Central Nervous System Lymphoma Research Articles

ABCL-129 Current Management Strategies for Primary CNS Lymphoma in Children and Their Impact on Patient Survival

ABCL-129 Current Management Strategies for Primary CNS Lymphoma in Children and Their Impact on Patient Survival

480P Clinical utility of ctDNA detection by NGS for diagnosis of CNS lymphoma

480P Clinical utility of ctDNA detection by NGS for diagnosis of CNS lymphoma

Double-hit primary central nervous system lymphoma with histogenetically proven bone marrow infiltration: a case report and a review of the literature.

Double-hit lymphoma (DHL) formerly referred to high-grade B-cell lymphoma with concurrent MYC and BCL2 or BCL6 rearrangements, however, the updated 2022 World Health Organization Classification (5th edition online) excludes those with MYC and BCL 6 rearrangements from the high-grade category. DHL confined to the central nervous system (CNS), known as double-hit primary CNS lymphoma (DH-PCNSL), is rare with poorly understood clinical features. Here, we report a case of a 64-year-old man with multiple brain tumors diagnosed with DH-PCNSL who showed bone marrow (BM) infiltration early in the clinical course. The histological diagnosis was high-grade B-cell lymphoma with MYC and BCL6 rearrangements. Fluorodeoxyglucose positron emission tomography (FDG-PET) revealed no abnormal accumulation except in the CNS. The patient received whole-brain radiotherapy following the failure of high-dose methotrexate. After completion of radiotherapy, the patient developed thrombocytopenia, and BM biopsy showed infiltration of DHL cells, which were not detected by repeated FDG-PET. This is the first report of DH-PCNSL where identical gene rearrangements were confirmed in both the resected CNS tumor and BM tissue. Patients with DH-PCNSL require careful follow-up because they may be at a potential risk of BM infiltration, which may be undetectable by FDG-PET, particularly early in the disease course.

Isolated primary CNS lymphoma after liver transplantation for autoimmune hepatitis: a case report

Post-transplantation primary central nervous system lymphoma (PT-PCNSL) is a rare neoplasm that occurs in immunocompromised patients. It can manifest months or years after transplantation, presenting with various neurological symptoms. A 64-year-old woman, who had received a liver transplant due to autoimmune hepatitis, presented with generalized weakness, headache, and confusion. Further investigation revealed multiple ring-enhancing lesions in the right frontal and temporoparietal regions on brain MRI. A brain biopsy confirmed the diagnosis of PT-PCNSL. This case underscores the importance of considering PT-PCNSL in the differential diagnosis of contrast-enhancing brain lesions in post-transplant patients. Timely recognition of PT-PCNSL is crucial for appropriate management and improved outcomes. To the best of our knowledge, this report describes the first instance of isolated CNS lymphoma in a liver transplant recipient, due to autoimmune hepatitis, successfully brought to complete remission with a rituximab-methotrexate regimen.

Improvements in activities of daily living among patients with brain tumors are associated with age, baseline physical function, duration of rehabilitation, and tumor recurrence but not type.

Genetic testing has improved the accuracy of diagnosis of brain tumors, and treatment is now tailored to the type of brain tumor. In contrast, the factors that influence the improvement in independence in activities of daily living (ADLs) following rehabilitation have not been clarified, particularly the role of tumor type. In this retrospective cohort study of 358 participants, we analyzed changes in the Functional Independence Measure (FIM) from pre-rehabilitation to post-rehabilitation provided in an acute care hospital. Multiple regression was used to determine whether FIM gain is associated with age, gender, preadmission Karnofsky Performance Status (KPS), number of rehabilitation days, average duration of daily therapy (min/day), and tumor recurrence and type (WHO grade 1, 2, 3, and 4 gliomas; primary central nervous system lymphomas; and metastatic brain tumors). The results showed that older age (β -0.183), tumor recurrence (β -0.137), preadmission KPS < 80 (β -0.180), and higher baseline total FIM score (β -0.470) were associated with lower FIM gain whereas the average duration of daily therapy (β 0.153) was associated with higher FIM gain. Brain tumor type was not associated with FIM gain. Improved independence in ADLs is more influenced by demographic, functional status, and treatment factors than differences in brain tumor type.

