Reduced dose prednisone plus eltrombopag for the treatment of newly diagnosed adult primary immune thrombocytopenia: A prospective, multicentre, phase 2 clinical trial

Primary immune thrombocytopenia (ITP) is an autoimmune disorder involving low platelet (PLT) counts and impaired bone marrow megakaryopoiesis. First-line therapy for newly diagnosed (ND) ITP with PLT ≤30 × 109/L employs corticosteroids (CIS), intravenous immunoglobulin or anti-D immunoglobulin.1 While high-dose CIS induces rapid responses, prolonged use causes significant toxicity, prompting guideline-recommended tapering to ≤5 mg/day prednisone-equivalent within 6–8 weeks.2, 3 However, frequent relapses post-CIS withdrawal often necessitate second-line therapies like thrombopoietin receptor agonists (TPO-RAs). Eltrombopag (EPAG), the first oral non-peptide TPO-RAs, achieved ~80% response in chronic ITP patients. Chinese guidelines recommend 25 mg initial dosing,4 with dose-dependent efficacy: 22.22% (25 mg), 45.45% (50 mg) and 65.52% (75 mg) response rates.5 Nevertheless, although the approval of multiple generic versions has substantially reduced treatment costs, dose escalation and maintenance therapy may still impose financial burdens, especially in developing countries, highlighting the need for cost-effective protocols that ensure rapid CIS withdrawal, sustained responses, reduction of toxicity and reduced relapse. Thus, we conducted a multicentre, prospective phase 2 clinical trial to evaluate the efficacy of reduced-dose prednisone (RD-Pred) plus low-dose eltrombopag (LD-EPAG) in ND, treatment-naïve ITP patients. The study was registered at chictr.org.cn (#ChiCTR2200058259). Eligible patients were ND ITP, ≥18 years of age, without previous therapy, baseline PLT <30 × 109/L or PLT <50 × 109/L with significant bleeding symptoms. Participants were excluded if they had positive serology for HIV, hepatitis B or C, inherited or congenital thrombocytopenia or secondary thrombocytopenia. This study was approved by the ethical committee of the First Affiliated Hospital of Zhejiang Chinese Medical University (2022-KL-014-01), which was performed in accordance with the Declaration of Helsinki. The study included three phases: (1) core treatment period (8 weeks), in which patients received a fixed dose of RD-Pred (weight ≤ 50 kg, 20 mg/day; weight > 50 kg, 0.4 mg/kg/day) for 3 weeks, followed by a gradual taper to the target dose within 8 weeks. LD-EPAG (25 mg/day) was administered concurrently; (2) decrement and discontinuation period (12 weeks): EPAG was gradually tapered if PLT remained ≥50 × 109/L (Figure S1); (3) follow-up period (6 months): Both RD-Pred and LD-EPAG were discontinued. Patients were observed for a sustained response over 6 months. Response and complete response (CR) were defined as a PLT count ≥30 × 109/L and ≥ 100 × 109/L respectively. The primary end-point was the proportion of patients who discontinued prednisone or maintained a dose <5 mg/day within 8 weeks while maintaining PLT ≥50 × 109/L. The secondary end-point was the proportion of patients who discontinued EPAG or maintained a dose ≤25 mg twice weekly (BIW) by Week 20 with PLT ≥50 × 109/L. Additional assessments included the relapse (PLT <30 × 109/L) rate, relapse-free survival (RFS), sustained response off-treatment (SRoT, defined as PLT ≥50 × 109/L in the absence of bleeding events and without any rescue therapy) in patients who completed EPAG discontinuation, changes in bleeding scores, fatigue and health-related quality of life (HRQoL). Bleeding scores were evaluated using the bleeding assessment table outlined in the 2020 version of the Chinese guidelines for the diagnosis and management of adult primary ITP,4 which included metrics for both mucocutaneous and visceral haemorrhages. Fatigue and HRQoL were assessed using validated questionnaires, including the Functional Assessment of Chronic Illness Therapy-Fatigue and the Short Form-36 (SF-36). Treatment adverse effects (AEs) were assessed according to the Common Terminology Criteria for Adverse Events version 5.0. The Kaplan–Meier method was used to calculate the probability of RFS. Statistical analysis was conducted using SPSS version 25. Participants across 16 centres between July 2022 and March 2024 were enrolled. Following initial screening of 42 eligible patients from five actively recruiting sites, 33 patients received uniform treatment with RD-Pred plus LD-EPAG. Early discontinuations occurred in 10 cases (Table S1 for details). Ultimately, 22 completed the 20-week treatment protocol (Figure S2). Baseline characteristics of the treatment completers are reported in Table 1. Median PLT count at diagnosis was 17 × 109/L (range: 1–28 × 109/L). Median bleeding score was 2 (range: 0–4). Three patients required up-titration of EPAG to 50 mg daily, while the remaining 19 maintained the 25 mg/day dosage. All patients experienced increases in PLT counts from baseline. CR was achieved in 63.64% (14/22) of patients by the end of Week 2 and increased to 86.36% (19/22) by Week 12. The overall response rate reached 100% by Week 2 and remained above 90% throughout the study. Median time to response was 5 days (range: 2–16) and to CR 14.5 days (4–45). During a median follow-up of 23.5 months (range: 7–35), in 17 evaluable patients (excluding 1 prednisone-dependent and 4 lost to follow up), 3 experienced