Central Nervous System Lymphoma Patients Research Articles

RADT-39. CENTRAL NERVOUS SYSTEM BRIDGING RADIOTHERAPY (CNS-BRT) ACHIEVES RAPID CYTOREDUCTION PRIOR TO CAR T-CELL THERAPY FOR AGGRESSIVE B-CELL LYMPHOMAS

Abstract BACKGROUND CAR T-cell therapy (CART) for central nervous system lymphoma (CNSL) is a promising strategy, yet responses are frequently not durable. Bridging radiotherapy (BRT) is used for extra-cranial lymphoma to improve CART outcomes through cytoreduction of high-risk lesions. We hypothesized that CNS-BRT would achieve similar, significant cytoreduction prior to CART for CNSL. METHODS We analyzed CNSL patients with non-Hodgkin B-cell lymphomas who received CNS-BRT prior to commercial CART. Best CNS response post-CART was evaluated using the International Primary CNS Lymphoma Collaborative Group (IPCG) or RANO for parenchymal or leptomeningeal lesions, respectively. Cytoreduction from CNS-BRT was calculated as change in lesion size prior to CART. RESULTS Twelve patients received CNS-BRT, with median follow up of 11.8m (IQR: 8.5–21.9). Ten had CNSL (9 secondary, 1 primary) and 2 patients had epidural disease (evaluable for toxicity). All ten CNSL patients had progressive disease at the time of CNS-BRT. RT targets included whole brain (n=3), involved site (partial) brain (n=4), involved site spine (n=4), and orbits (n=1) with median dose 24Gy (range: 15-33). 1/12 patients experienced grade ≥3 cytokine release syndrome (CRS), and 3/12 patients experienced grade ≥3 immune effector cell-associated neurotoxicity syndrome (ICANS). CNS-BRT achieved a 74.0% (95%CI: 62.0–86.0) mean reduction in lesion size from baseline (p=0.014) at a median of only 12d from BRT completion and pre-CART infusion. Best CNS response included 8 complete responses (CR), 1 partial response (PR), and 1 progressive disease (PD). Three patients experienced CNS relapse outside the BRT field for a 12-month estimated risk of CNS progression post-CART of 20.0% (95%CI: 3–49). CONCLUSIONS Early data suggest CNS-BRT achieves rapid cytoreduction and favorable CNS response. The rates of severe CRS/ICANS were similar to comparison series of CNSL patients treated with CART without BRT suggesting an acceptable safety profile. Our data support further study of BRT as a bridging strategy for CNSL-directed CART.

Assessing the intracranial metabolic score as a novel prognostic tool in primary CNS lymphoma with end of induction-chemotherapy 18F-FDG PET/CT and PET/MR

Abstract Background The metabolic response of primary central nervous system lymphoma (PCNSL) patients has yet to be evaluated. This study aimed to assess the prognostic value of a novel scoring scale, the intracranial metabolic score (IMS), in PCNSL patients receiving end-of-therapy 18F-FDG PET/CT (EOT-PCT) and PET/MR (EOT-PMR). Methods The IMS was determined based on the metabolism of normal intracranial structures, including gray matter, white matter, and cerebrospinal fluid. The EOT-PCT cohort was evaluated using the IMS and commonly used Deauville score (DS). Another cohort of patients who underwent the EOT-PMR was used to validate the accuracy of the IMS. Results In total, 83 patients were included in the study (38 in PET/CT cohort, and 45 in PET/MR cohort). The area under the curve (AUC) values of the IMS for predicting PFS and OS were superior to those of the DS. When patients in the PET/CT cohort were stratified into five groups (respectively labeled IMS 1–5), three groups (IMS1-2, IMS 3–4, and IMS 5), or two groups (IMS1-3 and IMS4-5; IMS 1–4 and IMS 5), a higher IMS score was significantly correlated with poorer PFS and OS (p < 0.001). Similar results were observed for PFS in the PET/MR cohort (p < 0.001). The IMS and DS scale were found to be independent prognostic indicators for PFS and OS in the PET/CT cohort, and the IMS was identified as the sole independent prognostic indicator for PFS in the PET/MR cohort. Conclusion The IMS as a novel and effective prognostic tool for PCNSL patients, showing superior predictive value for patients’ outcomes compared to the DS when assessed with EOT-PET scans.

