Outcomes in patients with refractory/relapsed CNS lymphoma treated in complete remission：autologous transplantation vs. CAR-T therapy

Outcomes in patients with refractory/relapsed CNS lymphoma treated in complete remission：autologous transplantation vs. CAR-T therapy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Outcomes in patients with refractory/relapsed CNS lymphoma treated in complete remission：autologous transplantation vs. CAR-T therapy Fan Yang, Rui Liu, Zhonghua Fu, Yuelu Guo, Lixia Ma, Miaomiao Cao, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7350145/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Mar, 2026 Read the published version in Cancer Immunology, Immunotherapy → Version 1 posted 10 You are reading this latest preprint version Abstract Background Autologous hematopoietic cell transplantation (ASCT) is a reasonable approach as a consolidation therapy for fit patients with chemosensitive relapsed central nervous system lymphoma (CNSL) who have achieved complete remission (CR). Chimeric antigen receptor T-cell (CAR-T) therapy is an effective treatment option for patients with relapsed CNSL, although there is limited evidence regarding the outcomes of these patients in CR. Aim To compare the efficacy of ASCT versus CAR-T therapy in patients with relapsed CNSL during CR. Methods A retrospective observational study was conducted on patients who underwent ASCT or CAR-T therapy at the Department of Lymphoma, Beijing Gobroad Hospital between 2021 and 2024. The CAR-T therapy was part of the clinical trial “Different B-cell Target CAR-T cells for relapsed/refractory CNSL (ChiCTR2200058972)”. Results Sixty patients, including 42 (70%) with primary CNSL and 18 (30%) with diffuse large B-cell lymphoma (DLBCL) presenting secondary CNS involvement, were enrolled. The median follow-up duration was 12.1 months (1.28–59.9 months). Patients who received ASCT while in CR had superior progression-free survival (PFS) [3-year PFS 80% (95% CI: 48.4–93.4) vs. 64.8% (95% CI:38.9–81.9); P = 0.026] and a lower cumulative incidence of relapse/progression [3-year relapse rate 20% (95% CI: 4.12–44.39) vs. 30.2% (95% CI: 11.0-52.2); P = 0.038] compared to patients in the CAR-T group. Conclusion Compared to CAR-T therapy, ASCT was associated with improved PFS in patients with relapsed CNSL who had achieved CR. Clinical Trials Number: ChiCTR2200058972 Figures Figure 1 Figure 2 Figure 3 Figure 4 Key Points • This is the first study to compare the outcomes in chemosensitive relapsed/refractory (R/R) CNSL patients who underwent either ASCT or CAR-T therapy after achieving CR. • ASCT is associated with longer progression-free survival (PFS) and a lower incidence of relapse/progression in R/R CNSL patients compared to CAR-T therapy when the patients are in CR. The findings will have to be validated on larger cohorts. • Our findings provide preliminary evidence that could translate into clinical benefits for chemosensitive R/R CNSL patients. BACKGROUND Patients with refractory/relapsed central nervous system lymphoma (R/R CNSL) have poor prognosis, with overall survival (OS) duration of only 4–10 months [ 1 , 2 ]. Even if their effectiveness is disappointing with second-line therapies, for which new drugs such as Bruton's tyrosine kinase inhibitors (BTKi), lenalidomide and immune checkpoint inhibitors are available, some patients can achieve a complete remission (CR) [ 3 – 6 ]. R/R CNSL patients who received salvage therapy followed by intensive consolidation experienced longer survival compared to those who did not receive consolidation therapy [ 7 ]. High-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT) is a reasonable approach for fit patients with chemosensitive R/R CNSL and may be associated with better outcomes [ 8 – 10 ], especially for patients with primary CNSL (PCNSL) who did not opt for ASCT consolidation during the first remission phase due to poor physical condition, comorbidities or personal reasons. However, some patients cannot opt for ASCT as a consolidation therapy due to their state of health or lack of hematopoietic stem cells (HSCs). Chimeric antigen receptor T cell (CAR-T) therapy is an effective and relatively safe treatment option for R/R CNSL patients [ 11 – 14 ]. Recent studies have reported durable remissions in R/R CNSL patients who are sensitive to salvage therapy and receive consolidative CAR-T therapy while undergoing CR [ 15 ]. In this study, we retrospectively compared the outcomes of chemosensitive R/R CNSL patients who underwent either ASCT or CAR-T therapy after achieving CR. METHODS Study population Patients with a diagnosis of R/R CNSL who underwent ASCT or CAR-T therapy as part of a clinical trial (Clinical Trials Number: ChiCTR2200058972) at the Department of Lymphoma, Beijing Gobroad Hospital (See supplementary Material) between 2021 and 2024 while in CR, as indicated by MRI or PET scan and per the International PCNSL Collaborative Group Response Criteria and Lugano Criteria, were included in the study [ 14 – 16 ]. The patients achieved CR on at least two courses of second-line chemotherapy. Patients in the CAR-T group with a previous history of auto-HCT were excluded. Second-line chemotherapy The design of second-line chemotherapy have been provided in the Supplementary material. Procedures CAR-T therapy The patients who underwent CAR-T therapy had been enrolled in a clinical trial investigating the outcomes of B-cell-targeting CAR-T cells for non-Hodgkin's lymphoma with CNS involvement (Clinicaltrials.gov registry: ChiCTR2200058972). This study was approved by the Ethics Committee, and all patients provided signed informed consent. The full list of inclusion and exclusion criteria have been provided in the Supplementary material. B cell-specific CARs were constructed as previously described [ 16 , 17 ]. Prior to the treatment, patients received lymphodepleting chemotherapy comprising of cyclophosphamide (300mg/m 2 ) and fludarabine (30mg/m 2 ) to reduce the number of competing T cells. .(See supplementary material for detailed program) ASCT ASCT was performed as per the standard procedures of the hospital. The patients who had responded to chemotherapy were injected with granulocyte colony-stimulating factor (G-CSF) to mobilize the autologous HSCs prior to collection. The conditioning regimen consisted of TEAM and BEAM-based protocols. The procedure for ASCT has been described in detail in the supplementary material. Definitions Relapsed cases are defined as patients who achieved CR following treatment but later experienced recurrence in the CNS, spinal cord, or vitreoretinal areas. Refractory cases are defined as patients who do not respond to therapy and have never achieved CR. Therapeutic efficacy was assessed by positron emission tomography/computed tomography (PET/CT) and enhanced magnetic resonance imaging (MRI). The CSF was analyzed to determine tumor reduction and changes in MRD. Response was evaluated as per the International PCNSL Collaborative Group Response Criteria and Lugano Criteria [ 18 – 20 ]. The other definitions has been described in detail in the supplementary material. Statistical analysis Time-to-event estimates of OS and PFS were calculated by the Kaplan-Meier method, and the treatment groups were compared using the log-rank test. Multivariate analysis was performed using a Cox proportional-hazards model, and the Breslow approach was used to handle tied events. Competing-risk survival analysis was used to compute the non-parametric estimate of the cumulative relapse incidence function, and the differences between groups were analyzed using Gray’s test (1988). The baseline characteristics were summarized using descriptive statistics. The categorical variables were compared by Fischer’s test when more than 20% of the cells had expected frequencies < 5 or at least one cell had an expected frequency < 1; otherwise, Pearson Chi-squared test was used. Continuous variables were presented as medians [min, max] and compared using the Wilcoxon rank-sum test. Statistical analyses were performed using SAS software, version 9.4. RESULTS Baseline characteristics A total of 189 patients diagnosed with R/R CNSL were treated at our hospital between March 2021 and September 2024. This study included 60 patients who were diagnosed with R/R primary or secondary