This is a prospective, multicenter, real-world study to evaluate the efficacy and safety of pirtobrutinib in patients with mature B-cell lymphoma who are resistant or intolerant to prior covalent BTK inhibitors. The primary endpoint is overall response rate (ORR). Secondary endpoints include best overall response (BOR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. A total of 40 patients will be enrolled across 8 centers in China.

This prospective, multicenter, observational real-world study enrolls 40 patients with histologically confirmed mature B-cell lymphoma who have failed or are intolerant to at least one covalent BTK inhibitor. Patients receive pirtobrutinib 200 mg once daily until disease progression or unacceptable toxicity. Efficacy is assessed per Lugano 2014, iwCLL 2018, and IWWM-11 criteria. Safety is evaluated using CTCAE v5.0. The primary outcome is ORR. Secondary outcomes include BOR, DOR, PFS, OS, and safety profile.

Inclusion Criteria:

• Age ≥18 years;
• Histopathological confirmation of mature B-cell lymphoma, primarily including CLL/SLL, MCL, FL, MZL, WM/LPL, etc.;
• Disease progression and/or intolerance after prior treatment with ≥1 cBTKi (including ibrutinib, ibrutinib, zanubrutinib, or acitinib);
• ECOG PS 0-2;
• Adequate liver and kidney function: the following criteria must be met simultaneously: 1) AST and ALT ≤ 3×ULN; 2) Total bilirubin ≤ 1.5×ULN; 3) Creatinine clearance rate ≥ 30 mL/min;
• Participants must be voluntary and capable of completing the study procedures and follow-up examinations;
• Informed consent must be obtained voluntarily prior to screening.

Exclusion Criteria:

• Patients with known allergic reactions to any component or excipient of piteutinib;
• Patients concurrently participating in other clinical studies;
• A history of clinically significant, uncontrolled cardiac,
• Cardiovascular disease, or myocardial infarction within 6 months prior to planned initiation of piteutinib therapy;
• Uncontrolled systemic bacterial, viral, fungal, or parasitic infections; current use of potent CYP3A4 inhibitors or inducers and/or potent P-gp inhibitors;
• Positive human immunodeficiency virus (HIV) testing;
• Active hepatitis B or C: 1) Patients with positive hepatitis B virus (HBV) DNA testing and controlled disease status may be enrolled with investigator approval. For HBV DNA-positive patients, concurrent antiviral therapy is required. 2) Patients with prior hepatitis C virus (HCV) infection history who have completed antiviral therapy with viral loads below the quantitative limit may be enrolled;
• Based on the investigator's assessment, participants may be unable to complete all study protocol requirements, including follow-up visits, and/or adhere to all study procedures;
• A history of other clinically significant diseases or comorbidities; and any safety risks or potential interference with study completion as evaluated by investigators.

This study enrolls 40 adult patients (≥18 years old) with histologically confirmed mature B-cell lymphoma who are resistant or intolerant to at least one prior covalent BTK inhibitor (cBTKi) therapy, across 8 clinical centers in China.