Iguratimod plus low-dose rituximab as second-line treatment in adults with primary immune thrombocytopenia: A multicenter, open-label, randomized, controlled, Phase 2 trial Free

Introduction The optimal treatment for corticosteroid-resistant or relapsed immune thrombocytopenia (ITP) remains uncertain. Iguratimod is a small molecule compound that is widely used as a novel antirheumatic drug in the treatment of several autoimmune diseases. Our previous study revealed that iguratimod could regulate CD4⁺ T-cell homeostasis and function by restoring PINK1/parkin-mediated mitophagy in ITP patients (the 65th ASH oral presentation). Rituximab (RTX), a chimeric anti-CD20 monoclonal antibody that targets B cells, has been frequently used in treating ITP. Previous studies on low-dose rituximab (100 mg weekly for 4 weeks, LD-RTX) in ITP patients revealed an OR comparable to that of standard-dose rituximab (375 mg/m² weekly for 4 weeks, SD-RTX). However, LD-RTX was reported to have a longer time to response and a lower sustained response rate than SD-RTX. Since iguratimod and rituximab target T cells and B cells respectively, their combination may exert synergistic effects and potentially overcome the long time to response and improve sustained response. This study aimed to compare the efficacy and safety of iguratimod plus LD-RTX with those of LD-RTX monotherapy in corticosteroid-resistant or relapsed ITP patients.

Methods Adult ITP patients from 6 tertiary medical centers in China participated in this randomized, controlled, multicenter, open-label trial. Eligible corticosteroid-resistant or relapsed ITP patients with a platelet count <30×10⁹/L or bleeding symptoms at enrollment were randomly allocated at a 1:1 ratio to receive oral iguratimod at 25 mg twice daily for 12 weeks plus low-dose rituximab or low-dose rituximab monotherapy. RTX was given at a fixed dose of 100 mg weekly for 4 weeks. The primary endpoint was the initial overall response (OR), defined as achieving a platelet count of ≥30 × 10⁹/L, at least a doubling of the baseline platelet count without any other ITP-specific treatment, and the absence of bleeding. The second endpoint included a 6-month sustained response (SR), defined as platelet counts of ≥50 × 10⁹/L for two-thirds or more during the 26-week follow up in the absence of rescue therapy. This trial was registered with ClinicalTrials.gov (NCT07057778).

Results From September 1, 2022, to December 31, 2024, a total of 151 patients were screened for eligibility; 31 were excluded, and 120 were randomly assigned. A total of 120 patients were included in the intention-to-treat analysis: 60 in the iguratimod plus LD-RTX group and 60 in the LD-RTX group. The median age of the patients was 45 years, and 66.7% (80/120) of them were females. All patients enrolled failed to respond to first-line treatment with corticosteroids, and 70 (58.3%) of all patients had received three or more therapies. An OR was observed in more patients in the iguratimod plus LD-RTX group (75.0%) than in the LD-RTX monotherapy group (51.7%) (between-group difference, 0.23; 95% CI, 0.05–0.41). In patients who achieved an overall response, the median time to treatment response was 18 days in the iguratimod plus LD-RTX group, whereas it was 35 days in the LD-RTX monotherapy group. SR was achieved by 33 (55.0%) patients in the combination group and 23 (38.3%) patients in the monotherapy group (between-group difference, 0.17; 95% CI, 0.03–0.39).

Compared with baseline, both groups showed improvements in the mean scores of all the ITP-PAQ scales at week 26. For the scales of psychological health and social activity, the changes in the scores exceeded the minimal important difference estimates in both groups. Compared with those in the LD-RTX monotherapy group, the scores for symptoms, fatigue, work, social activity, and overall quality of life of the participants in the combination therapy group significantly improved. Serious adverse events (AEs), rescue treatment, and treatment side effects were similar in the two groups, and all patients tolerated the treatment well, without any grade 4 AEs or treatment-related deaths reported.

Conclusions Our findings demonstrate that iguratimod plus LD-RTX significantly increased the initial and sustained response rates, and shortened the time to response, indicating that it is a promising treatment option for corticosteroid-resistant or relapsed adult ITP.