This study is designed as an open-label, prospective, single-arm, single-center trial aimed at evaluating the efficacy and safety of MTX or Thiotepa combined with Orelabrutinib and standard chemotherapy regimens in the treatment of DLBCL patients with central nervous system involvement.

Inclusion Criteria:

• Fully understand the study and voluntarily sign the informed consent form.

• Age: 14-80 years.

• Expected survival of more than 3 months, as determined by the investigator.

• Pathologically or cytologically confirmed diffuse large B-cell lymphoma (DLBCL) of B-cell origin through pathology or flow cytometry.

• Central nervous system (CNS) involvement, confirmed by at least one of the following:

  1. Symptoms related to CNS involvement.
  2. Abnormal findings on imaging.
  3. Pathological evidence (positive cerebrospinal fluid cytology, positive brain lesion biopsy or positive cerebrospinal fluid ctDNA).

• Any non-hematologic toxicity related to prior treatments must have resolved to Grade 1 or normal levels (per NCI CTCAE Version 5.0), except for alopecia.

• Bone marrow and organ function must meet the following criteria (without blood transfusion, G-CSF administration, or pharmacological correction within 14 days prior to screening):

Bone marrow function:

1)Absolute neutrophil count (ANC) ≥ 1.0 × 10⁹/L. 2)Platelet count ≥ 50 × 10⁹/L. 3)Hemoglobin ≥ 60 g/L.

• Liver function:

  1. Total bilirubin ≤ 1.5 × ULN (≤ 3.0 × ULN if liver metastasis is present).
  2. AST and ALT ≤ 2.5 × ULN (≤ 5.0 × ULN if liver metastasis is present).

• Coagulation function:

International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN.

• Renal function: Serum creatinine ≤ 1.5 × ULN or estimated creatinine clearance rate ≥ 30 mL/min (calculated using the Cockcroft-Gault formula): Male: Cr (mL/min) = (140 - age) × weight (kg) / [72 × serum creatinine (mg/dL)]. Female: Cr (mL/min) = (140 - age) × weight (kg) / [85 × serum creatinine (mg/dL)].

• Women of childbearing potential (WOCBP) and men with reproductive potential must agree to use effective contraception during the study and for 3 months after discontinuing treatment.
• Good compliance, with willingness to adhere to visit schedules, dosing regimens, laboratory tests, and other study procedures.-

Exclusion Criteria:

• Contraindications to any of the drugs included in the treatment regimen.
• History of active liver disease, including viral or other hepatitis or liver cirrhosis (Hepatitis B is defined as HBV-DNA exceeding the upper limit of normal; active Hepatitis C is defined as seropositive for HCV antibodies, but patients with HCV-RNA negative results can be included).
• Human immunodeficiency virus (HIV) infection.
• Congestive heart failure classified as greater than NYHA Class II by the New York Heart Association; history of acute myocardial infarction, unstable angina, stroke, or transient ischemic attack within the past six months.
• Congenital long QT syndrome or QTc > 480 ms (Note: QTc must be calculated using Friederica's formula: QTcF = QT / (RR)^0.33).
• Pregnant or breastfeeding women, or those planning to become pregnant during the study.
• History of confirmed neurological or psychiatric disorders, or a history of substance abuse or drug addiction.