Primary central nervous system lymphomas in children and adolescents

High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HDT-ASCT) is listed as a consolidation therapy option for primary central nervous system (CNS) lymphoma in the guidelines of western countries. The advantages of HDT-ASCT for primary CNS lymphoma as consolidation are believed to be high rates of long-term remission and lower neurotoxicity, even though its eligibility is limited to younger fit patients. In the Japanese guideline, HDT-ASCT for primary CNS lymphoma is however not recommended in daily practice, mainly because thiotepa was unavailable since 2011. The Japanese registry data for hematopoietic transplantation have shown that primary CNS lymphoma patients were treated with various HDT regimens and thiotepa-containing HDT was associated with better progression free survival (P=.019), lower relapse (P=.042) and a trend toward a survival benefit (Kondo E et al, Biol Blood Marrow Transplant 2019). A pharmacokinetic study of thiotepa(DSP-1958) in HDT-ASCT for lymphoma was conducted in 2017, and thiotepa was approved for HDT-ASCT in lymphoma this March, meaning that optimal HDT regimen for CNS lymphoma is now available in Japan. The treatment strategy of CNS lymphoma needs further development to improve survival and reduce toxicity.

e23012 Background: Primary central nervous system lymphoma (PCNSL) is a rare and aggressive malignancy. Prognosis remains poor, and data on clinical characteristics or outcomes are limited, particularly in the elderly. In the literature, age over 50 is a major poor prognostic factor. Herein, we report our experience of PCNSL in elderly patients. Methods: The electronic medical records from 2007 to 2015 of the Beaumont Health System were analyzed. Patients with non-Hodgkin’s Lymphoma (NHL) were reviewed and those with PCNSL were identified. Results: Of the 617 NHL patients, 21 (3.4%) had PCNSL, 12 (57.1%) were male and 17 (81.0%) Caucasian. Median age was 76 (range, 55 to 83), and the majority 18 (85.7%) were above age 65. Deep brain lesions occurred in 11 (52.4%) patients. Eighteen (85.7%) received treatment, including 3/18 (16.7%) with high-dose methotrexate (HD-MTX) only, 5/18 (27.8%) HD-MTX plus rituximab (MR), 2/18 (11.1%) HD-MTX with vincristine and procarbazine, 7/18 (38.9%) MR and other chemotherapy, and 1/18 (5.6%) temozolomide and rituximab. MTX dose ranged from 1.8 to 8 g/m2 (median, 3.5 g/m2). The number of treatment cycles ranged from 1 to 11 (median, 3). Whole brain radiation was given to 4 (22.2%) patients with refractory disease after systemic chemotherapy. None of the patients received definitive radiation. Overall response rate was 44.4%, including 4/18 (22.2%) CR and 4/18 (22.2%) PR. Median survival was 4.0 months (95% CI, 2.3 to 5.7 months). At the time of data collection (November, 2018), only four patients were alive. Causes of death included disease progression (58.8%), neutropenic sepsis (23.5%), and MTX toxicity, predominantly acute kidney injury and severe gastrointestinal mucositis (17.7%). Age, lesion depth, treatment, and other clinical characteristics did not impact survival (all p > 0.05). Conclusions: Although HD-MTX remained the backbone of therapy for most patients, we observed a heterogeneous treatment pattern in our elderly patient population. More than 50% had primary refractory diseases, while about 40% had treatment related mortality. This study further emphasized the need for more trials enrolling elderly patients with PCNSL, utilizing novel agents, and investigating molecular prognostic markers.

Primary Central Nervous System Lymphoma in Children: A Report of 12 Cases.

