Central Nervous System Lymphoma Research Articles

Outcomes and relapse patterns in primary central nervous system lymphoma: Longitudinal analysis of 559 patients diagnosed from 1983 to 2020.

Contemporary outcomes and relapse patterns in primary CNS lymphoma (PCNSL) are lacking. We analyzed factors associated with relapse in a large cohort with extensive follow-up. T1-post-contrast-enhancing disease was characterized in immunocompetent PCNSL (diffuse large B-cell) patients from 1983 to 2020. Patients were stratified by response to induction and consolidation (complete/unconfirmed [CR/CRu], partial, stable, progression [POD]). Refractory was POD during (or relapse ≤3 months of) induction. Initial relapse site was categorized as local (involving/adjacent to baseline), distant intraparenchymal, leptomeningeal, or other. Progression-free (PFS) and overall survival (OS) were assessed with proportional hazards. Cumulative incidence with competing risks was used to assess local relapse. Median follow-up was 7.4 years (N = 559). Most (321, 57%) were recursive partitioning analysis class 2 (age ≥50, Karnosfky Performance Status [KPS] ≥70). Most had supratentorial (420, 81%), multifocal (274, 53%), bilateral (224, 43%), and deep structure involvement (314, 56%). Nearly all received methotrexate-based induction (532, 95%). There was no difference in PFS or OS from consolidation based on initial response to induction (CR/CRu vs PR) in patients who ultimately achieved a CR/CRu to consolidation. PFS at 1-, 5 years for 351 patients with CR/CRu to consolidation was 80% (95% confidence interval [95% CI]: 76%-84%) and 46% (95% CI: 41%-53%), respectively; 1-year cumulative incidence of local versus nonlocal relapse was 1.8% versus 15%, respectively. For 97 refractory patients, 1-year cumulative incidence of local versus nonlocal relapse was 57% versus 42%, respectively. Deep structure involvement (HR 1.89, 95% CI: 1.10%-3.27%) was associated with local relapse in refractory patients. We report the first comprehensive relapse patterns in a large PCNSL cohort. While relapses post-CR to consolidation are typically distant and unpredictable, refractory patients had a relatively high incidence of local relapse. These findings can help optimize multimodality therapy for this highest-risk population.

Imaging Features of Immunodeficiency-Associated Primary CNS Lymphoma: A Review.

In the immunocompromised setting, there are distinct radiologic findings of primary central nervous system lymphoma (PCNSL), including necrotic ring-enhancing lesions, increased propensity for intralesional haemorrhage, and multiplicity. In this clinical context, advanced imaging with MR perfusion, spectroscopy, and diffusion-weighted imaging can be used to increase accuracy in the diagnosis of lymphoma over mimics such as high-grade glioma, metastases, or infection. This review summarizes the histology and pathophysiology of PCNSL in immunodeficient hosts, which provide a basis for its imaging appearances, prognosis, and treatment. This discussion is important for the general radiologist as the incidence of immunodeficiency-related PCNSL may be increasing.

CNS bridging radiotherapy achieves rapid cytoreduction before CAR T-cell therapy for aggressive B-cell lymphomas

AbstractChimeric antigen receptor (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 extracranial lymphoma in which it can improve CART outcomes through cytoreduction of high-risk lesions. We hypothesized that BRT would achieve similar, significant cytoreduction before CART for CNSL (CNS-BRT). We identified patients with CNSL with non-Hodgkin B-cell lymphoma who received CNS-BRT before commercial CART. Cytoreduction from CNS-BRT was calculated as change in lesion size before CART. Twelve patients received CNS-BRT, and the median follow-up among survivors is 11.8 months (interquartile range, 8.5-21.9). Ten patients had CNSL (9 secondary, 1 primary) and 2 patients had epidural disease (evaluable for toxicity). All 10 patients with CNSL had progressive disease at the time of CNS-BRT. Of 12 patients, 1 experienced grade ≥3 cytokine release syndrome, and 3 of 12 patients experienced grade ≥3 immune effector cell–associated neurotoxicity syndrome. CNS-BRT achieved a 74.0% (95% confidence interval, 62.0-86.0) mean reduction in lesion size from baseline (P = .014) at a median of 12 days from BRT completion and before CART infusion. Best CNS response included 8 complete responses, 1 partial response, and 1 progressive disease. Three patients experienced CNS relapse outside the BRT field. Preliminary data suggest CNS-BRT achieves rapid cytoreduction and is associated with a favorable CNS response and safety profile. These data support further study of BRT as a bridging modality for CNSL CART.

Primary central nervous system lymphomas in immunocompromised patients require specific response criteria.