Liquid biopsy for CNS lymphoma: CSF exosomes and CSF exosomal miR-15a, miR-21, miR-155, miR-210, and miR-19b are promising biomarkers for diagnosis.

Central nervous system lymphoma (CNSL) is a devastating disease with a poor prognosis. Early diagnosis, monitoring of the treatment response, and outcome prediction carry the utmost importance in the management of patients with CNSL. Surgical biopsy is the gold standard for tissue diagnosis, however, this procedure has potential complications. Therefore, there is a need for a method that provides information about diagnosis and patient monitoring to avoid surgical risks. The study aimed to investigate potential diagnostic biomarkers for patients with CNSL. Patients with secondary CNSL were included in this study. Serum and cerebrospinal fluid (CSF) samples were collected before treatment and after completion of the treatment. Cell-free DNA (cfDNA), exosomes, free and exosomal microRNA (miR)-15a, miR-21, miR-155, miR-210, and miR-19b in both serum and CSF were examined, and they were compared with the controls. Also, their levels before and after treatment were compared. Nine patients with the diagnosis of secondary CNSL were reviewed. cfDNA, miR-15a, and miR-155 in serum, and exosome in CSF were found to be significantly higher in CNSL patients compared to the controls. Exosomal miR-15a, miR-21, miR-155, miR-210, and miR-19b in CSF were found to be significantly higher in CNSL patients compared to controls, whereas their levels in serum were not significantly high. Our findings suggested that exosomes and exosomal miR-15a, miR-21, miR-155, miR-210 and miR-19b in CSF would be promising biomarkers for the diagnosis of patients with CNSL. Further studies are needed to confirm our findings.

Phase IB part of LOC-R01, a LOC network non-comparative randomized phase IB/II study testing R-MPV in combination with escalating doses of lenalidomide or ibrutinib for newly diagnosed primary central nervous system lymphoma (PCNSL) patients

BackgroundResults of conventional induction chemotherapies in primary central nervous system lymphoma (PCNSL) need to be improved. Ibrutinib, a BTK inhibitor, and lenalidomide, an immunomodulatory drug, have shown promising results at relapse, supporting to further assess their individual use in combination with high-dose methotrexate-based chemotherapy.MethodsPatients with newly diagnosed PCNSL were randomized to receive four 28-day cycles of ibrutinib or lenalidomide in combination with R-MPV (rituximab, methotrexate, procarbazine, vincristine and prednisone) in a 3 + 3 design. Responders then received a consolidation with R-Cytarabine and an intensive chemotherapy with autologous stem cell transplantation. The objective of the phase IB study was to define the recommended phase II dose (RP2D) based on the dose-limiting toxicity (DLT) occurring during the first induction cycle.ResultsTwenty-six patients (median age 52) were randomized. Four DLTs were observed: one grade 5 aspergillosis and pneumocystosis, one grade 4 catheter-related infection and two grade 3 increased alanine aminotransferase levels. RP2D of ibrutinib and lenalidomide were 560 mg daily (D3-14 and D17-28) and 15 mg daily (D1-21) respectively, in combination with R-MPV. In both arms, the most frequent grade ≥3 treatment-related adverse events were hepatic cytolysis, neutropenia and infections. One grade 4 Lyell’s syndrome was reported at cycle 2 in the lenalidomide arm. After 4 induction cycles, the overall response rates were 76.9% and 83.3% in the lenalidomide and ibrutinib arm, respectively.ConclusionTargeted induction therapies combining lenalidomide or ibrutinib with R-MPV are feasible for first-line PCNSL. The safety profile is consistent with the known safety profiles of R-MPV and both targeted therapies. The phase II part of the study is ongoing.Trial registrationNCT04446962.

The Prognostic Significance of Pontine-White Matter Score in Primary Central Nervous System Lymphoma Patients.

