Immune thrombocytopenia (ITP) is an autoimmune disorder associated with the production of autoantibodies directed against platelet glycoprotein complexes, resulting in both accelerated destruction of platelets and a relative reduction in platelet production. In adults, the majority of the acute cases respond to initial steroid therapy, but 50% relapse by 6 months and an additional 25% relapse beyond 1 year [1]. The non-responders and early relapsers can be difficult to manage and require additional therapies. These include intravenous immunoglobulin (IVIg), splenectomy, and rituximab, all of which can be problematic with variable and non-sustained responses, and specific thrombotic and infective risks with splenectomy [2].

Thrombopoietin receptor agonists (TPO-RA) exert their effects in ITP by increasing platelet production. Clinical trials have shown that TPO-RA are efficacious and well tolerated in chronic ITP patients, with some patients achieving a lasting response after cessation [3]. At the time, the study described in this manuscript was designed (2014), little was known about the short- and long-term response to TPO-RA in patients with newly diagnosed ITP. Hence, this study was initiated to evaluate the early- and long-term efficacy and safety of eltrombopag in adult non-splenectomized patients with steroid-unresponsive or dependent ITP within 6 months of diagnosis.

Patients at six Australian centers were enrolled into this multicenter, single arm, prospective open-label study between February 2014 and February 2016. Patients were 18 years or older and with ITP diagnosed within the prior 6 months which was steroid-unresponsive or -dependent and, if used, without a sustained response to IVIg. Full inclusion and exclusion criteria can be found in the Supporting Information. The study was conducted following approval from the ethics committees of participating institutions and patients provided written informed consent. The study was registered as a clinical trial [ACTRN12613000721707].

Patients with platelets < 10 × 10⁹/L commenced 75 mg eltrombopag daily; those with a platelet count ≥ 10 × 10⁹/L commenced 50 mg daily. The dose was progressively increased by 25 mg increment every 2 weeks to maximum of 150 mg daily (100 mg daily if East Asian) if the platelet count remained ≤ 30 × 10⁹/L or there was clinically significant bleeding. The dose in responding patients was maintained until the week 12 response assessment, unless the platelet count was ≥ 200 × 10⁹/L. Subsequently, the dose was adjusted to the minimum required to maintain a platelet count > 30 × 10⁹/L but ideally > 50 × 10⁹/L, preferably in the absence of concomitant steroids. After 6 months and beyond, patients who achieved at least a stable partial response (PR; platelets > 50 × 10⁹/L) had eltrombopag tapered by 25 mg each 3 weeks, with resumption of the previous therapeutic dose if the platelet count fell below 30 × 10⁹/L.

Response was assessed in all patients weekly until week 12, then at further time points to week 52 or 130 (see Study schema in Supporting Information). The primary endpoint was the overall response rate (ORR) at week 12: the composite of patients achieving a complete response (CR; platelet > 100 × 10⁹/L), PR (platelets 50–100 × 10⁹/L) or minor response (MR; platelet 30–49 × 10⁹/L with ≥ 50% reduction in the dose intensity of concomitant ITP therapy compared with screening). The protocol specified if a PR or greater was reached at week 12 then the platelet count should be confirmed at week 14–16. However, after noting eight patients did not have a confirmatory platelet count the analysis was modified to allow inclusion of these patients in the response outcome assessment; this is subsequently referred to as “amended analysis.” Secondary endpoints included CR, PR and MR rates at weeks 4, 8, and 26, therapeutic response at week 26 and 130, and safety profile. Although not specified in the original study design, long-term follow up of participants beyond week 130 was conducted to assess long-term responses and ITP management.

Thirty-nine patients were enrolled. The median age was 52 years (range 18–82), 18 (46%) were female and the median ITP duration at enrolment was 2.2 months (range 0.3–6). Prior therapies apart from prednisolone included IVIg in 27 (69%) and azathioprine in 10 (26%) patients.

