Secondary Central Nervous System Lymphoma Research Articles

Retrospective Review of Patients Treated with Intrathecal Rituximab for Primary and Secondary CNS Lymphoma and Leukemia

Background: Rituximab has been studied and incorporated into the treatment of primary and secondary CNS lymphoma (Grommes 2017; Bobillo 2023). Systemic rituximab, a CD20-targeting monoclonal antibody, is widely used in the treatment of various B-cell malignancies (Klein 2021); however penetration into the central nervous system (CNS) is limited (Petereit 2009; Harjunpää 2001). Although there are conflicting data regarding the efficacy of IV rituximab in primary CNS lymphoma (Schmitt 2019; Ferrari 2022; Bromberg 2019), its role in other B-cell malignancies with CNS involvement has not been adequately described. In particular, its role in treating the cerebrospinal fluid (CSF) space is unclear. The rationale for direct administration of rituximab into the CSF via lumbar puncture or Ommaya reservoir is to allow for consistent treatment of this compartment in order to effectively clear the CSF of lymphoma cells (Kadoch 2014). Limited data exist regarding the efficacy and safety of intrathecal rituximab (Bonney 2011 Aslan 2022; van de Fling 2008; Santiago 2021; Soares 2019). Current intrathecal armamentarium for leptomeningeal lymphoma is very limited and more data on the efficacy and safety of intrathecal rituximab is needed in these patients. Methods: This is a retrospective, single center study of adult patients with a diagnosis of leukemia or lymphoma who received intrathecal (IT) rituximab between 1/1/2016 and 12/31/2022 at Hackensack Meridian Health. Rituximab 25 mg IT was administered weekly either via lumbar puncture or into an Ommaya reservoir. The primary objective of this study was to evaluate the efficacy and safety of IT rituximab. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan Meier method. Descriptive statistics were used to summarize data for categorical and continuous variables. Results: Twelve patients were identified to have received IT rituximab at our institution between 1/1/2016 and 12/31/2022. Median age was 60 years (range 45-81), 54% were male, and 69% white. Disease types included primary CNS lymphoma (67%), diffuse large B-cell lymphoma (17%), PTLD of the CNS (8%), and chronic lymphocytic leukemia (8%). In regards to CNS disease involvement, 58% of patients presented with parenchymal and leptomeningeal disease, 33% with leptomeningeal disease only, and 8% with parenchymal disease only. There were 12 patients who received IT rituximab for the treatment of malignant CNS disease with characteristics and outcomes as shown in Table 1. The median number of IT rituximab treatments administered were 8 (range 2-9). Of the 10 patients evaluable for response, 92% of patients achieved complete response in the CSF following treatment with IT rituximab as evaluated by flow cytometry, cytology, cell count and protein levels in CSF. One patient that did not achieve CSF remission has an unusual case of relapsing/remitting CLL and leukemic meningitis. There were 2 patients unevaluable for response to IT rituximab: one patient received only 2 treatments prior to switching to hospice care; and the other patient had a severe adverse reaction (tightening of throat, flushing, toe numbness) after IT rituximab and was not continued on treatment. At a median follow-up of 19.7 months, median PFS was not reached (NR) (95% CI, 0.5-NR) ( Figure 1). Median OS was 70.1 months (95% CI, 1.2-NR). Six (50%) patients experienced adverse reactions from IT rituximab treatment, including perioral numbness, headache, nausea, and flushing ( Table 1). No treatment-related deaths occurred. One (8%) patient experienced a severe adverse reaction following administration of IT rituximab. This patient developed tightening of the throat, flushing, and toe numbness after the first IT rituximab and symptoms resolved with administration of hydrocortisone and diphenhydramine. No further IT rituximab doses were administered. Another patient experienced a mild reaction consisting of headache, fatigue, nausea, diaphoresis, hypotension, and bradycardia following the fourth dose of IT rituximab in combination with IV rituximab, but was able to complete his treatment course. Conclusions: The use of IT rituximab appears safe and showed promising activity in B cell malignancies, specifically as part of induction in patients with leptomeningeal disease and PCNSL as those patients achieved cytologic response.

Functional Outcome and Overall Survival in Patients with Primary or Secondary CNS Lymphoma after Surgical Resection vs. Biopsy

Background: Central nervous system lymphoma (CNSL) is rare form of brain tumour. It manifests either as primary CNS lymphoma (pCNSL) originating within the central nervous system or as secondary CNS lymphoma (sCNSL), arising as cerebral metastases of systemic lymphoma. For a significant period, surgical resection was considered obsolete due to the favourable response to chemotherapy and the associated risk of postoperative deficits. The objective of the present study was to demonstrate the benefits of resection in CNSL patients, including extended survival and improved postoperative function. Methods: A retrospective study involving patients diagnosed with either PCNSL or SCNSL that were surgically approached at our neurosurgical department between 2010 and 2022 was conducted. Patients were categorised into three subgroups based on their neurosurgical approach: (1) stereotactical biopsy, (2) open biopsy, (3) resection. We then performed statistical analyses to assess overall survival (OS) and progression-free survival (PFS). Additionally, we examined various secondary factors such as functional outcome via Karnofsky Performance Index (KPS) and prognosis scoring. Results: 157 patients diagnosed with PCNSL or SCNSL were enclosed in the study. Of these, 101 underwent stereotactic biopsy, 21 had open biopsy, and 35 underwent resection. Mean age of the cohort was 64.94 years, with majority of patients being female (54.1%). The resection group showed longest OS at 44 months (open biopsy = 13 months, stereotactic biopsy = 9 months). Calculated median follow-up was 34.5 months. In the Cox regression model, postoperative KPS 70% (p < 0.001) and resection vs. stereotactic biopsy (p = 0.040) were identified as protective factors, whereas older age at diagnosis was identified as a risk factor (p < 0.001). In the one-way analysis of variance, differences in postoperative KPS were found among all groups (p = 0.021), while there was no difference in preoperative KPS among the groups. Conclusions: Our data show a favourable outcome when resection is compared to either stereotactic or open biopsy. Additionally, the marginally improved postoperative functional status observed in patients who underwent resection, as opposed to in those who underwent biopsy, provides further evidence in favour of the advantages of surgical resection for enhancing neurological deficits.