Comparative analyses of immune cells and alpha-smooth muscle actin-positive cells under the immunological microenvironment between with and without dense fibrosis in primary central nervous system lymphoma.

Histopathologic examinations of primary central nervous system lymphoma (PCNSL) reveal concentric accumulation of lymphocytes in the perivascular area with fibrosis. However, the nature of this fibrosis in "stiff" PCNSL remains unclear. We have encountered some PCNSLs with hard masses as surgical findings. This study investigated the dense fibrous status and tumor microenvironment of PCNSLs with or without stiffness. We evaluated by silver-impregnation nine PCNSLs with stiffness and 26 PCNSLs without stiffness. Six of the nine stiff PCNSLs showed pathological features of prominent fibrosis characterized by aggregation of reticulin fibers, and collagen accumulations. Alpha-smooth muscle actin (αSMA)-positive spindle cells as a cancer-associated fibroblast, the populations of T lymphocytes, and macrophages were compared between fibrous and control PCNSLs. Fibrous PCNSLs included abundant αSMA-positive cells in both intra- and extra-tumor environments (5/6, 87% and 3/6, 50%, respectively). Conversely, only one out of the seven control PCNSL contained αSMA-positive cells in the intra-tumoral area. Furthermore, the presence of extra-tumoral αSMA-positive cells was associated with infiltration of T lymphocytes and macrophages. In conclusion, recognizing the presence of dense fibrosis in PCNSL can provide insights into the tumor microenvironment. These results may help stratify patients with PCNSL and improve immunotherapies for these patients.

Fast intraoperative detection of primary CNS lymphoma and differentiation from common CNS tumors using stimulated Raman histology and deep learning.

Accurate intraoperative diagnosis is crucial for differentiating between primary CNS lymphoma (PCNSL) and other CNS entities, guiding surgical decision-making, but represents significant challenges due to overlapping histomorphological features, time constraints, and differing treatment strategies. We combined stimulated Raman histology (SRH) with deep learning to address this challenge. We imaged unprocessed, label-free tissue samples intraoperatively using a portable Raman scattering microscope, generating virtual H&E-like images within less than three minutes. We developed a deep learning pipeline called RapidLymphoma based on a self-supervised learning strategy to (1) detect PCNSL, (2) differentiate from other CNS entities, and (3) test the diagnostic performance in a prospective international multicenter cohort and two additional independent test cohorts. We trained on 54,000 SRH patch images sourced from surgical resections and stereotactic-guided biopsies, including various CNS tumor/non-tumor lesions. Training and test data were collected from four tertiary international medical centers. The final histopathological diagnosis served as ground-truth. In the prospective test cohort of PCNSL and non-PCNSL entities (n=160), RapidLymphoma achieved an overall balanced accuracy of 97.81% ±0.91, non-inferior to frozen section analysis in detecting PCNSL (100% vs. 78.94%). The additional test cohorts (n=420, n=59) reached balanced accuracy rates of 95.44% ±0.74 and 95.57% ±2.47 in differentiating IDH-wildtype diffuse gliomas and various brain metastasis from PCNSL. Visual heatmaps revealed RapidLymphoma's capabilities to detect class-specific histomorphological key features. RapidLymphoma is valid and reliable in detecting PCNSL and differentiating from other CNS entities within three minutes, as well as visual feedback in an intraoperative setting. This leads to fast clinical decision-making and further treatment strategy planning.

Trial in Progress: Phase 1 Study With Dose Expansion of Acalabrutinib and Durvalumab (MEDI 4736) in Primary Central Nervous System Lymphoma

Trial in Progress: Phase 1 Study With Dose Expansion of Acalabrutinib and Durvalumab (MEDI 4736) in Primary Central Nervous System Lymphoma

ABCL-607 Trial in Progress: Phase 1 Study With Dose Expansion of Acalabrutinib and Durvalumab (MEDI 4736) in Primary Central Nervous System Lymphoma

ABCL-607 Trial in Progress: Phase 1 Study With Dose Expansion of Acalabrutinib and Durvalumab (MEDI 4736) in Primary Central Nervous System Lymphoma

Current Management Strategies for Primary CNS Lymphoma in Children and Their Impact on Patient Survival

Current Management Strategies for Primary CNS Lymphoma in Children and Their Impact on Patient Survival