Immunosuppression is a well-established risk factor for primary central nervous system lymphomas (PCNSLs), which present in this context distinct radiological characteristics. Our aim was to describe the radiological evolution of treated PCNSL in immunocompromised patients and suggest adapted MRI response criteria. We conducted a multicenter retrospective study of patients from the French LOC, K-Virogref and CANCERVIH network databases and enrolled adult immunocompromised patients with newly diagnosed PCNSL. We evaluated the baseline, intermediate, end-of-treatment and follow-up MRI data of 31 patients (9 living with HIV, 16 with solid organ transplantation and 6 with an autoimmune disease under chronic immunosuppressive therapy). At baseline, 23/30 (77%) patients had necrotic lesions with ring enhancement and 28% of the lesions were hemorrhagic. At the end of the first-line treatment, 12/28 (43%) patients could not be classified according to the IPCG criteria. Thirteen of 28 (46%) patients still harbored contrast enhancement, and 11/28 (39%) patients had persistent large necrotic lesions with a median diameter of 15mm. These aspects were not associated with a pejorative outcome and progressively diminished during follow-up. Six patients relapsed; however, we failed to identify any neuroimaging risk factors on the end-of-treatment MRI. In immunocompromised patients, PCNSLs often harbor alarming features on end-of-treatment MRI, with persistent contrast-enhanced lesions frequently observed. However, these aspects seemed to be related to the necrotic and hemorrhagic nature of the lesions and were not predictive of a pejorative outcome. Specific response criteria for this population are thereby proposed.

Diagnostic Algorithm for Intracranial Lesions in the Emergency Department: Effectiveness of the Relative Brain Volume and Hounsfield Unit Value Measured by Perfusion Tomography.

Background Early treatment of intracranial lesions in the emergency department is crucial, but it can be challenging to differentiate between them. This differentiation is essential because the treatment of each type of lesion is different. Cerebral computed tomography perfusion (CTP) imaging can help visualize the vascularity of brain lesions and provide absolute quantification of physiological parameters. Compared to magnetic resonance imaging, CTP has several advantages, such as simplicity, wide availability, and reproducibility. Purpose This study aimed to assess the effectiveness of Hounsfield units (HU) in measuring the density of hypercellular lesions and the ability of CTP to quantify hemodynamics in distinguishing intracranial space-occupying lesions. Methods A retrospective study was conducted from March 2016 to March 2022. All patients underwent CTP and CT scans, and relative cerebral blood volume (rCBV) and HU were obtained for intracranial lesions. Results We included a total of 244 patients in our study. This group consisted of 87 (35.7%) individuals with glioblastomas (GBs), 48 (19.7%) with primary central nervous systemlymphoma (PCNSL), 45 (18.4%) with metastases (METs), and 64 (26.2) with abscesses. Our study showed that the HUs for METs were higher than those for GB (S 57.4% and E 88.5%). In addition, rCBV values for PCNSL and abscesses were lower than those for GB and METs. The HU in PCNSL was higher than those in abscesses (S 94.1% and E 96.6%). Conclusion PCT parameters provide valuable information for diagnosing brain lesions. A comprehensive assessment improves accuracy. Combining rCBV and HU enhances diagnostic accuracy, making it a valuable tool for distinguishing between lesions. PCT's widespread availability allows for the use of both anatomical and functional information with high spatial resolution for diagnosing and managing brain tumor patients.

Exploring the diagnostic potential of cerebrospinal fluid (CSF) IL-10:IL-6 ratio in patients with primary central nervous system lymphoma (PCNSL).

e14041 Background: Primary Central Nervous System Lymphomas (PCNSL) present significant diagnostic challenges due to their aggressive nature. Current diagnostic methods include neuroimaging, CSF cytology, FDG-PET scans, and biopsies. Building upon the success of the IL-10:IL-6 ratio as a diagnostic biomarker in intraocular lymphoma, this study investigates its potential in PCNSL diagnosis. CSF IL-10:IL-6 ratio emerges as a promising, easily accessible biomarker for early PCNSL detection. Methods: Fifteen histopathologically confirmed PCNSL patients were compared with fifteen CNS inflammatory condition patients and ten patients with other CNS malignancies. Detailed clinical assessments were conducted, and IL-10:IL-6 levels were measured in serum and CSF using Flow cytometry. Results: The CSF IL-10:IL-6 Ratio was elevated (> 1) compared to serum levels in PCNSL patients in contrast to other control groups. The mean age ± SD of PCNSL patients was 55.47 ± 17.29, with a male-to-female ratio of 8:7. The mean (SD) for CSF IL-10:IL-6 ratio in PCNSL was 3.35 (3.88), while the mean (SD) for serum IL-10:IL-6 ratio was 0.438 (1.54). The statistical analysis revealed a significant difference (P = 0.0058 < 0.05). Conversely, comparing the CSF IL-10:IL-6 ratio with serum levels in controls with CNS inflammatory conditions and CNS malignancies showed no statistical significance (P > 0.05). Conclusions: Elevated CSF IL-10 and CSF IL-10/IL-6 ratios suggest their potential as early diagnostic markers for large B cell PCNSL. The IL-10:IL-6 ratio holds promise as a novel, easily accessible biomarker in readily available body fluids for PCNSL diagnosis.