Whole Exome Sequencing Analysis of Diffuse Large B-Cell Lymphoma That Progressed to Central Nervous System

Background: Recent sequencing analyses have identified distinct genetic subtypes of diffuse large B-cell lymphoma (DLBCL). The MCD subtype, characterized by MYD88 L265P and CD79B gene mutations, is frequently found in DLBCL that progresses to the central nervous system (CNS), known as secondary CNS lymphoma (sCNSL) (Ollila, Blood 2021). In addition, the MCD subtype is also frequently found in primary CNS lymphoma (PCNSL) (Radke, Nat commun 2022). Therefore, we hypothesized that specific genetic alterations that are present in the initial DLBCL tumors are associated with their progression to the CNS. We aimed to investigate i) the clinical impact of genetic subtypes of DLBCL and ii) genomic mutations that may be associated with sCNSL. To this end, genetic alterations in DLBCL samples at diagnosis that later developed into sCNSL were evaluated using whole-exome sequencing (WES). Methods: A total of 44 patients with DLBCL who developed sCNSL after receiving standard rituximab-containing chemotherapy between 2009 and 2020 were identified from five institutions. sCNSL was diagnosed on the basis of imaging and/or pathological findings. Genomic DNA (gDNA) was extracted from formalin-fixed, paraffin-embedded tumor samples obtained at the initial diagnosis of DLBCL. Finally, 26 of the 44 samples with sufficient gDNA were subjected to WES at BGI Genomic Co. Ltd. Single-nucleotide variants and short indels were detected using Mutect2 and filtered as described in Figure 1. Genetic subtypes were determined using the LymphGen algorithm (https://llmpp.nih.gov/lymphgen/index.php). The association between the clinicopathological features and genetic subtypes was also evaluated. In addition, recurrently mutated genes (>10% in our cohort) were identified and their alteration frequencies were compared with those in a representative general DLBCL cohort (N=574, available in the article by Schmitz, NEJM 2018) and PCNSL cohort (N=30, whole genome sequencing performed, available in the article by Radke, Nat Commun 2022) (Figure 1a). Results: The median age of the 26 patients was 69 years (range, 34-87). At the time of CNS progression, 54, 27, and 19% of the patients had parenchymal CNS disease, extraparenchymal CNS disease, and both, respectively. Immunohistological analysis showed that the non-germinal center B-cell-like (GCB) type, as defined using the Hans algorithm, and dual expression of MYC and BCL2 (DEL) were identified in 65% and 69% of patients, respectively. The median overall survival (OS) from CNS relapse was 16 months (95% confidence interval, 2-30). WES analysis showed that the median mean coverage depth of the 26 samples was 140 (range, 53-299). The median mapping rate was 94% (range, 80-99). As expected, the most frequently mutated genes in our cohort were MYD88 (50%), PIM1 (50%), BTG2 (31%), and CD79B (31%), corresponding to the MCD subtype. The LymphGen algorithm classified the 26 samples into MCD (n=12, 46%), EZB (n=5, 19%, including one with a composite feature of ST2), BN2 (n=1, 4%) and “not classified” (n=8, 31%) (Figure 1b). The CNS-IPI risk, DEL status, and CNS relapse sites did not differ among the genetic subgroups. In addition, univariate analysis showed that non-GCB status, DEL status, and genetic subtype at initial diagnosis did not influence OS. Next, we shortlisted 38 genes whose mutations were identified in three or more samples (>10%) of our cohort as well as in >10% of the PCNSL cohort (by Radke, Nat Commun 2022). We further selected genes that were less frequent (<3%) in the general DLBCL cohort and identified several genes, such as MUC16 and FAT4, that were more enriched in PCNSL and our sCNSL cases (Figure 1a). Metascape analysis (https://metascape.org/gp/index.html#/main/step1) revealed that the top three enriched processes associated with these genes were sensory organ development, cell adhesion via plasma membrane adhesion molecules, and morphogenesis of epithelium. Conclusion: Our study confirmed that MCD was a major genetic subtype of DLBCL that developed sCNSL. We identified recurrently mutated genes that were common in both sCSNL and PCNSL but not in the general DLBCL cohort; these genes may be associated with CNS progression. Validation of our results and investigation of the functions of these genes will help to understand the mechanisms of CNS relapse and develop more accurate markers to predict sCNSL. *Suzuki T and Yokomori R equally contributed to this study.

Efficacy and Safety of TLR2 Co-Stimulated CAR T Cells in CD19-Positive Lymphoid Malignancies with Central Nervous System Involvement

