scholarly journals The genomic and transcriptional landscape of primary central nervous system lymphoma

2021 ◽  
Author(s):  
Josefine Radke ◽  
Naveed Ishaque ◽  
Randi Koll ◽  
Zuguang Gu ◽  
Elisa Schumann ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
B Cell ◽  
Signaling Pathways ◽  
Genetic Alterations ◽  
Recurrent Mutations ◽  
Mutational Hotspots ◽  
The Central Nervous System ◽  
Transcriptional Landscape ◽  
Systemic Dlbcl

Primary lymphomas of the central nervous system (PCNSL) are mainly diffuse large B-cell lymphomas (DLBCLs) confined to the central nervous system (CNS). Despite extensive research, the molecular alterations leading to PCNSL have not been fully elucidated. In order to provide a comprehensive description of the genomic and transcriptional landscape of PCNSL, we here performed whole-genome and transcriptome sequencing and integrative analysis of 51 lymphomas presenting in the CNS, including 42 EBV-negative PCNSL, 6 secondary CNS lymphomas (SCNSL) and 3 EBV+ CNSL and matched controls. The results were compared to an independent validation cohort of 31 FFPE CNSL specimens (PCNSL, n = 19; SCNSL, n = 9; EBV+ CNSL, n = 3) as well as 39 FL and 36 systemic DLBCL cases outside the CNS. Somatic genomic alterations in PCNSL mainly affect the JAK-STAT, NFkB, and B-cell receptor signaling pathways, with hallmark recurrent mutations including MYD88 L265P (67%) and CD79B (63%), CDKN2A deletions (83%) and also non-coding RNA genes such as MALAT1 (70%), NEAT (60%), and MIR142 (80%). Kataegis events, which affected 15 of 50 identified driver genes and 21 of the top 50 mutated ncRNAs, played a decisive role in shaping the mutational repertoire of PCNSL. Compared to systemic DLBCL, PCNSLs exhibited significantly more focal deletions in 6p21 targeting the HLA-D locus that encodes for MHC class II molecules as a potential mechanism of immune evasion. Mutational signatures correlating with DNA replication and mitosis (SBS1, ID1 and ID2) were significantly enriched in PCNSL (SBS1: p = 0.0027, ID1/ID2: p < 1x10-4). Furthermore, TERT gene expression was significantly higher in PCNSL compared to ABC-DLBCL (p = 0.027). Although PCNSL share many genetic alterations with systemic ABC-DLBCL in the same signaling pathways, transcriptome analysis clearly distinguished both into distinct molecular subtypes. EBV+ CNSL cases may be distinguished by lack of recurrent mutational hotspots apart from IG and HLA-DRB loci.

scholarly journals Genetic Basis of Primary Central Nervous System Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2687-2687
Author(s):  
Kenichi Yoshida ◽  
Rie Nakamoto-Matsubara ◽  
Kenichi Chiba ◽  
Yusuke Okuno ◽  
Nobuyuki Kakiuchi ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
B Cell ◽  
Copy Number ◽  
Genetic Basis ◽  
Snp Array ◽  
Central Nervous System Lymphoma ◽  
Genetic Alterations ◽  
Targeted Sequencing ◽  
Systemic Dlbcl