DLBCL with CNS involvement (42 PCNSL and 18 SCNSL). Thirty-three patients underwent ASCT and 27 patients received CAR-T therapy, all while in CR after the second line treatment (Fig. 1). The baseline characteristics of the patients have been summarized in Table 1. The ASCT group had a higher proportion of younger patients compared to the CAR-T group (median age 53 vs. 65 years; p = 0.001). On the other hand, the proportion of male patients (p = 0.428), disease pathology (p = 0.101), proportion of high-risk patients (p = 0.469), site of CNS involvement (p = 0.123), and proportion of patients with refractory disease (p = 0.469) were similar in both groups. Thirty-five patients were tested for mutations, and the median number of mutations in the ASCT group (range: 1–21) and CAR-T (range: 1–38) group was seven. Tp53 mutation was detected in 3/11 patients (27.3%) in the ASCT group and 5/24 patients (20.8%) in the CAR-T group. In addition, 10 patients (90.9%) in the ASCT group and 16 patients (66.7%) in the CAR-T group were positive for MYD88 and/or CD79b mutations. The type and number of mutations by next-generation sequencing (NGS) in both groups are described in detail in Supplementary Table. S1 and Supplementary Fig. S1 . Survival outcomes The median follow-up duration was 12.1 months (range: 1.28–59.9 months). The 3-year PFS and OS rates for the overall population were 71.5% (95% CI: 51.8–82.2) and 87.5% (95% CI: 65.2–92.5) respectively (Fig. 2A and 2B). Patients who received ASCT while in CR had superior PFS [3-year PFS 80% (95% CI: 48.4–93.4) vs. 64.8% (95% CI:38.9–81.9); P = 0.026] (Fig. 3A), and a lower cumulative incidence of relapse/progression [3-year relapse rate 20% (95% CI: 4.12–44.39) vs. 30.2% (95% CI: 11.0-52.2); P = 0.038] compared to patients in the CAR-T group (Fig. 3C). The 3-year OS for ASCT was 93.3% (95% CI: 61.3–99.0) compared to 80.1% (95% CI:49.4–93.3) in the CAR-T group (P = 0.115); Fig. 3B). Subgroup analyses Among patients with PCNSL who received ASCT (n = 26) or CAR-T (n = 16) in CR, the 2-year PFS was significantly higher in the ASCT group [92.9% (95% CI: 59.1–99.9) vs. 65.7% (95% CI: 31.0–86.0); p = 0.026]. Although the difference did not reach statistical significance, the 2-year OS was numerically higher in the ASCT group compared to that in the CAR-T group [91.7% (95% CI: 53.9–98.8) vs. 74.1% (95% CI: 28.9–93.0); p = 0.101] (Fig. 4A and 4B). Likewise, for patients with SCNSL who received ASCT (n = 7) or CAR-T (n = 11) in CR, the 2-year PFS was higher in the ASCT group [75% (95% CI: 12.8–96.1) vs. 64.9% (95% CI: 24.9–87.4); p = 0.409], and the 2-year OS was also numerically higher in the ASCT group [100% (95% CI: 100–100) vs. 87.5% (95% CI: 38.7–98.1)]. However, these differences were not statistically significant (Fig. 4C and 4D). Outcomes for patients with mutations All patients with detectable Tp53 or MYD88/CD79b mutations in the ASCT group survived. Among those with Tp53 mutations, one experienced disease progression and two achieved CR. In contrast, only one of the patients with MYD88/CD79b mutations showed disease progression and the remaining nine achieved CR. In the CAR-T group, all five patients with Tp53 mutations survived, with one experiencing disease progression and four maintaining CR. Among the 16 patients with MYD88/CD79b mutations, one died due to disease progression, two survived with tumor, and 13 maintained the CR (Table 2). Univariable and multivariable analysis The risk factors for PFS and OS were determined by univariable and multivariable analyses. In the univariate Cox regression model, the duration of the first remission period and ASCT/CAR-T therapy in CR were significantly correlated to PFS and OS (all P ≤ 0.15; Table 3A and 3B). The multivariate COX regression analysis showed that CAR-T therapy in CR was associated with inferior PFS [HR 5.744 (95%CI: 1.096–30.114, P = 0.0386] compared to ASCT. There was no significant difference in the OS between the ASCT and CAR-T groups (P = 0.2356; Table 3C). CAR-T cell kinetics The median number of infused CAR-T cells was 1.75×10 6 cells/kg (range: 0.16×10 6 cells/kg to 10×10 6 cells/kg). We observed a marked expansion CAR-T cells in the PB of 36/37 patients after infusion. The median peak number of CD19 + CAR-T cells was 7465 lentivirus copies/µg DNA (range: 1246–36107 lentivirus copies/µg DNA), and the median time to achieve peak levels was ten days (range: 6–28 days). The CSF of ten patients was tested after infusion, and CAR-T cells were detected in four of these patients. The peak number of CD19 + CAR-T cells was 2415 lentivirus copies/µg DNA (range: 81-2914 lentivirus copies/µg DNA) (Fig. 5A and 5B). Toxicity and causes of death The most common side effect was neutropenia [57 (95%)], followed by infection [34 (56.7%)] and hypogammaglobulinemia [28 (46.7%)] (Supplementary table S2 ). In the CAR-T group, six patients (22.3%) developed grade 1 CRS, and three (11.1%) developed grade 1–2 ICANS (Supplementary Table S3 ). The neurotoxicity-related symptoms were successfully treated with siltuximab and corticosteroids, with no recorded fatalities. One patient (3%) in the ASCT group and five patients (18.5%) in the CAR-T group died during the follow-up. The most common causes of death in both groups were related to disease progression (4/6,66.7%), followed by infections (2/6,33.3%). DISCUSSION We have shown for the first time that ASCT is associated with a longer PFS and a lower incidence of relapse/progression in R/R CNSL patients compared to CAR-T therapy when the patients are in CR. While the small sample size and the retrospective study design preclude definitive conclusions, our findings provide preliminary evidence that may translate to clinical benefits for chemosensitive R/R CNSL patients. The combination of HDC and ASCT is a viable treatment option for R/R CNSL patients who are sensitive to salvage chemotherapy, particularly those who achieve CR with salvage therapy [ 8 ]. A previous study reported median PFS/OS of 82 months in R/R PCNSL patients with CR or PR after induction therapy [ 21 ]. Furthermore, the 2-year disease-free survival (DFS) rate of SCNSL patients after ASCT is 39% [ 22 ]. A retrospective study evaluating the outcomes of ASCT in 17 patients with R/R CNS lymphoma (8 PCNSL and 9 SCNSL) showed that the patients achieved CR after salvage induction chemotherapy, along with 93% PFS and OS rates [ 1 ]. While ASCT is effective as a consolidation therapy, it is contraindicated for some patients. Whole brain radiation therapy (WBRT) is a feasible alternative for such cases, although it should be avoided as a standalone therapy, particularly in elderly populations, due to delayed neurotoxic effects [ 23 , 24 ]. CAR-T therapy has also been established as a safe and effective option for R/R CNSL [ 25 ]. In one study, ASCT was associated with improved clinical outcomes compared to CAR-T therapy in patients with relapsed LBCL who achieved a CR [ 11 ]. However, there is limited information on the efficacy of CAR-T consolidation therapy in R/R CNSL patients. To the best of our knowledge, our study is the first to compare the long-term outcomes of ASCT and CAR-T therapy in R/R CNSL patients in CR. Significant CAR T-cell expansion was detected in the PB and CSF of patients after infusion, indicating that these cells can migrate to the CSF regardless of the absence of systemic lymphoma or non-measurable disease. This is consistent with a previous study that reported expansion of Relmacabtagene autoleucel (relma-cel) CD19 + CAR-T cells in the CSF of eight R/R B cell lymphoma patients in CR [ 15 ]. Similar amplification of CAR-T cells was observed in the PB in our study. Six patients did not have any discernible CAR-T cells in the CSF, which may be attributed to the fact that the detection time point was 90 days after infusion. Nevertheless, the use of CAR-T cells as a consolidation treatment did not attain the same depth of remission as ASCT in R/R CNSL patients who are sensitive to salvage therapy and have achieved CR. While the exact mechanism underlying the absence of long-lasting responses remains to be elucidated, one potential explanation could be the rapid depletion of CAR-T cells in the CNS [ 13 ]. Some tumor-associated macrophages/microglia subsets can lead to antigen-specific T-cell dysfunction and the failure