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

Intrathecal Thiotepa as an Effective and Well-tolerated Strategy for Central Nervous System (CNS) Prophylaxis in High-risk Diffuse Large B-cell Lymphoma (DLBCL): a Prospective Phase II Study

This is a prospective, single-arm clinical study to evaluate the efficacy and safety of intrathecal thiotepa for the prevention of central nervous system (CNS) involvement in patients with high-aggressive B-cell lymphoma.

A total of 32 subjects will be enrolled, and the study is planned to last for 2 years.

Outcomes including CNS recurrence rate, time to CNS involvement, progression-free survival (PFS), overall survival (OS), and safety parameters will be assessed during the study.

Inclusion Criteria:

1. 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.

2. Age ≥ 18 years, male or female.

3. 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.

4. No prior anti-tumor therapy including chemotherapy, radiotherapy, immunotherapy, or other anti-lymphoma treatments.

5. Intermediate or high risk of central nervous system (CNS) involvement (meeting any one of the following):

   1. Primary breast lymphoma or primary testicular lymphoma;
   2. Involvement of any of the following sites: testis, breast, kidney, adrenal gland, paranasal sinus, epidural space, uterus;
   3. CNS-IPI score ≥ 4;
   4. Double-protein expression of MYC (≥40% positive) and BCL2 (≥50% positive);
   5. Gene rearrangements of MYC, BCL2 and/or BCL6.

6. ECOG performance status ≤ 2.

7. Life expectancy ≥ 3 months.

8. No evidence of CNS involvement (no brain parenchymal lesions on MRI and no malignant cells in CSF).

9. Adequate organ and bone marrow function without severe hematologic, cardiac, pulmonary, hepatic, renal dysfunction or immunodeficiency:

   1. 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.

   2. 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).

   3. Renal function: serum creatinine ≤ 1.5 × ULN.

   4. Coagulation: INR ≤ 1.5 × ULN; PT and APTT ≤ 1.5 × ULN (unless on therapeutic anticoagulation with values within expected range).

10. Negative serum pregnancy test for females of childbearing potential. Effective contraception required from informed consent until 6 months after the last chemotherapy.

11. Negative ophthalmologic evaluation, including dilated fundoscopy, slit-lamp examination, and color fundus photography.

Exclusion Criteria:

1. History of other malignancy within the past 5 years.

2. Burkitt lymphoma, primary central nervous system lymphoma, or B-cell lymphoma transformed from indolent lymphoma.

3. Existing brain parenchymal or meningeal lymphoma involvement.

4. Patients who have received any form of CNS prophylaxis.

5. Patients who have received whole-brain radiotherapy or craniospinal irradiation.

6. Patients with obstructive hydrocephalus requiring neurosurgical intervention.

7. Presence of any of the following known infections or conditions:

   1. Active meningeal infection
   2. Known human immunodeficiency virus (HIV) infection
   3. Active tuberculosis
   4. Active autoimmune disease
   5. Interstitial lung disease or infectious pneumonia

8. 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.