Limited data exist on the significance of PET imaging and quantitative PET parameters in primary central nervous system (CNS) lymphoma due to its relative rarity. This study was conducted to investigate the prognostic value of a novel internal standardization indicator, the pontine-white matter (PW) score, in primary CNS lymphoma patients undergoing post-treatment 18F-FDG PET/CT and PET/MR imaging. From January 2014 to December 2022, eligible patients with primary CNS lymphoma who underwent post-treatment PET imaging were enrolled. Using the FDG uptake of the pons and white matter as an internal reference, the PW score was graded based on the metabolism of the post-therapeutic lesion for each patient, and its associations with patients' prognosis were investigated. In total, 41 patients with post-treatment PET/CT and 49 patients with post-treatment PET/MR imaging were enrolled. ROC curve analysis indicated that the PW score possessed robust discriminative ability in distinguishing patients with worse outcomes. Furthermore, a higher PW score was significantly correlated with and identified as an independent prognostic indicator for, worse prognosis in both the PET/CT and PET/MR cohorts. The study demonstrated that the PW score was an effective prognostic indicator for identifying post-treatment primary CNS lymphoma patients with worse outcomes.

Glofitamab stimulates immune cell infiltration of CNS tumors and induces clinical responses in secondary CNS lymphoma

AbstractAlthough CD20×CD3 bispecific antibodies are effective against systemic B-cell lymphomas, their efficacy in central nervous system (CNS) lymphoma is unknown. Here, we report the CD20×CD3 bispecific glofitamab penetrates the blood-brain barrier, stimulates immune-cell infiltration of CNS tumors, and induces clinical responses in patients with secondary CNS.

Interim FDG-PET improves treatment failure prediction in primary central nervous system lymphoma: An 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) positron emission tomography (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 immunocompetent patients who received induction HD-MBC as part of the BLOCAGE01 phase III trial. FDG-PET/MRI were acquired at baseline, post 2 cycles (PET/MRI2), and posttreatment (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 the 48 PET2 scans performed, 9 were positive and aligned with a partial response (PR) on MRI2. Among these, 8 (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. Eighty-seven percent of the PET2-negative patients were disease free at 6 months versus 11% of the PET2-positive patients (P < .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 a 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. LOCALYZE, NCT03582254, ancillary of phase III clinical trial BLOCAGE01, NCT02313389 (Registered July 10, 2018-retrospectively registered) https://clinicaltrials.gov/ct2/show/NCT03582254?term=LOCALYZE&draw=2&rank=1.

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.

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.

Germinal Center B-Cell-like (GCB) Phenotype Predicts Improved Outcomes in Central Nervous System Diffuse Large B-Cell Lymphoma Patients Receiving Stereotactic Radiosurgery (SRS)

Background: Diffuse large B cell lymphoma (DLBCL) constitutes most cases of both primary and secondary central nervous system lymphoma (CNSL). They represent a highly aggressive subset of non-Hodgkin lymphoma and prognosis varies depending on the cell of origin. Immunohistochemistry using antibodies for CD10, BCL-6, and MUM-1, also known as the Hans algorithm, is the most common method for determining the cell of origin and predicting outcomes in DLBCL. The study by Hans et al. found that the germinal center B-cell-like (GCB) group had a much better prognosis compared to the non-GCB group, with 5-year overall survival (OS) of 76% and 34% respectively. Despite chemotherapy, recurrence is common in these patients, and up to 40-50% do not achieve durable remission. It is important to identify who may benefit from more aggressive or experimental therapy at diagnosis. Stereotactic radiosurgery (SRS) is the administration of a localized, high dose of ionizing radiation and limited studies exist exploring SRS as a treatment modality in relapsed/refractory (r/r) CNSL or prognostic implications of the Hans algorithm in these patients. Aim/Objective: To perform a retrospective analysis of outcomes of patients with CNSL, phenotypes determined by the Hans algorithm, treated with SRS at a single comprehensive cancer center. Methods: We studied the demographic, clinical, pathological, and treatment characteristics of r/r CNSL patients (N=27), age ≥ 18 years, who received SRS at Roswell Park Comprehensive Cancer Center between 01/2000 and 01/2023. The Hans algorithm was used to group the patients into non-GCB (N=17) and GCB (N=10) cohorts. Overall survival (OS) and progression-free survival (PFS) were calculated and reported using Kaplan-Meier analyses and log-rank tests. Cox regression models were used to describe cross-cohort comparisons of survival. Results: The median Karnofsky performance status at diagnosis was 70 for both groups. The overall response rate (ORR) to SRS in GCB-type was 80% (7 complete response and 1 partial response; CR, PR). The ORR in non-GCB type was 58% (6 CR and 4 PR). Post-SRS, stem cell transplant (SCT) was avoided in 100% of the patients in the GCB group, while 17% of the patients in the non-GCB group received SCT. The 6-month overall survival (OS) rate was 100% and 46% for the GCB-type and non-GCB type respectively (p=0.096, Figure 1A). The 6-month progression-free survival (PFS) rate was 80% for the GCB-type and 33% for the non-GCB type (p=0.024, Figure 1B). In the GCB group, the median OS was 18.0 months while the median PFS was 13.8 months. In the non-GCB group, the median OS was 4.9 months while the median PFS was 3.6 months. The median time from chemotherapy completion to SRS administration was 8.0 months in the GCB-type and 2.0 months in the non-GCB type. Conclusion: Our data support that the GCB-type predicts a more favorable outcome in CNSL, with improved OS and PFS rates compared to the non-GCB type. In addition, the non-GCB type patients required earlier SRS administration and had a lower ORR to SRS. Classifying CNSL into GCB and non-GCB phenotypes using the Hans algorithm might help characterize patients into groups with different prognoses.