of CAR-T cell therapy [ 13 , 26 ]. On the other hand, Yu et al noted that patients with R/R CNSL who received relma-cel during CR achieved durable remission, and five patients remained progression-free for over 12 months. In their study, CAR-T therapy was more effective in eradicating chemo-refractory subclones at MRD levels compared to ASCT [ 15 ]. The lack of consistency in results may be attributed to the small sample size of only 8 patients and the short follow-up period. The application of CAR-T cells as consolidation therapy for R/R CNSL patients in CR can significantly extend their PFS and OS compared to that of patients who do not receive consolidation therapy. In a previous study, R/R CNSL patients who received salvage treatment without consolidation achieved median PFS of 2.6 months and median OS of 6.7 months [ 7 ]. We found that consolidative CAR-T therapy resulted in a median PFS of 27.7 months, while the median OS could not be determined as yet. Thus, consolidation therapy with CAR-T cells is safe and effective for R/R CNSL patients in CR who do not meet the criteria for autologous transplantation. Toxicity is a major concern of CAR-T therapy in patients with CNSL. In R/R CNSL patients infused with CAR T cells expressing the 41BB costimulatory domain, the incidence of ICANS of any grade is 33.3–44.4%, and that of grade 3 ICANS is 4.5–11.1% [ 15 , 25 , 27 ]. On the other hand, PCNSL patients usually have lower ICANS rates due to the lack of systemic disease burden and less systemic inflammation [ 25 ]. The incidence of ICANS was only 8.1% (grade 1–2) in our cohort, which may be related to the fact that all patients had achieved CR. In addition, four patients with CAR-T amplification in the CSF did not experience ICANS, indicating that CR period is safe for CAR-T consolidation therapy in R/R CNSL patients. Due to the small number of cases, it was not possible to analyze the correlation between TP53 or MYD88/CD79b mutation and the efficacy of consolidation therapy. Therefore, further studies with larger cohorts are needed to guide treatment selection on the basis of mutation data. The primary limitation of this study arises from its retrospective design. Furthermore, the choice of treatment regimen was usually influenced by factors such as age, availability of HSCs for transplantation, comorbidities, and the personal preferences of patients. ASCT consolidation significantly improved PFS compared to CAR-T consolidation in PCNSL patients who achieved CR. Although a comparable trend was observed in SCNSL patients, the difference did not reach statistical significance, possibly due to the limited sample size in this subgroup. A clinical trial with larger sample size and longer follow-up period could provide insights into the duration of response to ASCT and CAR-T therapy among these patients. CONCLUSION ASCT consolidation therapy remains an option for R/R CNSL patients who are sensitive to second-line chemotherapy and achieve CR. Nevertheless, CAR-T therapy as a consolidative approach appears to be a potentially viable option for R/R CNSL patients in CR who are not eligible for ASCT. Abbreviations CAR-T chimeric antigen receptor T-cell therapy R/R CNSL refractory/relapsed central nervous system lymphoma CR complete remission DLBCL diffuse large B-cell lymphoma PFS progression-free survival OS overall survival ASCT autologous transplantation PCNSL primary central nervous system lymphoma SCNSL secondary central nervous system lymphoma WBRT whole-brain radiotherapy ICANS immune effector cell-associated neurotoxicity syndrome CRS cytokine release syndrome PBMNCs peripheral blood mononuclear cells RT-qPCR real-time quantitative polymerase chain reaction PET/CT positron emission tomography/computed tomography MRI magnetic resonance imaging Declarations Author contributions Conception and design: Kai Hu. Manuscript writing: Fan Yang. Data acquisition: Yuelu Guo, Lixia Ma, Miaomiao Cao, Biping Deng, Xiaoyan Ke Collection and assembly of data: Rui Liu and Zhonghua Fu. Data analysis: Haifeng Wu and Chen chen. Interpretation: All authors. Final approval of manuscript: All authors. All authors provided critical and insightful comments. Ethics approval and consent to participate Approval of the research protocol by an Institutional Reviewer Board. The study was approved by the Ethics Committee at the Beijing Gobroad Hospital in Beijing Informed Consent. The study adheres to the Declaration of Helsinki. Written informed consent was obtained in accordance with the Declaration of Helsinki from each patient. The Registration No. of the study/trial: ChiCTR2200058972.Registration Date:2022/2/21. Availability of data and materials All the data and materials are included in the manuscript and supplemental materials. The detailed and original data can be accessed by contacting the corresponding author’s email. Acknowledgements We would like to express our gratitude to Shanghai YaKe Biotechnology Ltd., Shanghai, China, and all the medical staff and patients who participated in this study. Funding None. Consent for publication Not applicable. Conflicts of interest The authors confirm that there are no conflicts of interest. References Welch, M.R., et al., Autologous stem cell transplant in recurrent or refractory primary or secondary central nervous system lymphoma using thiotepa, busulfan and cyclophosphamide. Leuk Lymphoma, 2015. 56 (2): p. 361-7. Grommes, C., Central Nervous System Lymphomas. Continuum (Minneap Minn), 2020. 26 (6): p. 1476-1494. Houillier, C., et al., Lenalidomide monotherapy as salvage treatment for recurrent primary CNS lymphoma. Neurology, 2015. 84 (3): p. 325-6. Yang, C., et al., Orelabrutinib Combined With Lenalidomide and Immunochemotherapy for Relapsed/Refractory Primary Central Nervous System Lymphoma: A Retrospective Analysis of Case Series. Front Oncol, 2022. 12 : p. 901797. Lin, Z., et al., Zanubrutinib plus Cytarabine in Patients with Refractory/Relapsed Primary Central Nervous System Lymphoma. Acta Haematol, 2024. 147 (5): p. 555-563. 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Seidel, S., et al., High-Dose Chemotherapy with Autologous Hematopoietic Stem Cell Transplantation in Relapsed or Refractory Primary CNS Lymphoma: A Retrospective Monocentric Analysis of Long-Term Outcome, Prognostic Factors, and Toxicity. Cancers (Basel), 2022. 14 (9). van Besien, K., et al., Impact of preexisting CNS involvement on the outcome of bone marrow transplantation in adult hematologic malignancies. J Clin Oncol, 1996. 14 (11): p. 3036-42. Ferreri, A.J.M., et al., Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma: results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase 2 trial. Lancet Haematol, 2017. 4 (11): p. e510-e523. Ferreri, A.J., et al., Whole-brain radiotherapy in primary CNS lymphoma. Lancet Oncol, 2011. 12 (2): p. 118-9; author reply 119-20. Cook, M.R., et al., Toxicity and efficacy of CAR T-cell therapy in primary and secondary CNS lymphoma: a meta-analysis of 128 patients. Blood Adv, 2023. 7 (1): p. 32-39. Rodriguez-Garcia, A., et al., CAR-T cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy. Nat Commun, 2021. 12 (1): p. 877. Lacan, C., et al., CAR T-cell therapy for central nervous system lymphomas: blood and cerebrospinal fluid biology, and outcomes. Haematologica, 2023. 108 (12): p. 3485-3490. Tables Tables 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Tab1.tif Tab2.tif Tab3.tif supplementary.docx FigS1.tif TabS1.tif TabS2.tif TabS3.tif Cite Share Download PDF Status: Published Journal Publication published 24 Mar, 2026 Read the published version in Cancer Immunology, Immunotherapy → Version 1 posted Editorial decision: Revision requested 14 Sep, 2025 Reviews received at journal 28 Aug, 2025 Reviews received at journal 21 Aug, 2025 Reviewers agreed at journal 21 Aug, 2025 Reviewers agreed at journal 20 Aug, 2025 Reviewers agreed at journal 18 Aug, 2025 Reviewers invited by journal 18 Aug, 2025 Editor assigned by journal 11 Aug, 2025 Submission checks completed at journal 11 Aug, 2025 First submitted to journal 11 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Hu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAklEQVRIiWNgGAWjYBACAwY2xgcMDAdAbDMgtgCKENbCbICkRUKCGC1sEqRpMZdIS6v8UnEnn5/98LYHH2ok6szZDz/78IHBTk63AbsWyxlpx27LnHlmObMnrdxwxjEJCcueNOOZMxiSjc0O4HDYjfS225Jthw0MDuSYSfOwAR12g8GYmYfhQOI2PFqKwVrOvzGT/vMPpIX9M/MfvFrSjjF+BGm5AbSFsQ2khceYmQGfljPPkqUZzjwzkJzxrEyyt09CcsOZnGLGHgM8fjmeZvjxR8UdA37+5G0SP77Z8BscP76Z4UeFnRwuLSAA9CymUbiVgwDjD/zyo2AUjIJRMNIBAF0/XpI4T6fHAAAAAElFTkSuQmCC","orcid":"","institution":"Beijing Gobroad Hospital","correspondingAuthor":true,"prefix":"","firstName":"Kai","middleName":"","lastName":"Hu","suffix":""}],"badges":[],"createdAt":"2025-08-12 01:08:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7350145/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7350145/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00262-026-04334-x","type":"published","date":"2026-03-24T16:13:13+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":89986960,"identity":"3a953741-7fe1-47b1-a208-eb4d9113458a","added_by":"auto","created_at":"2025-08-27 06:56:43","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":494735,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"Fig1.