2040 Background: There has been significant improvement in treatment outcomes of Primary Central Nervous System Lymphoma (PCNSL) at specialized centers over past decades, and it is unclear if these changes have translated to benefits in the general population. In this study, we utilized national databases to examine survival trends over time. Methods: Incidence rates were obtained from the Central Brain Tumor Registry of the United States (CBTRUS, 2000 – 2013) and 18 Surveillance, Epidemiology and End Results (SEER, 1973 – 2013) registries. Data for survival analysis was obtained from SEER and analyzed using SEER*STAT. To focus on non-HIV-associated PCNSL, patients with “other infectious and parasitic diseases including HIV” as cause of death and follow up were excluded. CBTRUS identified 19,027 patients over 13 years and SEER 6,765 over 40 years. Results: The annual incidence of PCNSL in 2013 was 0.4 per 100,000 population (CBTRUS/SEER). Incidence increased from 0.1 per 100,000 in the 1970s to 0.4 per 100,000 in the 1980s, correlating with an increase in the diagnosis of elderly patients, ≥70 (1973:0.2 vs 2013:2.1 – SEER). Incidence rates differed greatly between young and elderly patients (20-29: 0.08 vs 70-79: 4.32 – CBTRUS). The median overall survival (mOS) of all patients is 17 months (m) with no survival benefit based on sex. Survival doubled from 12.5 m in the 1970s to 26 m in the 2010s. There was a significant difference in survival based on age: < 50: 83 m vs 50-69: 25 m vs ≥70: 6 m (p-value < 0.0001). In patients < 50, mOS increased from 35.5 m in the 1970s to 134 m in the 2000s (mOS not achieved in 2010s). In patients 50-69, mOS increased from 8 m in the 1970s to 35 m in the 2010s. However, mOS in the elderly population, ≥70, has not changed in the last 40 years (6 m in the 1970s vs 7 m in the 2010s, p-value = 0.1). Conclusions: PCNSL is a disease that more frequently affects the elderly. Although overall survival has increased over the past 4 decades, reflecting current literature in PCNSL, survival in the elderly has not changed since the 1970s. Identification of this vulnerable patient population highlights the need for clinical trials targeting the elderly in hopes of improving treatment strategies and ultimately outcomes.

This chapter covers the main aspects of management of glioblastomas, low-grade gliomas, and primary central nervous system (CNS) lymphomas in the elderly. An extensive use of available geriatric scales is recommended to distinguish fit versus unfit patients before deciding any treatment. In the case of fit patients with high-grade glioma, surgical resection as complete as possible followed by radiotherapy and concomitant/adjuvant temozolomide is the standard of care. In the case of unfit patients with high-grade glioma, biopsy followed either by hypofractionated radiotherapy in case of O6-methylguanine DNA methyltransferase (MGMT) unmethylated tumors or temozolomide in case of MGMT methylated tumors should be proposed. Supportive care should be reserved to patients with low performance status or high burden of comorbidities. Low-grade gliomas in elderly patients are rare and should be treated with surgery, radiotherapy, and adjuvant temozolomide when appropriate. Primary CNS lymphomas following biopsy should receive an up-front methotrexate-based regimen. In case of a complete response to chemotherapy whole brain-radiation therapy should be reserved at tumor progression to delay neurocognitive deterioration.

<div>Abstract<p><b>Purpose:</b> Despite advances, there is an urgent need for effective therapeutics for relapsed diffuse large B-cell lymphoma, particularly in elderly patients and primary central nervous system (CNS) lymphoma. Temozolomide (TMZ), an oral DNA-alkylating agent routinely used in the therapy of glioblastoma multiforme, is active in patients with primary CNS lymphoma but the response rates are low. The mechanisms contributing to TMZ resistance are unknown.</p><p><b>Experimental Design:</b> We undertook an unbiased and genome-wide approach to understand the genomic methylation and gene expression profiling differences associated with TMZ resistance in diffuse large B-cell lymphoma cell lines and identify mechanisms to overcome TMZ resistance.</p><p><b>Results:</b> TMZ was cytotoxic in a subset of diffuse large B-cell lymphoma cell lines, independent of MGMT promoter methylation or protein expression. Using Connectivity Map (CMAP), we identified several compounds capable of reversing the gene expression signature associated with TMZ resistance. The demethylating agent decitabine (DAC) is identified by CMAP as capable of reprogramming gene expression to overcome TMZ resistance. Treatment with DAC led to increased expression of SMAD1, a transcription factor involved in TGF-β/bone morphogenetic protein (BMP) signaling, previously shown to be epigenetically silenced in resistant diffuse large B-cell lymphoma. <i>In vitro</i> and <i>in vivo</i> treatment with a combination of DAC and TMZ had greater antilymphoma activity than either drug alone, with complete responses in TMZ-resistant diffuse large B-cell lymphoma murine xenograft models.</p><p><b>Conclusions:</b> Integrative genome-wide methylation and gene expression analysis identified novel genes associated with TMZ resistance and demonstrate potent synergy between DAC and TMZ. The evidence from cell line and murine experiments supports prospective investigation of TMZ in combination with demethylating agents in diffuse large B-cell lymphoma. <i>Clin Cancer Res; 20(2); 382–92. ©2013 AACR</i>.</p></div>

