Real-world study on thrombopoietin receptor agonists combined with rituximab in the treatment of Relapsed/Refractory primary immune thrombocytopenia

Abstract Background Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder, but the management of relapsed/refractory cases remains clinically challenging. Thrombopoietin receptor agonists (TPO-RAs), which stimulate megakaryocytes in the bone marrow to produce platelets, represent an important second-line treatment option for ITP. However, only approximately 20% of ITP patients achieved sustained remission after discontinuation of TPO-RAs. The combination of TPO-RAs with rituximab may represent an durative therapeutic option for relapsed/refractory ITP, as this dual mechanism simultaneously promotes platelet production while suppressing autoimmune platelet destruction. Objective Despite the potential synergy between TPO-RAs and rituximab in ITP, real-world data from Chinese patients are limited. We therefore conducted a multicenter study to assess the effectiveness and safety of this combination in clinical practice. Methods In this retrospective analysis, we enrolled consecutive cohorts of 88 adult ITP patients who received TPO-RAs combined with rituximab in 4 centers from January 2018 to August 2024. The median duration of follow-up of these patients was 28.5 months (range from 3 to 79 months). Results The study included 88 ITP patients with median age of 42 years and median disease duration of 30 months. All the patients have experienced at least one relapse. Forty patients (45.5%) had received ≥1 immunosuppressant prior to combination therapy. Of 63 patients (71.6%) with prior TPO-RAs exposure, 47 (74.6%) showed inadequate response or failure. Combination regimens utilized avatrombopag (n=23), eltrombopag (n=32), or hetrombopag (n=33). Rituximab was administered as standard-dose (375 mg/m² weekly ×4; n=41) or reduced-dose regimens (n=47). At the initiation of combination therapy, the median platelet count was 18×10⁹/L (range: 1-420). The response rates (platelets ≥30×10⁹/L) were 62.5% (n=55) at 1 month (including 29 complete responses [CR; ≥100×10⁹/L]), 59.1% (n=52) at 3 months (30 CR), and 52.2% (n=46) at 6 months (29 CR). At the last follow-up, 46 patients remained on TPO-RAs from the combination therapy, with 37 achieving response (including 21 maintaining CR). Among these 46 patients, 8 had previously demonstrated suboptimal response to TPO-RAs during monotherapy, of whom 7 subsequently attained therapeutic response when continuing the agents in combination. Of 42 patients who discontinued TPO-RAs from the combination regimen, cessation reasons included: drug-related hepatotoxicity (n=2), inadequate therapeutic response (n=27), and 13 patients achieving sustained remission after complete treatment withdrawal. After combination therapy, only 4 cases (4.5%) experienced grade ≥3 adverse events (2 cases of pulmonary infection and 2 cases of abnormal liver function). Conclusion This multicenter study demonstrates that combination therapy with TPO-RAs and rituximab appears to be a favorable option for relapsed/refractory ITP patients, including patients with prior TPO-RAs failure.