosteroids or IVIg. The high relapse rate of patients on corticosteroids suggests that these do not shorten the disease course, and evidence from a randomized clinical trial indicates that the use of IVIg in children with newly diagnosed ITP might not decrease the rate of developing chronic disease [
43,
44]. The extent to which TPO-RAs lead to long-term treatment-free durable platelet responses or lasting remission in children with newly diagnosed or persistent ITP thus warrants further investigation. However, before clinicians consider the use of TPO-RAs in the first-line setting, further studies are required to directly compare the efficacy and safety of TPO-RAs versus the current first-line standard of care in children with newly diagnosed ITP.
Second-line treatment of children with newly diagnosed or persistent ITP
As previously mentioned, the collective body of evidence supports the use of romiplostim for second-line treatment in children with newly diagnosed or persistent ITP. Other than romiplostim, the only other TPO-RA currently approved for use in children in Europe is eltrombopag, which is indicated for the treatment of patients ≥ 1 year of age for ITP lasting ≥ 6 months from diagnosis and who are refractory to other treatments [
45]. Eltrombopag is an oral drug taken daily, compared with romiplostim which is administered by weekly subcutaneous injection [
19,
45]. While oral dosing may be more convenient for patients, eltrombopag absorption has been shown to be severely impacted by some dietary components [
46,
47]. As a result, it should be taken ≥ 2 h before, or 4 h after, calcium-containing food products [
45]. Overall, patients can have varying responses to different TPO-RAs; further studies including comparative clinical trials between romiplostim and eltrombopag are warranted to help guide second-line treatment decisions.
The most recent TPO-RA in clinical use, avatrombopag, is approved in Europe for the treatment of primary chronic ITP in adult patients who are refractory to other treatments (e.g., corticosteroids and immunoglobulins) [
48]. It is also approved in the USA for the treatment of adult patients with chronic ITP who have had an insufficient response to a previous treatment [
49].
Other subsequent management options for children with ITP include rituximab, which is currently not approved for the treatment of ITP and splenectomy. The ASH guidelines suggest the use of TPO-RAs rather than rituximab for second-line therapy in children [
17], while the International Consensus Report recommends consideration of rituximab in children with persistent/chronic ITP only in those that first fail on TPO-RAs [
7]. Additionally, TPO-RAs avoid the immunosuppression risks associated with rituximab [
40]. Finally, splenectomy is now very rarely indicated in children with ITP and should only be considered in those that fail all available therapies, given the ongoing lifelong risks following the procedure [
7,
17].
Clinical decision-making for the selection of second-line treatments has been investigated by the ICON1 study, which included 120 children with ITP; of these, 16% and 31% had newly diagnosed and persistent ITP, respectively [
50]. Clinicians indicated expected efficacy as a reason for choosing romiplostim versus other second-line agents, including eltrombopag, while parental or patient preference was also important for choosing romiplostim. The perceived side-effect profiles were another key reason for choosing romiplostim and eltrombopag rather than rituximab and oral immunosuppressants. A further analysis of the ICON1 study cohort evaluated the effect of the second-line agents on fatigue [
15]. Overall, fatigue significantly improved in children and adolescents while taking the second-line treatments. When individual treatments were analyzed separately, rituximab significantly reduced fatigue, while there was a trend for a reduction with romiplostim and eltrombopag.
Recent data suggest that the TPO-RAs are increasingly being used for the second-line treatment of ITP in children. A retrospective review of second-line treatments for persistent or chronic ITP from the UK pediatric ITP registry evaluated the changing pattern of treatment between 2006 and 2019 [
51]. Out of the 1915 children on the registry during this period, 212 were eligible for second-line therapy, and 23% of these received treatment. The use of TPO-RAs increased from 23% (2006–2011) to 48% (2015–2019) and was the most frequently used second-line therapy during the latter time period compared with rituximab (24%) and splenectomy (9.5%).
Collectively, the available data on clinical decision-making and changing treatment patterns support the efficacy and safety results from clinical studies, as well as guideline recommendations that TPO-RAs may be a preferred choice for children with newly diagnosed or persistent ITP that fail on corticosteroid therapy. The selection of a particular TPO-RA for an individual child should be made together with the patient/parent, based on preference (i.e., for an oral or once-weekly injected product), totality of evidence, cost, and adverse events.