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7350145/v1/2fca7b50b1c6a000651d852a.jpg"},{"id":89986959,"identity":"2d83892e-88f6-4340-85ab-ef6ac5282904","added_by":"auto","created_at":"2025-08-27 06:56:43","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":486776,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"Fig2.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7350145/v1/d1391113d695050517f05cfe.jpg"},{"id":89986967,"identity":"6fb37b80-a09a-4325-b50e-21e320f945ac","added_by":"auto","created_at":"2025-08-27 06:56:44","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":901744,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"Fig3.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7350145/v1/a31dbcfce955907611534e70.jpg"},{"id":89986972,"identity":"aaf30c7e-d0e7-4efe-b420-ad990a16134a","added_by":"auto","created_at":"2025-08-27 06:56:44","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":973435,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"Fig4.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7350145/v1/44cd18ed9247d12fd0c41f09.jpg"},{"id":105755770,"identity":"d3bb25f5-4023-4eba-b4ef-5ee3da9ecaf0","added_by":"auto","created_at":"2026-03-30 16:30:21","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3530572,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7350145/v1/1003e7c7-b300-4bed-8779-d2bd7122f25e.pdf"},{"id":89986956,"identity":"3af89a3f-467e-461c-b2d8-64ef21f3c6e1","added_by":"auto","created_at":"2025-08-27 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06:56:44","extension":"tif","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":44237106,"visible":true,"origin":"","legend":"","description":"","filename":"Tab3.tif","url":"https://assets-eu.researchsquare.com/files/rs-7350145/v1/ff9f70057da613828d75fe9b.tif"},{"id":89988647,"identity":"ef955d2e-06cb-40cc-bdae-5348dadefc84","added_by":"auto","created_at":"2025-08-27 07:04:44","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":15998,"visible":true,"origin":"","legend":"","description":"","filename":"supplementary.docx","url":"https://assets-eu.researchsquare.com/files/rs-7350145/v1/8f520af4f0c372bdfc579cbf.docx"},{"id":89986969,"identity":"c7fe9b94-95d5-414d-8786-44e18b1dc85c","added_by":"auto","created_at":"2025-08-27 06:56:44","extension":"tif","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":14745850,"visible":true,"origin":"","legend":"","description":"","filename":"FigS1.tif","url":"https://assets-eu.researchsquare.com/files/rs-7350145/v1/157147b549dcb7bc95edb4b3.tif"},{"id":89986983,"identity":"8beef445-7bf0-44c1-bd08-88500bd6ff78","added_by":"auto","created_at":"2025-08-27 06:56:45","extension":"tif","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":14745850,"visible":true,"origin":"","legend":"","description":"","filename":"TabS1.tif","url":"https://assets-eu.researchsquare.com/files/rs-7350145/v1/e7e4f4dd67f3f6435e41e10d.tif"},{"id":89986975,"identity":"425aaf87-0a8b-4408-94b0-ffe6f9e668a0","added_by":"auto","created_at":"2025-08-27 06:56:44","extension":"tif","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":14745850,"visible":true,"origin":"","legend":"","description":"","filename":"TabS2.tif","url":"https://assets-eu.researchsquare.com/files/rs-7350145/v1/d0566c41ca0cba35e4041766.tif"},{"id":89986982,"identity":"04e00a61-6670-422e-9820-c5cefeede7cc","added_by":"auto","created_at":"2025-08-27 06:56:44","extension":"tif","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":14745850,"visible":true,"origin":"","legend":"","description":"","filename":"TabS3.tif","url":"https://assets-eu.researchsquare.com/files/rs-7350145/v1/8b61d7433cf00d58aa26f17c.tif"}],"financialInterests":"No competing interests reported.","formattedTitle":"Outcomes in patients with refractory/relapsed CNS lymphoma treated in complete remission：autologous transplantation vs. CAR-T therapy","fulltext":[{"header":"Key Points","content":"\u003cp\u003e\u0026bull; This is the first study to compare the outcomes in chemosensitive relapsed/refractory (R/R) CNSL patients who underwent either ASCT or CAR-T therapy after achieving CR.\u003c/p\u003e\u003cp\u003e\u0026bull; ASCT is associated with longer progression-free survival (PFS) and a lower incidence of relapse/progression in R/R CNSL patients compared to CAR-T therapy when the patients are in CR. The findings will have to be validated on larger cohorts.\u003c/p\u003e\u003cp\u003e\u0026bull; Our findings provide preliminary evidence that could translate into clinical benefits for chemosensitive R/R CNSL patients.\u003c/p\u003e"},{"header":"BACKGROUND","content":"\u003cp\u003ePatients with refractory/relapsed central nervous system lymphoma (R/R CNSL) have poor prognosis, with overall survival (OS) duration of only 4\u0026ndash;10 months [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Even if their effectiveness is disappointing with second-line therapies, for which new drugs such as Bruton's tyrosine kinase inhibitors (BTKi), lenalidomide and immune checkpoint inhibitors are available, some patients can achieve a complete remission (CR) [\u003cspan additionalcitationids=\"CR4 CR5\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. R/R CNSL patients who received salvage therapy followed by intensive consolidation experienced longer survival compared to those who did not receive consolidation therapy [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. High-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT) is a reasonable approach for fit patients with chemosensitive R/R CNSL and may be associated with better outcomes [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], especially for patients with primary CNSL (PCNSL) who did not opt for ASCT consolidation during the first remission phase due to poor physical condition, comorbidities or personal reasons. However, some patients cannot opt for ASCT as a consolidation therapy due to their state of health or lack of hematopoietic stem cells (HSCs). Chimeric antigen receptor T cell (CAR-T) therapy is an effective and relatively safe treatment option for R/R CNSL patients [\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Recent studies have reported durable remissions in R/R CNSL patients who are sensitive to salvage therapy and receive consolidative CAR-T therapy while undergoing CR [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In this study, we retrospectively compared the outcomes of chemosensitive R/R CNSL patients who underwent either ASCT or CAR-T therapy after achieving CR.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy population\u003c/h2\u003e\u003cp\u003ePatients with a diagnosis of R/R CNSL who underwent ASCT or CAR-T therapy as part of a clinical trial (Clinical Trials Number: ChiCTR2200058972) at the Department of Lymphoma, Beijing Gobroad Hospital (See supplementary Material) between 2021 and 2024 while in CR, as indicated by MRI or PET scan and per the International PCNSL Collaborative Group Response Criteria and Lugano Criteria, were included in the study [\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The patients achieved CR on at least two courses of second-line chemotherapy. Patients in the CAR-T group with a previous history of auto-HCT were excluded.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eSecond-line chemotherapy\u003c/h3\u003e\n\u003cp\u003eThe design of second-line chemotherapy have been provided in the Supplementary material.