Introduction Existing studies have demonstrated that combining BTK inhibitors with anti-CD20 monoclonal antibodies yields favorable outcomes in marginal zone lymphoma (MZL). As the first BTK inhibitor approved for MZL in China, orelabrutinib is expected to act synergistically with obinutuzumab.

Methods This is a prospective, single-arm, phase II clinical trial. Untreated MZL at ECOG 0~2 criteria, in need of treatment, were eligible. All patients received 6-8 cycles of orelabrutinib (150 mg QD, days 1-21) and Obinutuzumab (1000 mg intravenously on days 1, 8, and 15 in cycle 1 and on day 1 in cycles 2-6), followed by 2 years of orelabrutinib monotherapy maintenance (150 mg once daily on days 1–28 of each cycle). The primary endpoint is the overall response rate (ORR). Secondary endpoints include complete response (CR) rate, partial response (PR) rate, and survival indicators such as duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Safety is assessed by monitoring adverse events (AEs).

Results From January 2024 to June 2025, a total of 14 patients with MZL (10 MALT, 3 NMZL, 1 SMZL) were enrolled. The median age at diagnosis of 64 years (34-72) and 84.6% (11/13) were male. Most patients had an ECOG score of 0-1 (13/14) and Ann Abor Stage Ⅲ-IV disease (9/14). Five of eleven evaluable patients had an MZL-International Prognostic Index score of ≥2. The sites of extranodal involvement of MALT include the stomach, parotid gland, Ocular adnexal, and tonsil.

Among nine efficacy-evaluable patients, the ORR was 100% (9/9), 87.5% ( 8/9) CR, with a median time to response of 3.2months. Eight patients successfully completed the induction treatment and smoothly transitioned into the maintenance treatment. With a median follow-up of 13.5 months, the median DOR, PFS, and OS were not reached. The 12-month PFS and OS rates were both 100%.

Preliminary NGS analysis was performed on tumor tissue samples from three patients with MZL. A total of 45 mutated genes were identified, with missense mutations predominating (80%). Mutations in 12 genes—including NOTCH2, TCF3, and KMT2C—were detected in all three samples. Pathway analysis revealed alterations in NOTCH signaling, transcriptional misregulation in cancer, and Epstein–Barr virus infection-related genes across all cases. Two of the three patients (67%) harbored mutations in NF-κB and antigen processing/presentation pathways. The remaining mutated genes were predominantly associated with metabolic pathways, RNA degradation, and broader cancer-related processes. Notably, BTK inhibitor-associated mutation sites were identified in two patients, further supporting the therapeutic potential of orelabrutinib in MZL. However, given the small cohort size, these findings cannot fully capture MZL heterogeneity; thus, the cohort will be expanded for further validation.

Treatment was generally well tolerated, with only two treatment-related adverse events reported: thrombocytopenia and mild cutaneous bleeding. After one week of hematopoietic-stimulating therapy, the platelet count normalized, and the medication was resumed.

ConclusionsThe combination of Orelabrutinib and Obinutuzumab shows significant activity in MZL, with a manageable toxicity profile. NGS of tumor tissue is instrumental for elucidating the molecular pathogenesis of MZL and for guiding individualized therapeutic strategies. Future updates will incorporate additional follow-up data.

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2025
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