Orelabrutinib, rituximab, temozolomide and high-dose methotrexate (RMOT) in newly diagnosed primary central nervous system lymphoma (PCNSL): A retrospective analysis on efficacy and safety.

e19041 Background: PCNSL is a rare, aggressive malignant tumor and has a poor prognosis. HD-MTX-based regimen is the first-line treatment of PCNSL. Orelabrutinib is a novel, potent, highly selective BTK inhibitor with a high CSF concentration. Recent evidence has shown the efficacy and safety of orelabrutinib in PCNSL. Therefore, we conducted a retrospective study of clinical outcomes in newly diagnosed PCNSL patients (pts) treated with RMOT regimen in routine clinical care. Methods: This retrospective cohort included the pts (aged 18-80 years) with newly diagnosed PCNSL who received 6 cycles of RMOT regimen (rituximab 375 mg/m2 iv day 1; MTX 3.5 g/m2 iv day 1; temozolomide 150 mg/m2 po day 1 to day 5; orelabrutinib 150 mg qd po; 4 weeks per cycle) as the first-line induction therapy between Nov. 2021 and Aug. 2023. All the pts were proposed to receive orelabrutinib monotherapy as maintenance after RMOT therapy. We recommend to receive autologous stem cell transplantation (ASCT) or whole brain radiation therapy (WBRT) as consolidation after RMOT therapy. Efficacy was assessed by MRI/PET per the International PCNSL Collaborative Group (IPCG) criteria. The primary endpoint was overall response rate (ORR); secondary endpoints were CR rate, progression-free survival (PFS), overall survival (OS), and safety. Results: Ten pts (6 males) with PCNSL were included, with a median age of 61 years (range, 45-77). All pts had a histologically confirmed diffuse large B-cell lymphoma. 4 pts (40%) underwent WBRT after induction therapy. As of the cut-off date (December 31, 2023), the median follow-up time was 9.7 (range, 4.8-25.7) month. All pts were evaluated for the treatment response. An interim evaluation after 4 cycles was available for 10 pts, showing complete remission (CR) rate of 80% (8/10), partial response (PR) rate of 20% (2/10), giving an ORR of 100.0% (10/10, Table). At data cutoff, the best ORR was 100.0% (10/10), with all pts achieved CR. Of 10 responders, 9 had an ongoing response, and 1 died of covid-19 infection. Median PFS/OS was not reached (NR) (95% CI NR-NR). The most common AEs were anemia, other include white blood cell or platelet count decreased. Reported AEs were generally manageable and resolved soon after supportive treatment. Only 1 (10%) pts experienced ≥grade 3 AEs—acute kidney injury. No treatment-related death occurred. Conclusions: This retrospective data suggested that RMOT had an encouraging anti-tumor activity in newly diagnosed PCNSL pts, with a toleratable safety profile. This orelabrutinib-containing regimens may provide a potential treatment strategy for pts with PCNSL. [Table: see text]

Whole Exome Sequencing Reveals Gene Mutation Characteristics of Primary Central Nervous System Lymphoma

To investigate gene mutation characteristics of primary central nervous system lymphoma (PCNSL) through whole exome sequencing (WES) to 18 patients with PCNSL. Tumor tissues from 18 patients with diffuse large B-cell lymphoma who were diagnosed with PCNSL in Department of Hematology, Lanzhou University Second Hospital from September 2018 to December 2020 and had normal immune function, no history of HIV or immunosuppressant therapy were collected. High-throughput-based WES was performed on the tumor tissues, with an average sequencing depth of >100×. After data processing and bioinformatics analysis of sequencing results, the mutation maps and mutation characteristics of 18 PCNSL patients were obtained. Obvious somatic mutations were detected in all 18 patients. The median number of somatic mutations was 321. Missense mutations were most prominent (accounting for about 90%), and the mutation type was dominated by C>T (50.2%), reflecting the age-related mutation pattern. Among the top 15 frequently mutated genes, PSD3, DUSP5, MAGEB16, TELO2, FMO2, TRMT13, AOC1, PIGZ, SVEP1, IP6K3, and TIAM1 were the driver genes. The enrichment results of driver gene pathways showed that RTK-RAS, Wnt, NOTCH, Hippo and Cell-Cycle pathways were significantly enriched. The tumor mutation burden was between 3.558 48/Mb and 8.780 89/Mb, and the average was 4.953 32/Mb, which was significantly higher than other cancer research cohorts in the TCGA database. PCNSL occurs somatic missense mutations frequently, mainly point mutations, and the mutation type is mainly C>T. The driver genes are mainly involved in RTK-RAS, Wnt, NOTCH and Hippo pathways, indicating that the above pathways may be related to the pathogenesis of PCNSL. PCNSL has a significantly high tumor mutation burden, which may explain the efficacy of PD-1 inhibitors in PCNSL.

Differentiation between primary central nervous system lymphomas and gliomas according to pharmacokinetic parameters derived from dynamic contrast-enhanced magnetic resonance imaging