\u003c/p\u003e\n\u003ch3\u003eProcedures\u003c/h3\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003eCAR-T therapy\u003c/h2\u003e\u003cp\u003eThe patients who underwent CAR-T therapy had been enrolled in a clinical trial investigating the outcomes of B-cell-targeting CAR-T cells for non-Hodgkin's lymphoma with CNS involvement (Clinicaltrials.gov registry: ChiCTR2200058972). This study was approved by the Ethics Committee, and all patients provided signed informed consent. The full list of inclusion and exclusion criteria have been provided in the Supplementary material.\u003c/p\u003e\u003cp\u003eB cell-specific CARs were constructed as previously described [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Prior to the treatment, patients received lymphodepleting chemotherapy comprising of cyclophosphamide (300mg/m\u003csup\u003e2\u003c/sup\u003e) and fludarabine (30mg/m\u003csup\u003e2\u003c/sup\u003e) to reduce the number of competing T cells. .(See supplementary material for detailed program)\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eASCT\u003c/h3\u003e\n\u003cp\u003eASCT was performed as per the standard procedures of the hospital. The patients who had responded to chemotherapy were injected with granulocyte colony-stimulating factor (G-CSF) to mobilize the autologous HSCs prior to collection. The conditioning regimen consisted of TEAM and BEAM-based protocols. The procedure for ASCT has been described in detail in the supplementary material.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eDefinitions\u003c/h2\u003e\u003cp\u003eRelapsed cases are defined as patients who achieved CR following treatment but later experienced recurrence in the CNS, spinal cord, or vitreoretinal areas. Refractory cases are defined as patients who do not respond to therapy and have never achieved CR. Therapeutic efficacy was assessed by positron emission tomography/computed tomography (PET/CT) and enhanced magnetic resonance imaging (MRI). The CSF was analyzed to determine tumor reduction and changes in MRD. Response was evaluated as per the International PCNSL Collaborative Group Response Criteria and Lugano Criteria [\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The other definitions has been described in detail in the supplementary material.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eTime-to-event estimates of OS and PFS were calculated by the Kaplan-Meier method, and the treatment groups were compared using the log-rank test. Multivariate analysis was performed using a Cox proportional-hazards model, and the Breslow approach was used to handle tied events. Competing-risk survival analysis was used to compute the non-parametric estimate of the cumulative relapse incidence function, and the differences between groups were analyzed using Gray\u0026rsquo;s test (1988). The baseline characteristics were summarized using descriptive statistics. The categorical variables were compared by Fischer\u0026rsquo;s test when more than 20% of the cells had expected frequencies\u0026thinsp;\u0026lt;\u0026thinsp;5 or at least one cell had an expected frequency\u0026thinsp;\u0026lt;\u0026thinsp;1; otherwise, Pearson Chi-squared test was used. Continuous variables were presented as medians [min, max] and compared using the Wilcoxon rank-sum test. Statistical analyses were performed using SAS software, version 9.4.\u003c/p\u003e\u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eBaseline characteristics\u003c/h2\u003e\u003cp\u003eA total of 189 patients diagnosed with R/R CNSL were treated at our hospital between March 2021 and September 2024. This study included 60 patients who were diagnosed with R/R primary or secondary DLBCL with CNS involvement (42 PCNSL and 18 SCNSL). Thirty-three patients underwent ASCT and 27 patients received CAR-T therapy, all while in CR after the second line treatment (Fig.\u0026nbsp;1). The baseline characteristics of the patients have been summarized in Table\u0026nbsp;1.\u003c/p\u003e\u003cp\u003eThe ASCT group had a higher proportion of younger patients compared to the CAR-T group (median age 53 vs. 65 years; p\u0026thinsp;=\u0026thinsp;0.001). On the other hand, the proportion of male patients (p\u0026thinsp;=\u0026thinsp;0.428), disease pathology (p\u0026thinsp;=\u0026thinsp;0.101), proportion of high-risk patients (p\u0026thinsp;=\u0026thinsp;0.469), site of CNS involvement (p\u0026thinsp;=\u0026thinsp;0.123), and proportion of patients with refractory disease (p\u0026thinsp;=\u0026thinsp;0.469) were similar in both groups. Thirty-five patients were tested for mutations, and the median number of mutations in the ASCT group (range: 1\u0026ndash;21) and CAR-T (range: 1\u0026ndash;38) group was seven. Tp53 mutation was detected in 3/11 patients (27.3%) in the ASCT group and 5/24 patients (20.8%) in the CAR-T group. In addition, 10 patients (90.9%) in the ASCT group and 16 patients (66.7%) in the CAR-T group were positive for MYD88 and/or CD79b mutations. The type and number of mutations by next-generation sequencing (NGS) in both groups are described in detail in Supplementary Table. S1 and Supplementary Fig.\u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eSurvival outcomes\u003c/h2\u003e\u003cp\u003eThe median follow-up duration was 12.1 months (range: 1.28\u0026ndash;59.9 months). The 3-year PFS and OS rates for the overall population were 71.5% (95% CI: 51.8\u0026ndash;82.2) and 87.5% (95% CI: 65.2\u0026ndash;92.5) respectively (Fig.\u0026nbsp;2A and 2B). Patients who received ASCT while in CR had superior PFS [3-year PFS 80% (95% CI: 48.4\u0026ndash;93.4) vs. 64.8% (95% CI:38.9\u0026ndash;81.9); P\u0026thinsp;=\u0026thinsp;0.026] (Fig.\u0026nbsp;3A), and a lower cumulative incidence of relapse/progression [3-year relapse rate 20% (95% CI: 4.12\u0026ndash;44.39) vs. 30.2% (95% CI: 11.0-52.2); P\u0026thinsp;=\u0026thinsp;0.038] compared to patients in the CAR-T group (Fig.\u0026nbsp;3C). The 3-year OS for ASCT was 93.3% (95% CI: 61.3\u0026ndash;99.0) compared to 80.1% (95% CI:49.4\u0026ndash;93.3) in the CAR-T group (P\u0026thinsp;=\u0026thinsp;0.115); Fig.\u0026nbsp;3B).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eSubgroup analyses\u003c/h2\u003e\u003cp\u003eAmong patients with PCNSL who received ASCT (n\u0026thinsp;=\u0026thinsp;26) or CAR-T (n\u0026thinsp;=\u0026thinsp;16) in CR, the 2-year PFS was significantly higher in the ASCT group [92.9% (95% CI: 59.1\u0026ndash;99.9) vs. 65.7% (95% CI: 31.0\u0026ndash;86.0); p\u0026thinsp;=\u0026thinsp;0.026]. Although the difference did not reach statistical significance, the 2-year OS was numerically higher in the ASCT group compared to that in the CAR-T group [91.7% (95% CI: 53.9\u0026ndash;98.8) vs. 74.1% (95% CI: 28.9\u0026ndash;93.0); p\u0026thinsp;=\u0026thinsp;0.101] (Fig.\u0026nbsp;4A and 4B). Likewise, for patients with SCNSL who received ASCT (n\u0026thinsp;=\u0026thinsp;7) or CAR-T (n\u0026thinsp;=\u0026thinsp;11) in CR, the 2-year PFS was higher in the ASCT group [75% (95% CI: 12.8\u0026ndash;96.1) vs. 64.9% (95% CI: 24.9\u0026ndash;87.4); p\u0026thinsp;=\u0026thinsp;0.409], and the 2-year OS was also numerically higher in the ASCT group [100% (95% CI: 100\u0026ndash;100) vs. 87.5% (95% CI: 38.7\u0026ndash;98.1)]. However, these differences were not statistically significant (Fig.\u0026nbsp;4C and 4D).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eOutcomes for patients with mutations\u003c/h2\u003e\u003cp\u003eAll patients with detectable Tp53 or MYD88/CD79b mutations in the ASCT group survived. Among those with Tp53 mutations, one experienced disease progression and two achieved CR. In contrast, only one of the patients with MYD88/CD79b mutations showed disease progression and the remaining nine achieved CR. In the CAR-T group, all five patients with Tp53 mutations survived, with one experiencing disease progression and four maintaining CR. Among the 16 patients with MYD88/CD79b mutations, one died due to disease progression, two survived with tumor, and 13 maintained the CR (Table\u0026nbsp;2).