Use of thrombopoietin receptor agonists in adults with immune thrombocytopenia: a systematic review and Central European expert consensus

Immune thrombocytopenia (ITP) is a rare, acquired autoimmune disorder resulting from the destruction of platelets in the reticuloendothelial system due to anti-platelet antibodies and other immune processes [1, 2]. The cause of this platelet-specific autoimmunity is complex and poorly understood, but recent evidence suggests that B- and T-cell dysregulation may play a central role [2]. ITP is estimated to have an annual incidence rate of about 3 per 100 000 persons [3‐5]. However, the incidence has reportedly increased in recent years, especially among young women and older men [3, 5, 6]. Most adult cases (about 80%) are classified as primary ITP [7], with 20% of cases attributable to secondary causes such as medications or concurrent diseases (e.g., autoimmune conditions such as systemic lupus erythematosus or chronic infections) [5, 8].

The condition is characterized by isolated low platelet counts (less than 100 × 10⁹/L) due to increased turnover and inadequate production of platelets, leading to an increased risk of bleeding, the predominant symptom [9, 10]. The severity of bleeding varies for individual patients, from asymptomatic to intractable bleeding at presentation [11]. The treatment goal, therefore, is to increase and maintain a hemostatic platelet count above 30‒50 × 10⁹/L and is typically initiated in patients who have a platelet count less than 30 × 10⁹/L and bleeding diathesis [12, 13]. The clinical course in adults is described as three separate phases: (1) newly diagnosed phase (ITP less than 3 months), (2) persistent phase (ITP lasting between 3 and 12 months), and chronic phase (ITP lasting greater than 12 months) [12‐14]. The standard first-line treatment for the majority of newly diagnosed adult ITP cases (approx. 80%) is corticosteroids (e.g., dexamethasone, prednisone, or methylprednisolone) administered ideally for no more than 6 weeks and supplemented as needed with intravenous immunoglobulin (IVIG) or anti‐D (available in some countries) [12, 13]. Note, many experts prefer pulse-dose dexamethasone to other steroids. Second-line treatments are required for patients who do not respond to first-line therapy (20% cases) or relapse when corticosteroids are reduced or stopped (70–90% cases) [15, 16]. Second-line pharmacological agents include thrombopoietin receptor agonists (TPO-RAs), rituximab, and other immune‐modulating medications such as fostamatinib or splenectomy [12, 13]. Three TPO-RAs are currently approved for use in Europe for adult patients with primary ITP who are refractory to first-line therapies: romiplostim (Nplate®), approved by the European Medicines Agency (EMA) in 2009 as a once-weekly subcutaneous injection [17]; eltrombopag (Revolade®)[18], a once-daily oral treatment, first approved by the EMA in 2010; and avatrombopag (Doptelet®), approved by the EMA in 2021 as a once-daily oral treatment for primary chronic ITP [19]. Notably, existing international and American Society of Hematology (ASH) ITP treatment guidelines from 2019 do not consider the most recently approved TPO-RA, avatrombopag [12, 13]. Despite having similar mechanisms of action, administration considerations and binding sites to TPO receptors may differ; however, no direct comparisons of TPO-RAs have been made in the clinical setting [20]. Robust clinical trials on the management of ITP, including when and how to safely taper or discontinue TPO-RAs, are also lacking [21].

To help address this gap, we conducted a systematic review on the use of TPO-RAs in adult ITP published in the last 10 years and since the approval of avatrombopag. We assessed the quality of evidence in the literature in order to develop expert consensus statements. In circumstances where clinical evidence is lacking, evidence-based data, together with expert opinion and clinical experience, can help guide busy clinicians in clinical decision-making to improve patient outcomes.

These current consensus statements aim to provide guidance by reviewing the emerging literature and providing expert opinion specific to using TPO-RAs in adult ITP to help address real-world clinical practice issues. We found 40 relevant publications from the literature to support clinical decision-making in the adult ITP population, including five meta-analyses comprising a total of 31 unique RCTs. Consensus (> 75% agreement) was reached on seven statements for the second-line use of TPO-RAs in the management of adult ITP patients (Table 3).

The expert panel reached a 100% consensus on using TPO-RAs as the preferred second-line treatment for chronic ITP patients who are refractory to a previous treatment, such as corticosteroids or immunoglobulins [17‐19]. The use of second-line TPO-RAs before 3 months after ITP diagnosis is not recommended in current international and ASH 2019 treatment guidelines [12, 13, 40]. Unsurprisingly, experts’ opinions on whether to avoid using TPO-RAs before 3 months of ITP were variable [12, 24, 39], suggestive of differing views regarding strict adherence to existing guidelines on managing ITP patients. However, for persistent ITP (≥ 3–12 months) in adults, both the ICR and ASH 2019 guidelines state that TPO-RAs can be used as second-line treatment in patients who are corticosteroid-dependent or unresponsive to corticosteroids [12, 13]. In addition, in adults with newly diagnosed ITP, the ASH guideline panel recommends against a prolonged course (> 6 weeks, including treatment and taper) of prednisone in favor of a short course (≤ 6 weeks) [13]. The ICR 2019 recommend stopping corticosteroids for newly diagnosed adult ITP by 6 weeks (maximum 8 weeks) [12]. Therefore, some ITP patients will need second-line treatment (with TPO-RAs or other) before 3 months of duration of ITP. In addition, it is important to mention that different TPO-RAs (eltrombopag, romiplostim, and avatrombopag) have different labels/official approvals regarding ITP duration in adults, which differ for the EMA and FDA [62]. For example, romiplostim and more recently eltrombopag have an EMA indication for the treatment of primary ITP in adult patients who are refractory to other treatments (e.g., corticosteroids, immunoglobulins) with no time restrictions [17, 18]. In contrast, avatrombopag is currently indicated for primary chronic ITP in adult patients who are refractory to other treatments (e.g., corticosteroids, immunoglobulins) [19, 62]. In addition, avatrombopag is also indicated for the treatment of severe thrombocytopenia in adults with CLD who are scheduled to undergo an invasive procedure [19, 62]. Furthermore, the Central European experts highlight the need for an individualized treatment approach. As increasing evidence becomes available on the effective use of early TPO-RAs in newly diagnosed ITP patients (i.e., ITP less than 3 months of duration), recommendations in future guidelines for treating ITP earlier in the second-line setting are likely to be revised.