Efficacy and Safety of Selinexor-Based Combination Therapy in CNS Lymphoma: A Retrospective Experience

Introduction ： Primary central nervous system lymphoma (PCNSL) is a rare diffuse large B-cell lymphoma (DLBCL) with distinct clinical and biological features, characterized by an aggressive course and poor prognosis. Patients with relapsed/refractory (R/R) disease have an unmet medical need due to a median overall survival (OS) of only 6.8 months. Novel therapies are urgently required for patients with R/R CNSL. In June 2020, the U.S. Food and Drug Administration granted accelerated approval to selinexor for the treatment of adult patients with R/R DLBCL. Selinexor has demonstrated central nervous system (CNS) penetration and activity in secondary CNS lymphoma (SCNSL) patients. Thus, we conducted a retrospective review of PCNSL/SCNSL cases treated with a selinexor-based regimen to preliminarily evaluate its effectiveness and safety. Methods: We retrospectively analyzed the medical records of 13 patients with CNSL who received selinexor-based combination therapy between June 2021 and June 2023 at three research centers in China. Among these cases, 2 were previously untreated, and 11 were relapsed or refractory patients. All patients had histopathologically confirmed DLBCL at the time of initial diagnosis. Data collection included baseline characteristics, treatment efficacy and safety evaluation. Results: A total of 13 patients (10 PCNSL and 3 SCNSL) were included in the study, with a median age of 62 years (range, 28-73), including three male patients. The median international extranodal lymphoma study group (IELSG) score for PCNSL cases was 3 (range, 1-3). The median International Prognosis Index (IPI) score for the three systemic DLBCL cases was 5 (range, 3-5), and three cases were at Ann Arbor stage IV. Among the patients, 11 had relapsed or refractory disease with a median of 2 prior treatments (range, 1-4), and 10 of them were refractory to previous treatments. The main patient characteristics, responses, and toxicities of the selinexor-based combination regimen are summarized in Table 1. Figure 1 presents the response of all evaluable patients. The overall response rate (ORR) of the patients was 84.6% (11 /13), with a complete response (CR) rate of 76.9% (10/13). Both treatment-naïve patients achieved CR after four and six cycles of the selinexor-containing first-line regimen, respectively. They are currently experiencing sustained remission, with the longest duration reaching 13 months. For relapsed/refractory CNSL, the ORR and CR rate were 81.8% (9/11) and 72.7% (8/11), respectively. Two patients had stable disease (SD). Among the 9 patients who achieved remission, 4 patients are still in remission, with the longest duration reaching 20 months, 2 patients received CART bridging therapy, one received radiation therapy, and 2 patients experienced disease progression after 5 months, but all are currently still alive. These patients are currently under continuous observation. Due to the heterogeneity of the selinexor-based regimens, the categories and severity of adverse events (AEs) varied greatly among the different regimens. The median treatment cycle number was six (range, 2-22). One patient died due to pneumonia infection, one patient was lost to follow-up, three patients successfully bridged to CART/RT, and eight patients completed the treatment as planned. The common AEs included thrombocytopenia, infection, nausea, vomiting, and gastrointestinal bleeding(Table 1). Conclusion: This report provides encouraging evidence of the efficacy and tolerable safety of the selinexor-based regimen in the treatment of CNSL. However, further prospective studies with a larger sample size are needed to provide more comprehensive evidence regarding the efficacy of selinexor in central nervous system lymphoma and to determine the appropriate dosage and optimal combination strategies.v

