Orelabrutinib plus rituximab-based chemoimmunotherapy regimens in relapsed or refractory marginal zone lymphoma: A multicentric phase II trial

Abstract

Abstract Background:Marginal zone lymphoma (MZL) is a heterogeneous B-cell malignancy that is often managed with chemoimmunotherapy (CIT) in the front line; however, limited treatment options exist for patients at relapse (Cancer Commun (Lond) 2019;39(1):58). Bruton's tyrosine kinase inhibitors (BTKis) have reshaped the treatment landscape of B-cell lymphomas, including MZL (Mol Ther Oncolytics 2021: 21:158-170). Orelabrutinib (O) is a novel, selective, irreversible BTKi with minimal off-target activity; however, its clinical efficacy combined with chemotherapy in MZL remains largely understudied. This study aimed to evaluate the efficacy and safety of O plus chemotherapy in the treatment of patients with relapsed or refractory MZL (R/R MZL). Methods: In this multicenter phase II study, patients with R/R MZL were enrolled. Eligible patients who failed to achieve partial response (PR) after 4 cycles of 1L CIT or relapsed < 2 years were switched to O plus bendamustine and rituximab (BR). Those who achieved PR after 4 cycles or relapsed ≥ 2 years after 1L therapy received O added to the previous regimen (rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone or with cyclophosphamide, vincristine, and prednisone [R-CHOP/R-CVP]) for continued treatment. Primary endpoint was objective response rate (ORR). The secondary endpoints included complete response (CR), progression-free survival (PFS), overall survival (OS), and safety. Results: From October 2024 to March 2025, a total of 10 patients with R/R MZL were enrolled in this study, including 6 with refractory disease and 4 with relapsed disease. The median age was 68 years (range 55-82), and 60% (6/10) were female. At baseline, 20% (2/10) of patients were in stage III while 70% (7/10) were in stage IV; 90% with EMZL subtype. Other baseline characteristics included 30% with comorbidities, 100% with intermediate and high-risk MZL-IPI scores, 20% with bone marrow involvement, 30% with splenomegaly, and 30% with multiple metastatic lesions. Of the 10 patients, the 2 who relapsed after 2 years were treated with the O+R-CHOP and O+R-CVP regimens, respectively, while the remaining patients all received the O+BR regimen. At the end of cycle 3, 2 (20%) patients achieved CR and 8 (80%) patients achieved PR. At the time of data cut-off, all patients completed 6 cycles of treatment, among whom 5 (50%) achieved CR, and 5 (50%) achieved PR, resulting in an ORR of 100%. All patients are under follow-up, with median PFS and OS not yet reached. Among the 10 patients in the study, 6 (60%) experienced adverse events, all of which were grade 1-2. The main adverse events were rash (30%) and bleeding (20%). No grade 3 or higher adverse events occurred. Conclusion: Our preliminary data demonstrate that orelabrutinib in combination with rituximab-based chemoimmunotherapy is effective and well-tolerated in R/R MZL. These findings warrant further prospective studies to validate, and longer follow-up is needed to confirm PFS and OS outcomes.