Dysregulation of cell morphology and cell-cell interaction results in cancer cell growth, migration, invasion, and metastasis. Besides, a balance between the extracellular matrix (ECM) and matrix metalloprotease (MMP) is required for cancer cell morphology and angiogenesis. Here, we determined gene signatures associated with the morphology and microenvironment of primary central nervous system lymphoma (PCNSL) to enable prognosis prediction. Next-generation sequencing (NGS) on 31 PCNSL samples revealed gene signatures as follows: ACTA2, ACTR10, CAPG, CORO1C, KRT17, and PALLD in cytoskeleton, CDH5, CLSTN1, ITGA10, ITGAX, ITGB7, ITGA8, FAT4, ITGAE, CDH10, ITGAM, ITGB6, and CDH18 in adhesion, COL8A2, FBN1, LAMB3, and LAMA2 in ECM, ADAM22, ADAM28, MMP11, and MMP24 in MMP. Prognosis prediction formulas with the gene expression values and the Cox regression model clearly divided survival curves of the subgroups in each status. Furthermore, collagen genes contributed to gene network formation in glasso, suggesting that the ECM balance controls the PCNSL microenvironment. Finally, the comprehensive balance of morphology and microenvironment enabled prognosis prediction by a combinatorial expression of 8 representative genes, including KRT17, CDH10, CDH18, COL8A2, ADAM22, ADAM28, MMP11, and MMP24. Besides, these genes could also diagnose PCNSL cell types with MTX resistances in vitro. These results would not only facilitate the understanding of biology of PCNSL but also consider targeting pathways for anti-cancer treatment in personalized precision medicine in PCNSL.

The Nordic Lymphoma Group has conducted a phase ll trial in newly diagnosed primary central nervous system lymphoma patients applying an age-adjusted multi-agent immunochemotherapy regimen, which in elderly patients included temozolomide maintenance treatment. Patients aged 18-75 years were eligible. Thirty-nine patients aged 18-65 years and 27 patients aged 66-75 years were enrolled. The median age of the two age groups was 55 and 70 years, respectively. The overall response rate was 73.8% for the entire cohort: 69.9% in the younger and 80.8% in the elderly subgroup. With a median follow up of 22 months, the 2-year overall survival probability was 60.7% in patients aged 65 years or under and 55.6% in patients aged over 65 years (P=0.40). The estimated progression-free survival at two years was 33.1% (95%CI: 19.1%-47.9%) in patients aged under 65 years and 44.4% (95%CI: 25.6%-61.8%) in the elderly subgroup (P=0.74). Median duration of response was ten months in the younger subgroup, and not reached in the elderly patient subgroup (P=0.33). Four patients aged 64-75 years (6%) died from treatment-related complications. Survival in the two age groups was similar despite a de-escalation of induction treatment in patients aged over 65 years. Duration of response in elderly patients receiving maintenance temozolomide was longer than in the younger age subgroup. While toxicity during induction is still of concern, especially in the elderly patients, we conclude from these data that de-escalation of induction therapy in elderly primary central nervous system lymphoma patients followed by maintenance treatment seems to be a promising treatment strategy. (clinicaltrials.gov identifier:01458730).

Unlike primary central nervous system lymphomas (PCNSLs) in patients with AIDS or organ transplants, PCNSLs in the elderly are usually not considered to be mediated by Epstein Barr virus (EBV); hence, diagnostic studies for EBV are not routinely performed. We encountered 4 patients, 65 years or older, who developed EBV-associated PCNSLs and who had been treated with a variety of immunosuppressive drugs for different autoimmune/collagen vascular disorders, including autoimmune polyneuropathy (mycophenolate mofetil for 5 years), polymyositis (prednisone for 16 years with intermittent methotrexate, azathioprine, and cyclophosphamide), myasthenia gravis (azathioprine >10 years), and rheumatoid arthritis (methotrexate >10 years). All patients had multifocal, necrotic brain lesions typical of EBV-positive PCNSLs on neuroimaging. Withdrawing immunosuppressives lead to PCNSL regression in some patients. The patient who had received mycophenolate mofetil was treated successfully for his EBV-associated PCNSL with rituximab and methotrexate, but later developed fatal systemic malignant melanoma, which was likely immunosuppression related. The striking feature of these cases is the variety of underlying diseases-and hence accompanying medications-that can be associated with EBV-associated PCNSLs. They serve as a diagnostic alert for neuropathologists and suggest that increased testing of PCNSLs for EBV by immunohistochemistry or in situ hybridization may be warranted in any patient on any immunosuppressive medication, but particularly the elderly.