ABCL-262 EBV-Negative Primary CNS Lymphoma in a Post-Kidney Transplant Patient: A Case Report

ABCL-262 EBV-Negative Primary CNS Lymphoma in a Post-Kidney Transplant Patient: A Case Report

Evolving consolidation patterns and outcomes for a large cohort of patients with primary CNS lymphoma

AbstractConsolidation for primary central nervous system lymphoma (PCNSL) after induction chemoimmunotherapy include whole-brain radiotherapy (WBRT; ≤24 Gy reduced-dose [RD], >24 Gy standard-dose) and cytarabine, nonmyeloablative chemotherapy (NMC), or autologous hematopoietic cell transplantation (AHCT). Comparative outcomes are lacking. Outcomes from 1983-2020 were stratified by decade and Memorial Sloan Kettering Cancer Center recursive partitioning analysis (RPA) class. Clinicodemographic associations were analyzed by multinomial logistic regression. Progression-free survival (PFS) and overall survival (OS) were analyzed by proportional hazards. Of 559 patients, 385 (69%) were consolidated. Median follow-up and OS were 7.4 and 5.7 years, respectively. WBRT use declined (61% (1990s) vs 12% (2010s)), whereas AHCT (4% (1990s) vs 32% (2010s)) and NMC (27% (1990s) vs 52% (2010s)) rose. Compared with RPA 1, RPA 2 was more likely to receive NMC. Those with partial response to induction were less likely to receive AHCT (odds ratio, 0.36; P = .02). Among 351 with complete response to consolidation, only receipt of rituximab, methotrexate, procarbazine, and vincristine induction was associated with improved PFS (hazard ratio, 0.5; P = .006). Among RPA 1, median PFS and OS were not reached for AHCT or RD-WBRT, vs 2.5 and 13.0 years, respectively, after NMC. Among RPA class 3, median PFS and OS after RD-WBRT were 4.6 and 10 years, vs 1.7 and 4.4 years after NMC. No significant adjusted survival differences were seen across consolidation strategies. NMC is increasingly used in lieu of RD-WBRT despite a trend toward less favorable PFS. RD-WBRT can be considered in patients ineligible for AHCT.

Nivolumab in Relapsed or Refractory Primary CNS Lymphoma: Multicenter, Retrospective Study.

Given that 40~50% of primary central nervous system lymphoma (PCNSL) tissues exhibit aberrancy on 9p24.1, immune-checkpoint inhibitors (ICI) may work for the disease. To define the role of ICIs in PCNSL, we carried out a nationwide retrospect analysis for 22 patients who had been treated with nivolumab monotherapy for relapsed or refractory PCNSL. The median age at diagnosis was 66, and male: female ratio was 1:1. Patients received nivolumab after a median of 3 lines (range, 2 - 6) of therapy and at the median age of 67 (range, 37 - 82). Eleven patients (50%) were refractory to the last treatment prior to nivolumab. With a median follow-up duration of 22.3 months (95% CI, 13.1 - 31.5), nine patients (41%) had an objective response (6 complete responses, 3 partial responses), and the median duration of response was 20.9 months (95% CI, 1.7 - 40.0). The median progression-free survival and overall survival were 2.1 months (95% CI, 0.2 - 4.0) and 18.9 months (95% CI, 5.0 - 32.8), respectively. Nivolumab was generally well-tolerated as no patients required dose reduction and only 2 patients required delay of treatment. Our study suggests that nivolumab can be a reasonable option with the durable response for RR PCNSL.

Prognostic Impacts of Age, Diagnosis Time, and Relapses in Primary CNS Lymphoma.