Background CD19 chimeric antigen receptor (CAR) T cell therapy showed remarkable remission rates in patients with refractory or relapsed (R/R) non-Hodgkin's lymphoma (NHL) and acute lymphoblastic leukemia (ALL). However, data on outcomes of CAR T cell therapy for patients with central nervous system (CNS) involvement are limited, as most of them have been excluded from most pivotal CAR-T studies because of concerns about treatment-related neurotoxicity. Here, we show results of a third generation of CD19 CAR T cells for patients with R/R B cell cancers with CNS involvement in a single-center cohort study. Methods A total of 21 patients with R/R B cell malignancies (including ALL and NHL) with CNS involvement were included in this study. Patients derived peripheral lymphocytes were collected through apheresis and lentivirally transduced with a 3 rd generation CAR containing CD28 and TLR2 co-stimulatory domains. The cells were expanded ex vivo and administered in a single infusion (1×10 6 or 2×10 6 CAR T cells per kilogram of body weight) after a conditioning regimen of cyclophosphamide and fludarabine. Results Of the 21 patients with CNS involvement, 11 patients with ALL and 10 with NHL were included in this study, with a data cutoff of July 2023. All 11 patients with ALL had both bone marrow (BM) and cerebrospinal fluid (CSF) involvement. Of the 10 patients with NHL, 5 of the 10 lymphoma patients had parenchyma involvement, 6 patients (6/10) had CSF infiltration and 1 had oculus sinister involvement; the majority of patients (8/10) were diagnosed with secondary CNS lymphoma, whereas 2 patient was primary CNS lymphoma. Of the 21 patients who were treated, the overall response rate (ORR) was 71% (15/21), with 73% (8/11) in ALL and 70% (7/10) in NHL. 67% of patients with ALL (7/11) had a complete remission in both BM and CSF, while 40% of NHL patients (4/10) had a complete response and 30% (3/10) received a partial response. The median overall survival (OS) of ALL was 14.3 months, with a median follow-up of 20.3 months, while the median OS of NHL was not reached with a median follow-up of 14.2 months. Median progression-free survival (PFS) of ALL and NHL were 11.1 months (95% CI, 0.7-29.9 months) and 4.8 months (95% CI, 1.0-15.3 months), respectively (P = 0.84). In the total CNS cohort, cytokine release syndrome (CRS) of any grade was seen in 20 patients (95%), grade 3 in 3 patients (14%). ICANS occurred in 9 patients (42.8%, including 5 ALL and 4 NHL patients), grade 3 in 5 patients (23.8%), and there was no grade 4 event. Median time to ICANS was 5 days (range, 2-10 days) after CAR-T infusion. All the CRS or ICANS were manageable. No significant difference in occurrence of and time to ICANS was seen between ALL and NHL patients (P = 0.22 and 0.96). CAR T cells were identified in CSF of patients following infusion, and the median time to peak CAR T cells in CSF of ALL and NHL were 6.5 days and 10 days post-infusion, respectively (P = 0.141). Median time to last documented follow-up of all patients (alive or dead) was 18.1 months (range 1.0-31.2 months). At the end point of observation, 5 of the 11 ALL patients and 5 of 10 NHL patients were still alive with sustained CR of CNS disease and systemic disease (Figure 1). Conclusion TLR2-costimulated CAR T cell therapy for patients with R/R B cell malignancies with CNS involvement is safe, feasible, and results in high response rates and durable remission in both ALL and NHL patients with CNS disease. The clinical trial was registered at www.clinicaltrials.gov as # NCT04605666.

CD19/CD22 CAR T-Cell Therapy Following Autologous Transplantation Is an Optimizing Strategy in Relapsed/Refractory Central Nervous System Lymphoma

Background and Objectives: Relapsed/refractory (R/R) primary and secondary central nervous system lymphomas (PCNSL, SCNSL) are associated with short survival and represent an unmet need, requiring novel effective strategies. Methods: We retrospectively compared the safety and efficacy of CD19/22 CAR T-cell therapy combined with HDT-ASCT (ASCT+CAR-T group), CD19/22 CAR T-cell cocktail therapy (CAR-T group) and targeted drugs combined with chemotherapy (Targeted drugs group) in treating R/R CNSL patients. Results: The median age of the Targeted drugs group is older than that of the other two groups, 73.3%, 100% and 41.2% patients were secondary CNS lymphoma in ASCT+CAR-T group, CAR-T group and Targeted drugs group, respectively. The incidence of Grade 3/4 hematological toxicities in ASCT+CAR-T and CAR-T group was more than Targeted drugs group. Patients in two CAR-T therapy group exhibited comparable incidence and severity of CRS and ICANS. The ORR was 83.3% in ASCT+CAR-T group, 64.3% in CAR-T group and 58.8% in Targeted drugs group respectively (Figure 1). As of December 31, 2022, the median follow-up time after therapy was 15.53 months (range, 0.53-50.53 months). The median duration of OS and PFS was not reached in the ASCT+CAR-T group. The median PFS and OS in the CAR-T group were 3.07 months and 9.67 months, respectively. In the Targeted drugs group, the median PFS and OS were 6.63 months and 12.30 months, respectively. The 1-year PFS and OS rate of the patients in the ASCT+CAR-T group (66.67% and 76.52%) was significantly higher than that of the patients in the CAR-T group (18.75% and 50%) ( P=0.0006 and P=0.0253) and targeted drugs group (17.65% and 52.94%) ( P=0.0004 and P=0.0358) (Figure 1). In both univariable and multivariate analysis, PD before treatment was indicated worser PFS (HR: 3.134, 95% CI, 1.144 to 8.587, P=0.026), rather than OS, both in ASCT+CAR-T and CAR-T group and compared with CAR-T group, patients received ASCT+CAR-T treatment had better PFS (HR: 0.279, 95% CI, 0.120 to 0.651, P=0.003), rather than OS. PFS and OS of patients with PD before treatment, patients with ECOG ≥2, with high risk factors, and with＞3 prior lines of therapy in the ASCT+CAR-T group were superior to CAR-T group (Supplementary Figure 1). In the ASCT+CAR-T group, PFS, rather than OS, of patients without systemic disease in the ASCT+CAR-T group was superior to those with systemic disease ( P=0.0335). Discussion: Our results support the development of CAR T -cells in R/R CNSL. With the durability of remission and low toxicity, ASCT combined with CART therapy appears to be a more effective and safe treatment option for primary and secondary relapsed/refractory CNS lymphoma.

This Is a Title in Title Case: A Retrospective Study for 14 R/R DLBCL Patients

This study retrospectively analyzed 14 R/R DLBCL patients who received combined treatment of obutenib in Fujian Medical University Union Hospital from July 2021 to April 2023. Except for four patients using Orelabrutinib as post-second line treatment, all the other patients received 1 to 8 course Orelabrutinib as second line treatment. The combined chemotherapy regiments include R-EPOCH and R-DHAP. Among them, there were 8 males (57.1%) and 6 females (42.9%), with a median age of 56/57 (39-79) years. The median follow-up time was 11 (3-27) months. At the time of diagnosis, there were 12 cases (85.7%) in the Ann Arbor stage III-IV, 7 cases (50.0%) with an IPI score of 3-5, 6 cases (42.9%) with non GCB type, 8 cases (57.1%) with double expression, 2 cases (14.3%) with primary central nervous system lymphoma, and 6 cases (42.9%) with secondary central nervous system lymphoma. All patients had extranodal involvement, with 10 cases (71.4%) with ≥ 2 extranodal lesions and 8 cases (57.1%) with elevated LDH. At the end of treatment, the ORR and DCR were 42.9% and 28.6%, respectively, with a median PFS of 7 (95% Cl: 4-12) months and a median OS not achieved. Among them, the ORR and DCR of central nervous system lymphoma were 75.0% and 50.0%, respectively, with a median PFS of 9.5 (95% Cl: 6-22) months, and the median OS was not reached. Neutropenia (n=2, 14.3%) is the most common level 3/4 adverse event. No patient died due to adverse reactions.This study suggests that the combination of Orelabrutinib and chemotherapy has an excellent therapeutic effect in R/R DLBCL, especially in CNSL.