Orelabrutinib, Rituximab, and Thiotepa (ORT) in Combination with or without High-Dose Methotrexate in Untreated Primary Central Nervous System Lymphoma

First-Line Treatment and Outcome of Elderly Patients with Primary Central Nervous System Lymphoma (PCNSL) – A Systematic Review and Individual Patient Data Meta-Analysis

The Primary Results of R-MTO Regimen (Rituximab, Methotrexate, Thiotepa, and Orelabrutinib) As the First-Line Induction Therapy Followed By Autologous Stem Cell Transplantation in Newly Diagnosed Primary Central Nervous System Lymphoma

ABSTRACTObjective:Primary CNS lymphoma (PCNSL) in children is a rare disease, and this study aimed to document the experience of dealing with this in our geographical and resource settings.Methodology:It was an ambidirectional cohort study conducted at the Department of Pediatric Hematology/Oncology and the Department of Pediatric Neurosurgery at the University of Child Health Sciences, The Children’s Hospital Lahore, Pakistan from March 2024 to December 2024. This study included seven suspected and confirmed cases of PCNSL in children under the age of 16 years who presented to a public-sector specialized center in Pakistan over the three-year study period.Results:A total of seven cases of suspected PCNSL were included in the study. The median age at presentation was eight years, with a female-to-male ratio of 2.5:1. Most commonly presenting with a focal neurological deficit, with a median duration of symptoms of 12 weeks, and a median Lansky performance score of 50. Only 57% (04) of patients underwent surgical resection followed by adjuvant chemotherapy. Overall, 57% (03) of patients died, 29% (02) were lost to follow-up, and only 14% (01) are under treatment.Conclusion:PCNSL in children is equally rare in our part of the world, but has a dismal survival rate. Timely surgical intervention, improved supportive care, and a reduction in treatment abandonment might improve the prognosis.

Primary Central Nervous System Lymphoma (PCNSL) is an aggressive neoplasm with a poor prognosis. Although therapeutic progresses have significantly improved Overall Survival (OS), a number of patients do not respond to HD-MTX-based chemotherapy (15-25%) or experience relapse (25-50%) after an initial response. The reasons underlying this poor response to therapy are unknown. Thus, there is an urgent need to develop improved predictive models for PCNSL. In this study, we investigated whether radiomics features can improve outcome prediction in patients with PCNSL. A total of 80 patients diagnosed with PCNSL were enrolled. A patient sub-group, with complete Magnetic Resonance Imaging (MRI) series, were selected for the stratification analysis. Following radiomics feature extraction and selection, different Machine Learning (ML) models were tested for OS and Progression-free Survival (PFS) prediction. To assess the stability of the selected features, images from 23 patients scanned at three different time points were used to compute the Interclass Correlation Coefficient (ICC) and to evaluate the reproducibility of each feature for both original and normalized images. Features extracted from Z-score normalized images were significantly more stable than those extracted from non-normalized images with an improvement of about 38% on average (p-value < 10-12). The area under the ROC curve (AUC) showed that radiomics-based prediction overcame prediction based on current clinical prognostic factors with an improvement of 23% for OS and 50% for PFS, respectively. These results indicate that radiomics features extracted from normalized MR images can improve prognosis stratification of PCNSL patients and pave the way for further study on its potential role to drive treatment choice.

Primary central nervous system lymphoma (PCNSL) is an aggressive non-Hodgkin B-cell lymphoma with characteristic clinical behavior, biological features and poor prognosis despite complex treatment. PCNSL has a median survival of 17 to 45 months in immunocompetent patients, and only 20-30% of cases can be cured successfully. Clinical outcome has improved since the advances in combination chemotherapy protocols, addition of whole brain radiation therapy, encouraging responses of rituximab administration in refractory PCNSL and autologous hematopoietic stem-cell transplantation as consolidative therapy. The author review the recent data on pathogenesis, diagnostic methods and treatment strategies of PCNSL in immunocompetent patients.