Background: Despite advances in novel therapies, high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT) has been an critical treatment option for selected patients with non-Hodgkin lymphoma (NHL). Although central nervous system (CNS) relapse is a relatively uncommon, it is associated with dismal survival outcomes. To date, there is no consensus on standardized CNS prophylaxis, as the effectiveness of high-dose methotrexate (MTX) or intrathecal MTX remains controversial. Thiotepa, a non–cell-cycle-specific alkylating agent, has high penetration across the blood–brain barrier and possesses a favorable safety profile, making it a promising candidate for CNS-directed conditioning. We investigated whether ASCT with thiotepa-based conditioning could help prevent CNS relapse. In this study, we evaluated the efficacy and safety of the TEAM regimen (thiotepa, etoposide, cytarabine, and melphalan) in ASCT for NHL patients at high risk for CNS involvement.

Methods: We retrospectively analyzed the clinical data of NHL patients at high-risk of CNS relapse who underwent ASCT with TEAM conditioning between January 1, 2021, and May 31, 2025. The main inclusion criteria were as follows: 1) age 18-65 years with aggressive lymphoma,; 2) ECOG performance status 0-1; 3) high risk of CNS relapse, defined by at least one of the following: a) CNS-IPI score of 4-6; b) double/triple-hit high-grade B-cell lymphoma (HGBL); c) involvements of high-risk extranodal sites, including testicular, breast, renal/adrenal, and uterine. The exclusion criteria were: 1) indolent lymphomas; 2) primary or secondary CNS lymphoma. 3) significant organ dysfunction, such as renal, liver, cardiac or respiratory failures. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included overall survival, relapse rate, engraftment kinetics, treatment-related toxicities and transplant-related mortality.

Results: A total of 37 patients (male 24, female 13) were included, with an median age of 54 (range, 20-63) years. The NHL histologic subtypes were diffuse large B-cell lymphoma (86.5%), ALK-positive anaplastic large cell lymphoma (5.4%), NK/T-cell lymphoma (5.4%), and ALK-negative ALCL (2.7%). Common extranodal sites associated with risk of CNS relapse included: peripheral nerve roots (8.1%), uterine (24.3%), mammary gland (5.4%), kidney/adrenal glands (28.9%), multifocal bone (16.2%), and testis (17.1%). At diagnosis, 63.8% were Ann Arbor stage IV, 21.1% stage III, and 15.1% stage I–II. At the time of ASCT, 67.6% were in complete response, 27.0% in partial response, and 5.4% had progressive disease. The median CD34+ cell dose infused was 4.38 × 10⁶/kg. Median time to neutrophil and platelet engraftment was 9 (range 8-11) and 10 (range 9-11) days, respectively. In terms of common toxicities, mucositis occurred in 66% of patients (Grade 1–2: 41%; Grade 3–4: 25%), and gastrointestinal toxicity was reported in 86% (Grade 1–2: 63%; Grade 3–4: 23%). There was no transplant-related death. The CR rate at 3 months post-ASCT was 86.5%. With a median follow-up of 753 (66-1032) days, the median PFS and OS were not reached, and the estimated 3-year PFS rate and OS rate were 90% and 94.6%, respectively.

Conclusion: ASCT with TEAM conditioning appears to be effective and well-tolerated in NHL patients at high-risk of CNS relapse. The potential clinical benefit of ASCT in this difficult-to-treat population warrants further validation in prospective studies.

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2025
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