Treatment of Orelabrutinib+Hi-CVP Regimen for Previously Untreated MZL

This is an investigator-initiated, prospective, open-label, multicenter Phase II clinical trial evaluating the efficacy and safety of orelabrutinib in combination with anti-CD20 monoclonal antibody-CVP (rituximab or zebetutamab-cyclophosphamide-vincristine-prednisone) followed by orelabrutinib monotherapy maintenance in treatment-naïve patients with marginal zone lymphoma (MZL) .

The study aims to address the unmet clinical need for a highly effective, chemotherapy-free frontline regimen in MZL. While current standard immunochemotherapy regimens-such as bendamustine plus rituximab (BR) or R-CVP-demonstrate meaningful response rates, they are associated with high incidences (60-70%) of Grade 3-4 adverse events, compromising quality of life and long-term tolerability . Building upon promising retrospective data showing 90% ORR and 30% CR with orelabrutinib plus rituximab in frontline MZL , and robust single-agent activity in relapsed/refractory MZL (ORR 68.9%, CR 11.1%) , this trial introduces a novel sequential strategy:

Induction phase: 6 cycles of orelabrutinib (150 mg orally once daily) combined with anti-CD20 monoclonal antibody (375 mg/m² IV), cyclophosphamide (750 mg/m² IV), vincristine (1.4 mg/m² IV, max 2 mg), and prednisone (100 mg IV Days 1-5), administered per 3-week cycle ; Maintenance phase: 18 cycles (1.5 years) of orelabrutinib monotherapy (150 mg QD), extended up to 2 years total treatment duration.

A key scientific innovation lies in the prospective, serial assessment of measurable residual disease (MRD) using next-generation sequencing (NGS) of peripheral blood at three critical timepoints: baseline, end of induction, and 1 year after initiation of maintenance therapy . This exploratory objective seeks to determine whether MRD negativity correlates with prolonged progression-free survival (PFS), overall survival (OS), and critically, prevention of progression within 2 years (POD24)-the strongest prognostic factor in MZL, associated with median survival of only 3-5 years . While MRD has established predictive value in CLL and FL , its role in MZL remains investigational, with only limited retrospective evidence (e.g., 5-year PFS of 74.8% vs. 31.4% in MRD-negative vs. MRD-positive splenic MZL) .

The primary endpoint is the 2-year complete response rate (CR24), with secondary endpoints including ORR and CR at end of induction, 2-year PFS and OS, and MRD dynamics . The study plans to enroll 65 patients across multiple centers, with the lead site-National Cancer Center/CICAMS-enrolling 36 participants . Eligibility requires confirmed CD20⁺ MZL (nodal, extranodal, or splenic), measurable disease, ECOG PS 0-2, and fulfillment of NCCN-defined treatment indications . Exclusion criteria include CNS involvement, active HBV/HCV infection, significant cardiovascular comorbidities (e.g., QTc ≥450/470 ms, LVEF \<50%), recent thromboembolic events, or major surgery within 4 weeks .