In the era of novel therapeutic agents, high-dose conditioning chemotherapy combined with autologous hematopoietic stem cell transplantation (auto-HSCT) remains an important and feasible consolidation strategy for non-Hodgkin lymphoma, especially for high-risk and relapsed/refractory patients. It can effectively prolong progression-free survival and even overall survival in chemotherapy-sensitive lymphoma patients, and its application in domestic clinical practice has become increasingly widespread.

With long-term and extensive use of carmustine-based conditioning regimens, their limitations have become increasingly apparent: the drug is expensive and has limited accessibility. Early treatment-related toxicities include mucositis, nausea, vomiting, diarrhea, and hepatotoxicity. Late toxicities include reduced pulmonary diffusion capacity, chronic interstitial pulmonary fibrosis, metabolic syndrome, and cardiovascular complications, all of which have attracted increasing attention.

Thiotepa, a cell-cycle-nonspecific alkylating agent, not only inhibits DNA synthesis and kills tumor cells but also readily crosses the blood-brain barrier, has a short half-life and rapid metabolism, and its safety has been widely confirmed in clinical practice. It is an ideal agent for transplant conditioning.

In recent years, various thiotepa-based conditioning regimens have been used in auto-HSCT for different types of non-Hodgkin lymphoma, achieving favorable efficacy and safety profiles, and can partially replace the classic BEAM regimen.

Investigators at our center observed that among non-Hodgkin lymphoma patients eligible for auto-HSCT, some have involvement at special sites, such as the central nervous system, nerve roots inside or outside the spinal canal, reproductive organs (uterus, ovary, breast, testis), kidney/adrenal gland, and multiple extranodal sites (bone, colorectum), all of which confer a high risk of central nervous system recurrence. Meanwhile, the high cost of thiotepa limits its clinical use.

To benefit more patients with CNS-high-risk lymphoma, our center has adjusted the dosage of the existing TEAM regimen. In a 4-year retrospective study, 29 lymphoma patients with involvement at the above sites received modified TEAM conditioning chemotherapy followed by auto-HSCT. With a maximum follow-up of 3 years, 2 patients died of disease progression, 1 patient remained in stable condition after radiotherapy for relapse, and all other patients achieved long-term survival with stable disease.

Therefore, our center is applying to conduct a prospective study of this conditioning regimen to obtain more convincing clinical evidence, provide a stronger theoretical basis for auto-HSCT conditioning for more CNS-high-risk lymphoma patients, and explore a more effective, less toxic, and cost reasonable therapeutic strategy.

Inclusion Criteria:

1. Histopathologically confirmed systemic non-Hodgkin lymphoma at initial diagnosis and meets one of the following:

   1. CNS IPI score (4-6 points)
   2. kidney or adrenal gland involvement
   3. testis or breast involvement
   4. primary cutaneous DLBCL, leg type

2. CR or PR after induction therapy

3. Age 18-70 years.

4. Adequate renal, hepatic, pulmonary, hematologic, and cardiac function:

   • Creatinine clearance (Cockcroft-Gault) ≥ 50 mL/min / serum creatinine ≤ 1.5 mg/dL
   • ALT and AST < 2.5 × upper limit of normal (ULN)
   • Total bilirubin < 1.5 × ULN
   • Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L
   • Platelet count ≥ 100 × 10⁹/L
   • Left ventricular ejection fraction ≥ 50%; no clinically significant pericardial effusion or ECG abnormalities
   • No clinically significant pleural effusion
   • Baseline oxygen saturation ≥ 95% at rest on room air

5. Negative serum or urine pregnancy test for females of childbearing potential (females who have undergone sterilization or are postmenopausal for ≥ 2 years are considered non childbearing). All patients must practice effective contraception during study treatment.

6. Able to comply with the study protocol per investigator judgment.

7. Voluntary participation, understanding study procedures, and provision of written informed consent; For illiterate patients (potentially vulnerable population), a literate family member must be present and provide written consent.

Exclusion Criteria:

1. Diagnosis of primary central nervous system lymphoma (PCNSL).
2. Concurrent malignancy or life-threatening disease; or prior malignancy cured < 2 years.
3. Grade ≥ 2 mucositis.
4. Congestive heart failure, uncontrolled hypertension, or unstable cardiovascular disease.
5. Uncontrolled infection.
6. Uncontrolled progressive disease during the study.
7. Prior allogeneic hematopoietic stem cell transplantation.
8. Any condition that may interfere with safety or efficacy assessment.
9. Severe hypersensitivity to any study drug.
10. Pregnant or breastfeeding females.
11. Males or females unwilling to use contraception from consent signature until 6 months after completion of study treatment.
12. Unlikely to complete all required study visits/procedures (including follow up) per investigator judgment.