relapse (17.6%), demonstrating superior outcomes than 35% reported by Zhang et al. with dexamethasone (DXM) 40 mg/day for 4 days plus EPAG 50 mg/day for 28 days, and the 33.3% reported by Gómez-Almaguer et al. with DXM 40 mg/day for 4 days per cycle (1–3 cycles) combined with EPAG 25–75 mg/day for 12 weeks.6, 7 The 24-month RFS probability reached 83.3% (Figure 1), with detailed findings presented in Table 1. To account for substantial attrition, end-point analyses employed both full analysis set (FAS; n = 33) and per-protocol set (PPS; n = 22) methodologies. Five of the 33 enrolled patients achieved the primary end-point with reduced dose prednisone plus low-dose eltrombopag but subsequently switched to eltrombopag at local hospitals due to its inclusion in China's national reimbursement drug list, while another five voluntarily withdrew within three treatment weeks precluding efficacy assessment; consequently, 78.8% (26/33) attained the primary end-point in FAS. Secondary end-points were met by 36.4% (12/33) with SRoT in 27.3% (9/33). Among the 22 PPS completers, 21 (95.45%) achieved the primary end-point (one prednisone-dependent case excluded from secondary analysis), with 57.1% (12/21) meeting the secondary end-point and 42.9% (9/21) achieving SRoT within 20 weeks. Among them, six patients maintained treatment-free remission for ≥6 months (median duration: 19.5 months, range: 12–30). Beyond haematological outcomes, the regimen demonstrated beneficial effects on bleeding risk and HRQoL. The median baseline bleeding score was 2 (range: 0–4), with significant reductions observed at all post-treatment follow-up time points (all p < 0.05 by paired t-test) (Figure S3). However, fatigue symptoms persisted despite PLT recovery (Figure S4A), aligning with findings from the ITP World Impact Survey (iWISh), which emphasized the multifactorial nature of ITP-related fatigue and the importance of holistic symptom management.8 HRQoL was further assessed using the Short Form-36 (SF-36). Improvements were observed in mental health scores (0.67 ± 0.39 vs. 0.50 ± 0.32, p = 0.014) and health transition scores (0.85 ± 0.13 vs. 0.75 ± 0.16, p = 0.043) at 1 and 11 months post-treatment, respectively (Figure S4B–J), suggesting that rapid PLT stabilization and reduced treatment burden may positively affect psychosocial well-being. All patients tolerated treatment well, and no Grade ≥3 adverse events (AEs) were reported. The overall incidence of treatment-related AEs with RD-Pred plus LD-EPAG was 13.6% (3/22), including Grade 1 upper respiratory tract infection (1/22, 4.5%) and Grade 1 diarrhoea (2/22, 9.1%). One case of alanine aminotransferase elevation was observed but did not meet the criteria for Grade 1. No patients discontinued EPAG due to hepatobiliary laboratory abnormalities or other AEs. These findings must be interpreted as preliminary due to important study limitations, including a small sample size, relatively short follow-up duration and lack of a randomized controlled comparator. Furthermore, as an investigator-initiated trial with inherent resource constraints, this study experienced significant early-stage attrition. Consequently, for cost-sensitive patients with ND ITP, a glucocorticoids plus all-trans-retinoic acid regimen represents a pragmatic alternative.9 Crucially, advancing medical insurance coverage for EPAG as front-line ITP therapy remains a core research objective. In conclusion, the combination of RD-Pred and LD-EPAG appeared to produce a rapid and durable response in ND ITP patients and partially improved quality of life, suggesting it could potentially represent a viable first-line treatment option; however, these findings are preliminary and require validation in further randomized controlled trials. D.J. Wu and Y.P. Shen conceived and designed the study. D.J. Wu, L.H. Shou, Y.M. Xia, M. Zhou, L.L. Xu, X.H. Xu, L.Q. Wu, S. Chen, J.Z. Zhao, W.B. Liu, Y.H. Zhou, Y.P. Shen and B.D. Ye treated and followed up the patients. Q. Liu, X.H. Dong, C.M. Rong, J.H. Cai, D. Qiu, H.J. Hu, Y.C. Zhao and Y. Zhang assisted in the acquisition of data. Q. Liu, Y.Y. Shen, P.L. Zhou and D.J. Wu analysed and interpreted the data. Q. Liu, Y.Y. Shen and D.J. Wu wrote, reviewed and revised the manuscript. All authors contributed towards data analysis, drafting and critically revising the paper and agree to be accountable for all aspects of the work. The present study was supported by the Clinical Medical Research Project of Zhejiang Medical Association (No. 2022ZYC-Z25), the Young Clinical Talents Training Program of Chinese Society of Traditional Chinese Medicine (No. CYJH2024043) and the Project of Academic Inheritance Studio of Famous and Aged Chinese Medicine Experts in Zhejiang Province (No. GZS2021022). The authors declare no conflicts of interest.x This study was approved by the ethical committee of the First Affiliated Hospital of Zhejiang Chinese Medical University (2022-KL-014-01). All the patients who gave consent to disclose their medical records. The study was registered at chictr.org.cn (#ChiCTR2200058259). The data used and/or analysed during the current study are available from the corresponding author upon a reasonable request. Figure S1. Figure S2. Figure S3. Figure S4. Table S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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