GLOBRYTE: A Phase III, Open-Label, Multicenter, Randomized Trial Evaluating Glofitamab Monotherapy in Patients with Relapsed or Refractory Mantle Cell Lymphoma

Background and Significance: There is currently no standard of care for patients (pts) with relapsed or refractory (R/R) mantle cell lymphoma (MCL). Although Bruton tyrosine kinase inhibitors (BTKi) have improved clinical outcomes in R/R MCL, there is a high unmet need for new treatment options for pts who do not respond to, or progress through, BTKi therapy. Chimeric antigen receptor (CAR) T-cell therapies, such as brexucabtagene autoleucel, have shown promising outcomes, but alternative systemic therapies are still needed in this pt population. Glofitamab is a CD20xCD3 T-cell-engaging bispecific antibody that redirects T cells to eliminate B cells. A Phase I/II trial of glofitamab monotherapy with step-up dosing (SUD) and obinutuzumab pretreatment (Gpt; 1000 or 2000mg) to mitigate the risk of cytokine release syndrome (CRS) showed high and durable complete response (CR) rates (73.0%) and manageable, mostly low-grade CRS in heavily pretreated pts with R/R MCL (n=37), most of whom had failed prior BTKi therapy (Phillips et al. ASH 2021, Phillips et al. ASH 2022). Study Design and Methods : The GLOBRYTE study (GO43878; EU CT: 2023-503206-37-00) is a Phase III, open-label, multicenter, randomized, controlled trial that will evaluate the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (biomarkers) of glofitamab monotherapy in pts with R/R MCL, in comparison with an investigator's choice of rituximab + bendamustine (BR) or rituximab + lenalidomide (R-Len). Pts with histologically confirmed R/R MCL who have received ≥1 prior line of systemic therapy (including a BTKi) and have an Eastern Cooperative Oncology Group performance status of 0-2 are eligible for enrollment. Exclusion criteria include leukemic, non-nodal MCL; prior CAR T-cell therapy or CD20xCD3 bispecific antibodies; primary or secondary central nervous system (CNS) lymphoma or history of CNS lymphoma; and current or prior CNS disease (including stroke or transient ischemic attack in the past 2 years and residual neurologic deficits, epilepsy, or CNS vasculitis). Eligible pts will be randomly assigned (1:1) to receive glofitamab or investigator's choice of BR or R-Len stratified by line of therapy (1 vs ≥2) and response to last therapy (relapsed vs refractory). Pts will receive intravenous (IV) Gpt (2000mg) on Day (D) 1 of Cycle (C) 1, 7 days prior to the first glofitamab dose (Gpt may be split over 2 days as 1000mg doses if needed: the second 1000mg dose must be administered ≥1 day before initial glofitamab treatment). Pts will receive glofitamab for a fixed duration of 12 cycles, unless progressive disease (PD) or unacceptable toxicity occurs earlier. Glofitamab IV SUD will be given on C1D8 (2.5mg), C1D15 (10mg), and then the target dose (30mg) on D1 of C2-12 (21-day cycles). Pts randomized to the investigator's choice will receive 375mg/m 2 IV rituximab on D1 in combination with either 90mg/m 2 IV bendamustine on D1-2 of each cycle (BR for six cycles) or 20mg/day oral lenalidomide on D1-21 of each cycle (R-Len until PD); the cycle length for BR or R-Len is 28 days. Crossover to glofitamab from the investigator's choice is permitted in pts with radiologic confirmation of PD ( Figure). The primary endpoint is progression-free survival (PFS) determined by independent review committee (IRC). Treatment comparisons will be made with a 2-sided, level 0.05 stratified log-rank test. Secondary endpoints include overall survival (OS); IRC- and investigator-assessed CR rate, objective response rate, duration of response, and duration of CR; PFS (investigator-assessed); safety; health-related quality of life including time to deterioration in physical functioning or fatigue evaluated by the EORTC QLQ-C30; glofitamab PK; and immune response to glofitamab (including presence of anti-drug antibodies). Response will be determined according to Lugano criteria (Cheson et al. J Clin Oncol 2014). Stratified hazard ratios with 95% confidence intervals (95% CI) will be calculated for PFS and OS, and odds ratios (95% CI) will be calculated for the difference in CR rate and overall response rate between treatment arms. Predictive and prognostic biomarkers (to characterize high-risk subgroups and minimal residual disease kinetics) will also be explored. An estimated 80 sites globally will enroll approximately 182 pts with R/R MCL (glofitamab n=91; BR or R-Len n=91 total) starting in Oct-Nov 2023 (APAC, US, and EU regions).

Evidence-based management of primary and secondary CNS lymphoma

Central nervous system (CNS) lymphoma has traditionally had very poor outcomes however advances in management have resulted in dramatic improvements and long-term survival of patients. We describe the evidence for treatment strategies for these aggressive disorders. In primary CNS lymphoma there are randomized trial data to inform treatment decisions but these are lacking to guide management in secondary CNS lymphoma. Dynamic assessment of patient fitness and frailty is key throughout treatment, alongside delivery of CNS-bioavailable therapy and enrolment in clinical trials, at each stage of the disease. Intensive high-dose methotrexate-containing induction followed by consolidation with autologous stem cell transplantation with thiotepa-based conditioning is recommended for patients who are fit. Less intensive chemoimmunotherapy, novel agents (including Bruton tyrosine kinase inhibitors, cereblon targeting immunomodulatory agents, and checkpoint inhibitors in the context of clinical trials), and whole brain radiotherapy may be reserved for less fit patients or disease which is chemoresistant. Data regarding the efficacy of chimeric antigen receptor T-cells therapy is emerging, and concerns regarding greater toxicity have not been realized. Future areas of prospective studies include the identification of those at high risk of developing CNS lymphoma, management in elderly or frail patients as well as incorporating novel agents into regimens, particularly for those with chemoresistant disease.

