Primary Central Nervous System Lymphoma Patients Research Articles

Survival outcomes and treatment experience of 124patients with primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is arare malignancy of the central nervous system with high invasiveness. There is little consensus on the treatment of PCNSL. This study retrospectively studied data from PCNSL patients in asingle center to summarize treatment experience and explore prognostic factors. Survival curves were drawn using the Kaplan-Meier method and prognostic factors were analyzed using Cox's hazards model. In multivariate analysis, cerebrospinal fluid lactic acid dehydrogenase (CSF LDH; p = 0.005 and p = 0.002), neutrophil to lymphocyte ratio (NLR; p = 0.014 and p = 0.038), and completion of four cycles of induction therapy (p < 0.001and p < 0.001) were significant and independent predictors of overall survival (OS) and progression-free survival (PFS), respectively. On the basis of this study, we propose that PCNSL patients should receive early induction therapy with sufficient cycles. Subsequent consolidation therapy can prevent relapses and improve survival. In patients with PCNSL, the independent prognostic factors for OS and PFS were CSF LDH level, NLR, and full cycles of induction therapy.

Interim FDG-PET improves treatment failure prediction in primary central nervous system Lymphoma: a LOC network prospective multicentric study.

The purpose of our study was to assess the predictive and prognostic role of 2-18F-fluoro-2-deoxy-D-glucose (FDG) PET/MRI during high-dose methotrexate-based chemotherapy (HD-MBC) in de novo primary central nervous system lymphoma (PCNSL) patients aged 60 and above. This prospective multicentric ancillary study included 65 immunocompetents patients who received induction HD-MBC as part of the BLOCAGE01 phase III trial. FDG-PET/MRI were acquired at baseline, post two cycles (PET/MRI2), and post-treatment (PET/MRI3). FDG-PET response was dichotomized, with "positive" indicating persistent tumor uptake higher than the contralateral mirroring brain region. Performances of FDG-PET and International PCNSL Collaborative Group criteria in predicting induction response, progression-free survival (PFS), and overall survival (OS) were compared. Of 48 PET2 scans performed, nine were positive and aligned with a partial response (PR) on MRI2. Among these, eight (89%) progressed by the end of the induction phase. In contrast, 35/39 (90%) of PET2-negative patients achieved complete response (CR). Among the 18 discordant responses at interim (PETCR/MRIPR), 83% ultimately achieved CR. 87% of the PET2-negative patients were disease-free at 6 months versus 11% of the PET2-positive patients (p<0.001). The MRI2 response did not significantly differentiate patients based on their PFS, regardless of whether they were in CR or PR. Both PET2 and MRI2 independently predicted OS in multivariate analysis, with PET2 showing stronger association. Our study highlights the potential of interim FDG-PET for early management of PCNSL patients. Response-driven treatment based on PET2 may guide future clinical trials.

18F-FACBC and 18F-FDG PET/MRI in the evaluation of 3 patients with primary central nervous system lymphoma: a pilot study

BackgroundThis PET/MRI study compared contrast-enhanced MRI, 18F-FACBC-, and 18F-FDG-PET in the detection of primary central nervous system lymphomas (PCNSL) in patients before and after high-dose methotrexate chemotherapy. Three immunocompetent PCNSL patients with diffuse large B-cell lymphoma received dynamic 18F-FACBC- and 18F-FDG-PET/MRI at baseline and response assessment. Lesion detection was defined by clinical evaluation of contrast enhanced T1 MRI (ce-MRI) and visual PET tracer uptake. SUVs and tumor-to-background ratios (TBRs) (for 18F-FACBC and 18F-FDG) and time-activity curves (for 18F-FACBC) were assessed.ResultsAt baseline, seven ce-MRI detected lesions were also detected with 18F-FACBC with high SUVs and TBRs (SUVmax:mean, 4.73, TBRmax: mean, 9.32, SUVpeak: mean, 3.21, TBRpeak:mean: 6.30). High TBR values of 18F-FACBC detected lesions were attributed to low SUVbackground. Baseline 18F-FDG detected six lesions with high SUVs (SUVmax: mean, 13.88). In response scans, two lesions were detected with ce-MRI, while only one was detected with 18F-FACBC. The lesion not detected with 18F-FACBC was a small atypical MRI detected lesion, which may indicate no residual disease, as this patient was still in complete remission 12 months after initial diagnosis. No lesions were detected with 18F-FDG in the response scans.Conclusions18F-FACBC provided high tumor contrast, outperforming 18F-FDG in lesion detection at both baseline and in response assessment. 18F-FACBC may be a useful supplement to ce-MRI in PCNSL detection and response assessment, but further studies are required to validate these findings.Trial registration ClinicalTrials.gov. Registered 15th of June 2017 (Identifier: NCT03188354, https://clinicaltrials.gov/study/NCT03188354).

The prognostic value of CD8+ CTLs, CD163+ TAMs, and PDL1 expression in the tumor microenvironment of primary central nervous system lymphoma

To explore immune cell infiltration and PDL1 expression in the tumor microenvironment (TME) of primary central nervous system lymphoma (PCNSL), we performed immunohistochemical staining on paraffin-embedded tumor tissues from 34 patients diagnosed with PCNSL. CD8 and CD163 positive cells were manually counted, and PDL1 expression was quantified by the H-score scoring method in the tumor center and around the tumor. The Kaplan–Meier method was used to analyze the prognostic value of the TME. We found obvious infiltration of CD8+ CTLs and CD163+ TAMs in the TME of PCNSL patients. And PDL1 was expressed in the tumor center as well as around the tumor. Survival analysis showed that high CD8+ CTLs levels and high intratumoral PDL1 expression were significantly correlated with longer OS. High CD8+ CTLs and CD163+ TAMs levels were associated with longer PFS.

Relevance of different prognostic scores in primary CNS lymphoma in the era of intensified treatment regimens: A retrospective, multicenter analysis of 174 patients.

Treatment intensification (including consolidative high-dose chemotherapy with autologous stem cell transplantation [HDT-ASCT]) significantly improved outcome in primary central nervous system lymphoma (PCNSL) patients. We conducted a multicenter, retrospective analysis of newly diagnosed PCNSL patients, treated with intensified treatment regimens. The following scores were evaluated in terms of overall survival (OS) and progression-free survival (PFS): Memorial Sloan-Kettering Cancer Center (MSKCC), International Extranodal Lymphoma Study Group (IELSG), and three-factor (3F) prognostic score. Further, all scores were comparatively investigated for model quality and concordance. Altogether, 174 PCNSL patients were included. One hundred and five patients (60.3%) underwent HDT-ASCT. Two-year OS and 2-year PFS for the entire population were 73.3% and 48.5%, respectively. The MSKCC (p = .003) and 3F score (p < .001), but not the IELSG score (p = .06), had the discriminatory power to identify different risk groups for OS. In regard to concordance, the 3F score (C-index [0.71]) outperformed both the MSKCC (C-index [0.64]) and IELSG (C-index [0.53]) score. Moreover, the superiority of the 3F score was shown for PFS, successfully stratifying patients in three risk groups, which also resulted in the highest C-index (0.66). The comparative analysis of established PCNSL risk scores affirm the clinical utility of the 3F score stratifying the widest prognostic spectrum among PCNSL patients treated with intensified treatment approaches.