ITP is a common cause of low platelet count (below 50 × 10⁹/L) during the first and second trimesters of pregnancy, accounting for about 3% of all thrombocytopenia cases [63]. Various studies show that up to 35% of affected mothers may require treatment even prior to the management of labor and delivery [63]. Corticosteroids and IVIGs are commonly used to treat acute ITP during pregnancy, but TPO-RAs are an attractive alternative [64]. However, none of the trials evaluating the use of TPO-RAs in adults with ITP included pregnant patients or lactating mothers [64]. Moreover, current literature evidence demonstrating the use of TPO-RAs in pregnancy is primarily limited to off-label use in individual patients [64]. One recent review suggests that TPO-RAs can help raise the platelet count within 2–3 weeks in pregnant patients with ITP [64]. The experts in this study agreed that in rare situations, temporary off-label use of TPO-RAs for severe and/or refractory ITP in pregnant women might be considered during late-stage pregnancy, i.e., even before delivery. Notably, TPO-RA use during the first trimester of pregnancy, i.e., when organogenesis is at its peak, must be avoided until studies demonstrating fetal and maternal safety become available [64].

In addition to the seven consensus statements, the experts also considered and discussed TPO-RA treatment in two further patient populations but failed to reach a consensus: chronic ITP patients with mild/moderate COVID-19 and treatment of ITP patients in the first-line setting. Hematologic complications of COVID-19 have been reported, including ITP secondary to COVID-19; however, the mechanisms involved remain unknown [65, 66]. Due to the increased potential for thrombotic complications and hepatotoxicity, interim COVID-19 guidance suggests using TPO-RAs only as a second-line agent in COVID-19 patients with no evidence of disseminated intravascular coagulation (DIC) [67]. Current ITP guidelines also recommend that patients with chronic ITP remain on their usual treatment if they test positive for COVID-19 [68]. In a comprehensive review of reported cases in the literature, Berger and Rodgers (2021) concluded that treatment regimens including TPO-RAs are most effective for obtaining a complete response, and steroids may be more effective than IVIG in patients with ITP secondary to COVID-19 [66]. An earlier systematic review by Bhattacharjee and Banerjee reported that no adverse effects were observed with a short duration of TPO-RA as second-line therapy in a few COVID-19 cases (n = 9) [65]. Furthermore, there are very few reports of ITP exacerbation following COVID-19 vaccine administration [69]. Given the limited cases, there are currently no guidelines for managing ITP caused by the COVID-19 vaccine or vaccination of individuals with predisposing conditions [69]. Unsurprisingly, the experts in this study did not concur on the possibility of switching to another TPO-RA for chronic ITP patients in case of relapse already on TPO-RA therapy with newly identified mild/moderate COVID-19. Further studies on using TPO-RAs in adult ITP patients with mild/moderate COVID-19 are required.

Platelet responses following TPO-RA treatment usually decrease gradually once medications are stopped, and questions on whether the combination of TPO-RAs with other drugs (e.g., corticosteroids) can exert additive effects and provide better clinical benefits than TPO-RAs alone have been raised [70]. However, there is a lack of data demonstrating the utility of TPO-RA combination therapy in the first-line setting, and no expert recommendations can be made at present. Corticosteroids are a mainstay first-line treatment of ITP but are frequently overused and associated with limiting toxicities [71]. Reductions in corticosteroid use may improve health-related quality of life in patients with ITP [72]. The experts concurred that TPO-RAs plus glucocorticoids could provide a promising first-line therapy with a dual action (i.e., immunosuppression and stimulation of platelet production) with the potential to decrease corticosteroid exposure for a significant number of ITP adults. Yu et al. (2020) showed that combination of TPO‐RA therapy plus corticosteroid therapy results in a higher incidence of initial response (89.0% vs 66.7%, P < 0.001) and CR (75.0% vs 42.7%, P < 0.001) compared with corticosteroids alone [59].

Due to a lack of head-to-head studies and evidence for specific ITP populations and scenarios, the consensus statements provided in this paper are based on expert opinion as well as on literature data. Therefore, we have drawn on evidence from clinical trials in the literature, where possible. However, we acknowledge the possibility of intra-publication bias and homogeneity of expert opinion. We believe that the consensus statements are applicable throughout the international ITP community; however, the information may be less transferable in nations not represented herein.

The findings from this systematic literature review have informed the development of consensus statements by a group of senior ITP hematologists from eight countries across Central Europe. The consensus statements aim to raise awareness, provide guidance, and facilitate informed decision-making on key issues that healthcare providers must consider when using TPO-RAs to treat their adult ITP patients in real-life practice. The expert panel achieved a high level of agreement on seven statements, including earlier usage of TPO-RA as a second-line treatment in ITP and switching and tapering TPO-RAs. In general, an individualized approach to managing adults with ITP is strongly recommended, taking into account patient preferences, comorbidities, and lifestyle. There are considerations with a lack of expert consensus in this work. Updated treatment guidelines will therefore be required if adequate new studies of TPO-RAs in the first-line setting or in specific patient groups such as COVID-19 ITP patients become available.