Thiotepa in Combination With Pirtobrutinib (a BTK Inhibitor) and Sintilimab (a PD-1 Inhibitor) for Frail or Relapsed/Refractory Primary or Secondary Central Nervous System Lymphoma

Inclusion Criteria:

1. Histopathologically confirmed relapsed primary central nervous system lymphoma (PCNSL) of B-cell lineage, or secondary central nervous system lymphoma (SCNSL) with a previously confirmed B-cell origin primary lesion but without evidence of active extracranial systemic involvement.
2. The patients or their legal guardians provide voluntary written informed consent.
3. Age\>=18 years, both male and female.
4. Karnofsky Performance Status (KPS) score\>=40.
5. Patients deemed unsuitable for methotrexate (MTX)-based systemic chemotherapy ("unfit"), including but not limited to: patients assessed as unsuitable for chemotherapy or frail according to a simplified Geriatric Assessment (sGA) criteria; patients with contraindications to MTX (e.g., renal insufficiency, serous cavity effusions, oral mucositis, etc.); or patients who refuse high-dose methotrexate (HD-MTX) chemotherapy.
6. Life expectancy of greater than 3 months, as judged by the investigator.
7. Patients with parenchymal lesions (\>10\*10mm ) on contrast-enhanced cranial MRI or those with leptomeningeal disease only, require cytological examination of cerebrospinal fluid (CSF) to confirm the presence of lymphoma cells and/or imaging findings consistent with CSF results. These assessments must be completed within 14 days prior to enrollment.
8. If the patients have received prior anti-tumor therapy, all treatment-related non-hematologic toxicities must have recovered to Grade 1 or baseline (according to NCI CTCAE version 5.0, with the exception of alopecia).
9. Bone marrow and organ function must meet the following criteria (without transfusion, G-CSF support, or corrective therapy within 14 days prior to informed consent):

   1. Hematological: Absolute neutrophil count (ANC) \>=1.5\*10\^9/L (1500/mm\^3), platelets \>=75\*10\^9/L, hemoglobin\>=8 g/dL (If bone marrow is involved, then platelets\>=50\*10\^9/L, ANC \>=1.0\*10\^9/L, and hemoglobin\>=7 g/dL are acceptable).
   2. Hepatic: Total bilirubin \<=1.5 × upper limit of normal (ULN); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \<=2.5 × ULN.
   3. Renal: Serum creatinine \<=1.5 × ULN or estimated creatinine clearance \>=60 mL/min.
   4. Coagulation: INR \<=1.5 × ULN; PT and APTT \<=1.5 × ULN (unless the subject is receiving anticoagulant therapy and, at screening, PT and APTT are within the anticipated therapeutic range for the anticoagulant regimen).
10. For the subjects of reproductive age women and fertile men, during the entire study period and within 3 months after the interruption of treatment, they must not have any conception plans with their partners. During the entire study period and within 3 months after the interruption of treatment, one of the following measures must be taken for effective contraception: abstinence, physical contraception (such as sterilization or condoms), and the use of hormonal contraceptive drugs (w hich must start at least 3 months before the first administration upon enrollment). For male subjects, sperm donation is prohibited from the start of treatment until 3 months after the cessation of treatment.
11. Willingness and ability to undergo multiple MRI/CT scans and an expected ability to undergo lumbar puncture.

Ability to swallow oral medication without difficulty.

Exclusion Criteria:

1. The patients with secondary central nervous system lymphoma (SCNSL) who have lesions outside the CNS and require systemic treatment.
2. Received chemotherapy, radiotherapy, immunotherapy or antibody-based treatments for anti-tumor purposes within 4 weeks prior to the first administration (or within 5 half-lives), those who had used small molecule targeted drugs or traditional Chinese medicine with anti-tumor indications within 2 weeks, and those who had received monoclonal antibody conjugate drug treatments within 10 weeks.
3. Receipt of any vaccine (including but not limited to vaccines for COVID-19, influenza, pneumonia, shingles, hepatitis B, etc.) within 4 weeks before taking the medicine for the first time.
4. Concurrent enrollment in another interventional clinical study, or less than 4 weeks between the last dose of prior clinical trial treatment and the first dose in this study.
5. Previous treatment with thiotepa, PD-1 inhibitors, or BTK inhibitors is not excluded by default but requires benefit-risk assessment by the investigator. Subjects with a history of Grade \>=3 immune-related adverse events (per NCI CTCAE v5.0) attributed to these agents are excluded.
6. History of active bleeding within 4 weeks before the first dose; need for therapeutic anticoagulation during the study (e.g., warfarin or vitamin K antagonists); or any condition associated with elevated bleeding risk or coagulopathy per investigator judgment (e.g., high-risk esophageal varices, active ulcer disease).
7. Treatment with moderate or strong CYP3A4/5 inhibitors or inducers is required within 2 weeks before the first administration or during the study period.
8. Concurrent presence of other malignant tumors requiring antineoplastic treatment.
9. Having uncontrolled or significant cardiovascular diseases, including (but not limited to):

   1. Any of the following conditions occurring within 6 months before the first administration: congestive heart failure with New York Heart Association class \>= 3, myocardial infarction, unstable angina pectoris, arrhythmia requiring treatment at screening, or left ventricular ejection fraction (LVEF) \< 50%;
   2. Primary cardiomyopathy (e.g., dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, unclassified cardiomyopathy);
   3. A history of clinically significant QTc interval prolongation, second-degree type II atrioventricular block, third-degree atrioventricular block, or a QTc interval \> 470ms (for females) and \> 450ms (for males);
   4. Atrial fibrillation (EHRA class\>= 2b);
   5. Poorly controlled hypertension, which is deemed unsuitable for study participation by the investigator.
10. Active uncontrolled infection requiring intravenous antimicrobial treatment.
11. Patients with active chronic hepatitis B, active chronic hepatitis C, or syphilis. Patients who test positive for hepatitis B surface antigen or hepatitis C virus antibody during the screening period must undergo further tests for HBV DNA titer (which must not exceed 1000 IU/ml) and HCV RNA (which must not exceed the lower detection limit of the assay) before being eligible for enrollment in the trial. Hepatitis B virus carriers, patients with hepatitis B stabilized after drug treatment, and patients with cured hepatitis C may be enrolled.
12. Patients with a known history of HIV infection and/or AIDS.
13. Clinically significant gastrointestinal abnormalities that may affect drug intake, transport, or absorption (e.g., inability to swallow, chronic diarrhea, intestinal obstruction), or total gastrectomy.
14. Autologous transplantation within 3 months, or organ or allogeneic stem cell transplantation within 6 months, before signing the informed consent form.
15. Pregnancy or lactation.
16. Stroke or intracranial hemorrhage within 6 months before first dosing, excluding post-surgical sequelae of intracranial bleeding.
17. History or current presence of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, or similar conditions, deemed by the researcher as rendering the subject unsuitable for participation in the trial.
18. Participants whom the investigator considers unsuitable for the study due to existing kidney, nerve/mental, liver, or endocrine diseases, or for any other reason judged by the researcher.
19. Exclude patients with active autoimmune disease or a history of it, including but not limited to: immune-related neurologic disorders, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barré syndrome, myasthenia gravis, SLE, connective-tissue disease, scleroderma, inflammatory bowel disease (Crohn's or ulcerative colitis), hepatitis, TEN, Stevens-Johnson syndrome, antiphospholipid syndrome.

    Note: allow subjects with vitiligo, eczema, type 1 diabetes, or endocrine disorders (e.g., thyroiditis on physiologic steroid replacement). Subjects with rheumatoid arthritis/other arthropathies, Sjögren's syndrome, controlled celiac disease, or psoriasis treated only topically, and those seropositive (ANA, anti-thyroid antibodies, etc.) must be assessed for target-organ involvement and need for systemic therapy; if neither is present, they may be enrolled.
20. Major surgery within 28 days prior to the first study dose, as determined by the investigator.