Efficacy, safety, and genetic analysis of orelabrutinib combined with rituximab as first-line systemic treatment for marginal zone lymphoma.

7059 Background: Marginal zone lymphoma (MZL) is a heterogeneous B-cell malignancy that is often managed with chemoimmunotherapy in the first-line setting, but chemotherapy entails considerable toxicity. Orelabrutinib, a novel oral BTK inhibitor which offers improved target selectivity and fewer off-target effects. This study evaluates the chemo-free combination of orelabrutinib plus rituximab in untreated MZL. Methods: This is a prospective, single-arm, multicenter phase II clinical trial (NCT07022223). Patients with untreated MZL who met ECOG criteria of 0–2 and were in need of treatment, or who had failed local, were eligible. All participants will receive induction therapy with the orelabrutinib and rituximab regimen. The treatment cycle is 28 days, with a total of 4~6 cycles. The induction treatment period is as follows: Cycle 1: Rituximab, 375 mg/m², on day 1. Cycles 2-6: Orelabrutinib, 150 mg, once daily orally, from day 1-28, plus rituximab 375 mg/m² on day 1. Patients who achieve a partial response (PR) or better will enter a 2-year maintenance period with orelabrutinib. The primary endpoint is the overall response rate (ORR). Secondary endpoints include complete response (CR) rate, PR rate, progression-free survival (PFS), and overall survival (OS). Safety is assessed by monitoring adverse events (AEs). Results: From March 2025 to December 2025, a total of 40 patients with MZL (32 MALT, 6 NMZL, 2 SMZL) were enrolled. The median age at diagnosis was 68 years (range 44–84), and 82.5 % of patients were older than 60 years. 21 (52.5%) were female. Most patients had an ECOG score of 0-1 (28/40), Ann Arbor Stage Ⅲ-IV disease (35/40). Twelve patients had an MZL-International Prognostic Index score of ≥2. Thirteen patients had failed prior local therapy, the majority of whom had undergone surgical resection. After three cycles, 25 patients were evaluable, with an ORR of 80 % (20/25) and a CRR of 24 %. Following six cycles, 13 patients were evaluable, achieving an ORR of 100 % (13/13) and a CRR of 62 % (8/13). The median time to response was 72 days. With a median follow-up of 5.7 months (range, 5.1-6.8), the median PFS and OS were not reached, the 1-year PFS rates were 97.2% and the 1-year OS rates were 100%. Next-generation sequencing (NGS) was performed on 16 patients, a total of 158 mutated genes were identified, with missense mutations predominating (62.7%). The most frequently mutated genes were NOTCH2, FAT4, LRP1B, PCLO, and SYNE1, all at 31.2 %. Treatment was generally well tolerated, only 13 patients experienced adverse events, the most common adverse events were anemia (15 %), infection (12.5 %) and neutropenia (10 %). Notably, BTK inhibitor–associated atrial fibrillation (0 %) and bradycardia (0 %) were absent. Conclusions: The combination of orelaburtinib and rituximab shows significant activity in MZL, with a manageable toxicity profile. Clinical trial information: NCT07022223 .