The median platelet count at baseline was 21 × 10⁹/L (range 2–94) and at week 12 was 117 × 10⁹/L (range 20–498). Figure 1 outlines responses at each time point. The ORR per protocol and per amended analysis at week 12 was 64% (90% CI 52–77; CR 41%, PR 15%, MR 8%) and 85% (90% CI 75–94) (CR 59%, PR 18%, and MR 8%), respectively. Platelet counts at week 12 in those who achieved an MR or greater were 127 × 10⁹/L (range 58–498) and 142 × 10⁹/L (range 42–377). The median eltrombopag dose at weeks 12 and 27 was 50 mg, and at weeks 52, 104, and 130 it was 25 mg. Of the 29 patients who completed the study at week 130, 12 (31% of the total study population) had ceased eltrombopag and remained in CR.

The median prednisolone dose at baseline was 25 mg (range, 5–100) and at week 12 was 2.25 mg (range, 0–15). Of the 23 patients who achieved a CR at week 12, 17 had ceased steroids and six remained on steroids at a median dose of 5 mg (range 5–15). Six required rescue therapies with steroids (6) and IVIg (2) for an ITP relapse throughout the study. Four of these participants subsequently came off study; the other two completed study and remained on eltrombopag with ongoing CR.

With long-term follow up (median of 83.5 months from enrolment), 16 patients (41%) had stopped all ITP therapies and maintained a MR or better. Twelve (31%) remained on eltrombopag alone (≤ 50 mg daily) with ongoing PR or better. Two (5%) remained on high dose eltrombopag (150 mg daily) with additional therapies (prednisolone, hydroxychloroquine) to maintain response. The remaining nine (23%) patients stopped eltrombopag, at time points indicated in Figure 1 and required alternative therapies.

A symptomatic adverse event occurred in 77% of participants. The most common were headache (28%), nausea (21%), musculoskeletal pain (15%), rash (15%), and diarrhea (15%). These were mild (grade 1–2) except for one grade 3 headache. Two patients had grade 2 transaminitis, who were on doses of 150 and 125 mg, respectively, which necessitated eltrombopag dose reduction. Serious AEs (SAEs) occurred in 9 patients (23%) of which three were considered treatment-related: one grade 3 transaminitis (while on a dose of 125 mg) which resolved with eltrombopag cessation and two venous thromboembolism (VTE)—deep venous thrombosis in a 76 year-old male, at a platelet count of 97 × 10⁹/L receiving 125 mg eltrombopag, which was subsequently ceased, and pulmonary embolism in a 71 year-old female with concurrent ANCA-positive vasculitis, with a platelet count of 230 × 10⁹/L receiving 50 mg eltrombopag which was continued. Bleeding occurred in 14 (36%) patients, most (9; 64%) were grade 1. Grade 2 bleeding occurred in four patients: menorrhagia; gastrointestinal bleed requiring endoscopy in a patient on aspirin with a platelet count > 100 × 10⁹/L; haematuria; and epistaxis. There was one grade 3 gastrointestinal bleeding in a non-responding patient early in the study. Four patients had thrombocytosis (platelet count ≥ 450 × 10⁹/L), which resolved with eltrombopag dose reductions without clinical sequelae.

This study is unique in describing both the efficacy and tolerability of eltrombopag in non-splenectomized adults with steroid unresponsive or dependent ITP within 6 months of diagnosis, as well as the natural history with long-term follow up. We observed a high initial response rate with 85% of participants achieving a response at week 12, and most able to wean prednisolone completely or to small doses. Most responses were durable with over 70% maintaining response (40% off all therapy and 30% on eltrombopag) at both week 130 and with follow up at 7 years, a sustained response rate similar to that seen with eltrombopag in chronic ITP [4].