Fully automated MR-based virtual biopsy of primary CNS lymphomas.

Primary central nervous system lymphomas (PCNSL) pose a challenge as they may mimic gliomas on magnetic resonance imaging (MRI) imaging, compelling precise differentiation for appropriate treatment. This study focuses on developing an automated MRI-based workflow to distinguish between PCNSL and gliomas. MRI examinations of 240 therapy-naive patients (141 males and 99 females, mean age: 55.16 years) with cerebral gliomas and PCNSLs (216 gliomas and 24 PCNSLs), each comprising a non-contrast T1-weighted, fluid-attenuated inversion recovery (FLAIR), and contrast-enhanced T1-weighted sequence were included in the study. HD-GLIO, a pre-trained segmentation network, was used to generate segmentations automatically. To validate the segmentation efficiency, 237 manual segmentations were prepared (213 gliomas and 24 PCNSLs). Subsequently, radiomics features were extracted following feature selection and training of an XGBoost algorithm for classification. The segmentation models for gliomas and PCNSLs achieved a mean Sørensen-Dice coefficient of 0.82 and 0.80 for whole tumors, respectively. Three classification models were developed in this study to differentiate gliomas from PCNSLs. The first model differentiated PCNSLs from gliomas, with an area under the curve (AUC) of 0.99 (F1-score: 0.75). The second model discriminated between high-grade gliomas and PCNSLs with an AUC of 0.91 (F1-score: 0.6), and the third model differentiated between low-grade gliomas and PCNSLs with an AUC of 0.95 (F1-score: 0.89). This study serves as a pilot investigation presenting an automated virtual biopsy workflow that distinguishes PCNSLs from cerebral gliomas. Prior to clinical use, it is necessary to validate the results in a prospective multicenter setting with a larger number of PCNSL patients.

Clinical outcomes of newly diagnosed primary central nervous system lymphoma treated with zanubrutinib-based combination therapy.

High-dose methotrexate (HD-MTX) combined with other chemotherapeutic agents is an effective treatment for patients with newly diagnosed primary central nervous system lymphoma (PCNSL); however, some patients have adverse reactions. To retrospectively evaluate disease outcomes and mutational profiles in newly diagnosed PCNSL patients treated with a zanubrutinib/HD-MTX combination regimen. Nineteen newly diagnosed PCNSL patients were treated with zanubrutinib/HD-MTX until disease progression, intolerable toxicities, or physician/patient-directed withdrawal. Safety and efficacy were assessed per the CTCAE v5.0 and RECIST v1.1 criteria, respectively. The primary endpoint was the objective response rate (ORR), and the secondary endpoints were progression-free survival, overall survival (OS), and safety. The median follow-up duration was 14.7 mo (range, 3.9-30 mo). The ORR for all patients was 84.2%, and 2-year progression-free- and OS rates were 75.6% and 94.1%, respectively. All patients completed the induction phase, and nine patients underwent autologous stem cell transplantation as consolidation therapy, resulting in an ORR of 88.9%. Ten patients received zanubrutinib as maintenance therapy and achieved an ORR of 80%. All patients showed an acceptable safety profile. The sequencing results for cerebrospinal fluid (CSF) and tumor tissue showed that PIM1 mutations were the most frequent genetic alterations. Circulating tumor DNA was correlated with disease relapse and response. Our empirical observations demonstrated that the combination of zanubrutinib with HD-MTX yielded a marked clinical response and tolerability among newly diagnosed PCNSL patients. Non-invasive CSF liquid biopsy profiling may be feasible for evaluating treatment response and tumor burden.

10150-GGE-16 INTRAOPERATIVE INTEGRATED DIAGNOSTIC SYSTEM FOR MALIGNANT CENTRAL NERVOUS SYSTEM TUMORS

Abstract INTRODUCTION As the most of adult malignant brain tumors are gliomas and primary central nervous system lymphomas (PCNSL)., differentiating between PCNSL and glioma during surgery is crucial for determining the treatment strategy. Also, the WHO CNS5 criteria indicates common genetic alterations according to tumor types. Thus, intraoperatively identifying these genomic abnormalities could aid diagnosis, which may contribute in more personalized therapeutic approaches. Here, we report an intraoperative integrated diagnostic system (i-ID system) that combines frozen section (FS) diagnosis with quantitative PCR (qPCR) based genotyping. MATERIAL &amp; METHODS Rapid histopathological diagnosis by FS was performed for all cases. For cases requiring differentiation from PCNSL, rapid immunohistochemical staining (R-IHC) for CD20 and GFAP was performed. qPCR genotyping was used for the rapid evaluation of IDH1R132H, IDH2R172K, TERTC228T, C250T, BRAFV600E, H3F3AK27M, MYD88L265P, and CDKN2A copy number alteration. The diagnostic accuracy for adult diffuse glioma and PCNSL using i-ID system was examined. RESULTS i-ID system was required 100 min to obtain complete information. After retrospectively analyzing of 151 cases for setting diagnostic algorithm, 101 cases were prospectively assessed for diagnostic potential. The matched ratios for IDH1/2, TERT, BRAF, H3F3A, and CDKN2A evaluations using qPCR were 100%, 98.8%, 100%, 100%, and 93.9%, respectively. In cases of glioblastoma, astrocytoma, and oligodendroglioma, the sensitivity of FS was low, with values of 0.18, 0.17, and 0.00, respectively. On the other hand by combining genotyping, the sensitivity improved up to 0.94, 1.00, and 0.88, respectively. The sensitivity for PCNSL improved from 0.47 (genotyping alone) to 0.95 with combination of R-IHC. Overall, i-ID based intraoperative diagnosis was matched to the permanent diagnosis in 80/82 (97.6%) patients with glioma and 18/19 (94.7%) PCNSL patients, respectively. CONCLUSIONS The i-ID system provides rapid and reliable integrated diagnosis of adult malignant CNS tumors.

Diagnostic utility of CSF IL-10:IL-6 ratio in diagnosing primary CNS lymphoma patients- a case series

Diagnostic utility of CSF IL-10:IL-6 ratio in diagnosing primary CNS lymphoma patients- a case series

Rituximab Ibrutinib Lenalidomide (R2I) Combination for Primary or Secondary Large B-Cell CNS Lymphoma: Last Resort or Bridge to Cellular Therapy?