Salvage Radiotherapy as a Bridge for Relapsed Secondary CNS Lymphoma.

Secondary CNS lymphoma (SCNSL) is a challenging clinical scenario observed in 2-5% of non-Hodgkin lymphoma patients, for which a standard of care has not been defined. We studied the indications for, and outcomes of SCNSL patients referred for radiotherapy (RT). We identified patients with aggressive B cell lymphoma who received brain RT for SCNSL between 1999-2023 at a tertiary cancer center. Patients were grouped and analyzed by RT indication. Overall survival (OS) was determined from RT start using the Kaplan-Meier method. OS analysis comparing patients who did and did not receive therapy after RT was landmarked at 60 days from start of RT to minimize immortal time bias. "SCNSL-directed therapy" is defined as systemic therapy for the treatment of SCNSL, as opposed to CNS prophylaxis. We identified 99 SCNSL patients treated with RT. To account for the heterogeneity of RT referrals, we focused on the most common indication: salvage of radiographic progression after SCNSL-directed systemic therapy (n = 58). Among this group, median age was 62 (interquartile range [IQR]: 48-69) and 86% had diffuse large B cell histology. At initial lymphoma diagnosis, 10% of patients had CNS involvement, 90% received Rituximab-based therapy, and 25% received prior CNS prophylaxis. For SCNSL directed therapy, 90% received methotrexate (MTX)-based regimen. Median time from initial SCNSL diagnosis to RT was 4.4 months (IQR 1.7-7.0), with a median of 2.0 lines of therapy prior to RT (IQR 1.0-3.0). 86% of patients were symptomatic at RT with median KPS of 70 (IQR: 60-80). RT targets included whole brain (86%) and partial brain (14%). 1 patient had craniospinal RT. Median RT dose was 30 Gy (IQR: 24-30) over 10 fractions. Median OS for the entire salvage cohort was 3.5 months (m). Landmark analysis 2m post RT showed that median OS differed when patients were stratified by receipt of further therapy: CAR-T (9.4m, n = 4), hematopoietic cell transplant (8.5m, n = 6), other systemic therapy (4.4m, n = 17), no systemic therapy (0.6m, n = 10) (p = 0.0004). 29% of patients who received further therapy after RT achieved long term survival. In our cohort, most SCNSL patients are referred for salvage RT, with a median OS of 3.5m. 86% of patients had neurologic symptoms after having failed a median of 2 lines of SCNSL-directed therapy; the clinical urgency of this scenario implies that without RT, patients may not have been suitable candidates for further therapy. However, among patients for whom RT was successfully used to bridge to additional therapy, 29% could achieve long-term survival. This study supports further investigation of RT as a combined modality strategy for relapsed/refractory SCNSL, including with emerging cellular therapies.

Stereotactic Radiosurgery as an Effective and Safe Treatment Modality in Central Nervous System Lymphoma, a Single Institution Experience

CNS lymphoma (CNSL) is an aggressive liquid cancer with the potential for rapid progression. Standard treatment regimens for CNSL have included chemotherapy and whole brain radiotherapy (WBRT). WBRT carries a high risk of leukoencephalopathy (LE) manifesting as cognitive decline and is identifiable on brain MRI as fluid attenuation inversion recovery (FLAIR) changes. Stereotactic radiosurgery (SRS) can precisely deliver higher biologically effective doses of radiation, while minimizing damage to surrounding healthy brain tissue. SRS offers enhanced local control in CNSL with minimal risk of LE. Patients undergoing SRS at an NCI-designated comprehensive cancer center from 2000 to 2022 were prospectively enrolled into a database. Twenty-nine consecutive patients diagnosed with relapsed primary CNSL (59%) or secondary CNSL (41%) were included in this study. Median age at diagnosis was 70 (range 23-91) years and 14 were female. Follow up MRI imaging was obtained at 1-, 3-, 6- and 12-months post-procedure. Measurement of tumor volumes was performed at treatment and each subsequent follow-up by image co-registration and tumor segmentation. Pre and post SRS brain MRIs were independently reviewed by a neuro-radiologist to score the grade of LE for each patient. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier analyses and Log-rank tests using statistical software. Twenty-nine patients treated for 50 tumors were studied. Twenty-four patients were treated for a single tumor, and 5 for multiple tumors. Six patients underwent repeat SRS treatment for 10 out-of-field recurrences and 1 patient for an in-field recurrence. Of the 35 SRS procedures performed, 32 (88%) were single session delivery and 3 were hypofractionated. Stereotactic immobilization was achieved with frame (57%) or thermoplastic mask (43%). Median prescribed dose was 14 Gy (range 10-21) to the 50% isodose line (range 40-100). Median coverage, selectivity and gradient index were 0.97, 0.69, and 2.9 respectively. Median follow-up time was 4.5 months (range 0.5-64). Twenty-six (52%) tumors completely responded to treatment with no residual enhancement, while the rest decreased in volume. No tumor failed to respond to treatment. Median time to best volumetric response was achieved in 2.9 months (range 1-6.1) and median volume of best response was zero cc (range 0-1.19). The median OS of the cohort was 7.0 months (95% CI 5.1-8.9), while the median PFS was 5.0 months (95% CI 1.2-8.8). Median score of LE was zero, and only one patient experienced grade 3 MRI FLAIR changes. With a median time to response of 2.9 months, a 100% initial response rate and a single in-field failure, our analysis demonstrates a rapid and effective response of CNSL to SRS. Distant failures were controlled with repeat SRS. The absence of LE in the treated patients provides further evidence for safety and tolerability of SRS in CNSL.