PurposeIt is difficult to differentiate between primary central nervous system lymphoma and primary glioblastoma due to their similar MRI findings. This study aimed to assess whether pharmacokinetic parameters derived from dynamic contrast-enhanced MRI could provide valuable insights for differentiation. MethodsSeventeen cases of primary central nervous system lymphoma and twenty-one cases of glioblastoma as confirmed by pathology, were retrospectively analyzed. Pharmacokinetic parameters, including Ktrans, Kep, Ve, and the initial area under the Gd concentration curve, were measured from the enhancing tumor parenchyma, peritumoral parenchyma, and contralateral normal parenchyma. Statistical comparisons were made using Mann–Whitney U tests for Ve and Matrix Metallopeptidase-2, while independent samples t-tests were used to compare pharmacokinetic parameters in the mentioned regions and pathological indicators of enhancing tumor parenchyma, such as vascular endothelial growth factor and microvessel density. The pharmacokinetic parameters with statistical differences were evaluated using receiver-operating characteristics analysis. Except for the Wilcoxon rank sum test for Ve, the pharmacokinetic parameters were compared within the enhancing tumor parenchyma, peritumoral parenchyma, and contralateral normal parenchyma of the primary central nervous system lymphomas and glioblastomas using variance analysis and the least-significant difference method. ResultsStatistical differences were observed in Ktrans and Kep within the enhancing tumor parenchyma and in Kep within the peritumoral parenchyma between these two tumor types. Differences were also found in Matrix Metallopeptidase-2, vascular endothelial growth factor, and microvessel density within the enhancing tumor parenchyma of these tumors. When compared with the contralateral normal parenchyma, pharmacokinetic parameters within the peritumoral parenchyma and enhancing tumor parenchyma exhibited variations in glioblastoma and primary central nervous system lymphoma, respectively. Moreover, the receiver-operating characteristics analysis showed that the diagnostic efficiency of Kep in the peritumoral parenchyma was notably higher. ConclusionPharmacokinetic parameters derived from dynamic contrast-enhanced MRI can differentiate primary central nervous system lymphoma and glioblastoma, especially Kep in the peritumoral parenchyma.

Clinical Features and Prognostic of Patients with Primary Central Nervous System Lymphoma

To explore the clinical features and prognosis of patients with primary central nervous system lymphoma（PCNSL）. A retrospective analysis was performed on the relationship between clinical features, treatment regimen and prognosis in 46 newly diagnosed patients with primary central nervous system lymphoma who were diagnosed and treated in The Second Hospital of Lanzhou University from January 2015 to September 2022. Fisher's exact probability method was used to analyze the differences in clinical data of different subgroups. Kaplan-Meier survival curve was used to analyze the overall survival rate and progression-free survival rate of patients with different treatments, and the factors influencing survival were analyzed. Among 46 patients with PCNSL, which pathological type were diffuse large B-cell lymphoma（DLBCL）. There were 26(56.5%) cases of male and 20(43.5%) of female, with a median age of 54(17-71) years. In Hans subtypes, 14 cases (30.4%) of GCB subtype, 32 cases (69.6%) of non-GCB subtype. 32 cases (69.6%) of Ki-67≥80%. Among 36 patients who completed at least 2 cycles of treatment with follow-up data, the efficacy evaluation was as follows: overall response rate(ORR) was 63.9%, complete response(CR) rate was 47.2%, 17 cases of CR, 6 cases of PR. The 1-year progression-free survival rate and 1-year overall survival rate was 73.6% and 84.9%, respectively. The 2-year progression-free survival rate and 2-year overall survival rate was 52.2% and 68.9%, respectively. The ORR and CR rate of 17 patients treated with RMT regimen was 76.5% and 52.9% (9 cases CR and 4 cases PR), respectively. Univariate analysis of 3 groups of patients treated with RMT regimen, RM-BTKi regimen, and RM-TT regimen as first-line treament showed that deep brain infiltration was associated with adverse PFS(P =0.032), and treatment regimen was associated with adverse OS in PCNSL patients（P =0.025）. Different treatment modalities were independent prognosis predictors for OS, the deep brain infiltration of PCNSL is a poor predictive factor for PFS. Patients with relapse/refractory (R/R) PCNSL have a longer overall survival time because to the novel medication BTKi. They have strong toleration and therapeutic potential as a first-line therapy for high-risk patients.

Outcomes of R-MPV followed by ara-c in primary central nervous system lymphoma: A single-center retrospective analysis.

e19046 Background: Primary central nervous system lymphoma (PCNSL) lymphoma is a rare non-Hodgkin’s Lymphoma. Currently, there is no uniform consensus in the optimal management of PCNSL. In patients that can tolerate systemic therapy, induction therapy is typically done with a high-dose methotrexate-based regimen, due to evidence of better penetration of the blood brain barrier. One such regimens is high dose methotrexate combined with rituximab, procarbazine, and vincristine (R-MPV). Options for consolidation therapy include high-dose systemic therapy with stem cell rescue (ASCT), whole brain radio therapy (WBRT) and high-dose cytarabine (ara-c) with or without etoposide (EA). At our institution we utilize an R-MPV induction approach with some form of ara-c consolidation without etoposide. We aimed to execute a retrospective cohort study to analyze outcomes of this approach. Methods: All the patients diagnosed with PCNSL who received an induction regimen of R-MPV from 10/01/2020 to 06/01/2023 were included. Data was then gathered by chart review of the electronic medical record. Treatment outcomes were evaluated based on imaging with brain MRIs and PET scans. Central findings such as complete response (CR) rate, progression free survival (PFS) and overall survival (OS) were ascertained. Results: 10 charts were reviewed. 9 out of the 10 patients had a histological presentation consistent with diffuse large B-cell lymphoma; 1 patient had a diagnosis of B-cell lymphoma. In terms of demographics, the patients ages ranged from 54 to 83 years, with a median of 74 years. Complete response was achieved in 5 out of the 10 patients (CR rate of 50%), and no relapse was noted in any of these patients. 2 out of the 10 patients progressed on treatment, with 1 dying from progression of the disease. The median follow-up for patients who were still alive was 24 months. 2-year PFS was 80%, and 2-year OS was 90%. Median PFS and OS were not reached. Mean PFS and OS were 28 months and 30.5 months respectively. Conclusions: Based on our study results, the CR rate we observed for R-MPV appears consistent with existing literature on this regimen and other methotrexate-based induction regimens. Our results for R-MPV with ara-c consolidation provides similar outcomes to existing studies on treatment with different methotrexate-based induction and consolidation with ASCT, particularly the 80% PFS we observed. This percent PFS also appears similar to studies of consolidation with ara-c and EA, and superior to PFS with WBRT. Overall, these results are reassuring as in a specific set of older patients who might not be candidates for ASCT, our specific nonmyeloablative approach could be worthwhile. However, our study does have the limitation of being a single center retrospective perspective. [Table: see text]