Background: The incidence of lymphomatous involvement of the central nervous system (CNS) has been increasing in recent years. However, the rarity of the disease has resulted in a scarcity of available data regarding its clinical presentation, natural history, and prognosis. We aimed to investigate the neurological characteristics of uncommon lymphomatous involvements confined to the CNS and to identify key variables that could serve as predictive biomarkers for treatment outcomes. Methods: We identified patients presenting with neurological symptoms and diagnosed with CNS-restricted lymphomatous involvement between 2005 and 2023. Results: We identified 44 cases, 93% of which were diagnosed with primary central nervous system lymphoma (PCNSL) and 7% with intravascular lymphoma. The median time from symptom onset to diagnosis was 47 days (range: 6-573 days), with no statistically significant difference between patients older and younger than 60 years (p = 0.22). The median follow-up time was 1144 days (range: 27-3501 days). Cognitive deterioration was the most common presenting symptom, occurring in 19 out of 44 patients (43%). Brain MRI revealed that lobar lesions were the most frequent location of lesions, found in 24 out of 44 patients (55%). By the end of the study period, 30 patients (68%) had died, with a median survival of 666 days (range: 17-3291 days). Death was significantly more common in patients who experienced relapses (p = 0.04; 95% CI: 0.99-0.03), with these patients having a four times higher chance of death (HR = 4.1; 95% CI: 1.01-16.09). The time to diagnosis significantly correlated with survival (p = 0.02; 95% CI: 0.005-0.54), as did the Eastern Cooperative Oncology Group (ECOG) performance status at the last follow-up (p = 0.006; 95% CI: 0.0012-0.62). Patients aged over 60 years did not exhibit a higher likelihood of death (p = 0.19; HR = 2.3; 95% CI: 0.63-8.61); however, the threshold age at diagnosis for the maximally predicted mortality was 64 years (ROC = 0.73; p = 0.03). Conclusions: Patients had significant delays in diagnosis, affecting patient outcomes. Cognitive deterioration and lobar lesions were prominent clinical and radiological features. Mortality was notably higher in patients with relapses and those who had a longer time to diagnosis.

Bruton's tyrosine kinase inhibitor zanubrutinib-based regimens in relapsed/refractory primary diffuse large B-cell lymphoma of central nervous system.

30 Background: Patients with relapsed/refractory primary central nervous system lymphoma (R/R PCNSL) usually have a poor prognosis. Ibrutinib-based regimens revealed promising efficacy but showed off-target effects and drug resistance in some cases. Here, we conducted a retrospective study to evaluate the efficacy and safety of regimens based on second-generation bruton's tyrosine kinase (BTK) inhibitor zanubrutinib in R/R PCNSL. Methods: We respectively reviewed 23 patients with R/R PCNSL treated with zanubrutinib in our center from Apr. 2021 to Jan. 2024. The primary end points were overall response rate (ORR) and progression-free survival (PFS). Secondary end points included complete response rate (CRR), disease control rate (DCR), overall survival (OS) and adverse events (AEs). Response was assessed according to International Primary CNS Lymphoma Collaborative Group criteria. The severity of AEs was graded using the NCI Common Toxicity Criteria, version 5.0. Validated next-generation sequencing (NGS) panels were used to analyze the mutational status of the BCR pathway genes or other solid tumor-related genes. Results: The median follow-up at the cutoff date (15 Jan 2024) was 17.0 months (range, 2-33 months). The ORR, CRR and DCR were 78.3%, 39.1% and 91.3%. The median PFS was 31.0 months, but the median OS was not reached. Compared to germinal center B-cell like (GCB) group, non-GCB group showed a better ORR (76.9% vs 66.7%) and CRR (46.2% VS 33.3%). Multivariate analysis revealed that overall response (vs. no response, HR=0.20, P=0.027), long duration of zanubrutinib (≥6months vs. 2-5 months, HR=0.07, P=0.009) and refractory disease status (vs. relapse disease status, HR=0.12, P=0.014) were independent factors for longer PFS. The most commonly mutated genes are MYD88(15/17,88.2%), PIM1(9/17 52.9%), CD79B (8/17,47.1%), ETV6(7/17,41.2%), BTG1(5/17,29.4%) and GNA13(5/17,29.41%). The mutational status of MYD88/CD79B did not lead to any difference in PFS and OS. We obtained the Tumor Mutational Burden (TMB) information from 11 patients. The median TMB was 15.96 (range: 3.82-28.11) muts/Mb. Kaplan-Meier analysis demonstrated that PFS was significantly longer in patients with higher TMB (≥15.96 muts/Mb) after zanubrutinib-based treatment(P=0.005). Grade ≥3 and serious treatment-emergent AEs (TEAEs) were not found. The most commonly TEAEs were hematologic toxicity (8/23,34.8%) and skin rash (5/23,21.7%). Conclusions: Our study demonstrates that zanubrutinib-based therapy is effective and safe for the treatment of R/R PCNSL. We advocate for the prolonged administration of zanubrutinib to maintain treatment response. Patients with higher TMB derive greater benefits from zanubrutinib-based regimens.