The few studies evaluating eltrombopag in newly-diagnosed ITP have reported similar outcomes but with short follow-up. A single-center study of 25 patients with steroid-nonresponsive newly-diagnosed ITP, found 76% had a sustained response to eltrombopag at 3 months [5]. Retrospective and real-world studies confirm that response to eltrombopag is similar between newly diagnosed, persistent, and chronic ITP patients [6]. It is likely that the ability to maintain sustained responses represents the natural history of ITP rather than a unique effect of TPO-RAs as similar trajectories are seen in patients responding to other therapies such as rituximab and corticosteroids [1]. Therefore the main benefit in our patients was avoiding the side-effects of other therapies, such as splenectomy or prolonged high-dose steroid use, while allowing the natural history of acute ITP to run its course. This is even more relevant now with updated guidelines recommending short-courses of steroids (< 6 weeks), whereby there should be earlier movement towards second-line therapies if there has been an inadequate response.

Bleeding events in this study were infrequent in responding patients. Three patients with transaminitis resolved with drug cessation or dose reduction. Of note, these were patients all on an eltrombopag doses of > 100 mg and close monitoring of liver function should be undertaken in patients on higher doses. While the current dosing guideline of eltrombopag is the maximum dose of 75 mg, higher doses are used for other indications such as aplastic anemia. There were two cases of VTE treated with anticoagulation.

The strengths of our study are the multicenter design and long-term follow up. Limitations include the lack of a control arm with which to compare the rate of response to eltrombopag.

In conclusion, we found a high response rate to eltrombopag in a high-risk group of recently diagnosed steroid-refractory or dependent ITP patients, who have few other rapidly-acting treatment options. This may obviate the need for splenectomy and other more toxic therapies in a significant proportion of patients.

免疫性血小板减少症 （ITP） 是一种自身免疫性疾病，与产生针对血小板糖蛋白复合物的自身抗体有关，导致血小板加速破坏和血小板生成相对减少。在成人中，大多数急性病例对初始类固醇治疗有反应，但 50% 病例在 6 个月时复发，另有 25% 病例在 1 年后复发 [1]。无反应者和早期复发者可能难以管理，需要额外的治疗。这些方法包括静脉注射免疫球蛋白 （IVIg）、脾切除术和利妥昔单抗，所有这些方法都可能存在可变和非持续反应的问题，并且脾切除术存在特定的血栓形成和感染风险 [2]。

血小板生成素受体激动剂 （TPO-RA） 通过增加血小板生成在 ITP 中发挥作用。临床试验表明，TPO-RA 在慢性 ITP 患者中有效且耐受性良好，一些患者在停药后获得持久反应 [3]。当时，本手稿中描述的研究是设计的 （2014），对新诊断的 ITP 患者对 TPO-RA 的短期和长期反应知之甚少。因此，本研究旨在评估艾曲波帕在诊断后 6 个月内患有类固醇无反应或依赖性 ITP 的成年非脾切除术患者中的早期和长期疗效和安全性。

2014 年 2 月至 2016 年 2 月期间，六个澳大利亚中心的患者被纳入这项多中心、单臂、前瞻性开放标签研究。患者年龄在 18 岁或以上，并且在过去 6 个月内被诊断为 ITP，对类固醇无反应或依赖性，如果使用，则对 IVIg 没有持续反应。完整的纳入和排除标准可以在支持信息中找到。该研究是在获得参与机构伦理委员会的批准后进行的，患者提供了书面知情同意书。该研究被注册为临床试验 [ACTRN12613000721707]。

血小板 < 10 × 10⁹/L 的患者开始每天 75 mg 艾曲波帕;血小板计数≥ 10 ×^{10 9}/L 的患者开始每天 50 毫克。如果血小板计数保持在 30 ×^{10 9}/L 或有临床显着出血，则剂量每 2 周以 25 mg 的增量逐渐增加至最大剂量≤每天 150 mg （如果是东亚人，则每天 100 mg）。反应患者的剂量维持到第 12 周反应评估，除非血小板计数≥ 200 × 10⁹/L。随后，将剂量调整到维持血小板计数 > 30 × 10⁹/L 但理想情况下 > 50 × 10⁹/L 所需的最低剂量，最好在没有伴随类固醇的情况下。6 个月及更长时间后，达到至少稳定部分缓解 （PR;血小板 > 50 × 10⁹/L） 的患者每 3 周减少 25 mg 艾曲波帕，如果血小板计数低于 30 × 10⁹/L，则恢复先前的治疗剂量。