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eUnivariable and multivariable analysis\u003c/h2\u003e\u003cp\u003eThe risk factors for PFS and OS were determined by univariable and multivariable analyses. In the univariate Cox regression model, the duration of the first remission period and ASCT/CAR-T therapy in CR were significantly correlated to PFS and OS (all P\u0026thinsp;\u0026le;\u0026thinsp;0.15; Table\u0026nbsp;3A and 3B). The multivariate COX regression analysis showed that CAR-T therapy in CR was associated with inferior PFS [HR 5.744 (95%CI: 1.096\u0026ndash;30.114, P\u0026thinsp;=\u0026thinsp;0.0386] compared to ASCT. There was no significant difference in the OS between the ASCT and CAR-T groups (P\u0026thinsp;=\u0026thinsp;0.2356; Table\u0026nbsp;3C).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eCAR-T cell kinetics\u003c/h2\u003e\u003cp\u003eThe median number of infused CAR-T cells was 1.75\u0026times;10\u003csup\u003e6\u003c/sup\u003e cells/kg (range: 0.16\u0026times;10\u003csup\u003e6\u003c/sup\u003e cells/kg to 10\u0026times;10\u003csup\u003e6\u003c/sup\u003e cells/kg). We observed a marked expansion CAR-T cells in the PB of 36/37 patients after infusion. The median peak number of CD19\u0026thinsp;+\u0026thinsp;CAR-T cells was 7465 lentivirus copies/\u0026micro;g DNA (range: 1246\u0026ndash;36107 lentivirus copies/\u0026micro;g DNA), and the median time to achieve peak levels was ten days (range: 6\u0026ndash;28 days). The CSF of ten patients was tested after infusion, and CAR-T cells were detected in four of these patients. The peak number of CD19\u0026thinsp;+\u0026thinsp;CAR-T cells was 2415 lentivirus copies/\u0026micro;g DNA (range: 81-2914 lentivirus copies/\u0026micro;g DNA) (Fig.\u0026nbsp;5A and 5B).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003eToxicity and causes of death\u003c/h2\u003e\u003cp\u003eThe most common side effect was neutropenia [57 (95%)], followed by infection [34 (56.7%)] and hypogammaglobulinemia [28 (46.7%)] (Supplementary table \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e). In the CAR-T group, six patients (22.3%) developed grade 1 CRS, and three (11.1%) developed grade 1\u0026ndash;2 ICANS (Supplementary Table \u003cspan refid=\"MOESM3\" class=\"InternalRef\"\u003eS3\u003c/span\u003e). The neurotoxicity-related symptoms were successfully treated with siltuximab and corticosteroids, with no recorded fatalities. One patient (3%) in the ASCT group and five patients (18.5%) in the CAR-T group died during the follow-up. The most common causes of death in both groups were related to disease progression (4/6,66.7%), followed by infections (2/6,33.3%).\u003c/p\u003e\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eWe have shown for the first time that ASCT is associated with a longer PFS and a lower incidence of relapse/progression in R/R CNSL patients compared to CAR-T therapy when the patients are in CR. While the small sample size and the retrospective study design preclude definitive conclusions, our findings provide preliminary evidence that may translate to clinical benefits for chemosensitive R/R CNSL patients.\u003c/p\u003e\u003cp\u003eThe combination of HDC and ASCT is a viable treatment option for R/R CNSL patients who are sensitive to salvage chemotherapy, particularly those who achieve CR with salvage therapy [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. A previous study reported median PFS/OS of 82 months in R/R PCNSL patients with CR or PR after induction therapy [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Furthermore, the 2-year disease-free survival (DFS) rate of SCNSL patients after ASCT is 39% [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. A retrospective study evaluating the outcomes of ASCT in 17 patients with R/R CNS lymphoma (8 PCNSL and 9 SCNSL) showed that the patients achieved CR after salvage induction chemotherapy, along with 93% PFS and OS rates [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. While ASCT is effective as a consolidation therapy, it is contraindicated for some patients. Whole brain radiation therapy (WBRT) is a feasible alternative for such cases, although it should be avoided as a standalone therapy, particularly in elderly populations, due to delayed neurotoxic effects [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. CAR-T therapy has also been established as a safe and effective option for R/R CNSL [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In one study, ASCT was associated with improved clinical outcomes compared to CAR-T therapy in patients with relapsed LBCL who achieved a CR [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, there is limited information on the efficacy of CAR-T consolidation therapy in R/R CNSL patients.\u003c/p\u003e\u003cp\u003eTo the best of our knowledge, our study is the first to compare the long-term outcomes of ASCT and CAR-T therapy in R/R CNSL patients in CR. Significant CAR T-cell expansion was detected in the PB and CSF of patients after infusion, indicating that these cells can migrate to the CSF regardless of the absence of systemic lymphoma or non-measurable disease. This is consistent with a previous study that reported expansion of Relmacabtagene autoleucel (relma-cel) CD19\u0026thinsp;+\u0026thinsp;CAR-T cells in the CSF of eight R/R B cell lymphoma patients in CR [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Similar amplification of CAR-T cells was observed in the PB in our study. Six patients did not have any discernible CAR-T cells in the CSF, which may be attributed to the fact that the detection time point was 90 days after infusion.\u003c/p\u003e\u003cp\u003eNevertheless, the use of CAR-T cells as a consolidation treatment did not attain the same depth of remission as ASCT in R/R CNSL patients who are sensitive to salvage therapy and have achieved CR. While the exact mechanism underlying the absence of long-lasting responses remains to be elucidated, one potential explanation could be the rapid depletion of CAR-T cells in the CNS [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Some tumor-associated macrophages/microglia subsets can lead to antigen-specific T-cell dysfunction and the failure of CAR-T cell therapy [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. On the other hand, Yu et al noted that patients with R/R CNSL who received relma-cel during CR achieved durable remission, and five patients remained progression-free for over 12 months. In their study, CAR-T therapy was more effective in eradicating chemo-refractory subclones at MRD levels compared to ASCT [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The lack of consistency in results may be attributed to the small sample size of only 8 patients and the short follow-up period.\u003c/p\u003e\u003cp\u003eThe application of CAR-T cells as consolidation therapy for R/R CNSL patients in CR can significantly extend their PFS and OS compared to that of patients who do not receive consolidation therapy. In a previous study, R/R CNSL patients who received salvage treatment without consolidation achieved median PFS of 2.6 months and median OS of 6.7 months [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. We found that consolidative CAR-T therapy resulted in a median PFS of 27.7 months, while the median OS could not be determined as yet. Thus, consolidation therapy with CAR-T cells is safe and effective for R/R CNSL patients in CR who do not meet the criteria for autologous transplantation.\u003c/p\u003e\u003cp\u003eToxicity is a major concern of CAR-T therapy in patients with CNSL. In R/R CNSL patients infused with CAR T cells expressing the 41BB costimulatory domain, the incidence of ICANS of any grade is 33.3\u0026ndash;44.4%, and that of grade 3 ICANS is 4.5\u0026ndash;11.1% [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. On the other hand, PCNSL patients usually have lower ICANS rates due to the lack of systemic disease burden and less systemic inflammation [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. The incidence of ICANS was only 8.1% (grade 1\u0026ndash;2) in our cohort, which may be related to the fact that all patients had achieved CR. In addition, four patients with CAR-T amplification in the CSF did not experience ICANS, indicating that CR period is safe for CAR-T consolidation therapy in R/R CNSL patients.