The candidate novel markers PIV and PILE score to predict survival outcomes and therapeutic response in patients with primary central nervous system lymphoma.

24 Background: Recent studies highlighted the predictive value of easily measurable blood-based biomarkers, such as the neutrophil-to-lymphocyte ratio (NLR), the monocyte-to-lymphocyte ratio (MLR), the platelet-to-lymphocyte ratio (PLR), and the systemic immune-inflammation index (SII). Recently, a novel comprehensive marker that represents the pan-immune-inflammation value (PIV) has been proposed as a more reliable predictor of clinical outcomes. We aimed to investigate the prognostic significance of PIV and PILE score (a score based on PIV, lactate dehydrogenase (LDH), and Eastern Cooperative Oncology Group Performance Status (ECOG PS)), in patients with PCNSL. Methods: A total of 109 patients were enrolled. PIV was calculated as follows: (neutrophil count × platelet count × monocyte count)/lymphocyte count. The PILE score was calculated with the sum of individual values (for PIV &lt; median = 0, ≥ median = 1; for LDH ≤ upper limit of normal (ULN) = 0, &gt; ULN = 1; for ECOG PS &lt; 2 = 0, ≥ 2 = 1). The Kaplan–Meier method and Cox hazards regression models were used for survival analyses. The relationship between PIV, PILE, and therapeutic response was examined. Results: Pretreatment high PIV was confirmed to be an independent significant factor for overall survival (OS) in univariate (HR 3.990, 95%CI 1.778-8.954, p &lt; 0.001) and multivariate (HR 3.047, 95%CI 1.175-7.897, p = 0.022) analyses. Baseline PIV was also associated with worse progression-free survival (PFS). Regarding OS, PIV showed a better predictive performance than other widely used systemic inflammation parameters. Significantly shorter OS and PFS were observed in the high PILE group (median OS: 25.60, 95% CI 15.60-NR vs. NR months, 95% CI 26.10-NR, p = 0.008; median PFS: 26.13, 95% CI 23.30-NR vs. 7.13 months, 95% CI 4.87-NR, p &lt; 0.001). High PILE was associated with primary resistance to therapy (high PILE group: 21/42 patients, 50.00%; low PILE group: 5/45 patients, 11.11%; p &lt; 0.001). A significantly lower response rate to initial treatment was found in patients in the high PILE group (23/42, 54.76%) as compared to patients in the low PILE group (7/45, 15.56%; p &lt; 0.001). PILE was independently associated with therapeutic response to initial treatment (OR 0.17, 95% CI 0.05–0.46; p &lt; 0.001). Conclusions: High PIV and high PILE were correlated with worse clinical outcomes in PCNSL patients, indicating that PIV and PILE might be a powerful predictor of prognosis and a potential predictive indicator for treatment response in PCNSL.

Clinical relevance of brain MRI changes in primary central nervous system lymphoma after high-dose-chemotherapy and autologous stem cell transplantation.

Primary central nervous system lymphoma (PCNSL) is a potentially curable disease, but affected patients often struggle in everyday life due to disease- and therapy-associated sequelae. High-dose chemotherapy followed by autologous stem cell transplantation (HDC/ASCT) is the standard consolidation therapy, replacing whole brain radiation therapy (WBRT) amongst others due to less long-term cognitive decline. Nevertheless, white matter lesions (WML) are common findings in brain MRI after HDC/ASCT, but their clinical significance remains underexplored. Here, we correlate WML and brain atrophy with neuropsychological and quality-of-life evaluations collected post-treatment. We found that a significant part of PNCSL long-term survivors develop a high WML burden after HDC/ASCT, but we fail to associate them with specific patient or therapy characteristics. Intriguingly, even a high WML burden does not seem to affect QoL, basic neurocognition testing or performance status negatively. These results contrast findings in previous neuroimaging studies on healthy and cancer patients.

Combination of rituximab and methotrexate followed by rituximab and cytarabine in elderly patients with primary central nervous system lymphoma.