Background: Primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL) each carry a poor prognosis. About 50% of patients with PCNSL will have refractory or relapsed disease correlating with dismal survival. SCNSL is associated with median overall survival (OS) of &amp;lt;6 months. (El-Galaly et al . Eur. J. Cancer 2018) Lenalidomide and ibrutinib each have single agent activity in PCNSL and SCNSL, albeit with limited duration of response (DOR). In combination, they have synergistic activity through modulation of NF-kappa B pathway. The regimen rituximab, lenalidomide, and ibrutinib (R2I) has demonstrated complete and durable responses in a subset of patients with good tolerability. (Houllier et al . Neurology 2021). We report our institutional outcomes with this regimen and its potential role as a bridge to autologous stem cell transplantation (ASCT) or CD19-targeted CAR T-cell therapy. Methods: This retrospective study included ten large B-cell lymphoma (LBCL) patients with PCNSL or SCNSL who received R2I regimen at Miami Cancer Institute from December 2020 to March 2023. Treatment response was assessed using International PCNSL Collaborative Group's criteria. (Abrey et al. J Clin Oncol 2005) Efficacy was evaluated from the start of R2I regimen. Progression free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results: The median age at R2I initiation was 71 (range, 57-85) years. Six of 10 (60%) patients were ≥65 years. Five of 10 (50%) patients had PCNSL. The median number of prior lines of therapy was 2 (range, 1-7). None of the patients had prior ASCT. The median number of cycles of R2I was 4 (range, 1-23). Four patients received a higher dose of rituximab (500mg/m 2). Overall response rates (ORR) and complete response (CR) rates were 80% (95% CI, 55.2 to 100) and 40% (95% CI, 9.6 to 70.3), respectively. The median time to best response was 1.5 (range, 1.0-13.0) months and the median DOR was 5.5 (range, 2.5-18.0) months. The 1-year PFS and OS were 38.8% (95% CI: 4.9 to 72.8) and 56% (95% CI: 22.5 to 89.4), respectively (Figure 1). In the PCNSL subgroup, the 1-year OS was 80% (95% CI, 44.9 to 100) and PFS was 60% (95% CI, 17 to 100). No differences in response rates to R2I between PCNSL and SCNSL were observed (p=0.9). There were no deaths or treatment discontinuations due to R2I toxicity. Two patients on R2I underwent subsequent cellular therapy. One PCNSL patient in CR received carmustine (BCNU) and thiotepa conditioning followed by autograft rescue and remains in remission 16 months post-ASCT. The second patient received CD19-targeted CAR T-cell therapy with axicabtagene ciloleucel for SCNSL. The patient expired 119 days after CAR T-cell therapy due to systemic disease relapse. Another patient, initially deemed ineligible for any cellular therapy due to poor performance status, has achieved a durable response with improvement of performance status and is currently awaiting ASCT. Conclusion: R2I is an effective and safe regimen in patients with PCNSL and SCNSL. Although responses without consolidation may be durable, R2I should be considered as an active drug combination and well-tolerated bridge to cellular therapy to achieve long term survival.

Single Cell Multi Omics and Spatial Analysis Reveals Plasmablast Signature Malignant Cells As a Key of Intratumor Heterogeneity in Primary Central Nervous System Lymphoma

Background: Primary central nervous system lymphoma (PCNSL) constitutes approximately 5% of extranodal lymphomas. More than 90% of PCNSL are diagnosed as diffuse large B-cell lymphomas (DLBCL), mainly classified as the activated B cell (ABC) subtype. Recent genetic analyses have identified key molecular drivers of PCNSL, including MYD88, CARD11 and CD79B. However, molecular analyses using bulk samples have provided limited insights into the heterogeneity in lymphoma cells of PCNSL. To improve our understanding in the biology of PCNSL, we conducted a multimodal single-cell analyses and integrated single-cell and spatial analyses to characterize the molecular properties of PCNSL tumors. Methods:Our study included seven PCNSL patients and two patients with reactive lymph nodes (RLN). We performed Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) combined with B-cell and T-cell receptor (BCR and TCR) analysis on samples from 3 PCNSL and 2 RLN patients, while the remaining PCNSL patients' samples were subjected to single-cell transcriptomic sequencing. Additionally, six formalin-fixed and paraffin-embedded (FFPE) tissues from the patients analyzed in the single-cell sequencing (except for one patient) were performed with GeoMx digital spatial profiling (DSP). Result: To ensure data quality, we filtered out low-quality cells and doublets, resulting in a dataset of 41,556 single cells. B cells represented the most abundant cluster, followed by T cells and monocytes. Copy number alterations (CNAs) data derived from InferCNV analysis showed distinct CNAs patterns in lymphoma cells of each patient. UMAP plot projection analysis revealed the presence of a distinct subtype of malignant cells within the B-cell population, which was characterized as high expression of plasmablast (PBL)-associated surface proteins, including SLAMF7, CD39, and CD38. Enrichment analysis based on germinal center (GC) gene expression signatures (Holmes AB et al. J Exp Med. 2020) revealed a broader spectrum of B-cell differentiation states in malignant B cells. Single-cell BCR sequencing further demonstrated that different GC signature state cells harbored the same BCR repertoire within each patient, suggesting a common origin of malignant cells. Non-negative matrix factorization (NMF) analysis confirmed the enrichment of PBL signature scores in the distinct malignant cell population observed in the UMAP plot, consistent with DPE analysis (Figure A). Interestingly, the proportion of PBL signature cells varied among patients. Signaling interaction analysis highlighted CD70-CD27 and SPP1-CD44 pathways as enriched in tumor cells. PBL signature cells received TNFSF13B and TNFSF13 signaling through TNFRSF17 (BCMA), whereas other tumor cells expressed TNFRSF13C (BAFF-R) and received TNFSF13B signaling alone. We further analyzed two public bulk RNA-seq data (Bruno A et al. Neuro Oncol 2018, n = 6; Radke J et al. Nat Commun 2022, n=38) in PCNSL to decompose tumor components. Tumor PBL components were identified in most PCNSL cases, although several cases exhibited a low presence of tumor PBL population. Of note, analysis including these public datasets with our single-cell cohort showed that PCNSL samples with high tumor PBL proportion had unfavorable prognosis . Additionally, we performed DSP to integrate the single-cell and spatial multi-omics analyses. We deconvoluted the cell composition by using transcriptomic data derived from each region of interest (ROI) and found that the cell proportions in ROI were consistent with the corresponding single-cell results. However, there were differential profiles of cell composition according to patients rather than ROIs, suggesting that PCNSL tumors may display spatial homogeneity (Figure B). Conclusion: Through the application of single-cell and spatial transcriptomic analysis, we identified a distinct subtype expressing the PBL signature gene. These findings have important therapeutic implications and provide new insights into the mechanisms of relapse in PCNSL.