Predictors for the Differentiation between Glioblastoma, Primary Central Nervous System Lymphoma, and Metastasis in Patients with a Solitary Enhancing Intracranial Mass.

Introduction Differentiation between glioblastoma (GBM), primary central nervous system lymphoma (PCNSL), and metastasis is important in decision-making before surgery. However, these malignant brain tumors have overlapping features. This study aimed to identify predictors differentiating between GBM, PCNSL, and metastasis. Materials and Methods Patients with a solitary intracranial enhancing tumor and a histopathological diagnosis of GBM, PCNSL, or metastasis were investigated. All patients with intracranial lymphoma had PCNSL without extracranial involvement. Demographic, clinical, and radiographic data were analyzed to determine their associations with the tumor types. Results The predictors associated with GBM were functional impairment ( p = 0.001), large tumor size ( p < 0.001), irregular tumor margin ( p < 0.001), heterogeneous contrast enhancement ( p < 0.001), central necrosis ( p < 0.001), intratumoral hemorrhage ( p = 0.018), abnormal flow void ( p < 0.001), and hypodensity component on noncontrast cranial computed tomography (CT) scan ( p < 0.001). The predictors associated with PCNSL comprised functional impairment ( p = 0.005), deep-seated tumor location ( p = 0.006), homogeneous contrast enhancement ( p < 0.001), absence of cystic appearance ( p = 0.008), presence of hypointensity component on precontrast cranial T1-weighted magnetic resonance imaging (MRI; p = 0.027), and presence of isodensity component on noncontrast cranial CT ( p < 0.008). Finally, the predictors for metastasis were an infratentorial ( p < 0.001) or extra-axial tumor location ( p = 0.035), smooth tumor margin ( p < 0.001), and presence of isointensity component on cranial fluid-attenuated inversion recovery MRI ( p = 0.047). Conclusion These predictors may be used to differentiate between GBM, PCNSL, and metastasis, and they are useful in clinical management.

Outcome of patients with primary CNS lymphoma treated with methotrexate based regimens: A retrospective study.

e19051 Background: Primary central Nervous system Lymphoma is an aggressive Non-Hodgkins Lymphoma with 5-year survival of only 30 percent. Few studies have addressed the comparison of induction treatment regimens with various risk stratification groups with no consensus on the optimal methotrexate dose for best complete overall response and survival outcome. Our retrospective study compares induction treatment regimens, identifies different risk stratification factors, and provides insight into the best induction treatment regimen with determination of optimal methotrexate dose. Methods: Design: Retrospective Primary Outcomes: Complete response rate, overall survival rate with risk stratification based on histology, Ki-67, and initial albumin level. Results: 77 patients 18 years of age and older with PCNSL at NCC and LAC between June 2015 and July 2022 were included in the study. Overall, 50% of patients were treated with CALGB50202 induction regimen,19% with R-MPV,12 % with De-Angelis regimen. CALGB 50202 has the highest survival rate of 63.4% followed by R-MPV with 22% survival rate followed by De-Angelis regimen with 0% survival rate with chi-square test P-value &lt; 0.001 during the study period. Similarly, CALGB 50202 has the highest CR rate of 61.9% followed by R-MPV with CR rate of 16% followed by De-Angelis regimen with the lowest CR rate of 2.4%.CR rate comparison is statistically significant with P-value of &lt; 0.0001. The study assessed optimum methotrexate dose. The mean and median total methotrexate dose in patients who were alive during the study period was 74.3 grams and 81.7 grams respectively as compared to mean value of 34.2 grams and median of 19.3 grams in patients who died with a p-value of 0.0019.Comparing survival based on histology as germinal center versus non-germinal center PCNSL, the later has higher mortality rate of 64.7 % as compared to 11.8 % in patient with germinal center PCNSL.Ki-67 was assessed as &gt;80% and &lt;80%.Among patients who were alive during the study period,48.8% have Ki-67 &gt; 80% as compared to only 12.2%.On the other hand, among the patients who died,47.1% of patients have Ki-67 &lt;80%,indicating lower ki-67 associated a lower survival outcome as depicted on the Kaplan Meier curve with P-value of 0.004. Patients with normal initial albumin have a higher chance of survival (78%) vs 22% in the group with low albumin level with p-value of 0.0005. Conclusions: CALGB 50202 had the highest CR and survival rates followed by R-MPV regimen in patients with primary CNS lymphoma. The total dose of methotrexate patient receives was an important factor for survival and CR and the optimal total methotrexate dose was 70-80 grams. Normal initial albumin, high Ki-67, and germinal center histology favored better survival.