The optimal treatment strategy for newly diagnosed primary central nervous system lymphoma (PCNSL) has yet to be established, especially in the elderly. In the current study, we conducted a phase II study to evaluate the efficacy and safety of rituximab plus high-dose MTX followed by rituximab plus cytarabine in patients aged ≥60 years newly diagnosed with PCNSL. Patients received an induction treatment of high-dose methotrexate plus rituximab followed by two cycles of a consolidation treatment of cytarabine plus rituximab. The primary end-point was a 2-year progression-free survival (PFS) rate. A total of 35 patients were recruited, and their median age was 73 (range: 60-81). After induction treatment, the complete and partial responses (PRs) were 56% and 20% respectively. Twenty-six patients proceeded to the consolidation treatment; the complete and PRs were 59% and 9% respectively. After a median follow-up duration of 36.0 months, the 2-year PFS rate was 58.7%. Treatment was generally well-tolerated as only three patients were withdrawn from the study due to toxicity, and no treatment-related mortality was reported. The 2-year overall survival rate was 77.9%. The current study may suggest the feasibility of administering high-dose MTX plus cytarabine in PCNSL patients aged ≥60 years and the potential role of additive rituximab.

Establishing the utility of multi-platform liquid biopsy by integrating the CSF methylome and proteome in CNS tumours.

Liquid biopsy represents a major development in cancer research, with significant translational potential. Similarly, it is increasingly recognized that multi-omic molecular approaches are a powerful avenue through which to understand complex and heterogeneous disease biology. We hypothesize that merging these two promising frontiers of cancer research will improve the discriminatory capacity of current models and allow for improved clinical utility. We have compiled a cohort of patients with glioblastoma, brain metastasis, and primary central nervoussystem lymphoma. Cell-free methylated DNA immunoprecipitation (cfMeDIP) and shotgun proteomic profiling wasobtained from the cerebrospinal fluid (CSF) of each patient and used to build tumour-specific classifiers. We show that the DNA methylation and protein profiles of cerebrospinal fluid can be integrated to fully discriminate lymphoma from its diagnostic counterparts with perfect AUC of 1 (95% confidence interval 1-1) and 100% specificity, significantly outperforming single-platform classifiers. We present the most specific and accurate CNS lymphoma classifier to date and demonstrates the synergistic capability of multi-platform liquid biopsies. This has far-reaching translational utility for patients with newly diagnosed intra-axial brain tumours.

Enhancing Prognostication and Treatment Response Evaluation in Primary CNS Lymphoma with 18F-FDG PET/CT.

The role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in the prognostication and response evaluation of primary central nervous system lymphoma (PCNSL) remains inadequately defined. We conducted a retrospective analysis of 268 consecutive newly diagnosed patients with PCNSL between 2006 and 2020. Of these patients, 105 and 110 patients were included to evaluate the prognostic value of baseline and post-treatment 18F-FDG-PET/CT scans, respectively. Tumor uptake was considered positive when it exceeded that of the contralateral brain upon visual assessment. Quantitative analysis of baseline 18F-FDG-PET/CT included measurement of the maximal standardized uptake value (SUVmax), total metabolic tumor volume (TMTV), and total lesion glycolysis (TLG). The median age of the 268 patients was 62 years (range: 17-85), with 55% being male. The median progression-free survival (PFS) was 24.5 months (95% confidence interval [CI], 19.9-29.1), and the median overall survival (OS) was 34.5 months (95% CI, 22.9-46.1). The average SUVmax was 15.3 ± 5.7 and the mean TMTV and TLG were 12.6 ± 13.9cm3 and 135.0 ± 152.7g, respectively. Patients with a baseline TMTV ≥17.0cm3 had significantly shorter OS (12.5 vs. 74.0 months, p=0.011). Post-treatment metabolic response by 18F-FDG-PET/CT significantly predicted PFS (median: 10.5 vs. 46.0 months, p=0.001) and OS (median: 21.0 vs. 62.0 months, p=0.002), whereas anatomic response by contrast-enhanced MRI showed no statistically significant differences in PFS (p=0.130) or OS (p=0.540). Baseline TMTV and post-treatment metabolic response, as assessed by 18F-FDG-PET/CT, are significant prognostic factors in patients with PCNSL.