CNS Radiotherapy As Bridging Prior to CAR T-Cell Therapy for Non-Hodgkin B-Cell Lymphoma

Introduction: Up to 80% of patients who receive CAR T-cell therapy (CAR T) for central nervous system lymphoma (CNSL) require bridging therapy, yet optimal regimens remain undefined. Radiotherapy is an established strategy for extracranial lymphoma that provides beneficial cytoreduction. However, CNS bridging radiotherapy (CNS-BRT) prior to CAR T is controversial due to concerns of potential enhanced neurotoxicity. We explored the safety and response profiles in patients treated with CNS-BRT prior to CAR T. Methods: We identified patients with non-hodgkin B-cell lymphoma who received CNS-BRT at our institution prior to commercial CAR T infusion. CNS-BRT was defined as treatment delivered between apheresis and CAR T infusion or within 30 days prior to apheresis, targeting the CNS parenchyma, leptomeninges, or epidural spine. Patients with epidural spine disease were included since the adjacent spinal cord is part of the treatment field. Safety was evaluated by rate of cytokine release syndrome (CRS) and immune effector associated neurotoxicity syndrome (ICANS) after CAR T. Best CNS response post CAR T was evaluated using the International Primary CNS Lymphoma Collaborative Group (IPCG) or Response Assessment in Neuro-Oncology (RANO) for parenchymal or leptomeningeal lesions, respectively. Cytoreduction from CNS-BRT was estimated by calculating the change in lesion size (sum of product diameter) from before and after CNS-BRT, but before CAR T infusion. Risk of any CNS relapse after CAR T was estimated using the Gray's method with death as a competing risk. Patients with epidural spine disease were not evaluate for CNS response or relapse. Results: 12 patients received CNS-BRT with median follow up of 8.5 months (range: 3.2 - 30.2), median age of 60 (30-76), median Karnofsky Performance Status (KPS) of 80 (range: 50 - 90). Histologies included diffuse large B cell (DLBCL) (n = 9), mantle cell (n = 2), and Burkitt lymphoma (n = 1), with disease localizing to the brain parenchyma (n = 6), leptomeninges (n = 4), and epidural spine (n = 2). 9 patients had secondary CNSL and 1 patient had primary CNSL. Prior to CNS-BRT, 11/12 patients had progressive disease. 5/12 patients had disease outside of the CNS. 5/12 patients received prior autologous hematopoietic stem cell transplantation. 9/12 patients received prior high dose methotrexate with median 46-day interval to CNS-BRT (range: 0 - 393). RT targets included whole brain (n = 3), involved site (partial) brain (n = 4), involved site spine (n = 4), and orbits (n = 1) with median dose 24 Gy (range: 15 - 33). CAR T products included Tisagenlecleucel (n = 4), Lisocabtagene maraleucel (n = 7), and Axicabtagene ciloleucel (n = 1). Among 10 patients with available toxicity grading, 6/10 experienced CRS (n = 1 grade (G) 1, n = 4 G2, and n = 1 G3), and 3/10 experienced ICANS (n = 1 G1, n = 1 G3, n = 1 G4). 6/10 patients required tocilizumab and/or steroids. CNS-BRT achieved a 74.4% (95% CI, 62.9 - 85.9) mean reduction in lesion size prior to CAR T infusion. Best CNS response after CAR T infusion included 3 complete responses (CR), 6 partial responses (PR), and 1 progressive disease (PD). The patients who achieved PR remained in PR at last follow up. The 12-month estimated risk of CNS progression after CNS-BRT and CAR T infusion was 20.0% (95% CI, 3- 49). CNS progression was not observed in patients who received involved site brain RT. Conclusion: Preliminary data suggest CNS-BRT achieves rapid cytoreduction prior to CAR T therapy and is associated with a favorable CNS response profile. While overall numbers are limited to date, the rate of severe CRS and ICANS is similar to that of historical series of CNSL patients treated with CAR T. However, a larger cohort will be required to determine the safety of CNS-BRT. These data support further study of RT, and exploration of involved site brain RT, as an effective bridging modality for CAR T-cell therapy in CNSL.

