Orelabrutinib Combined With Obinutuzumab and Short-Course Venetoclax in Patients With Treatment-Naïve Mantle Cell Lymphoma (MCL)

MCL is difficult to cure, and the conventional treatment paradigm comprises a three-phase strategy: induction therapy based on intermediate- or high-dose cytarabine, consolidation with autologous stem cell transplantation (ASCT), and maintenance therapy with anti-CD20 monoclonal antibodies. Although this approach can yield long-term efficacy in young patients with MCL, it has notable limitations: it is less effective in patients with high-risk features such as a high Ki-67 index, TP53 mutations, or blastoid morphology, and elderly patients or those unfit for ASCT often cannot tolerate such intensive therapy. Studies such as WINDOW-2 and BOVen have demonstrated that chemotherapy-free regimens combining a BTK inhibitor (BTKi), a BCL-2 inhibitor (BCL-2i), and an anti-CD20 monoclonal antibody are not limited by age and are equally effective in high-risk patients, making them a promising area of exploration for induction therapy in treatment-naïve MCL. However, the OASIS series of trials suggested that while the triplet regimen shows substantial efficacy and deeper responses in treatment-naïve MCL, it is also associated with a marked increase in adverse events (AEs). The safety concerns of triplet therapy should not be overlooked, and there is a need to explore novel therapeutic strategies that maintain efficacy while reducing the myelosuppression and treatment discontinuation rates associated with the addition of venetoclax. This study aims to evaluate the safety and efficacy of orelabrutinib (O) in combination with obinutuzumab (G) and short-course venetoclax (V) in patients with treatment-naïve MCL. The induction phase consists of 6 cycles, in which venetoclax is introduced with dose ramp-up in Cycle 2 and subsequently administered for 14 days per cycle (thereby shortening the per-cycle exposure duration of venetoclax). This is followed by a maintenance phase in which orelabrutinib, obinutuzumab, and short-course venetoclax are continued up to Cycle 24. The primary endpoints are the complete response (CR) rate at the end of induction and the minimal residual disease (MRD) negativity rate assessed by immunoglobulin next-generation sequencing (IG-NGS) of plasma circulating tumor DNA (ctDNA). Secondary endpoints include safety, progression-free survival (PFS), overall survival (OS), and the correlation between ctDNA MRD dynamics and clinical outcomes.