Diffuse large B-cell lymphoma involving the central nervous system: biologic rationale for targeted therapy.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell lymphoma curable even in advanced stages. DLBCL involving the central nervous system (CNS) is more difficult to cure and fewer treatment options exist. Primary CNS lymphoma (PCNSL) refers to aggressive lymphomas confined to the CNS, and are almost always DLBCL. Standard approaches for PCNSL use high-dose methotrexate-based combinations as induction therapy and younger patients often receive dose-intensive consolidation. However, dose-intensive therapies are not suitable for all patients, and older patients have fewer effective treatment options. Patients with relapsed or chemotherapy-refractory disease have a very poor prognosis. Secondary CNS lymphoma (SCNSL) describes aggressive lymphomas involving the CNS at initial presentation or relapses within the CNS after treatment for systemic DLBCL. Isolated CNS relapse is often managed as PCNSL, but patients with synchronous involvement of DLBCL in both the periphery and the CNS pose a unique clinical challenge. Insights into the molecular circuitry of DLBCL have identified distinct genetic subtypes including cases with a predilection for CNS invasion. PCNSL and subsets of SCNSL are characterized by chronically activated B-cell receptor and NFκB signaling along with genetic evidence of immune evasion which may be exploited therapeutically. Improved mechanistic understanding of targetable pathways underpinning CNS lymphomas has led to numerous clinical trials testing targeted agent combinations and immunotherapy approaches with promising early results. Biologically rational strategies may further improve the cure rate of CNS lymphomas, either by overcoming intrinsic or acquired treatment resistance and/or by being broadly applicable to patients of all ages.

P06.11.B NEUROTOXICITY AND MANAGEMENT OF PRIMARY AND SECONDARY CNS LYMPHOMA AFTER ADOPTIVE IMMUNOTHERAPY WITH CD19-DIRECTED CAR T-CELLS

Abstract BACKGROUND Chimeric antigen receptor (CAR) T-cells targeting CD19 have been established as a leading engineered T-cell therapy for systemic B-cell lymphomas; however, data for patients with CNS involvement are limited. Whether CAR T-cells represent a viable therapeutic avenue for such patients remains therefore unclear. MATERIAL AND METHODS We retrospectively searched our institutional database for patients with primary and secondary CNS lymphoma who were treated with CD19-directed CAR T-cells for active CNS disease. Clinical data, CNS-specific toxicities, imaging findings, and outcome were analyzed. RESULTS We identified 45 consecutive CAR T-cell transfusions for active CNS lymphoma at the Massachusetts General Hospital over a five-year period. This cohort includes 17 patients with primary CNS lymphoma (PCNSL; one patient with two CAR T-cell transfusions) and 27 patients with secondary CNS lymphoma (SCNSL). Mild neurotoxicity (grade 1-2) was observed after 19/45 transfusions (42.2%) and severe neurotoxicity (grade 3-4) after 7/45 transfusions (15.6%). A larger increase in C-reactive protein (CRP) levels and higher rates of neurotoxicity were detected in SCNSL. Early fever and baseline C-reactive protein levels predicted neurotoxicity occurrence. CNS response was seen in 31 cases (68.9%), including a complete response of CNS disease in 18 cases (40.0%) which lasted for a median of 11.4 ± 4.5 months. Dexamethasone dose at time of lymphodepletion (but not at or after CAR T-cell transfusion) was associated with an increased risk for CNS progression (HR per mg/d: 1.16, p = 0.031). If bridging therapy was warranted, the use of Ibrutinib translated into favourable CNS-progression free survival (5 versus 1 month, HR 0.28, CI 0.1-0.7; p = 0.010). CONCLUSION CD19-directed CAR T-cells exhibit promising anti-tumor effects and a favourable safety profile in patients with CNS lymphoma. Further evaluation on the role of bridging regimens and corticosteroids is urgently warranted.

JS03.6.A NEUROTOXICITY IN PATIENTS WITH CNS LYMPHOMAS TREATED WITH CAR T CELL THERAPY. A LOC NETWORK STUDY

Abstract BACKGROUND CAR-T cell therapy represents one of the major progress of the last years in aggressive B-cell lymphomas. Its use in central nervous system (CNS) lymphomas has been limited due to the fear of neurotoxicity but several recent studies have showed promising efficacy in this setting. The aim of this study was to focus on neurotoxicy in CNS lymphoma patients treated with CAR-T cells. MATERIAL AND METHODS Patients with isolated CNS relapse of DLBCL treated with commercial CAR-T cells at Pitié-Salpêtrière hospital were retrospectively selected. We considered only neurological deterioration for which other causes than CAR-T cell toxicity had been reasonably ruled out. RESULTS 30 patients (median age: 65, 17 women, 19 primary, 11 secondary CNS lymphomas) were treated with CAR-T cells (Tisa-cel: N=23, axi-cel, N=7) between May 2020 and December 2022. At the time of CAR-T, 15 (50%) had stable or progressive disease, median Karnofsky Performans Status (KPS) was 70, median Montreal Cognitive Assessment (MoCA) score was 22, and median immune effector cell-associated encephalopathy (ICE) score was 10. 12 (40%) patients didn’t experience any neurotoxicity after CAR-T, whereas 9 (30%), 3 (10%), 2 (7%), 4 (13%) patients experienced grade 1, 2, 3 or 4 toxicity according to ASCTC classification. The signs of neurotoxicity began at a median of 5 days after CAR-T. The most common symptoms were cognitive disorders (N=18), motor deficit (N=4), balance disorders (N=8), consciousness disorders (N=5), epilepsy (N=3) and movement disorders (N=3). Among cognitive symptoms, there was predominantly a worsening of pre-existing symptoms regarding memory impairment (12/15 patients) or dysexecutive syndrome (11/13), while dysgraphia or dyscalculia were most frequently new symptoms (in 14/15 and 7/11 patients). Brain MRI showed pseudo-progression in 4 cases. On lumbar puncture, median IL-6 level and median cellularity were higher in patients with grade 2-3-4 neurotoxicity compared to other patients (243 vs 41 pg/ml, 15 vs 3 cells/mm3). We found no association between risk of neurotoxicity and age, gender, pre-CART KPS, MoCA or ICE score, primary vs secondary CNS lymphoma or type of CAR-T. 12 patients (40%) received steroids, for a median of 10 days, leading to an improvement in a median of 5 days; one received anakinra. Median duration with neurological impairment was 13 days, but was >3 months in 3 patients, including one who finally died from neutoxicity. CONCLUSION The majority of CNS lymphoma patients didn’t experience severe neurotoxicity following CAR-T cell therapy, so that this treatment shouldn’t be contraindicated in this population. However, the percentage of severe and prolonged neurotoxicity is probably higher than in systemic lymphomas and a close neurological follow-up is warranted in these complex situations. Further studies are needed to better predict severe neurotoxicity.