\u003c/p\u003e\u003cp\u003eDue to the small number of cases, it was not possible to analyze the correlation between TP53 or MYD88/CD79b mutation and the efficacy of consolidation therapy. Therefore, further studies with larger cohorts are needed to guide treatment selection on the basis of mutation data. The primary limitation of this study arises from its retrospective design. Furthermore, the choice of treatment regimen was usually influenced by factors such as age, availability of HSCs for transplantation, comorbidities, and the personal preferences of patients. ASCT consolidation significantly improved PFS compared to CAR-T consolidation in PCNSL patients who achieved CR. Although a comparable trend was observed in SCNSL patients, the difference did not reach statistical significance, possibly due to the limited sample size in this subgroup. A clinical trial with larger sample size and longer follow-up period could provide insights into the duration of response to ASCT and CAR-T therapy among these patients.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eASCT consolidation therapy remains an option for R/R CNSL patients who are sensitive to second-line chemotherapy and achieve CR. Nevertheless, CAR-T therapy as a consolidative approach appears to be a potentially viable option for R/R CNSL patients in CR who are not eligible for ASCT.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCAR-T\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003echimeric antigen receptor T-cell therapy\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eR/R CNSL\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003erefractory/relapsed central nervous system lymphoma\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ecomplete remission\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eDLBCL\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ediffuse large B-cell lymphoma\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePFS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eprogression-free survival\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eOS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eoverall survival\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eASCT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eautologous transplantation\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePCNSL\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eprimary central nervous system lymphoma\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSCNSL\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003esecondary central nervous system lymphoma\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eWBRT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ewhole-brain radiotherapy\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eICANS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eimmune effector cell-associated neurotoxicity syndrome\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCRS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ecytokine release syndrome\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePBMNCs\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eperipheral blood mononuclear cells\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eRT-qPCR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ereal-time quantitative polymerase chain reaction\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePET/CT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003epositron emission tomography/computed tomography\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMRI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003emagnetic resonance imaging\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConception and design: Kai Hu.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eManuscript writing: Fan Yang.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData acquisition: Yuelu Guo, Lixia Ma, Miaomiao Cao, Biping Deng, Xiaoyan Ke\u003c/p\u003e\n\u003cp\u003eCollection and assembly of data: Rui Liu and Zhonghua Fu.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData analysis: Haifeng Wu and Chen chen.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eInterpretation: All authors.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFinal approval of manuscript: All authors.\u003c/p\u003e\n\u003cp\u003eAll authors provided critical and insightful comments.\u003c/p\u003e\n\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eApproval of the research protocol by an Institutional Reviewer Board. The study was approved by the Ethics Committee at the Beijing Gobroad Hospital in Beijing Informed Consent. The study adheres to the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained in accordance with the Declaration of Helsinki from each patient. The Registration No. of the study/trial: ChiCTR2200058972.Registration Date:2022/2/21.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the data and materials are included in the manuscript and supplemental materials. The detailed and original data can be accessed by contacting the corresponding author\u0026rsquo;s email.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to express our gratitude to Shanghai YaKe Biotechnology Ltd., Shanghai, China, and all the medical staff and patients who participated in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors confirm that there are no conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWelch, M.R., et al., \u003cem\u003eAutologous stem cell transplant in recurrent or refractory primary or secondary central nervous system lymphoma using thiotepa, busulfan and cyclophosphamide.\u003c/em\u003e Leuk Lymphoma, 2015. \u003cstrong\u003e56\u003c/strong\u003e(2): p. 361-7.\u003c/li\u003e\n\u003cli\u003eGrommes, C., \u003cem\u003eCentral Nervous System Lymphomas.\u003c/em\u003e Continuum (Minneap Minn), 2020. \u003cstrong\u003e26\u003c/strong\u003e(6): p. 1476-1494.\u003c/li\u003e\n\u003cli\u003eHouillier, C., et al., \u003cem\u003eLenalidomide monotherapy as salvage treatment for recurrent primary CNS lymphoma.\u003c/em\u003e Neurology, 2015. \u003cstrong\u003e84\u003c/strong\u003e(3): p. 325-6.\u003c/li\u003e\n\u003cli\u003eYang, C., et al., \u003cem\u003eOrelabrutinib Combined With Lenalidomide and Immunochemotherapy for Relapsed/Refractory Primary Central Nervous System Lymphoma: A Retrospective Analysis of Case Series.\u003c/em\u003e Front Oncol, 2022. \u003cstrong\u003e12\u003c/strong\u003e: p. 901797.\u003c/li\u003e\n\u003cli\u003eLin, Z., et al., \u003cem\u003eZanubrutinib plus Cytarabine in Patients with Refractory/Relapsed Primary Central Nervous System Lymphoma.\u003c/em\u003e Acta Haematol, 2024. \u003cstrong\u003e147\u003c/strong\u003e(5): p. 555-563.\u003c/li\u003e\n\u003cli\u003eNayak, L., et al., \u003cem\u003ePD-1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma.\u003c/em\u003e Blood, 2017. \u003cstrong\u003e129\u003c/strong\u003e(23): p. 3071-3073.\u003c/li\u003e\n\u003cli\u003eLangner-Lemercier, S., et al., \u003cem\u003ePrimary CNS lymphoma at first relapse/progression: characteristics, management, and outcome of 256 patients from the French LOC network.\u003c/em\u003e Neuro Oncol, 2016. \u003cstrong\u003e18\u003c/strong\u003e(9): p. 1297-303.\u003c/li\u003e\n\u003cli\u003eHoldhoff, M., N. 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Baehring, \u003cem\u003eTreatment Options for Recurrent Primary CNS Lymphoma.\u003c/em\u003e Curr Treat Options Oncol, 2022. \u003cstrong\u003e23\u003c/strong\u003e(11): p. 1548-1565.\u003c/li\u003e\n\u003cli\u003eShadman, M., et al., \u003cem\u003eAutologous transplant vs. CAR-T therapy in patients with DLBCL treated while in complete remission.\u003c/em\u003e Blood Cancer J, 2024. \u003cstrong\u003e14\u003c/strong\u003e(1): p. 108.\u003c/li\u003e\n\u003cli\u003eChoquet, S., et al., \u003cem\u003eCAR T-cell therapy induces a high rate of prolonged remission in relapsed primary CNS lymphoma: Real-life results of the LOC network.\u003c/em\u003e Am J Hematol, 2024. \u003cstrong\u003e99\u003c/strong\u003e(7): p. 1240-1249.\u003c/li\u003e\n\u003cli\u003eEpperla, N., et al., \u003cem\u003eOutcomes of patients with secondary central nervous system lymphoma following CAR T-cell therapy: a multicenter cohort study.\u003c/em\u003e J Hematol Oncol, 2023. \u003cstrong\u003e16\u003c/strong\u003e(1): p. 111.\u003c/li\u003e\n\u003cli\u003eShumilov, E., et al., \u003cem\u003eCAR-T Cell Therapy Shows Similar Efficacy and Toxicity in Patients With DLBCL Regardless of CNS Involvement.