Emavusertib (CA-4948) in combination with ibrutinib in patients with relapsed/refractory primary central nervous system lymphoma (R/R PCNSL).

2087 Background: PCNSL is a rare and aggressive form of NHL in the central nervous system or vitreoretinal space. Despite high initial rates of responses to HD-MTX-based induction chemotherapies, most patients relapse in two years. R/R PCNSL is associated with poor prognosis, representing a clear unmet medical need, as there are no currently approved treatments for this disease. IRAK4 kinase activity is required for TLR and IL-1R signaling in a variety of myeloid and lymphoid cell types, including PCNSL. Recruitment of IRAK4 to these receptors and subsequent activation is facilitated by the MyD88 adaptor protein, which is mutated in ~70% of PCNSL. This leads to constitutive activation of the NF-κB signaling pathway, increased inflammation, and tumor growth. Emavusertib is a novel and potent oral inhibitor of IRAK4 and FLT3, which has demonstrated the ability to cross the blood-brain barrier in PCNSL xenografts. In preclinical studies, the combination of emavusertib with ibrutinib overcomes resistance to BTK inhibitors. This combination has an acceptable safety profile across a broad population of R/R NHL patients, including PCNSL. Here we present updated safety and efficacy data for emavusertib in combination with ibrutinib in patients with R/R PCNSL. Methods: The safety, clinical activity, and potential biomarkers of emavusertib in R/R PCNSL are being investigated in the ongoing open-label, Phase 1/2 TakeAim Lymphoma trial (NCT03328078). The eligible patients with R/R PCNSL received emavusertib (100-300 mg BID) in combination with ibrutinib (560 mg QD) in a 21-day cycle until tumor progression or unacceptable toxicity. Results: Here, we present updated data from R/R PCNSL patients with prior ibrutinib exposure who were treated with emavusertib in combination with ibrutinib. The median number of prior lines of anti-cancer therapies was 3 (range: 2-5), all patients were R/R to both frontline therapy and subsequent ibrutinib regimens. Prior responses to ibrutinib based regimens included only 1 CR. Here, we report a higher CR rate when these patients are subsequently treated with emavusertib in combination with ibrutinib.Results revealed no dose-limiting toxicities. Conclusions: Emavusertib in combination with ibrutinib was well tolerated with an acceptable safety profile and promising efficacy in R/R PCNSL patients with previous exposure to ibrutinib (BTKi). Enrollment in this trial is ongoing (NCT03328078). Clinical trial information: NCT03328078 .

Primary central nervous system lymphomas: EHA-ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.

This EHA-ESMO Clinical Practice Guideline provides key recommendations for managing primary DLBCL of the CNS.The guideline covers clinical, imaging and pathological diagnosis, staging and risk assessment, treatment and follow-up.Algorithms for first-line and salvage treatments are provided.The author group encompasses a multidisciplinary group of experts from different institutions and countries in Europe.Recommendations are based on available scientific data and the authors' collective expert opinion.

Phase 3 trial evaluating efficacy and safety of odronextamab plus CHOP vs rituximab plus CHOP in previously untreated diffuse large B-cell lymphoma (DLBCL; OLYMPIA-3).

TPS7086 Background: Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) remains a standard of care first-line (1L) treatment for patients (pts) with DLBCL. However, poor outcomes persist for certain DLBCL pt subgroups, including those with high-risk features: activated B-cell-like (ABC) cell of origin (5-yr progression-free survival [PFS]/overall survival [OS] 48%/56%), MYC and BCL2 rearrangements (median OS 15 months), or International Prognostic Index [IPI] score 4–5 (5-yr PFS/OS 46%/54%). Improving outcomes through effective 1L treatment continues to be important, highlighted by the dismal prognosis in pts who are primary refractory (2-yr OS 24%) or who relapse early after 1L treatment (4-yr OS 30%). Odronextamab, a CD20×CD3 bispecific antibody, showed encouraging efficacy (objective response rate 52%; complete response [CR] rate 31%; 47% maintained CR at 2 years) and generally manageable safety as a monotherapy in pts with heavily pretreated relapsed/refractory DLBCL, including in pts who were anti-CD20 antibody refractory (Ph 2 ELM-2 study; Ayyappan, et al. ASH 2023). These data provide the rationale to evaluate the efficacy and safety of odronextamab plus CHOP (O-CHOP) vs R-CHOP in pts with previously untreated DLBCL. Methods: OLYMPIA-3 (NCT06091865) is a Ph 3, randomized, open-label, multicenter study of O-CHOP vs R-CHOP in pts with previously untreated DLBCL and intermediate- or high-risk features. The study consists of Part 1A (dose escalation), Part 1B (dose optimization), and Part 2 (randomized controlled). Part 1A will assess the safety of O-CHOP. In Part 1B, pts will be randomized 1:1 to one of two O-CHOP regimens, selected based on Part 1A results. In Part 2, pts will be randomized 1:1 to O-CHOP or R-CHOP, with odronextamab dosing dependent on Part 1 results, and R-CHOP given per standard practice. Intravenous odronextamab will be administered weekly from Cycle (C) 1 Day (D) 8 until C5D8, with step-up dosing during C1 and C2, then every 2 weeks until the end of C6. CHOP will be administered in six 21-day cycles, starting on C1D1. Key inclusion criteria: aged ≥18 years; untreated CD20+ DLBCL; ECOG PS ≤2; and IPI score ≥2. Pts with central nervous system lymphoma, Grade ≥3 peripheral neuropathy, or an active infection are excluded. The primary endpoints are the incidence of dose-limiting toxicities, and incidence and severity of treatment-emergent adverse events (Part 1), and PFS by independent central review (Part 2). Part 2 key secondary endpoints are event-free survival and CR rate (both by independent central review), as well as OS. Other secondary endpoints are minimal residual disease (by ctDNA) and patient-reported outcomes (EORTC QLQ-C30, FACT-LymS, PGIS, PGIC, and EQ-5D-5L). The trial is currently recruiting and is expected to enroll up to 64 pts in Part 1 and ~840 pts in Part 2 at ~200 global sites. Clinical trial information: NCT06091865 .