EXABS-231-ABCL The Treatment of Primary and Secondary CNS Lymphoma

EXABS-231-ABCL The Treatment of Primary and Secondary CNS Lymphoma

Treatment Strategies and Prognostic Factors in Secondary Central Nervous System Lymphoma: A Multicenter Study of 124 Patients.

Secondary central nervous system lymphoma (SCNSL) is a rare and difficult to treat type of Non-Hodgkin lymphoma characterized by systemic and central nervous system (CNS) disease manifestations. In this study, 124 patients with SCNSL intensively treated and with clinical long-term follow-up were included. Initial histopathology, as divided in low-grade, other aggressive, and diffuse large B-cell lymphoma (DLBCL), was of prognostic significance. Overall response to induction treatment was a prognostic factor with early responding DLBCL-SCNSL in comparison to those non-responding experiencing a significantly better progression-free survival (PFS) and overall survival (OS). However, the type of induction regime was not prognostic for survival. Following consolidating high-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT), DLBCL-SCNSL patients had better median PFS and OS. The important role of HDT-ASCT was further highlighted by favorable responses and survival of patients not responding to induction therapy and by excellent results in patients with de novo DLBCL-SCNSL (65% long-term survival). SCNSL identified as a progression of disease within 6 months of initial systemic lymphoma presentation represented a previously not appreciated subgroup with particularly dismal outcome. This temporal stratification model of SCNSL diagnosis revealed CNS progression of disease within 6 months as a promising candidate prognosticator for future studies.

Neurotoxicity and management of primary and secondary central nervous system lymphoma after adoptive immunotherapy with CD19-directed chimeric antigen receptor T-cells.

Chimeric antigen receptor (CAR) T-cells targeting CD19 have been established as a leading engineered T-cell therapy for B-cell lymphomas; however, data for patients with central nervous system (CNS) involvement are limited. We retrospectively report on CNS-specific toxicities, management, and CNS response of 45 consecutive CAR T-cell transfusions for patients with active CNS lymphoma at the Massachusetts General Hospital over a 5-year period. Our cohort includes 17 patients with primary CNS lymphoma (PCNSL; 1 patient with 2 CAR T-cell transfusions) and 27 patients with secondary CNS lymphoma (SCNSL). Mild ICANS (grade 1-2) was observed after 19/45 transfusions (42.2%) and severe immune effector cell-associated neurotoxicity syndrome (ICANS) (grade 3-4) after 7/45 transfusions (15.6%). A larger increase in C-reactive protein (CRP) levels and higher rates of ICANS were detected in SCNSL. Early fever and baseline C-reactive protein levels were associated with ICANS occurrence. CNS response was seen in 31 cases (68.9%), including a complete response of CNS disease in 18 cases (40.0%) which lasted for a median of 11.4 ± 4.5 months. Dexamethasone dose at time of lymphodepletion (but not at or after CAR T-cell transfusion) was associated with an increased risk for CNS progression (hazard ratios [HR] per mg/d: 1.16, P = .031). If bridging therapy was warranted, the use of ibrutinib translated into favorable CNS-progression-free survival (5 vs. 1 month, HR 0.28, CI 0.1-0.7; P = .010). CAR T-cells exhibit promising antitumor effects and a favorable safety profile in CNS lymphoma. Further evaluation of the role of bridging regimens and corticosteroids is warranted.

Central nervous system lymphomas-Assessment and treatment and prevention of central nervous system relapse.

In this review focused on lymphoma and the central nervous system (CNS), we summarize recent developments in the management of primary (PCNSL) and secondary CNS lymphoma (SCNSL), treatment of CNS lymphoma in the older population, the neuroradiological assessment of CNS lymphoma and finally highlight the ongoing debate on optimal CNS prophylaxis. The section on PCNSL focuses on the different approaches available for frontline treatment in Europe and the United States and discusses consolidation strategies. We then highlight available strategies to treat PCNSL in the elderly population, an area of unmet need. New therapies aiming at minimizing toxicity and prioritizing quality of life are emerging for these patients. Secondary CNS lymphoma, especially in the relapsed/refractory setting is another area of unmet need, and the efficacy of CAR-T cell therapy is being explored. We provide an overview of the imaging challenges in the neuroradiological assessment of CNS lymphoma. Finally, the section on CNS prophylaxis summarizes recent findings from large retrospective studies challenging the efficacy of present approaches to prophylaxis in higher-risk patients with lymphoma.