Trial in Progress: An Open-Label Expansion Trial Evaluating the Safety, PK/PD, and Clinical Activity of Emavusertib (CA-4948) + Ibrutinib in R/R Primary CNS Lymphoma

Background: Primary central nervous system lymphoma (PCNSL) is a rare and aggressive form of NHL isolated to the central nervous system or vitreoretinal space. Despite high initial rates of responses to available therapies, most PCNLS relapse in two years, presenting a very poor prognosis. Combination with novel therapies may overcome resistance (Guidetti 2023a). Upregulation of the B-cell receptor (BCR/NF-κB) and toll-like receptor (TLR)/NF-κB) signaling axis have been identified as key pathways in the pathogenesis of PCNSL. MYD88 L265P, a widely expressed somatic mutation in more than 70% of PCNSL patients, activates NF-κB signaling through stimulation of BTK and IRAK4. Emavusertib (CA-4948) is a novel, potent oral inhibitor of interleukin 1 receptor-associated kinase 4 (IRAK4), with additional inhibitory activity against FMS-like tyrosine kinase 3 (FLT3) and CDC-like kinases (CLK1/2/4). Targeted inhibition of IRAK4 with emavusertib in PCNSL xenografts indicated sufficient blood brain barrier penetration of emavusertib, target inhibition, and antitumor activity (von Roemeling 2022). Further preclinical studies have demonstrated that emavusertib synergizes with ibrutinib and can re-sensitize and overcome resistance to BTK inhibitors (Guidetti 2023a and 2023b). Initial clinical data have reported responses in BTK-resistant PCNSL and good tolerance of the combination (Iqbal 2022; Grommes 2023). Study Design: This is an ongoing multi-center, open-label trial (NCT03328078) in adult patients with hematologic malignancies to evaluate the safety, PK, and anti-cancer activity of oral administration of emavusertib alone or in combination with ibrutinib. Part Bis an open trial expansion cohort with BTKi relapsed or refractory PCNSL. About 20 evaluable PCNSL patients will be enrolled globally. Patients will receive oral CA-4948 at 100 or 200 mg BID in combination with ibrutinib at 560 mg QD in 28-day cycles until disease progression or intolerable toxicity. The primary endpoint is expanded safety/tolerability; secondary endpoints include ORR, DOR, PFS, OS, and pharmacokinetics. Key inclusion criteria for this expansion cohort: pathologically confirmed diagnosis of PCNSL with evidence of disease progression, measurable disease, relapsed or refractory with no more than 3 lines of prior anti-PCNSL therapy (including BTKi), and absence of residual Grade ≥2 toxicity from prior therapy. Key exclusion criteria: intraocular PCNSL without brain lesion or CSF involvement or significant co-morbidity. Key clinical assessments include brain imaging, CSF- and ocular examinations.

Combination of Selinexor with BTK Inhibitor for Central Nervous System Diffuse Large B-Cell Lymphoma, Possible Mechanisms and Therapeutic Potential Exploration

Background: Primary central nervous system lymphoma (PCNSL) is a rare aggressive extra-nodal non-Hodgkin lymphoma (NHL) of which over 90% are diffuse large B-cell lymphoma (DLBCL). High-dose methotrexate (HD-MTX)-based regimens are the dominant therapy for newly diagnosed PCNSL, but the patients' complete remission rate (CRR) is merely about 50%. Bruton tyrosine kinase (BTK), a critical kinase in the B cell receptor (BCR) signaling pathway, contributes to the degradation of FOXO3a and promotes abnormal B cell proliferation. Recent studies revealed that BTK inhibitors (BTKi) play a role in various B cell lymphomas, including DLBCL, and have also shown promising efficacy in PCNSL. However, the clinical management of PCNSL is still challenging for its limited treatment options and poor prognosis, especially when patients developed acquired resistance to BTKi. Selinexor (KPT-330) is a first-ever oral small molecule Exportin-1 (nuclear output protein XPO1) inhibitor with a molecular weight of 443.31 Da, which can efficiently cross the blood-brain barrier. Currently Selinexor was found to promote the aggregation of FOXO3a and could synergistically inhibit PI3K/AKT and NF-κB pathways with BTKi to overcome acquired BTKi resistance. To investigate the therapeutic potential of Selinexor and BTKi in PCNSL, we examined the combination both in DLBCL cells and A20 transplantation mice, and further explored the clinical efficacy in PCNSL patients. Methods and Results: ABC-DLBCL cell lines (OCI-LY3 and OCI-LY10) were treated with Selinexor for 48 hours. Western blot analysis showed that Selinexor inhibited NF-κB, P-STAT3, and NFATc1 signaling pathways in DLBCL in vitro. Combining Selinexor(1μM) with ICP-022(2μM), a BTKi, resulted in more notable inhibition of the above tumor signaling pathways. A20 murine B-cell lymphoma transplantation models were divided into a control group, Selinexor monotherapy group, ICP-022 monotherapy group, and combination group. Tumor volume was measured after 30 days (Figures 1A), and the number of CD4+ T cells and CD8+ T cells and the corresponding cellular expression of PD-1 and TIM-3 in the spleen and tumor tissues of mice were detected. The results showed that the tumor volume in the combination group was minimized, and the number of CD4+ T cells and CD8+ T cells in spleens and tumors in this group was significantly increased, while PD-1 and TIM-3 expression was downregulated (Figures 1B-C). Based on these results, a prospective, open-label, single-arm, multicenter study was conducted with MSZ regimen (MTX, BTKi, Selinexor) for the treatment of PCNSL (Trial Registration Number: ChiCTR2200062154). Newly diagnosed primary and secondary central DLBCL patients (18-80 years old) received a 6-cycle MSZ regimen (HDMTX 3.5 g/m 2 3-h infusion d1, Zanubrutinib 160 mg Bid po, Selinexor 40 mg Biw po, 3 weeks per cycle) and evaluated by MRI/PET. 5 patients (2 GCB-DLBCL, 3 ABC-DLBCL) were enrolled, with a median age of 65 years (range: 54-73 years), 100% achieved metabolic remission (Figure 2A) and maintained long-term efficacy. 4 patients achieved early deep remissions of over 75% reduction with 1 cycle of treatment, and 1 patient had a complete remission after 2 cycles of treatment (Figures 2B). 3 patients chose radiation therapy as consolidation after the end of induction chemotherapy. 2 others were on maintenance therapy with Selinexor combined with Zanubrutinib, one of them has completed the two-year maintenance treatment and maintained sustained remission till now. Only 1 patient experienced several grade 3 adverse events (AEs) including anemia, decreased white blood cell and platelet counts, and elevated alanine aminotransferase.1 patient developed mild renal insufficiency, which recovered 6 months after the end of treatment. Patients were generally well-tolerated and there were no treatment-related deaths. Conclusion: This is the first report describing that Selinexor combined with BTKi can synergistically inhibit the DLBCL tumor signaling pathway and repairing the immune microenvironment. Correspondingly, in treatment of central DLBCL patients, the novel therapeutic strategy of MSZ regimen has achieved impressive results, with a CRR of 100%. Most patients attained early and rapid deep remissions with durable efficacy. This study provides theoretical support and preliminary clinical data for the combined application of Selinexor and BTK inhibitors.

