Preliminary study results of orelabrutinib in combination with rituximab for treatment-Naïve marginal zone lymphoma: A prospective single-arm clinical trial

Abstract Background: Marginal zone lymphoma (MZL) is a subtype of non-Hodgkin lymphoma. Effective, low-toxicity regimens are lacking for treatment-naïve patients who have failed or are unsuitable for local therapy. Preclinical studies demonstrated that orelabrutinib, a novel BTK inhibitor, exhibits synergistic enhancement of antitumor activity when combined with rituximab. This study evaluates the efficacy and safety of orelabrutinib plus rituximab (OR) in treatment-naïve MZL. Methods This multi-center, single-arm, prospective phase II study (NCT06478472) enrolled treatment-naïve MZL patients meeting the following criteria: (1) Histologically confirmed CD20+ MALT lymphoma, splenic MZL (SMZL), or nodal MZL (NMZL); (2) Failure of or unsuitability for local treatment (e.g., ineffective surgery, radiotherapy, or anti-H. pylori therapy); (3) Requirement for systemic therapy (e.g., due to organ dysfunction, large tumor burden, or cytopenias). Patients received OR therapy as follows: Induction phase: Orelabrutinib 150 mg once daily (days 1-28) plus rituximab 375 mg/m² (day 0) in 28-day cycles for 6 cycles. Maintenance phase: Orelabrutinib 150 mg once daily for 24 cycles. The primary endpoint was the complete response rate (CRR). Secondary endpoints included overall response rate (ORR), 2-year progression-free survival (PFS), overall survival (OS), and safety (assessed per NCI CTCAE v5.0). Response rates and corresponding 95% confidence intervals (CIs) were calculated using the Clopper-Pearson method. Survival analyses utilized the Kaplan-Meier method (R Studio version 4.4.2). Results As of July 21, 2025, 16 patients had been enrolled, with a median follow-up of 5.5 months (range, 0–11.3 months). Baseline characteristics included a median age of 60.5 years. Lymphoma subtypes were MALT lymphoma (43.8%; 7/16), NMZL (43.8%; 7/16), and SMZL (12.5%; 2/16). Disease stage was III/IV in 62.5% (10/16) of patients. Bone marrow involvement was present in 57.1% (8/14 evaluable patients). An IPI score ≥2 was observed in 50% (8/16), and Ki-67 ≥20% in 25% (4/16). Eleven patients completed at least one efficacy assessment (median follow-up 7.8 months). The overall response rate (ORR) was 81.8% (9/11; 95% CI, 48.2–97.7), the complete response rate (CRR) was 72.7% (8/11; 95% CI, 39.0–94.0), and the disease control rate (DCR) was 81.8% (9/11). Subgroup analysis by subtype showed ORRs of 75.0% (3/4) for MALT lymphoma and 80.0% (4/5) for NMZL. Disease progression occurred in 2 patients. Median PFS and OS were not yet mature. Treatment-related adverse events (AEs) occurred in 7 patients, primarily hematologic toxicities (neutrophil count decreased, platelet count decreased, anemia), including 1 case of grade 3 platelet count decreased. Conclusion Orelabrutinib combined with rituximab demonstrates promising preliminary efficacy in treatment-naïve MZL patients who failed or were unsuitable for local therapy, with an ORR of 81.8% and a CRR of 72.7%. Clinical benefit appears consistent across MZL subtypes. Despite current limitations of small sample size and short median follow-up, the OR regimen represents a promising chemotherapy-free option for these patients. Extended follow-up is required to confirm survival benefits and long-term safety.