\u003c/em\u003e Hemasphere, 2023. \u003cstrong\u003e7\u003c/strong\u003e(12): p. e984.\u003c/li\u003e\n\u003cli\u003eYu, W., et al., \u003cem\u003eReal-world experience of commercial relmacabtagene autoleucel (relma-cel) for relapsed/refractory central nervous system lymphoma: a multicenter retrospective analysis of patients in China.\u003c/em\u003e J Immunother Cancer, 2024. \u003cstrong\u003e12\u003c/strong\u003e(5).\u003c/li\u003e\n\u003cli\u003ePan, J., et al., \u003cem\u003eHigh efficacy and safety of low-dose CD19-directed CAR-T cell therapy in 51 refractory or relapsed B acute lymphoblastic leukemia patients.\u003c/em\u003e Leukemia, 2017. \u003cstrong\u003e31\u003c/strong\u003e(12): p. 2587-2593.\u003c/li\u003e\n\u003cli\u003eLiu, Y., et al., \u003cem\u003eSequential different B-cell antigen-targeted CAR T-cell therapy for pediatric refractory/relapsed Burkitt lymphoma.\u003c/em\u003e Blood Adv, 2022. \u003cstrong\u003e6\u003c/strong\u003e(3): p. 717-730.\u003c/li\u003e\n\u003cli\u003eCheson, B.D., et al., \u003cem\u003eRecommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification.\u003c/em\u003e J Clin Oncol, 2014. \u003cstrong\u003e32\u003c/strong\u003e(27): p. 3059-68.\u003c/li\u003e\n\u003cli\u003eZelenetz, A.D., et al., \u003cem\u003eNCCN Guidelines Insights: B-Cell Lymphomas, Version 3.2019.\u003c/em\u003e J Natl Compr Canc Netw, 2019. \u003cstrong\u003e17\u003c/strong\u003e(6): p. 650-661.\u003c/li\u003e\n\u003cli\u003eHan, C.H. and T.T. Batchelor, \u003cem\u003eDiagnosis and management of primary central nervous system lymphoma.\u003c/em\u003e Cancer, 2017. \u003cstrong\u003e123\u003c/strong\u003e(22): p. 4314-4324.\u003c/li\u003e\n\u003cli\u003eSeidel, S., et al., \u003cem\u003eHigh-Dose Chemotherapy with Autologous Hematopoietic Stem Cell Transplantation in Relapsed or Refractory Primary CNS Lymphoma: A Retrospective Monocentric Analysis of Long-Term Outcome, Prognostic Factors, and Toxicity.\u003c/em\u003e Cancers (Basel), 2022. \u003cstrong\u003e14\u003c/strong\u003e(9).\u003c/li\u003e\n\u003cli\u003evan Besien, K., et al., \u003cem\u003eImpact of preexisting CNS involvement on the outcome of bone marrow transplantation in adult hematologic malignancies.\u003c/em\u003e J Clin Oncol, 1996. \u003cstrong\u003e14\u003c/strong\u003e(11): p. 3036-42.\u003c/li\u003e\n\u003cli\u003eFerreri, A.J.M., et al., \u003cem\u003eWhole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma: results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase 2 trial.\u003c/em\u003e Lancet Haematol, 2017. \u003cstrong\u003e4\u003c/strong\u003e(11): p. e510-e523.\u003c/li\u003e\n\u003cli\u003eFerreri, A.J., et al., \u003cem\u003eWhole-brain radiotherapy in primary CNS lymphoma.\u003c/em\u003e Lancet Oncol, 2011. \u003cstrong\u003e12\u003c/strong\u003e(2): p. 118-9; author reply 119-20.\u003c/li\u003e\n\u003cli\u003eCook, M.R., et al., \u003cem\u003eToxicity and efficacy of CAR T-cell therapy in primary and secondary CNS lymphoma: a meta-analysis of 128 patients.\u003c/em\u003e Blood Adv, 2023. \u003cstrong\u003e7\u003c/strong\u003e(1): p. 32-39.\u003c/li\u003e\n\u003cli\u003eRodriguez-Garcia, A., et al., \u003cem\u003eCAR-T cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy.\u003c/em\u003e Nat Commun, 2021. \u003cstrong\u003e12\u003c/strong\u003e(1): p. 877.\u003c/li\u003e\n\u003cli\u003eLacan, C., et al., \u003cem\u003eCAR T-cell therapy for central nervous system lymphomas: blood and cerebrospinal fluid biology, and outcomes.\u003c/em\u003e Haematologica, 2023. \u003cstrong\u003e108\u003c/strong\u003e(12): p. 3485-3490.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"cancer-immunology-immunotherapy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ciim","sideBox":"Learn more about [Cancer Immunology, Immunotherapy](http://link.springer.com/journal/262)","snPcode":"262","submissionUrl":"https://submission.nature.com/new-submission/262/3","title":"Cancer Immunology, Immunotherapy","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7350145/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7350145/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAutologous hematopoietic cell transplantation (ASCT) is a reasonable approach as a consolidation therapy for fit patients with chemosensitive relapsed central nervous system lymphoma (CNSL) who have achieved complete remission (CR). Chimeric antigen receptor T-cell (CAR-T) therapy is an effective treatment option for patients with relapsed CNSL, although there is limited evidence regarding the outcomes of these patients in CR.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAim\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo compare the efficacy of ASCT versus CAR-T therapy in patients with relapsed CNSL during CR.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA retrospective observational study was conducted on patients who underwent ASCT or CAR-T therapy at the Department of Lymphoma, Beijing Gobroad Hospital between 2021 and 2024. The CAR-T therapy was part of the clinical trial “Different B-cell Target CAR-T cells for relapsed/refractory CNSL (ChiCTR2200058972)”.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSixty patients, including 42 (70%) with primary CNSL and 18 (30%) with diffuse large B-cell lymphoma (DLBCL) presenting secondary CNS involvement, were enrolled. The median follow-up duration was 12.1 months (1.28–59.9 months). Patients who received ASCT while in CR had superior progression-free survival (PFS) [3-year PFS 80% (95% CI: 48.4–93.4) vs. 64.8% (95% CI:38.9–81.9); P = 0.026] and a lower cumulative incidence of relapse/progression [3-year relapse rate 20% (95% CI: 4.12–44.39) vs. 30.2% (95% CI: 11.0-52.2); P = 0.038] compared to patients in the CAR-T group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCompared to CAR-T therapy, ASCT was associated with improved PFS in patients with relapsed CNSL who had achieved CR.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trials Number:\u003c/strong\u003e ChiCTR2200058972\u003c/p\u003e","manuscriptTitle":"Outcomes in patients with refractory/relapsed CNS lymphoma treated in complete remission：autologous transplantation vs. CAR-T therapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-27 06:56:36","doi":"10.21203/rs.3.rs-7350145/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-14T19:31:16+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-28T21:23:51+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-21T21:58:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"268552113789277020172670110888500516869","date":"2025-08-21T05:49:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"230578734498698223207448284881043907809","date":"2025-08-20T06:18:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"318609601452972010486311062201565105983","date":"2025-08-18T23:59:52+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-18T12:52:16+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-12T03:19:09+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-12T03:17:24+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cancer Immunology, Immunotherapy","date":"2025-08-12T00:55:30+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cancer-immunology-immunotherapy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ciim","sideBox":"Learn more about [Cancer Immunology, Immunotherapy](http://link.springer.com/journal/262)","snPcode":"262","submissionUrl":"https://submission.nature.com/new-submission/262/3","title":"Cancer Immunology, Immunotherapy","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"987cbd1b-6a84-40dc-b3a4-4305f2e8b6a4","owner":[],"postedDate":"August 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-30T16:26:19+00:00","versionOfRecord":{"articleIdentity":"rs-7350145","link":"https://doi.org/10.1007/s00262-026-04334-x","journal":{"identity":"cancer-immunology-immunotherapy","isVorOnly":false,"title":"Cancer Immunology, Immunotherapy"},"publishedOn":"2026-03-24 16:13:13","publishedOnDateReadable":"March 24th, 2026"},"versionCreatedAt":"2025-08-27 06:56:36","video":"","vorDoi":"10.1007/s00262-026-04334-x","vorDoiUrl":"https://doi.org/10.1007/s00262-026-04334-x","workflowStages":[]},"version":"v1","identity":"rs-7350145","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7350145","identity":"rs-7350145","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}