Phase 3 trial evaluating the efficacy and safety of odronextamab versus investigator’s choice in previously untreated follicular lymphoma (OLYMPIA-1).

TPS7096 Background: Follicular lymphoma (FL) is an incurable disease in which patients will relapse despite the effectiveness of first-line (1L) rituximab-based chemoimmunotherapy (CIT), indicating the need for alternative 1L treatments that can deepen and prolong response. Odronextamab, an off-the-shelf, CD20×CD3 bispecific antibody, showed compelling efficacy and generally manageable safety as a monotherapy at 3L+ for patients with relapsed/refractory (R/R) FL in the Phase 2 ELM-2 study (Villasboas, et al. ASH 2023). Objective and complete response (CR) rates were 80% and 73%, respectively, median duration of response was 22.6 months, median progression-free survival (PFS) was 20.7 months, and median overall survival was not reached. The rate of treatment-related adverse events leading to treatment discontinuation was 7.8%. The activity of odronextamab monotherapy in this heavily pretreated R/R FL population, including among patients with rituximab-refractory disease, provides a strong rationale for developing odronextamab as a chemotherapy-free option that can improve long-term outcomes in 1L. Methods: OLYMPIA-1 (NCT06091254) is a Phase 3, randomized, open-label, multicenter study of odronextamab versus investigator’s choice of CIT (R-CHOP, R-CVP, or R-bendamustine) in patients with previously untreated FL. The study consists of Part 1 (safety run-in), followed by Part 2 (randomization). In Part 1, patients will receive six 21-day cycles (induction) of intravenous odronextamab, administered in a step-up regimen during Cycle (C) 1 to mitigate the risk of cytokine release syndrome, followed by full dose starting from C2. Patients with CR or partial response at the end of induction will receive 12 doses of odronextamab maintenance given Q8W. In Part 2, patients will be randomized 1:1 to receive induction of six cycles of odronextamab followed by odronextamab maintenance, or CIT followed by rituximab maintenance. Key inclusion criteria: aged ≥18 years; CD20+ FL Grade 1–3a, stage II bulky or stage III/IV; measurable disease; and ECOG performance status 0–2. Patients with central nervous system lymphoma or histological Grade 3b are excluded. The Part 2 primary endpoint is CR at 30 months (CR30) as assessed by independent central review. Key secondary endpoints include PFS, event-free survival, investigator-assessed CR30, and patient-reported outcomes. Biomarkers (including minimal residual disease by ctDNA) will be evaluated as exploratory endpoints. This trial is currently recruiting and is expected to enroll ~12–32 patients in Part 1 and ~446 patients in Part 2 at ~200 global sites. Clinical trial information: NCT06091254 .

Phase 3 trial evaluating the efficacy and safety of odronextamab plus chemotherapy versus rituximab plus chemotherapy in previously untreated follicular lymphoma (OLYMPIA-2).

