Low-Dose Corticosteroids and Eltrombopag in the Treatment of Newly Diagnosed Adult Immune Thrombocytopenia: A Multicenter, Phase 2 Clinical Trial

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by decreased platelet (PLT) count in peripheral blood and bone marrow megakaryocyte dysfunction. The standard first-line treatment of newly diagnosed ITP was still corticosteroids (CIS), intravenous immunoglobulin (IVIG) or anti-D IG for those PLT≤30×10⁹/L. According to the present international consensus or clinical guidelines, the timeline for cease or starting maintenance treatment (no more than 5mg daily) of CIS should within 6-8 weeks. However, many relapses happened practically, and need to switch into second line treatment such as thrombopoietin receptor agonist (TPO-RA). Eltrombopag (EPAG), the first oral non-peptide TPO-RA, achieved ~80% response in chronic ITP patients. The initial recommend dose of EPAG was 25mg according to Chinese Guideline, and the response rate increased if the daily dose increased to 50mg or 75mg (22.22%, 45.45 % and 65.52%, respectively), however the financial burden increased accordingly, especially for patients in developing country. It is of great clinical significance if we can invoke a treatment protocol that could gain all the benefits, including quick response, timely CIS withdrawal as well as high sustained response. Herein, we raise a multicenter phase 2 clinical trial, which aimed to explore the efficacy of low-dose corticosteroids (LD-CIS) plus low-dose eltrombopag (LD-EPAG) for newly diagnosed, treatment-naïve ITP patients.

The study included three phases: 1) core treatment period (8 weeks), patients received fixed LD-CIS (weight≤ 50kg, 20 mg/d; weight> 50kg, 0.4 mg/kg/d) for 3 weeks and reduced gradually to target dosage within 8 weeks, with fixed LD-EPAG (25 mg daily) treatment; 2) decrement and discontinuation period (12 weeks): EPAG gradually tapered if the PLT count maintain above 100×10⁹/L over 2/3 of the core treatment period; 3) follow-up period (6 months): LD-CIS and LD-EPAG ceased and observe the sustained response for 6 months. The primary endpoint was the ratio of CIS discontinuation or maintenance dose less than 5mg QD within 8 weeks with a PLT≥ 50×10⁹/L. The secondary endpoint of study was durable response after EPAG discontinuation or maintenance dose ≤ 25mg BIW. Between July 2022 and March 2024, 16 centers participate in, and 41 patients from 5 centers were screened for eligibility. Sixteen cases were excluded, and 23 patients were ultimately enrolled and finished the whole study. 23 patients were ultimately enrolled and finished the whole study. The median age was 53.83 (range 23-88) years old. For efficacy assessment, all the patients achieved an increased PLT from baseline. The complete response (CR, PLT ≥ 100×10⁹/L) was achieved in 60.87% (14/23) patients at the end of 2^nd week observation, which increased to 84.21% (16/19) at the end of 12^th weeks. As noted, the overall response rate (ORR) reached 100% in 2nd weeks and maintained above 90% throughout the study. The median intervals time required for platelet to reach 30×10⁹/L and 100×10⁹/L for the first time were 6 (2-18) and 14.5 (4-45) days, respectively.

Out of 23 patients received our treatment protocol, 22 (95.65%) patients achieved the primary endpoint, except for one patient exhibited CIS-dependent. The secondary endpoint of study was the proportion of patients who achieved EPAG discontinuation or maintenance dose ≤ 25mg BIW until Week 20, which was 52.94% in 9 out of evaluable 17 patients, of which, 8 cases accomplished SRoT with a median durable response of 5.5 (range 2.75-5) months. In addition, the median bleeding score pretreatment was 2 (0-4), which was decreased at each point post-treatment by paired t-test. Clinical assessment of ITP commonly focusses on platelet counts and risk of bleeding, fatigue and HRQoL were also longitudinally evaluated in our cohort. The results showed that there were no significant differences in fatigue score after the combination therapy, while mental health (MH) score was improved. In addition, no severe adverse events were observed during the whole study, the treatment related side effect such as impaired glucose tolerance, liver dysfunction, etc.

In summary, the combination of low-dose corticosteroids and eltrombopag can exert a quick and durable response in newly diagnosed ITP, and partly improve their quality of life. This regimen represents a potential first-line treatment, but further randomized controlled studies are needed to consolidate this conclusion.