Association between Microenvironment-Related Genes and Prognosis of Primary Central Nervous System Lymphoma

Background: Comprehensive gene mutation profiling of primary central nervous system lymphoma (PCNSL) revealed genomic abnormalities associated with the NFκB signaling pathway and immune escape (Chapuy B, et al. Blood 2016). Although this has led to advances in targeted therapy, there are only a few candidate biomarkers for diagnosis and prediction of survival in PCNSL. Recurrence still occurs at high rate of over 60% and therapeutic resistance is a significant challenge in the management of recurrent PCNSL. Until now, the systemic profiling of tumor micro-environment (TME) was performed through gene expression analysis by whole transcriptome analysis (WTA) and single-cell RNA sequencing analysis (Heming M, et al. Genome medicine 2022), and stratification in PCNSL was attempted by using spatial transcriptome analysis (Xia Y, et al. Leukemia 2023). However, TME of PCNSL and their impact on prognosis remain uncertain. Objective: We performed this study to investigate the prognostic impact on survival and establish novel prognostic biomarkers in PCNSL. Methods: We analyzed the expression levels of 770 neuroinflammation-related (NFR) genes by the NanoString nCounter technology in tumor samples from 30 PNCSL patients. The clinical significance of genes and their association with prognosis were assessed. Genes related to “worse prognosis (WP)” or “better prognosis (BP)” were identified. We performed the univariable analysis using a cox proportional hazards model to evaluate the predictive value of expression of genes related to WP and clinical risk factors, such as age, sex, serum lactate dehydrogenase level, Karnofsky Performance Status (KPS), consciousness levels at diagnosis and lymphoma involvement of the deep brain structure. Gene expression data related to WP were subjected to multivariate analysis with clinical variables with p values less than 0.15 in the univariate analysis. The genes associated with WP were further validated using WTA of an independent PCNSL cohort (n=30, previously published by Fukumura K, et al. Acta neuropathologica 2016). Results: The median age at diagnosis was 69 years old (range, 32-83). The median follow-up period was 25 months (range, 1-110 months), with overall survival (OS) at 3 years of 39.7% and progression free survival at 3 years of 25.4%. Notably, 48 of 770 NFR genes were highly expressed in the WP group (3-year OS, 22.2%), compared with the BP group (3-year OS, 66.7%) (Figure 1). We found that oligodendrocyte and astrocyte-related signatures were enriched in the WP-associated gene set. Among clinical prognostic factors, KPS &amp;gt; 70 (p=0.0293), and consciousness levels at diagnosis (other than JCS 0-1) (p=0.104) were relatively associated with poor OS (p &amp;lt; 0.15) in univariate analysis. Multivariate analysis revealed that high expressions of TUBB4A (p=0.028, HR:3.88), S100B (p=0.046, HR:3.093) and SLC6A1 (p=0.034, HR:3.765) were significantly related to death independent from KPS and consciousness levels at diagnosis. Expression levels of these 3 genes were also significantly associated with poor OS in a validation cohort. Conclusion: Our observations suggest high expression of TUBB4A, S100B and SLC6A1 are the clinical indicators to predict poor prognosis in PCNSL patients. Furthermore, these data suggest that genes related to TME may play a crucial role in the pathogenesis of PCNSL, complementing the well-known involvement of the NF-kB signaling pathway. Therefore it is necessary to continue research focused on TME-targeted therapeutics to encounter drug resistance and refractoriness in PCNSL.

Real-World Outcomes for Primary CNS Lymphoma from a Single Academic Institution: The Augusta Experience

Introduction: Primary central nervous system lymphoma (PCNSL) is a rare, aggressive, non-hodgkin lymphoma, characterized by exclusive confinement to the central nervous system. Outcomes are poor, with a 5 year overall survival of 30% with standard induction of high-dose-methotrexate (HD-MTX) based regimens followed by consolidation. Barring epidemiologic trends due to immunodeficiency disorders, PCNSL is a disease of the immunocompetent older patient (age &amp;gt;60 years). Incidence in those aged &amp;gt;70 years is 10 times higher than the general population. The overall survival hasn't significantly changed in 4 decades. We present retrospective data in a rural, elderly population in Georgia. Methods: We reviewed all patients diagnosed with PCNSL at our institution from January 1, 2013 to January 1, 2023. A retrospective chart review was conducted to assess for demographic factors, comorbidities, organ dysfunction, induction regimens, and consolidation treatments influencing patient care. Results: A total of 38 PCNSL patients were identified. 6 died and one was lost to follow-up prior to start of therapy and are not further analyzed here. All patients had DLBCL histology. The median age was 62.3 (21-82 years) with 54.8% male. Patients identified as non-Hispanic white (77.4%), African-American (9.68%), Asian (6.46%), Hispanic or Latino (3.23%), and multiracial (3.23%). The youngest patient aged 21 years had HIV/AIDS. 2 of 3 patients diagnosed in their 30s were on immunosuppression, for renal transplant and multiple sclerosis. No patients had hepatitis B or C. Medical comorbidities were common with 80.7% of patients having at least one which included HTN, TIIDM, history of CVA or CAD, and atrial fibrillation. 19.4% of patients had impaired renal function (CrCl &amp;lt;60 ml/min). Several patterns emerged when stratified by best treatment response at end of induction (EOI). Median follow-up was 12 mos (range: 0-66). Age, HIV status, gender, CrCl, positive CSF at baseline, or elevated LDH were not statistically significant predictors of response. This is probably due to the small sample size and missing data. Seizures at disease outset were associated with a statistically significant worse response to induction and all patients without seizures responded. This is likely a proxy for deep brain involvement and data are similar to CALGB 50202 where deep brain lesions independently correlated with a shorter progression-free-survival. Completion of ≥ 6 cycles of induction and a lower MTX level at discharge were predictors for response likely reflective of better organ function. Majority of patients with progressive disease received fewer than 6 cycles. A poorer EOI ECOG PS portended a worse response and all responders maintained an EOI PS of 0-2. Peak MTX level did not correlate with response. Sample size was too small to discriminate between discharge MTX thresholds of &amp;lt;0.05 vs 0.1 vs &amp;gt;0.15 however that will be an area of further investigation. Choice of induction regimen did not predict response statistically, however, all responders received HD-MTX-based combination chemotherapy (77.42%). 19.4% received HD-MTX alone and 3.2% received rituximab monotherapy. Only 8 (25.8%) of patients received consolidation. 7 received non-myeloablative therapy with 2 receiving additional WBRT and 1 patient received WBRT alone. Conclusion: PCNSL remains an area of high unmet need. Recently, IELSG43 and MARTA studies have shown that HD-MTX-based combination chemoimmunotherapy followed by autologous stem cell transplant leads to improved outcomes regardless of age; however, non-relapse mortality remains a concern. Our data comprising chiefly of an elderly cohort reiterate efficacy of combination chemo-immunotherapy and impact of number of induction cycles on response, despite age. Most common reasons for treatment discontinuation included performance status deterioration and death from disease or toxicity. A multidisciplinary approach with physical therapy, nutritionist, neurology, and geriatrics would be optimal, particularly for older and infirm patients. In addition, alternatives to consolidation such as targeted agent (e.g. Bruton tyrosine kinase inhibitor) maintenance should be considered to improve outcomes in the elderly. One patient at our center is receiving post-induction zanubrutinib with a complete remission to date (~16 mos). This will be a focus for a phase II clinical trial at our institution.

