A Prospective, Multicenter, Single-Arm Study on the Combination of Orelabrutinib and Rituximab in the Second-Line Treatment of Relapsed/Refractory Marginal Zone Lymphoma

Background: Relapsed or refractory Marginal Zone Lymphoma (rrMZL) remains a clinical challenge. The Bruton tyrosine kinase (BTK) inhibitor orelabrutinib has demonstrated an overall response rate (ORR) of 58.9% as a monotherapy for rrMZL, warranting further exploration of its combination therapy strategies. This study aims to evaluate the efficacy and safety of orelabrutinib in combination with rituximab in patients with relapsed or refractory MZL. Methods: This is a prospective, multicenter, single-arm, phase II clinical trial. The study plans to enroll 39 patients with MZL who have refractory disease or relapse after at least one line of systemic lymphoma treatment. The treatment regimen includes 150 mg of orelabrutinib daily and 375 mg/m² of rituximab on day 1, administered every 21 days for a total of 8 cycles, followed by a choice of orelabrutinib or rituximab for 2 years of maintenance therapy as decided by the investigator. 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: To date, 12 patients have been enrolled in the study, including 7 males and 5 females. The median follow-up time is 81 days, with a median age of 68 years (range: 51-80) at enrollment. MALT lymphoma accounts for 75% (9/12) of cases, NMZL for 16.7% (2/12), and splenic MZL for 8.3% (1/12). The primary sites of involvement include the lungs, kidneys, stomach, submandibular gland, lymph nodes, stomach, and tonsils. Performance status scores of 0-1 were seen in 91.7% (11/12) of patients. According to the Ann Arbor staging, 91.7% (11/12) of patients were in stages II or III. The MZL IPI score was 1-2 (intermediate risk) in 66.7% (8/12) of patients. Of the 12 enrolled patients, 6 have completed the interim efficacy assessment, achieving a CR rate of 50% (3/6) and a PR rate of 50% (3/6), culminating in an ORR of 100%. 3 patients completed the combination therapy and entered the maintenance phase, with 67.7% (2/3) maintaining CR and 33.3% (1/3) PR, keeping the ORR at 100%. All patients chose orelabrutinib for maintenance therapy. The median follow-up time for the 6 patients with efficacy assessment was 119 days (range: 43-198), with no disease progression observed, so PFS was not evaluated. During the study, all patients experienced grade 1-2 adverse reactions, with grade 3-4 adverse reactions occurring in 66.7%. Common grade 1-2 adverse reactions included infections, decreased hemoglobin, lymphocytopenia, and thrombocytopenia. Common grade 3-4 adverse reactions primarily included infections, neutropenia, and pneumonia. Only 8.3% (1/12) of patients experienced fever due to rituximab infusion, causing a delay in medication without any discontinuation or dose reduction. No bleeding, atrial fibrillation, or renal function adverse events were observed. Conclusion:The preliminary results of this study suggest that the combination therapy of orelabrutinib and rituximab is effective in patients with rrMZL and has manageable safety, with tolerable maintenance therapy. Further follow-up data will be updated in the future.