每周评估所有患者的反应，直到第 12 周，然后在进一步的时间点评估到第 52 周或第 130 周（参见支持信息中的研究方案）。主要终点是第 12 周的总缓解率 （ORR）：达到完全缓解 （CR;血小板 > 100 × 10⁹/L）、PR （血小板 50-100 × 10⁹/L） 或轻微缓解 （MR;血小板 30-49 × 10⁹/L，与筛查相比，伴随 ITP 治疗的剂量强度降低≥ 50% 的患者复合。该方案规定，如果在第 12 周达到 PR 或更高，则应在第 14-16 周确认血小板计数。然而，在注意到 8 名患者没有确认性血小板计数后，对分析进行了修改，以允许将这些患者纳入反应结果评估;这随后被称为 “修正分析”。次要终点包括第 4 周、第 8 周和第 26 周的 CR 、 PR 和 MR 率、第 26 周和第 130 周的治疗反应以及安全性。虽然在最初的研究设计中没有具体说明，但对第 130 周之后的参与者进行了长期随访，以评估长期反应和 ITP 管理。

共纳入 39 例患者。中位年龄为 52 岁 （范围 18-82），18 名 （46%） 为女性，入组时的中位 ITP 持续时间为 2.2 个月 （范围 0.3-6）。除泼尼松龙外，既往治疗包括 27 例 （69%） 患者使用 IVIg，10 例 （26%） 患者使用硫唑嘌呤。

基线时的中位血小板计数为 21 × 10⁹/L（范围 2-94），第 12 周为 117 × 10⁹/L（范围 20-498）。图 1 概述了每个时间点的响应。第 12 周时每个方案和每个修改后的分析的 ORR 为 64% （90% CI 52-77;分别为 CR 41%、PR 15%、MR 8） 和 85% （90% CI 75-94） （CR 59%、PR 18% 和 MR 8%）。在达到 MR 或更高的患者中，第 12 周的血小板计数为 127 × 10⁹/L（范围 58-498）和 142 × 10⁹/L（范围 42-377）。第 12 周和第 27 周的艾曲波帕中位剂量为 50 毫克，第 52 周、第 104 周和第 130 周为 25 毫克。在第 130 周完成研究的 29 名患者中，12 名 （占研究总人群的 31%） 已停止艾曲波帕并继续处于 CR 状态。

基线时泼尼松龙的中位剂量为 25 毫克（范围，5-100），第 12 周为 2.25 毫克（范围，0-15）。在第 12 周达到 CR 的 23 名患者中，17 名已停止类固醇，6 名仍在服用类固醇，中位剂量为 5 毫克（范围 5-15）。在整个研究过程中，6 例需要使用类固醇 （6） 和 IVIg （2） 进行挽救治疗以治疗 ITP 复发。其中四名参与者随后退出研究;另外 2 例完成了研究并继续服用艾曲波帕并进行了 CR。

通过长期随访 （入组后中位 83.5 个月），16 例患者 （41%） 停止了所有 ITP 治疗并维持了 MR 或更好。12 例 （31%） 仍单独使用艾曲波帕 （≤ mg/d），PR 持续或更好。2 例 （5%） 继续服用高剂量艾曲波帕 （每天 150 毫克） 并接受额外疗法 （泼尼松龙、羟氯喹） 以维持反应。其余 9 例 （23%） 患者在图 1 所示的时间点停止了艾曲波帕，需要替代疗法。

