IT-TT as an Effective and Well-Tolerated Strategy for CNS Prop in High-Risk DLBCL: a Prospective Ph II Study

Inclusion criteria

• Voluntary participation in the clinical study: full understanding of the study, provision of written informed consent, willingness and ability to comply with all study procedures.
• Age ≥ 18 years, male or female.
• Histopathologically confirmed high-grade B-cell lymphoma, including:

diffuse large B-cell lymphoma (DLBCL), NOS; T-cell/histiocyte-rich large B-cell lymphoma; EBV-positive DLBCL, NOS; primary mediastinal large B-cell lymphoma; ALK-positive large B-cell lymphoma; high-grade B-cell lymphoma, NOS; high-grade B-cell lymphoma with MYC, BCL2 and/or BCL6 rearrangements.

• No prior anti-tumor therapy including chemotherapy, radiotherapy, immunotherapy, or other anti-lymphoma treatments.
• Intermediate or high risk of central nervous system (CNS) involvement (meeting any one of the following):

• Primary breast lymphoma or primary testicular lymphoma;
• Involvement of any of the following sites: testis, breast, kidney, adrenal gland, paranasal sinus, epidural space, uterus;
• CNS-IPI score ≥ 4;
• Double-protein expression of MYC (≥40% positive) and BCL2 (≥50% positive);
• Gene rearrangements of MYC, BCL2 and/or BCL6.
• ECOG performance status ≤ 2.
• Life expectancy ≥ 3 months.
• No evidence of CNS involvement (no brain parenchymal lesions on MRI and no malignant cells in CSF).
• Adequate organ and bone marrow function without severe hematologic, cardiac, pulmonary, hepatic, renal dysfunction or immunodeficiency:

• Hematology: absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L, platelet ≥ 75 × 10⁹/L, hemoglobin ≥ 9.0 g/dL.

If bone marrow is involved: platelet ≥ 50 × 10⁹/L, ANC ≥ 1.0 × 10⁹/L, hemoglobin ≥ 8.0 g/dL.

• Hepatic function: serum bilirubin ≤ 1.5 × upper limit of normal (ULN); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 1.5 × ULN (≤ 5 × ULN if liver involvement).
• Renal function: serum creatinine ≤ 1.5 × ULN.
• Coagulation: INR ≤ 1.5 × ULN; PT and APTT ≤ 1.5 × ULN (unless on therapeutic anticoagulation with values within expected range).
• Negative serum pregnancy test for females of childbearing potential. Effective contraception required from informed consent until 6 months after the last chemotherapy.
• Negative ophthalmologic evaluation, including dilated fundoscopy, slit-lamp examination, and color fundus photography.

Exclusion criteria

• History of other malignancy within the past 5 years.
• Burkitt lymphoma, primary central nervous system lymphoma, or B-cell lymphoma transformed from indolent lymphoma.
• Existing brain parenchymal or meningeal lymphoma involvement.
• Patients who have received any form of CNS prophylaxis.
• Patients who have received whole-brain radiotherapy or craniospinal irradiation.
• Patients with obstructive hydrocephalus requiring neurosurgical intervention.
• Presence of any of the following known infections or conditions:

• Active meningeal infection
• Known human immunodeficiency virus (HIV) infection
• Active tuberculosis
• Active autoimmune disease
• Interstitial lung disease or infectious pneumonia
• Patients whose underlying conditions, in the investigator's judgment, may increase the risk associated with study drug treatment or confound the evaluation of adverse reactions.