TPS7099 Background: Odronextamab, an off-the-shelf, CD20×CD3 bispecific antibody, has shown compelling efficacy and generally manageable safety as monotherapy in patients with heavily pretreated relapsed/refractory (R/R) follicular lymphoma (FL), including those with rituximab-refractory disease (Villasboas et al. ASH 2023). In the Phase 2 ELM-2 study, odronextamab demonstrated objective and complete response (CR) rates of 80% and 73%, respectively, and median duration of response of 22.6 months; median overall survival was not reached. Treatment-related adverse events led to treatment discontinuation in 7.8% of patients. These encouraging results support an investigation into whether odronextamab plus chemotherapy is superior to the current FL first-line standard of care of rituximab plus chemotherapy. This study will also evaluate whether odronextamab maintenance is required to achieve progression-free survival (PFS), given the risks associated with sustained B-cell depletion. Methods: OLYMPIA-2 (NCT06097364) is a Phase 3, randomized, open-label, multicenter study of odronextamab plus chemotherapy (Odro-CHOP/Odro-CVP) versus R-CHOP/R-CVP in patients with previously untreated FL. The study consists of Part 1A (dose escalation), Part 1B (dose optimization), and Part 2 (randomization). In Part 1, patients will receive six 21-day cycles (induction) of Odro-CHOP, in which intravenous odronextamab will be administered in a step-up regimen starting on Cycle (C) 1 Day (D) 8 to mitigate the risk of cytokine release syndrome, followed by full dose starting from C2D8. Patients with CR or partial response at the end of induction will receive 12 doses of odronextamab maintenance given Q8W. In Part 2, patients will be randomized 1:1:1 to receive induction of 6 cycles of Odro-CHOP/Odro-CVP with no maintenance (Arm A), Odro-CHOP/Odro-CVP followed by odronextamab maintenance (Arm B), or R-CHOP/R-CVP followed by rituximab maintenance (Arm C). Key inclusion criteria: aged ≥18 years; CD20+ FL Grade 1–3a, stage II bulky or stage III/IV; measurable disease; and ECOG performance status 0–2. Part 1: patients with FL that is R/R (Part 1A only) or previously untreated with Follicular Lymphoma International Prognostic Index-1 (FLIPI-1) score 3–5. Part 2: previously untreated patients with FLIPI-1 score 0–5. Patients with central nervous system lymphoma or histological Grade 3b are excluded. The Part 2 primary endpoint is CR rate at 30 months (CR30) by independent central review. Key secondary endpoints include PFS, event-free survival, investigator-assessed CR30, and patient-reported outcomes. Biomarkers (including minimal residual disease by ctDNA) will be evaluated as exploratory endpoints. This trial is currently recruiting and is expected to enroll up to 64 patients in Part 1 and ~669 patients in Part 2 at ~200 global sites. Clinical trial information: NCT06097364 .

Teaching NeuroImage: Fundoscopic and Optical Coherence Tomography Changes in Primary CNS Lymphoma.

Teaching NeuroImage: Fundoscopic and Optical Coherence Tomography Changes in Primary CNS Lymphoma.

A pilot study of axicabtagene ciloleucel (axi-cel) for relapsed/refractory primary and secondary central nervous system lymphoma (PCNSL and SCNSL).

2006 Background: Prognosis of patients with relapsed/refractory (R/R) CNSL is poor with no standard of care treatment options. Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (axi-cel) has shown efficacy in R/R systemic large B-cell lymphoma (LBCL) and could be considered for R/R CNSL. Methods: We conducted a pilot study of axi-cel in patients with R/R CNS LBCL. No bridging therapy except corticosteroids was allowed after enrollment. Ommaya reservoir was placed before infusion. Patients underwent lymphodepletion with fludarabine and cyclophosphamide followed by axi-cel dosing of 2x106 cells/kg intravenous infusion. The study enrolled 18 patients, of whom the first 6 patients were observed for treatment-limiting toxicities (TLTs). Primary endpoint was safety, measured by rate of TLTs and grade 3+ adverse events (AEs). Secondary endpoints included objective response rate (ORR), complete response (CR) rate, duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Exploratory analyses include paired peripheral blood (PB) and CSF analyses for axi-cel pharmacokinetics, pharmacodynamics, flow cytometry, single-cell RNA-Seq. Results: We report the results of the entire cohort of 18 patients (13 PCNSL, 4 SCNSL, 1 concurrent systemic &amp; ocular L) enrolled. Median age was 62 years (33-80), 8/18 were women. Median number of prior therapies was 3 (1-7). No TLTs were observed; 16/18 (89%) patients developed cytokine release syndrome/CRS (grade 3+, 0%); 8/18 (44%) developed immune effector cell-associated neurologic syndrome/ICANS, 5/18 (28%) grade 3+. Two patients developed Ommaya-related meningitis requiring explant with recovery. One patient had grade 3 seizures that resolved with anti-epileptic agents. The ORR was 94% (17/18); 67% CR (12/18). The median time to best response was 3 months. As of January 25, 2024, the median follow up was 24.2 months, median DOR 13.4 months and 9 patients had progressed. The median PFS was 14.3 months (95% CI: 6.3-NR) and median OS, 26.4 months (95% CI: 11.2-NR). Seven patients have died, all from disease progression. At the time of presentation, there will be a minimum follow-up of 12 months. Correlative data on all 18 patients will be presented at the meeting. Axi-cel pharmacokinetics in the first 12 CNSL patients was similar to that previously reported for DLBCL patients without CNS involvement in ZUMA-1 and ZUMA-7. Patients with CR demonstrated increased peak levels of pro-inflammatory cytokines. CSF CAR T cells exhibit Type I interferon (IFN) transcriptomic signature compared to proliferative signature in blood. Conclusions: Axi-cel was safe and well-tolerated in CNSL patients with encouraging efficacy and median PFS and durability of response of more than 1 year. There was no apparent additional risk of adverse neurologic events including ICANS from axi-cel. Clinical trial information: NCT04608487 .