A Retrospective Analysis of Efficacy and Safety of Orelabrutinib Maintenance in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma

Introduction: R-CHOP/R-CHOP-like regimen remains the backbone for the first-line treatment of diffuse large B-cell lymphoma (DLBCL), yet over 30% of patients (pts) relapse post-treatment with a poor prognosis. Maintenance therapy post-response is promising for delaying disease progression and extending survival. The REMARC phase III trial showed that lenalidomide maintenance in pts responding to R-CHOP significantly improved progression-free survival but not overall survival (OS). Orelabrutinib, a novel highly selective Bruton's tyrosine kinase inhibitor, has shown encouraging efficacy and acceptable safety when combined with R-CHOP as first-line treatment in DLBCL. However, the clinical activity of orelabrutinib maintenance in DLBCL remains unclear. Thus, a retrospective study evaluated the efficacy and safety of orelabrutinib maintenance in pts with newly diagnosed DLBCL. Methods: Between Jan 2021, and Mar 2024, pts with newly diagnosed DLBCL from 10 centers who received at least 3 months of maintenance therapy with orelabrutinib (150 mg/day) were included in this retrospective study. Pts achieving complete response (CR) or partial response at the end of 6 or 8 cycles of induction therapy with R-CHOP-like, chemo-free, or methotrexate (MTX)-containing regimens were eligible for maintenance therapy. The primary endpoint was the event-free survival (EFS). Secondary endpoints included objective response rate (ORR), CR rate (CRR), OS, and safety. Results: Fifty-one pts were included, with a median age of 61.0 years (range, 48.0-72.0). Of the 51 pts, 42 were identified with DLBCL not otherwise specified (DLBCL-NOS), 7 with CNSL-DLBCL, and 2 with Richter transformation (RT)-DLBCL (1 follicular lymphoma; 1 small lymphocytic lymphoma). The majority of pts were male (26/51, 51.0%), had Ann Arbor Stage III/IV disease (33/51, 64.7%), an ECOG performance status of 0-1 (44/51, 88.0%), and an IPI score of 0-3 (31/51, 60.8%). Thirty-one (60.8%) pts presented with extranodal involvement, with genitourinary system being the most frequent extranodal site (21.6%), followed by gastrointestinal tract (19.6%), abdomen (17.6%), CNS (13.7%), and head and neck (13.7%). Nine (28.1%) pts showed MYC/BCL2 double expression and 2 (7.4%) were identified with double/triple-hit DLBCL. Before maintenance therapy with orelabrutinib monotherapy (46/51, 90.2%) or combination therapy (5/51, 9.8%), 39 (76.5%) pts had received induction therapy with R-CHOP-like regimens, 7 with chemo-free regimens, and 5 (9.8%) with MTX-containing regimens. With a median follow-up of 17.8 months (range, 7.6-53.3), the median duration of orelabrutinib maintenance was 10.2 months (range, 3.6-35.6). The ORR, CRR, 24-month EFS, and 24-month OS of overall population were 98.0% (95% CI, 89.6-100.0), 70.6% (95% CI, 56.2-82.5), 82.6% (95% CI, 68.4-99.7), and 96.6% (95% CI, 90.1-100.0), respectively. For pts with DLBCL-NOS, the ORR, CRR, 24-month EFS, and 24-month OS were 97.6%, 71.4%, 79.0%, and 96.0%, respectively; one pts achieved a conversion from PR to CR during maintenance therapy. Four (57.1%) pts with CNSL-DLBCL achieved CR, with ORR, 24-month EFS, and 24-month OS of 100.0%. Besides, the ORR, CRR, 24-month EFS, and 24-month OS for patients with RT-DLBCL were 100.0%. Grade 3-4 adverse events were reported in 41.2% of pts, with thrombocytopenia (17.6%), neutropenia (17.6%), and lymphocytopenia (11.8%) commonly reported. One patient died due to COVID-19 infection. Conclusions:Maintenance therapy with orelabrutinib was effective and well-tolerated in pts with newly diagnosed DLBCL after receiving R-CHOP-like, chemo-free, or methotrexate-based regimens as induction therapy. These findings support orelabrutinib as a potential maintenance treatment option for newly diagnosed DLBCL.