Single-Arm, Multicenter, Prospective Phase II Clinical Study of Rituximab Combined With Pirtobrutinib, Lisaftoclax and Liposomal Mitoxantrone for Richter Syndrome Transformed From Chronic Lymphocytic Leukemia

This single-arm, multicenter, open-label phase II trial evaluates the efficacy and safety of rituximab + pirtobrutinib + lisaftoclax + liposomal mitoxantrone in adults with CLL-transformed Richter syndrome (CLL-RS)。It is a innovative four-drug regimen combining rituximab, pirtobrutinib, lisaftoclax and liposomal mitoxantrone was designed, exerting synergistic anti-tumor effects through four distinct mechanisms: pirtobrutinib, a reversible non-covalent BTK inhibitor, overcomes BTK C481S-mediated drug resistance; lisaftoclax, a novel domestically developed BCL2 inhibitor, induces robust apoptosis independent of TP53 mutation status while carrying a lower risk of tumor lysis syndrome (TLS); liposomal mitoxantrone with low cardiac toxicity compensates for the insufficient cytotoxicity of targeted agents against highly proliferative tumor cells; and rituximab, an anti-CD20 monoclonal antibody, mediates dual immunological tumor killing. The entire study is divided into three phases: screening, treatment and follow-up. During the screening phase, a full set of baseline assessments must be completed within 30 days prior to enrollment, including pathological reconfirmation, IgHV clonal homology analysis, PET/CT scanning, bone marrow biopsy, organ function testing and TLS risk stratification. The treatment phase consists of four 21-day induction cycles with the following administration schedule: rituximab 375 mg/m² is intravenously infused on Day 0 of each cycle; pirtobrutinib 200 mg is orally administered once daily from Day 1 to Day 21; lisaftoclax is given via a stepwise dose ramp-up from 20 mg to 600 mg, followed by a daily maintenance dose of 600 mg; liposomal mitoxantrone 18 mg/m² is intravenously infused on Day 1 of each cycle. After completion of four induction cycles, subsequent therapeutic strategies are stratified by treatment response. Patients achieving complete response (CR) or partial response (PR) are prioritized for allogeneic hematopoietic stem cell transplantation (allo-HSCT); those ineligible for transplantation may receive sequential CAR-T cell therapy targeting CD19/BAFF-R. Patients unable to receive the above consolidation therapies will undergo two additional cycles of the four-drug regimen for consolidation, followed by one year of maintenance therapy with pirtobrutinib plus lisaftoclax. Patients with stable disease (SD) or progressive disease (PD) will switch to alternative anti-tumor regimens or receive palliative symptomatic treatment. Long-term follow-up is initiated upon treatment discontinuation until the end of the study period. Clear enrollment, exclusion, withdrawal and elimination criteria are predefined for this trial. Eligible patients must be aged ≥18 years, have an ECOG performance status score of 0-2, an estimated survival of more than 3 months, adequate function of all major organs, the ability to take oral medications, and full compliance with scheduled follow-up visits. Excluded subjects include those with transformation to non-DLBCL subtypes, non-CLL clonally unrelated lesions, central nervous system lymphoma involvement, prior exposure to pirtobrutinib/lisaftoclax, previous CAR-T therapy or allo-HSCT, uncontrolled severe active infection, severe cardiovascular and cerebrovascular diseases or bleeding history, concurrent requirement for strong CYP3A4/5 inhibitors or warfarin, pregnancy or lactation, hypersensitivity to any study drug, and cognitive or psychiatric disorders precluding study compliance. Subjects will be withdrawn from the trial if they experience disease progression after receiving at least two cycles of treatment, develop intolerable toxicities, voluntarily discontinue participation, or have an unplanned pregnancy. Subjects will be eliminated from analysis if they violate enrollment criteria, receive no study drug administration, lack valid evaluable laboratory data, or concurrently receive other anti-tumor agents. The primary efficacy endpoint of this study is the complete remission rate following four cycles of induction therapy, while secondary efficacy endpoints include best overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and bone marrow minimal residual disease (MRD) negative rate upon completion of four treatment cycles.