Primary Central Nervous System Lymphoma and Contemporary Clinical Prognostication

Background: Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma with two-year overall survival (OS) rates of 66-70% reported in prospective clinical trials. Induction therapy with high-dose methotrexate (HD-MTX) followed by consolidation has become the mainstay of treatment, however, there are few contemporary and robust prognostication indices widely available for clinical use. Some of the most used indices were developed prior to the routine use of rituximab and include the International Extranodal Lymphoma Study Group (IELSG; 1980-1999), Memorial Sloan-Kettering Cancer Center (MSKCC; 1983-2003), Nottingham/Barcelona (NB; 1986-2001), and Taipei Score (TS; 2003-2015). Herein, we describe a contemporary comparison of clinical prognostication indices using a single-center cohort of PCNSL patients treated at the Mayo Clinic. Methods: Patients with a diagnosis of PCNSL who received HD-MTX as part of induction therapy at Mayo Clinic between October 2010 and June 2022 were identified and retrospectively reviewed. Patients with prior or concurrent systemic lymphoma were excluded. Primary endpoints were progression-free survival (PFS) defined as time from diagnosis to relapse, progression, or death due to any cause; and OS defined as time from diagnosis to death due to any cause. PFS and OS were evaluated using Kaplan-Meier curves and compared by risk scores using a log-rank test. The association between baseline characteristics and survival outcome were assessed in univariate Cox regression models. Any characteristics showing significant (p-value &amp;lt;0.05) association with outcome were combined using a multivariate Cox regression model. All characteristics that maintained significant association with outcome were combined into a new prognostic model. We compared the performance of each prognostic index model using Harrell's C (HC). Results: A total of 148 patients were identified (50.7% female) with median age at diagnosis of 66 years (range 29-85), with 48 patients (32.4%) age &amp;gt;70 (Table 1). Most had multifocal disease (60.1%) and deep brain involvement (67.6%) at diagnosis with elevated CSF protein (58.1%) but no documented CSF involvement (93.9%). In total, 117 patients (79.1%) received methotrexate, rituximab, and temozolomide (MRT) induction therapy, and the remaining 31 patients (20.9%) received methotrexate and rituximab (MR) induction therapy with various consolidation strategies. The median follow-up for all patients was 4.5 years and the two-year OS was 79% (95% CI: 73-86%). This cohort was stratified using previously published prognostication indices (Table 1). Upon analysis, PFS was not accurately predicted using the IELSG (score 4-5: HR 0.7 (CI 0.3-2.0); HC 0.6), MSKCC (3: 1.3 (0.4-4.0); 0.5), NB (3: 0.9 (0.4-2.5); 0.6), or TS (3: 0.9 (0.1-7.2); 0.5) prognostication indices. Furthermore, OS was not accurately predicted using the IELSG (4-5: 1.5 (0.6-4.0); 0.6), MSKCC (3: 1.2 (0.5-3.2); 0.6), NB (3: 1.2 (0.5-3.2); 0.6), or TS (3: 1.3 (0.2-9.8); 0.6) prognostication indices. Upon multivariate analysis, no variables listed in Table 1 were associated with PFS within this cohort. The two variables predicting a worsened OS were an ECOG performance status of 2 or more (1.9 (1.01-3.6)) and an MR induction regimen instead of MRT (2.1 (1.05-4.3)) (Figure 1). The two-year OS with no risk factors was 86.1% (95% CI: 78.8-94.1%), one risk factor was 75.7% (95% CI: 63.6-90.1%), and two risk factors was 61% (95% CI: 43-86%) (Figure 1). Conclusions: This study reports overall improved outcomes in patients with PCNSL compared to prior prospective and retrospective cohorts, likely in part due to treatment advances and supportive care strategies. This single-center, retrospective cohort of rituximab-exposed patients with PCNSL were not well prognosticated using previously published indices, indicating that further study and more sophisticated approaches to prognostication are warranted. Although multivariate analysis did not demonstrate any variables associated with PFS, it did demonstrate an inferior OS with a performance score of 2 or more and in patients treated with MR rather than MRT.

High-Dose Methotrexate, Ibrutinib and Temozolomide (MIT) for the Treatment of Newly Diagnosed Primary Central Nervous System Lymphoma: A Multi-Center Prospective Phase II Study