SALVAGE TREATMENTS FOR RELAPSED/REFRACTORY SECONDARY CNS LYMPHOMA IN THE CAR T ERA: A REAL‐WORLD COMPARISON

Introduction: Secondary central nervous system lymphoma (SCNSL) is a rare and aggressive subtype of non-Hodgkin lymphoma that involves the neuraxis. Patients with refractory or relapsed (r/r) disease have limited treatment options and poor outcomes. Chimeric antigen receptor T-cell therapy (CAR T) has shown promise in clinical trials but lacks mature data in the r/r SCNSL setting. In this retrospective, real-world review, we evaluated salvage treatment patterns and survival outcomes of patients with r/r SCNSL, comparing historic regimens to CAR T. Methods: We retrospectively reviewed medical records of SCNSL patients treated at our institution between 2008 and 2022. Patients were included if they had r/r disease and received salvage treatment. Progression-free (PFS) and overall survival (OS) from initiation of first salvage therapy were calculated using the Kaplan-Meier method. Results: We identified 28 r/r SCNSL patients, 11 with de novo CNS disease and 17 with CNS relapse. Initial treatments were based on intrathecal or high-dose methotrexate. Six patients underwent consolidative autologous stem cell transplant. Upon relapse, 7 patients received supportive care with steroids only with rapid disease progression and death within one month. The remaining 21 patients had a median age of 60 years (range, 34-77 years) and median Karnofsky performance status of 80. The most common histological subtype was diffuse large B-cell lymphoma (DLBCL) (n=19, 90%). CNS disease was mostly parenchymal (52%), followed by spinal cord (29%) and leptomeningeal (19%) involvement. Salvage regimens included combinations of radiation (RT, n = 14), immunologic, targeted and chemotherapies [(rituximab, ibrutinib, polatuzumab; n = 15), methotrexate (n = 11), temozolomide (n = 8)], and CAR T (n = 7). The overall response rate was 67% for initial salvage therapy, with 9 patients having a sustained response. Median OS was 23 months and median PFS was 10 months. Seven patients who underwent salvage anti-CD19 CAR T had improved PFS and OS compared to other salvage regimens (p = 0.0014, Figure 1). Four of these patients received bridging therapy, either with RT (n = 2) or chemo-immunotherapy (n = 2). The majority (6/7) remain alive, and 4/7 patients remain in complete remission past 1.5 years. 6/7 patients had grade 1-2 CRS and 4/7 had grade 2-3 ICANS that was successfully managed per institutional guidelines. Median OS for other salvage regimens was 6.2 months. The addition of radiation to systemic therapy trended to improve OS. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Cellular therapies, Extranodal non-Hodgkin lymphoma This research was supported by the American Society of Hematology (ASH) HONORS Award. Conflicts of interests pertinent to the abstract G. Kaur Consultant or advisory role: SANOFI, BMS, Janssen, Cellectar, Arcellx Y. F. Madanat Consultant or advisory role: Sierra Oncology, Stemline Therapeutics, Blueprint Medicines, Morphosys, Taiho Oncology and Novartis. Honoraria: BluePrint Medicines, GERON, OncLive, and MD Education Travel grants: Blueprint Medicines and Morphosys P. Ramakrishnan Geethakumari Consultant or advisory role: PRG has provided consultancy services to Kite Pharma, Bristol Myers Squibb and Rafael Pharma and served on the advisory boards of Pharmacyclics LLC, ADC Therapeutics, Cellectar Biosciences and Ono Pharma.

Management of primary and secondary CNS lymphoma

AbstractCentral nervous system (CNS) lymphoma has traditionally had very poor outcomes however advances in management have seen dramatic improvements and long‐term survival of patients. In primary CNS lymphoma there are now randomised trial data to inform practice, however secondary CNS lymphoma has a lack of randomised trial data and CNS prophylaxis remains a contentious area. We describe treatment strategies in these aggressive disorders. Dynamic assessment of patient fitness and frailty is key throughout treatment alongside delivery of CNS‐bioavailable therapy and enrolment in clinical trials. Intensive high‐dose methotrexate‐containing induction followed by autologous stem cell transplantation is preferred for patients who are fit. Less intensive chemoimmunotherapy, whole brain radiotherapy and novel therapies may be reserved for patients unfit or chemoresistant. It is essential to better define patients at increased risk of CNS relapse, as well as effective prophylactic strategies to prevent it. Future prospective studies incorporating novel agents are key.

Neurotoxicity in patients with CNS lymphomas treated with CAR‐T cell therapy. A LOC network study

Introduction: CAR-T cell therapy represents one of the major progress of the last years in aggressive B-cell lymphomas. Its use in central nervous system (CNS) lymphomas has been limited due to the fear of neurotoxicity but several recent studies have showed promising efficacy in this setting. The aim of this study was to focus on neurotoxicity in CNS lymphoma patients treated with CAR-T cells. Methods: Patients with isolated CNS relapse of DLBCL treated with commercial CAR-T cells at Pitié-Salpêtrière hospital were retrospectively selected. We considered only neurological deterioration for which other causes than CAR-T cell toxicity had been reasonably ruled out. Results: Thirty patients (median age: 65, 17 women, 19 primary, 11 secondary CNS lymphomas, median of 3 previous lines) received CAR-T cells (Tisa-cel: N = 23, axi-cel, N = 7) between May 2020 and December 2022. At the time of CAR-T, 15 (50%) had stable or progressive disease, median Karnofsky Performance Status (KPS) was 70, median Montreal Cognitive Assessment (MoCA) score was 22 and median immune effector cell-associated encephalopathy (ICE) score was 10. Twelve (40%) patients didn’t experience any neurotoxicity after CAR-T, whereas 9 (30%), 3 (10%), 2 (7%), 4 (13%) patients experienced grade 1, 2, 3 or 4 toxicity according to ASTCT classification. The signs of neurotoxicity began at a median of 5 days after CAR-T. The most common symptoms were cognitive disorders (N = 18), motor deficit (N = 4), balance disorders (N = 8), consciousness disorders (N = 5), seizures (N = 3) and movement disorders (N = 3). Among cognitive symptoms, there was predominantly a worsening of pre-existing symptoms regarding memory impairment (12/15 patients) or dysexecutive syndrome (11/13), while dysgraphia or dyscalculia were most frequently new symptoms (in 14/15 and 7/11 patients). Brain MRI showed pseudo-progression in 4 cases. On lumbar puncture, median IL-6 level and median cellularity were higher in patients with grade 2 to 4 neurotoxicity compared to other patients (243 vs. 41 pg/ml, 15 vs. 3 cells/mm3). We found no association between risk of neurotoxicity and age, gender, pre-CART KPS, MoCA or ICE score, primary vs. secondary CNS lymphoma or type of CAR-T. Twelve patients (40%) received steroids, for a median of 10 days, leading to an improvement in a median of 5 days; one received anakinra. Median duration with neurological impairment was 13 days, but was >3 months in 3 patients, including one who finally died from neurotoxicity. Conclusions: The majority of CNS lymphoma patients didn’t experience severe neurotoxicity following CAR-T cells, so that this treatment shouldn’t be contraindicated in this population. However, the percentage of severe and prolonged neurotoxicity is probably higher than in systemic lymphomas and a close neurological follow-up is warranted in these complex situations. Further studies are needed to better predict severe neurotoxicity. Keyword: Cellular therapies Conflicts of interests pertinent to the abstract. S. Choquet Consultant or advisory role: Kite-Gilead, Novartis