Orelabrutinib plus R‐ CHOP in patients with newly diagnosed non‐ GCB double‐expressor DLBCL : A single‐arm, phase II study

Summary Double‐expressor diffuse large B‐cell lymphoma (DE‐DLBCL) patients, defined by co‐expression of MYC proto‐oncogene protein (≥40%) and B‐cell lymphoma 2 protein (≥50%), typically have poor outcomes with the traditional first‐line R‐CHOP regimen. We conducted a multicentre, single‐arm, phase II study to evaluate the efficacy and safety of first‐line orelabrutinib plus R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), designated O‐RCHOP, in patients with non‐germinal centre B‐cell‐like (non‐GCB) DE‐DLBCL. From 19 November 2021 to 6 February 2025, 49 patients were enrolled. With a median follow‐up of 26.6 months, median event‐free survival (EFS), progression‐free survival (PFS) and overall survival (OS) were not reached, and the estimated 2‐year EFS, PFS and OS rates were 82.0% (95% confidence intervals [CIs]: 71.2%–94.3%), 82.0% (95% CI: 71.2%–94.3%) and 97.9% (95% CI: 94.0%–100.0%) respectively. At the end of treatment, the complete response rate was 89.8% (44/49; 95% CI: 77.8%–96.6%), and the objective response rate was 95.9% (47/49; 95% CI: 86.0%–99.5%). Grade ≥3 adverse events (AEs) occurred in 51.0% of patients, with neutropenia (38.8%) being the most common. No patients died because of AEs. Genetic alteration profiling revealed that the frequently mutated genes were Pim‐1 proto‐oncogene, serine/threonine kinase ( PIM1 ; 63.6%), MYD88 innate immune signal transduction adaptor ( MYD88 ; (51.5%) and CD79b molecule ( CD79B ; 48.5%). O‐RCHOP achieved encouraging efficacy with a manageable safety profile in newly diagnosed DE‐DLBCL, supporting its feasibility as a first‐line regimen.