Abstract Background: Primary central nervous system lymphoma (PCNSL) is a rare and aggressive subtype of B-cell lymphoma with poor survival. Genetic alterations often occur in the chronic active B-cell receptor signaling which mediate the response to BTK inhibition (BTKi) in PCNSL. However, the efficacy of traditional high-dose methotrexate-based regimen as a first-line treatment was suboptimal with a short effective remission time and low response rate. Therefore, we initiated this phase II trial to investigate the efficacy of novel induction combination of high-dose methotrexate (HD-MTX) plus ibrutinib and temozolomide (MIT), in the treatment of newly diagnosed PCNSL for the first time (ClinicalTrials.gov identifier: NCT04514393). Methods: Patients aged 18-75 years, newly diagnosed PCNSL and at least one measurable or evaluable lesion were enrolled. The MIT induction treatment included six cycles of HD-MTX (3.5 g/m 2, every three weeks), ibrutinib (560 mg/d, after HD-MTX clearance), and temozolomide (150 mg/m2 d1-d5, every three weeks). After the completion of the six cycles of MIT induction treatment, ASCT consolidation (only for patients &amp;lt; 65 years) or daily ibrutinib maintenance (560 mg/d) were administered up to two years, or until disease progression, intolerable toxicity, or death. Treatment response was evaluated by brain MRI and FDG-PET and/or cerebrospinal fluid (CSF) examination every two cycles of MIT treatment. The primary objective of this study was to evaluate the overall response rate (ORR) of MIT induction treatment. The safety profile of MIT was also investigated. At the same time, next generation sequencing (NGS) of baseline tissues and dynamic monitoring with CSF/ plasma ctDNA were performed by Nanjing Geneseeq Technology Inc. Results: Between July 2021 and October 2022, thirty-three patients were enrolled in this open-label, multi-center phase II prospective clinical study. The median age was 56 years (range: 27-75) and 17 of them were male. Eye involvement occurred in 5 patients (15%). Twenty-five patients (76%) had multiple cerebral lesions. The best ORR was 94% and complete response rate was 73%. The median follow-up was 17.5 months (range: 5.8-21.3 months) for survivors. Twenty-three patients underwent ibrutinib maintenance after 6 cycles of induction therapy. The swimmer plot of the 33 patients was shown in Figure 1. The 1-year progression-free survival was 66.4% (95%CI: 58.1-74.7%) and overall survival was 90.5% (95%CI: 85.2-95.8%) (Figure 2). Treatment-related toxicities were acceptable, with grade 3-4 neutropenia occurring in 9%, thrombocytopenia in 6%, subdural hematoma (SH) in 6%, and atrial fibrillation in 3%. The 2 patients with SH recovered following discontinuation of ibrutinib. No fungal infections and treatment-related deaths were observed. NGS of Tissue/CSF was tested in 30 patients, 19 (63%) of whom were classified as MCD subtype, 2 (7%) as BN2 subtype. The mutational profiles of baseline tissue and/or CSF samples revealed that PIM1 and MYD88 mutations were present in 75.9% and 65.5% of the entire cohort followed by BTG2 (55.2%) and CD79B (51.7%). Patients with dynamic CSF ctDNA monitoring during MIT treatment were analyzed (Figure 1). The consistence of ctDNA clearance in CSF/plasma samples and imaging complete remission was observed. Patients with clearance of ctDNA in the CSF after 2 cycles of MIT treatment achieved better PFS. Conclusions: The novel induction treatment of MIT achieved encouraging responses in newly diagnosed PCNSL patients with acceptable toxicities. The early clearance of ctDNA in CSF may be related to favorable survival. Disclosures No relevant conflicts of interest to declare.

Paired Circulating Tumor DNA in Cerebrospinal Fluid and Peripheral Blood: Reliable Technology for Diagnosing and Monitoring Primary and Secondary Central Nervous Lymphoma

Objective: This research delineates the temporal alterations of cell-free circulating tumor DNA (ctDNA) in the plasma and cerebrospinal fluid (CSF) of patients harboring primary and secondary central nervous system (CNS) lymphoma. The aim is to establish that CSF serves as a superior reservoir of ctDNA compared to plasma, thereby aiding in diagnostic processes and monitoring therapeutic efficacy. Concurrently, this study underscores the enhanced response and survival rates in patients administered Bruton's tyrosine kinase (BTK) inhibitors over an extended period exceeding three months. Methods: Data including cranial-enhanced magnetic resonance imaging (MRI) scans, leukocyte and protein concentrations in the CSF, exfoliated CSF cytology, flow cytometry, interleukin-10 to interleukin-6 ratios, ctDNA in plasma and CSF, were gathered from patients presenting primary and secondary CNS lymphoma（7 PCNSL,9 SCNSL）. The temporal ctDNA modifications in plasma and CSF during the patient's disease progression-initial onset, remission, and relapse-were scrutinized. Additionally, the implications of BTK inhibitor usage on patient response rates and survival rates were assessed. Results: Within the cohort of primary CNS lymphoma patients, ctDNA was detected in the CSF and plasma of 2 and 5 patients, respectively. Conversely, in patients with secondary CNS lymphoma, CSF and plasma ctDNA were discovered in 8 and 4 cases, respectively. The detection rate was contingent upon the central lesion's magnitude and position and the patient's surgical history related to the brain. Four patients, including two from each group, underwent cranial-enhanced MRI to appraise tumor burden at various disease stages, simultaneously with the monitoring of ctDNA in plasma and CSF. It was revealed that ctDNA levels in the CSF were in synchrony with the tumor burden, whereas plasma ctDNA levels remained relatively static. This indicates that CSF ctDNA may serve as a viable tool to assess therapeutic responses in CNS lymphoma patients. In two patients where surgical biopsy was unfeasible and both CSF exfoliation cytology and flow cytometry returned negative results, CSF ctDNA was positive, thereby underscoring its auxiliary role in diagnosing CNS lymphoma. Furthermore, the study indicated improved response and survival rates in patients subjected to BTK inhibitors for over three months. Conclusion: CSF ctDNA demonstrates potential in detecting CNS lymphoma and in the dynamic monitoring of therapeutic responses. Compared to cranial-enhanced MRI, exfoliated CSF cytology, and flow cytometry, CSF ctDNA testing offers superior sensitivity. For patients for whom brain surgical biopsy is not an option, CSF ctDNA testing emerges as a valuable supplementary diagnostic tool. CSF ctDNA allows for dynamic monitoring of therapeutic responses in CNS lymphoma patients, enabling the detection of residual lesions, and thereby guiding the formulation and duration of the treatment regimen. Patients administered oral BTK inhibitors for more than three months demonstrate higher treatment response and survival rates.

Outcomes in Routine Clinical Practice with Methotrexate-Temozolomide-Rituximab Induction and Modified Etoposide-Cytarabine Consolidation in Newly Diagnosed Primary CNS Lymphoma