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 &lt; 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 &lt; 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.

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 &amp;gt;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.

Age-adjusted high-dose chemotherapy followed by autologous stem cell transplantation or conventional chemotherapy with R-MP as first-line treatment in elderly primary CNS lymphoma patients – the randomized phase III PRIMA-CNS trial

BackgroundOlder primary central nervous system lymphoma (PCNSL) patients have an inferior prognosis compared to younger patients because available evidence on best treatment is scarce and treatment delivery is challenging due to comorbidities and reduced performance status. High-dose chemotherapy and autologous stem cell transplantation (HCT-ASCT) after high-dose methotrexate (MTX)-based immuno-chemotherapy has become an increasingly used treatment approach in eligible elderly PCNSL patients with promising feasibility and efficacy, but has not been compared with conventional chemotherapy approaches. In addition, eligibility for HCT-ASCT in elderly PCNSL is not well defined. Geriatric assessment (GA) may be helpful in selecting patients for the best individual treatment choice, but no standardized GA exists to date. A randomized controlled trial, incorporating a GA and comparing age-adapted HCT-ASCT treatment with conventional chemotherapy is needed.MethodsThis open-label, multicenter, randomized phase III trial with two parallel arms will recruit 310 patients with newly diagnosed PCNSL > 65 years of age in 40 centers in Germany and Austria. The primary objective is to demonstrate that intensified chemotherapy followed by consolidating HCT-ASCT is superior to conventional chemotherapy with rituximab, MTX, procarbazine (R-MP) followed by maintenance with procarbazine in terms of progression free survival (PFS). Secondary endpoints include overall survival (OS), event free survival (EFS), (neuro-)toxicity and quality of life (QoL). GA will be conducted at specific time points during the course of the study. All patients will be treated with a pre-phase rituximab-MTX (R-MTX) cycle followed by re-assessment of transplant eligibility. Patients judged transplant eligible will be randomized (1:1). Patients in arm A will be treated with 3 cycles of R-MP followed by maintenance therapy with procarbazine for 6 months. Patients in arm B will be treated with 2 cycles of MARTA (R-MTX/AraC) followed by busulfan- and thiotepa-based HCT-ASCT.DiscussionThe best treatment strategy for elderly PCNSL patients remains unknown. Treatments range from palliative to curative but more toxic therapies, and there is no standardized measure to select patients for the right treatment. This randomized controlled trial will create evidence for the best treatment strategy with the focus on developing a standardized GA to help define eligibility for an intensive treatment approach.Trial registrationGerman clinical trials registry DRKS00024085 registered March 29, 2023.

Prognostic value of POD18 combined with improved IELSG in primary central nervous system lymphoma.

The International Extranodal Lymphoma Study Group (IELSG) score is widely used in clinical practice to stratify the risk of primary central nervous system lymphoma (PCNSL) patients. Our study aims to confirm and improve the IELSG score in PCNSL patients based on Chinese populations. A total of 79 PCNSL patients were retrospectively analyzed. All patients treated with high-dose methotrexate (HD-MTX)-based therapy collected clinical data. The receiver-operating characteristic (ROC) curve was used to determine the optimal cut-off values for the factors in IELSG score. Progression of disease (POD) at the most landmark time point was determine by Epanechnikov kernel and the area under the ROC curve (AUROC). Kaplan-Meier and multivariable regression methods were used to analyze survival data. Nomogram was generated for calculating the weight of each selected factor. The traditional IELSG score had no significant difference on OS and PFS except ECOG ≥ 2 and could not stratify the risk groups in PCNSL. The improved IELSG scoring system was established, which incorporated age ≥ 54years, ECOG ≥ 2, deep brain structure, elevated CSF protein, and LDH/ULN > 0.75. On the other hand, POD18 was identified as a new powerful prognostic factor for PCNSL. In multivariate analysis, POD18 and the improved IELSG scoring system were independent prognostic factors for OS. Nomogram including the two significant variables showed the best performance (C-index = 0.828). In this study, the IELSG score was improved and a new prognostic indicator POD18 was incorporated to construct a nomogram prognostic model, thereby further improving the predictive ability of the model.