Cost-effectiveness considerations
To our knowledge, no health economic analyses have been conducted to determine the cost-effectiveness of romiplostim for treating children and adolescents with newly diagnosed or persistent ITP. In adult patients with chronic ITP, romiplostim has been shown to be cost-effective [
52‐
54]. For example, from an Irish healthcare perspective, romiplostim was estimated to provide cost savings of €22,673 and gains of 1.17 quality-adjusted life years compared with standard of care in adults with chronic ITP [
54]. Savings were driven by higher response rates associated with romiplostim, which led to a reduction in bleeding events and less use of rescue therapies [
54]. Another adult study in chronic ITP also suggested that romiplostim had lower costs per response than “watch and rescue” [
55]. However, in pediatric chronic ITP, a cost–consequence analysis suggested that the cost per patient could be higher for romiplostim than for watch and rescue [
56]. It should be noted that there are a number of limitations with cost-effective analyses; not least the generalizability of the results and that the setting in which romiplostim is administered to patients via subcutaneous injection may vary depending on the country. Overall, further analyses are warranted, particularly in the context of evaluating the cost/benefits associated with avoiding long courses of corticosteroids and assessing the potential long-term benefits of early treatment with TPO-RAs.
Potential impact of COVID-19 on the treatment landscape of children with ITP
The treatment of ITP should be considered together with the risks of COVID-19. Several societies have issued guidance for COVID-19 and patients with ITP [
57‐
61]; however, specific guidance for children is limited. The available guidance suggests caution when using immunosuppressive agents, such as corticosteroids and rituximab, because of the potential risk of infection. This may be more applicable in at-risk adults, as COVID-19 is usually a mild self-limiting illness in children, even in those who are immunocompromised [
62]. While immunosuppression may increase the risk for severe COVID-19 illness in children [
63], clinical data demonstrating this are lacking [
64]. Nevertheless, the National Institute for Health and Care Excellence (NICE) guidance states that alternatives to immunosuppressive agents with a lower risk for COVID-19 should be considered for children [
62]. Additionally, children taking corticosteroids may have an atypical presentation of COVID-19 [
62], which has the potential to result in a delayed diagnosis. Overall, the perceived risks associated with immunosuppression may increase the usage of alternative treatments for children with ITP; however, further studies are required to investigate whether short-term and long-term corticosteroid use increase the risks associated with COVID-19 in children.
Another area for future research is whether COVID-19 has an impact on ITP in children and if treatment needs to be modified in these patients accordingly. There is evidence to suggest that COVID-19 may affect platelet counts and increase the risk of thrombotic complications in adults [
65‐
67], but there are currently no available data in children.
Conclusions
In Europe, romiplostim is currently indicated for the treatment of children with chronic ITP who are refractory to other treatments. However, the available evidence presented in this narrative review suggests that romiplostim is also efficacious and well tolerated in children with ITP < 1 year from diagnosis. Randomized clinical studies originally investigating romiplostim included children with persistent ITP (following the updated definition of the three phases of ITP), and therefore, the evidence is particularly robust in these patients versus those with newly diagnosed ITP. As a result of data from these randomized clinical studies, romiplostim (as well as other TPO-RAs) is generally recommended in guidelines for children with ITP who fail on first-line therapy, including in those with ITP < 1 year from diagnosis. Earlier treatment with TPO-RAs may help children to avoid the side effects associated with prolonged corticosteroid use. While narrative reviews are inherently susceptible to biases, the results presented herein provide the foundation for future systematic reviews and meta-analyses into the efficacy and safety of early TPO-RA use in children. Further studies are warranted to investigate the optimal sequence and timing of management options for children with newly diagnosed and persistent ITP.
Acknowledgements
Medical writing support, including development of a draft outline and subsequent drafts in consultation with the authors, collating author comments, copyediting, fact checking, and referencing, was provided by Josh Lilly and Ryan Woodrow at Aspire Scientific Limited (Bollington, UK).
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