Background: Emerging evidence suggests that triple-combination regimens incorporating Bruton tyrosine kinase (BTK) inhibitors, CD20-targeted agents, and immunomodulatory drugs (e.g., lenalidomide) may exhibit promising antitumor activity in indolent B-cell non-Hodgkin lymphomas (B-NHLs). In this study, we evaluated the efficacy and safety of orelabrutinib plus obinutuzumab and lenalidomide(GOL regimen) as a first-line therapy for MZL patients, aiming to assess its potential as a chemotherapy-free treatment option.

Methods: In this prospective single-arm multicenter phase II trial (NCT06454968), eligible treatment-naïve adults (≥18 years) with histologically confirmed marginal zone lymphoma requiring systemic therapy received six 21-day cycles of induction therapy (oral orelabrutinib 150 mg QD on days 1-21, intravenous obinutuzumab 1000 mg on day 1 of each cycle, and oral lenalidomide 25 mg QD on days 1-14) followed by six 28-day cycles of orelabrutinib monotherapy (150 mg QD). The primary endpoint of our study is complete response rate, secondary endpoints were overall response rate, duration of response, uMRD rate of SMZL by IgH-DNA sequencing, and safety.

Results: As of August 1, 2025, a total of 23 patients were enrolled in the study. The median age was 60 years (range: 36-81) with a male-to-female ratio of 0.92:1. Subtype distribution included: MALT/EMZL (n=9, 39.1%), SMZL (n=9, 39.1%), and dissMZL (n=5, 21.8%). All patients had Ann Arbor stage IV disease, with 6 cases (26.1%) presenting B symptoms. The MZL-IPI score distribution was: 0 points in 6 cases (26.1%), 1-2 points in 14 cases (60.9%), and 3-5 points in 3 cases (13.0%). Monoclonal gammopathy was observed in 9 out of 19 evaluable patients. All splenic marginal zone lymphoma (SMZL) patients exhibited massive splenomegaly, with 4 out of 9 showing baseline leukocytosis (peak WBC count 387.5×10⁹/L, lymphocyte count 371.9×10⁹/L). To date, 10 patients have completed 6 cycles of the three-drug combination (GOL) regimen, while 5 patients have completed all treatment and entered the follow-up phase. Among 18 response-evaluable patients, the overall response rate (ORR) was 88.9% (16/18) and the complete response rate (CRR) was 72.2% (13/18). By subtype analysis:SMZL patients demonstrated excellent outcomes with 100% ORR (6/6) and 100% CRR (6/6), all achieving complete remission by cycle 3, including 5 cases (83.3%) attaining MRD negativity by IgH-DNA sequencing;MALT/EMZL patients showed 77.8% ORR (7/9) and 66.7% CRR (6/9);dissMZL patients achieved 100% ORR (3/3) but a lower CRR of 33.3% (1/3). With a median follow-up of 8.1 months (range 2.3-13.1 months), none of the responding patients experienced disease progression, and the median duration of response (DOR) has not been reached. Regarding safety, all-grade adverse events included: infusion-related reactions (6/23), thrombocytopenia (6/23), rash (5/23), herpes zoster (2/23), petechiae (2/23), leukopenia (1/23), influenza A pneumonia (1/23), and invasive pulmonary aspergillosis (1/23). Grade 3 adverse events were limited to infusion-related reactions (2/23), thrombocytopenia (2/23), and rash (2/23), with no grade 4-5 adverse events reported.

Conclusion: This phase II study demonstrates that the novel triple-combination regimen shows promising efficacy in treatment-naïve MZL patients, with an impressive overall response rate (88.9%) and complete response rate (72.2%), particularly in SMZL patients who achieved 100% CR. The regimen exhibited a manageable safety profile with no grade 4-5 adverse events. Early MRD negativity in SMZL suggests potential for durable remissions. These results support further study of this chemotherapy-free approach.

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2025
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