Profiling Phosphoproteome Landscape in Circulating Extracellular Vesicles from Microliters of Biofluids through Functionally Tunable Paramagnetic Separation.

Many biological processes are regulated through dynamic protein phosphorylation. Monitoring disease-relevant phosphorylation events in circulating biofluids is highly appealing but also technically challenging. We introduce here a functionally tunable material and a strategy, extracellular vesicles to phosphoproteins (EVTOP), which achieves one-pot extracellular vesicles (EVs) isolation, extraction, and digestion of EV proteins, and enrichment of phosphopeptides, with only a trace amount of starting biofluids. EVs are efficiently isolated by magnetic beads functionalized with TiIV ions and a membrane-penetrating peptide, octa-arginine R8 + , which also provides the hydrophilic surface to retain EV proteins during lysis. Subsequent on-bead digestion concurrently converts EVTOP to TiIV ion-only surface for efficient enrichment of phosphopeptides for phosphoproteomic analyses. The streamlined, ultra-sensitive platform enabled us to quantify 500 unique EV phosphopeptides with only a few μL of plasma and over 1200 phosphopeptides with 100 μL of cerebrospinal fluid (CSF). We explored its clinical application of monitoring the outcome of chemotherapy of primary central nervous system lymphoma (PCNSL) patients with a small volume of CSF, presenting a powerful tool for broad clinical applications.

Profiling Phosphoproteome Landscape in Circulating Extracellular Vesicles from Microliters of Biofluids through Functionally Tunable Paramagnetic Separation

AbstractMany biological processes are regulated through dynamic protein phosphorylation. Monitoring disease‐relevant phosphorylation events in circulating biofluids is highly appealing but also technically challenging. We introduce here a functionally tunable material and a strategy, extracellular vesicles to phosphoproteins (EVTOP), which achieves one‐pot extracellular vesicles (EVs) isolation, extraction, and digestion of EV proteins, and enrichment of phosphopeptides, with only a trace amount of starting biofluids. EVs are efficiently isolated by magnetic beads functionalized with TiIV ions and a membrane‐penetrating peptide, octa‐arginine R8+, which also provides the hydrophilic surface to retain EV proteins during lysis. Subsequent on‐bead digestion concurrently converts EVTOP to TiIV ion‐only surface for efficient enrichment of phosphopeptides for phosphoproteomic analyses. The streamlined, ultra‐sensitive platform enabled us to quantify 500 unique EV phosphopeptides with only a few μL of plasma and over 1200 phosphopeptides with 100 μL of cerebrospinal fluid (CSF). We explored its clinical application of monitoring the outcome of chemotherapy of primary central nervous system lymphoma (PCNSL) patients with a small volume of CSF, presenting a powerful tool for broad clinical applications.

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

Patient-derived xenograft mouse models to investigate tropism to the central nervous system and retina of primary and secondary central nervous system lymphoma.

How and why lymphoma cells home to the central nervous system and vitreoretinal compartment in primary diffuse large B-cell lymphoma of the central nervous system remain unknown. Our aim was to create an in vivo model to study lymphoma cell tropism to the central nervous system. We established a patient-derived central nervous system lymphoma xenograft mouse model and characterised xenografts derived from four primary and four secondary central nervous system lymphoma patients using immunohistochemistry, flow cytometry and nucleic acid sequencing technology. In reimplantation experiments, we analysed dissemination patterns of orthotopic and heterotopic xenografts and performed RNA sequencing of different involved organs to detect differences at the transcriptome level. We found that xenografted primary central nervous system lymphoma cells home to the central nervous system and eye after intrasplenic transplantation, mimicking central nervous system and primary vitreoretinal lymphoma pathology, respectively. Transcriptomic analysis revealed distinct signatures for lymphoma cells in the brain in comparison to the spleen as well as a small overlap of commonly regulated genes in both primary and secondary central nervous system lymphoma. This in vivo tumour model preserves key features of primary and secondary central nervous system lymphoma and can be used to explore critical pathways for the central nervous system and retinal tropism with the goal to find new targets for novel therapeutic approaches.