Abstract
Introduction:
Marginal zone lymphoma (MZL) is the second most common indolent B-cell non-Hodgkin lymphoma (NHL), accounting for 5-15% of NHL cases (Ann Oncol 2020:31:17). Although immunochemotherapy has become the preferred first-line therapy regimen, early relapse or disease progression within 24 months of first-line therapy occurs in approximately 20% of patients with MZL, which is associated with an unfavorable prognosis (NEJM 2024:386:568). MZL remains a clinical challenge, with limited optimal treatment options in both first-line and later-line settings (Haematologica 2022:107:35). Emerging targeted therapies, particularly Bruton tyrosine kinase (BTK) inhibitors, are active in patients with MZL (Haematologica 2022:107:35). Orelabrutinib, a novel, highly selective next-generation covalent BTK inhibitor, demonstrated high response rates, durable disease control, and good tolerability in relapsed/refractory MZL patients, and was approved in China by the National Medical Products Administration in 2023 for this indication (Am J Hematol 2023:98:1742). In this retrospective study, we aimed to explore the efficacy and safety of orelabrutinib-based regimens in patients with MZL in a real-world setting.
Methods:
This real-world retrospective study included patients who received at least one dose of orelabrutinib induction therapy from Guizhou Provincial Cancer Hospital in China. The outcomes included overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and safety.
Results:
As of July 14, 2025, 57 patients (30 males) with a median age of 57 years (range, 19-84) were included. Extranodal MZL (82.5%) was the most common subtype, with involvement of the stomach (31.9%), lung (23.4%), ocular adnexa (14.9%), and other sites (29.8%). Nodal and splenic subtypes accounted for 10.5% and 7.0%, respectively. Most patients (77.2%) were in Ann-Arbor stage II-IV, 89.5% had an Eastern Cooperative Oncology Group performance status of 0-1, 40.4% had a Ki-67 index ≥20%, and 77.2% presented with B symptoms. According to the MZL IPI score, 49.1% of patients were classified as low risk, 42.1% as intermediate risk, and 8.8% as high risk. Among the 57 patients, 43 received orelabrutinib-based regimens as first-line therapy, and 14 as later-line therapy. Of 50 efficacy-evaluable patients, the overall ORR was 84.0% (95% confidence interval: 70.9%-92.8%), including 50.0% complete response (CR) and 34.0% partial response. The DCR reached 98.0%. For extranodal MZL, the CR rate was 48.8%, while 2 of 4 nodal MZL patients and 2 of 3 splenic MZL patients achieved CR. At a median follow-up of 6.9 months (range, 0.8-17.3), median PFS was not reached; the 12-month PFS rate was 94.2%. The first-line therapy group achieved an ORR of 91.7% and a DCR of 100.0%, with a 12-month PFS rate of 94.7%, while the later-line therapy group showed lower response rates (ORR 64.3%; DCR 92.9%) and a 12-month PFS rate of 92.3%. Across three orelabrutinib-based regimens, the chemo-free regimens with orelabrutinib ± radiotherapy (n=19) achieved the best efficacy, with an overall ORR of 94.4%, DCR of 100.0%, and a 12-month PFS rate of 100.0%, including ORRs of 93.3% in first-line and 100.0% in later-line patients. The orelabrutinib monotherapy ± radiotherapy (n=21) yielded an ORR of 68.8%, a DCR of 93.8%, and a 12-month PFS rate of 94.4%, with first-line and later-line ORRs of 88.9% and 42.9%, respectively. The orelabrutinib combined with immunochemotherapy ± radiotherapy (n=17) resulted in an ORR of 87.5%, a DCR of 100.0%, and a 12-month PFS rate of 88.9%, with ORRs of 91.7% in first-line and 75.0% in later-line settings. Nineteen of 57 patients received orelabrutinib maintenance therapy, with a median treatment duration of 7.0 months (range, 1-14). Grade ≥3 adverse events (AEs) occurred in 11 patients (19.3%), with neutrophil count decreased being the most common (10.5%). The chemo-free regimens with orelabrutinib ± radiotherapy and orelabrutinib monotherapy ± radiotherapy showed better safety profiles than orelabrutinib plus immunochemotherapy ± radiotherapy (grade ≥3 AEs: 5.3% versus 19.0% versus 35.3%). At data cut-off, no deaths, dose reductions, or discontinuations of orelabrutinib were reported.
Conclusions:
This real-world study demonstrated that orelabrutinib-based regimens are effective and well tolerated in patients with MZL, requiring further prospective validation.
