Pirtobrutinib+Sonrotoclax（PS) Regimen in the Treatment of B-Cell Lymphoma

This prospective, open-label, Phase II clinical trial evaluates the efficacy and safety of pirtobrutinib combined with sotoclax across three distinct B-cell lymphoma cohorts: histologically transformed diffuse large B-cell lymphoma (DLBCL), relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and relapsed/refractory marginal zone lymphoma (MZL). Dosing regimen ：pirtobrutinib 200 mg orally once daily plus sotoclax with a 4-week dose escalation schedule (1, 2, 5, 10, 20, 40, 80, 160 mg/day, then 320 mg/day on days 1-28, starting Cycle 2) administered orally. Cohorts 1 and 2 additionally incorporate obinutuzumab 1000 mg intravenously on Cycle 1 days 1, 8, and 15, followed by days 1 of Cycles 2 through 6, with a maximum of six cycles. Each treatment cycle spans 28 days. For Cohort 1 (RT DLBCL), the primary objective centers on early response assessment following three cycles of the PSO regimen (pirtobrutinib-sotoclax-obinutuzumab), with PET/CT evaluation serving as the critical decision point. Patients demonstrating progressive disease or stable disease discontinue study treatment, while those achieving complete or partial response may proceed to investigator-selected bridging therapies including bispecific antibodies, CAR-T cell therapy, or hematopoietic stem cell transplantation, or alternatively continue PSO combination therapy. Obinutuzumab is capped at six cycles, whereas pirtobrutinib and sotoclax may continue for up to 25 cycles. Comprehensive biomarker strategies include ctDNA analysis from peripheral blood at baseline and after Cycle 1 (following full-dose sotoclax exposure), with serial assessments at Cycles 3, 7, 14, and every six cycles during Year 2 for patients continuing PSO beyond Cycle 3. Patients with measurable baseline tumor cells in peripheral blood or bone marrow undergo flow cytometry-based MRD detection at 10-⁴ sensitivity at corresponding timepoints. T-cell subset and functional analyses are performed at baseli