Background: Recent studies have reported improved outcomes for patients with Primary CNS lymphoma (PCNSL) with addition of agents in induction (for e.g. cytarabine, thiotepa and rituximab in IELSG studies), intense consolidation (Autologous stem cell transplant (ASCT) as in IELSG 43) and intense non-myeloablative chemotherapy with etoposide/cytarabine (EA) as in CALGB 50202). Delivery of such an intense therapy is often difficult in clinical practice due to advanced age, comorbidities, poor performance status and resource constraints. We started using induction with methotrexate, temozolomide and rituximab (MTR) as per CALGB 50202 study however the intense non-myeloablative EA consolidation was not feasible. We used a strategy of reduced dose EA consolidation for 2 cycles with etoposide at 100 mg/m 2 over 2 hours and cytarabine 2 gm/m 2 twice daily for 2 or 3 days based on clinical judgement of the treating physician. Here we report outcomes with this approach in newly diagnosed PCNSL patients treated at our centre. Method: We did a retrospective analysis of patients with newly diagnosed PCNSL treated with MTR induction followed by modified EA consolidation. Kaplan-Meier was used to estimate progression free (PFS) and overall survival (OS). Variables influencing the outcomes with P less than 0.05 were considered significant. Results: Between January 2015 to December 2022, 72 patients were treated with above protocol with a median age of 46.5 years (range, 17 to 68 years) and 50 (69.4%) were males. Median ECOG performance score at presentation was 1 with 16 (22%) patients having ECOG performance score of 3 or more. IELSG scores were high and intermediate risk in 26 (36.1%) and 27 (37.5%) respectively while only 7 (9.7%) were in the low risk (data was not available for remaining 12 (17%) patients). MSKCC scores were available for all patients with 43 (59%) patients in class 1, 14 (19%) patients in class 2 and 15 (20%) patients in class 3. MTR induction with a dose of 8 gm/m2 could be delivered for all 4 cycles in 64 (88%) patients. Dose reduction was required in 14 (19.4%) patients; reasons were renal dysfunction in 8 (11%), infections in 3 (4%), liver dysfunction in 2 (3%). Nine patients (12.5%) had disease progression during induction. Total of 54 patients received consolidation with systemic therapy. Dose reduced EA consolidation was delivered in 46 (63%) patients while 8 patients received single agent high dose cytarabine consolidation and only 3 patients underwent ASCT. Seven patients received WBRT consolidation. EA consolidation was given for 2 days in 30 (65%) patients while 16 (35%) patients received 3 days of EA consolidation. Twenty six patients received maintenance lenalidomide. With a median follow up of 39.2 months (range, 2.1 to 91), median PFS is 46.9 months and median overall OS has not reached. Three years PFS &amp; OS for all patients is 59.5% and 78% respectively ( Fig 1A &amp;B). Median PFS and OS of patients receiving EA consolidation has not been reached with a 3-year PFS and OS of 77% and 79% respectively. MSKCC score was predictive of OS with 3 year OS in class 1, 2 and 3 of 89.5%, 68% and 58% respectively. Consolidation with split dose EA was associated with better OS and PFS as compared to single agent cytarabine alone. None of the 3 patients receiving ASCT have relapsed. Patients receiving full dose methotrexate had better OS compared to patients requiring dose reduction. Two versus 3 day EA consolidation had no impact on OS. MTR induction was well tolerated with grade 3 or more toxicity as follows: renal dysfunction in 8 (11%) patients, transaminitis in 4 and febrile neutropenia in 4 patients with no treatment related deaths. EA consolidation resulted in 18 episodes of febrile neutropenia with two deaths. Grade 3 or more hematologic toxicities were common with grade 3 or more anaemia, neutropenia and thrombocytopenia in 15 (32%), 40 (86%), 33 (71%) patients respectively. There were two deaths in the consolidation phase, one due to intracranial bleeding and another due to febrile neutropenia. Conclusion: MTR induction with modified EA consolidation is feasible and results in optimal outcomes in real world setting. Higher cumulative methotrexate dose and use of EA consolidation were associated with better OS. These outcomes compare favourably to CALGB 50202 study and represent a feasible option in resource limited setting.

High-Dose Methotrexate Containing Induction Chemotherapy Followed By Nivolumab Consolidation in Older (≥ 65) Patients with Previously Untreated Primary CNS Lymphoma

Introduction: High-dose methotrexate (HD-MTX)-containing chemotherapy followed by either autologous stem cell transplant (ASCT) or whole-brain irradiation (WBI) is widely considered the standard for primary CNS lymphoma (PCNSL) treatment. However, many older frail patients with PCNSL are unable to undergo ASCT or WBI due to increased risk of treatment-related toxicity, such as infections and neurotoxicity. Without consolidation, survival outcomes are significantly worse, with a 3-year progression free survival (PFS) rate of ~ 30%. Therefore, novel therapeutic approaches are urgently needed for older PCNSL patients. Recently, nivolumab, an anti-PD1 antibody, showed promising clinical activities in relapsed/refractory PCNSL, and we hypothesized that addition of nivolumab in the frontline setting would be safe and improve survival outcomes of older PCNSL patients who are deemed poor candidates for ASCT or WBI. Methods: In this phase 1/1B single-arm multicenter study, patients ≥ 65, who were deemed poor candidates for ASCT and WBI, with previously untreated PCNSL received at least 3 cycles of HD-MTX-containing chemotherapy followed by nivolumab consolidation for 6 cycles (NCT 04022980). Patients with systemic lymphoma or known ocular involvement were excluded from the study. Stage 1 was designed to evaluate the safety of nivolumab consolidation after HD-MTX-containing induction chemotherapy. A 3+3 design was used as safety run-in, initiating 6 patients on nivolumab at the FDA-approved single-agent dose and monitoring for dose-limiting toxicities (DLTs) during Cycle 1. If less than 2 out of 6 subjects experienced a DLT, then the stage 2 part of study would initiate to evaluate the efficacy of nivolumab consolidation in terms of the 2-year PFS. The patient's neurological function was assessed at baseline and throughout the study follow-up using the Neurologic Assessment in Neuro-Oncology (NANO) scale. Results: A total of 14 patients enrolled in the study between April 2020 and December 2022 at 4 US sites. In 14 evaluable patients who underwent the study treatment, the median age was 72 years (range, 65-79), 71% patients were female, and 35% patients had ECOG score of 2 or 3. Variations of the following regimens were used for induction: 43% R-MPV (rituximab, methotrexate, procarbazine, and vincristine) (43%), 29% MRT (methotrexate, rituximab, and temozolomide), 21% MR (methotrexate and rituximab), and 7% MATRix (methotrexate, cytarabine, thiotepa, and rituximab). After induction, 58% achieved a complete response (CR), 33% achieved a partial response (PR), and 8% had a stable disease (SD). Patients received a median of 6 cycles of nivolumab consolidation. Patients who received at least 1 cycle of nivolumab consolidation achieved an overall response rate of 83% with a CR rate of 75%. With a median follow-up duration of 18 months, the 1-year overall survival (OS) and PFS rates were 91.7% and 66.1%, respectively. No DLTs were observed during Cycle 1 of nivolumab consolidation in Stage 1. The most common grade ≥ 3 Adverse Events (AEs) associated with nivolumab consolidation included neutropenia (14%) and fatigue (7%). One patient (7%) developed a grade 4 Stevens-Johnson syndrome associated with sepsis and acute kidney injury, requiring discontinuation of nivolumab after Cycle 1. Conclusion: The current study demonstrates encouraging safety and clinical outcomes of nivolumab consolidation in older PCNSL patients who are deemed poor candidates for ASCT or WBI. No DLT was observed during the safety run-in phase, and there was no unexpected toxicity associated with nivolumab although 1 patient discontinued the study treatment due to Stevens-Johnson syndrome, a rare but known AE associated with nivolumab, after Cycle 1. Overall, nivolumab consolidation was associated with favorable survival rates in a group of patients with poor-risk PCNSL. We are in the process of identifying various clinical and biological factors, including 9p24.1 copy number alteration, in association with the response to nivolumab consolidation. Furthermore, changes in the neurological function based on the NANO scale assessed before and after the nivolumab consolidation are being analyzed.