77% 的参与者发生了有症状的不良事件。最常见的是头痛 （28%）、恶心 （21%）、肌肉骨骼疼痛 （15%）、皮疹 （15%） 和腹泻 （15%）。这些症状很轻微（1-2 级），除了一次 3 级头痛。2 例患者患有 2 级转氨酶炎，剂量分别为 150 和 125 mg，需要减少艾曲波帕剂量。9 名患者 （23%） 发生严重 AE （SAE），其中 3 名被认为与治疗相关：1 例 3 级转氨酶炎（剂量为 125 mg）随着艾曲波帕的停止而消退，2 例静脉血栓栓塞 （VTE）——一名 76 岁男性的深静脉血栓形成，血小板计数为 97 × 10⁹/L，接受 125 mg 艾曲波帕， 随后停止，一名 71 岁女性并发 ANCA 阳性血管炎，血小板计数为 230 × 10⁹/L，接受 50 mg 艾曲波帕并继续治疗。14 例 （36%） 患者发生出血，大多数 （9;64%） 为 1 级。4 例患者发生 2 级出血： 月经过多;血小板计数 > 100 × 10⁹/L 的服用阿司匹林的患者需要内窥镜检查的胃肠道出血;血尿;和鼻出血。在研究早期，一名无反应的患者有 1 例 3 级胃肠道出血。4 例患者有血小板增多症 （血小板计数 ≥ 450 × 10⁹/L），减少艾曲波帕剂量后消退，无临床后遗症。

这项研究在描述艾曲波帕在诊断后 6 个月内患有类固醇无反应或依赖性 ITP 的非脾切除成人中的疗效和耐受性，以及长期随访的自然病程方面具有独特性。我们观察到较高的初始缓解率，85% 的受试者在第 12 周达到缓解，并且大多数受试者能够完全或小剂量停用泼尼松龙。大多数反应是持久的，超过 70% 的患者在第 130 周和随访 7 年时维持反应 （所有治疗中 40%，艾曲波帕 30%），持续反应率与艾曲波帕在慢性 ITP 中观察到的相似 [4]。

少数评估艾曲波帕在新诊断的 ITP 中的研究报告了相似的结果，但随访时间短。一项针对 25 例类固醇无反应的新诊断 ITP 患者的单中心研究发现，76% 的患者在 3 个月时对艾曲波帕有持续反应 [5]。回顾性和真实世界研究证实，新诊断、持续性和慢性 ITP 患者对艾曲波帕的反应相似 [6]。维持持续反应的能力可能代表了 ITP 的自然病程，而不是 TPO-RAs 的独特作用，因为在对其他疗法（如利妥昔单抗和皮质类固醇）有反应的患者中也观察到类似的轨迹 [1]。因此，我们患者的主要好处是避免了其他疗法的副作用，例如脾切除术或长期使用大剂量类固醇，同时让急性 ITP 的自然病程顺其自然。现在，随着更新的指南推荐短期类固醇治疗（< 6 周），这一点更加相关，因此，如果反应不足，应更早地转向二线治疗。

本研究中的出血事件在有反应的患者中并不常见。3 例转氨酶转移患者通过停药或减少剂量而消退。值得注意的是，这些患者均服用 > 100 mg 的艾曲波帕剂量，应密切监测较高剂量患者的肝功能。虽然目前艾曲波帕的剂量指导是最大剂量 75 毫克，但更高剂量用于其他适应症，例如再生障碍性贫血。有 2 例 VTE 接受抗凝治疗。

我们研究的优势在于多中心设计和长期随访。局限性包括缺乏对照组来比较对艾曲波帕的反应率。

总之，我们发现最近诊断的类固醇难治性或依赖性 ITP 患者的高危组对艾曲波帕的反应率很高，他们几乎没有其他速效治疗选择。这可能避免很大一部分患者需要脾切除术和其他毒性更强的治疗。