Abstract Introduction Primary central nervous system lymphoma (PCNSL) is a rare subtype of non-Hodgkin lymphoma, of which approximately 95% are diffuse large B-cell lymphomas (DLBCLs). Despite the substantial development of intensive chemotherapy during the past two decades, overall clinical outcome of PCNSL has been poorly improved especially in elderly and so has been our knowledge about the molecular pathogenesis of PCNSL, in terms of driver alterations that are relevant to the development of PCNSL. Method To delineate the genetic basis of PCNSL pathogenesis, we performed a comprehensive genetic study. We first analyzed paired tumor/normal DNA from 35 PCNSL cases by whole-exome sequencing (WES). Significantly mutated genes identified by WES and previously known mutational targets in PCNSL and systemic DLBCL were further screened for mutations using SureSelect-based targeted deep sequencing (Agilent) in an extended cohort of PCNSL cases (N = 90). Copy number alterations (CNAs) have been also investigated using SNP array-karyotyping (N =54). We also analyzed WES and SNP array data of systemic DLBCL cases (N = 49) generated by the Cancer Genome Atlas Network (TCGA) to unravel the genetic difference between PCNSL and systemic DLBCL. Results The mean number of nonsynonymous mutations identified by WES was 183 per sample, which was comparable to the figure in systemic DLBCL and characterized by frequent somatic hypermutations (SHMs) involving non-Ig genes. A higher representation of C>T transition involving CpG dinucleotides and hotspot mutations within the WRCY motif targeted by SHM further suggested the involvement of activation-induced cytidine deaminase (AID) in the pathogenesis of PCNSL. We found 12 genes significantly mutated in PCNSL (q < 0.1), including MYD88, PIM1, HLA-A, TMEM30A, B2M, PRDM1, UBE2A, HIST1H1C, as well as several previously unreported mutational targets in systemic DLBCL or PCNSL, such as SETD1B, GRB2, ITPKB, EIF4A2. Copy number analysis identified recurrent genomic segments affected by focal deletions (N = 27) and amplifications (N = 10), most of which included driver genes targeted by recurrent somatic mutations or known targets of focal CNAs such as CDKN2A and FHIT. Subsequent targeted sequencing finally identified a total of 107 significantly mutated genes, of which 43 were thought to be targeted by SHM according to their mutational signature and genomic distribution. Most cases with PCNSL (98%) had mutations and CNAs involving genes that are relevant to constitutive NF-KB/Toll-like receptor (TLR)/BCR activity, including those in MYD88 (80%), CD79B/A (60%), CARD11 (18%), TNFAIP3 (26%), GRB2 (24%) and ITPKB (23%). Genetic alterations implicated in escape from immunosurveillance were also frequently identified in as many as 76% of cases. Mutations of HLA-B (64%), HLA-A (36%), HLA-C (28%), B2M (14%) and CD58 (12%) were commonly detected in addition to CNAs in 6p21.32 (HLA class II), 1p13.1 (CD58) and 15q15.2 (B2M), suggesting the importance of immune escape in the pathogenesis of PCNSL. SHMs were also seen in most cases (98%), which affected not only known targets of AID including PIM1, IGLL5 and BTG2 but also previously unreported genes involved in cell proliferation, apoptosis, or B cell development. The pattern of frequently mutated genes in PNCSL was more uniform compared with that in systemic DLBCL, and similar to that found in the activated B cell subtype of DLBCL (ABC-DLBCL), which was in accordance with the previous report of immunophenotypic analysis of PCNSL. On the other hand, mutations of HLA class I genes (HLA-B, HLA-A) were more frequently mutated in PCNSL compared with ABC-type DLBCL. Conclusion WES, SNP array karyotyping and follow-up targeted sequencing of a large cohort of PCNSL cases revealed the genetic landscape of PCNSL, which were more homogeneous than that of systemic DLBCL, and thought to be involved in activation of constitutive NF-KB/TLR/BCR signaling, escape from immunosurveillance, as well as highly frequent SHMs. Disclosures No relevant conflicts of interest to declare.

Genome-Wide Analysis Uncovers Recurrent Alterations in Primary Central Nervous System Lymphomas

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 420-420
Author(s):  
Esteban Braggio ◽  
Brian Patrick O'Neill ◽  
Jan Egan ◽  
Riccardo Valdez ◽  
Ellen McPhail ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Central Nervous System ◽  
Nervous System ◽  
Germinal Center ◽  
Research Funding ◽  
Genetic Alterations ◽  
Negative Regulator ◽  
Recurrent Mutations ◽  
Chromosomal Breakpoints ◽  
Systemic Dlbcl

Abstract Abstract 420 Primary central nervous system lymphoma (PCNSL) is a rare and aggressive non-Hodgkin lymphoma that is confined to the CNS because of a poorly understood neurotropism. Most of PCNSL (90%) are part of the immune-privileged site-associated DLBCL (IPDLBCL). IPDLBCL consist in late–germinal center or post–germinal center lymphoid cells but that show very distinct characteristics that separate them from systemic DLBCL. It is still a matter of debate whether the PCNSL differ from nodal DLBCL with respect to molecular features and pathogenesis and also if there is a genomic signature specific of PCNSL. Only few genetic studies have been performed in PCNSL, partly due to the rarity of the tumors and the limited amount of available tissue. To gain insight into the genomic basis of PCNSL, we performed an integrated, high-throughput, genomic analysis in 17 immunocompetent, EBV- and HIV- cases. B-cell differentiation status was characterized by immunostains for CD10, MUM-1, and BCL-6. Either frozen samples or formalin fixed embedded paraffin sections from 17 PCNSL were studied by array-based comparative genomic hybridization (aCGH) using Sureprint G3 (1 million probes) array. Massively parallel whole-exome sequencing was performed in 4 of these cases. Additionally, 2 cases were analyzed by mate-pair whole genome sequencing searching for chromosomal breakpoints. Sanger DNA sequencing was used for validation. All cases were characterized by complex genomic aberrations with a median of 21 copy-number abnormalities (CNA, range 10–49), 4 structural abnormalities, 6 frameshift indels and 99 nonsynonymous exonic mutations. Focal deletion affecting CDKN2A (9p21) was the most common CNA, found in 14 of 17 cases (82%); with 6 of these cases (35%) having homozygous deletion. The second most frequent CNA involved the HLA genes (6p21), found in 11 of 17 (65%) cases; 4 of them (23%) with homozygous deletions. We identified recurrent CNA and mutations in several genes previously found in systemic DLBCL. Thus, PRDM1 (BLIMP1) was deleted or mutated in 47% of cases and the translocation IgH-BCL6 was found in 30% of PCNSL. Furthermore, recurrent mutations were found in NF-kB genes CD79B (75%, 3 of 4 cases analyzed), MYD88 (70%, 7 of 10), TNFAIP3 (50%, 2 of 4) and CARD11 (50%, 2 of 4). Additionally, recurrent abnormalities were found in B2M, BCL7A, CD58, CIITA, ETV6, GNA13, PAX5, TMEM30A and TP53. Nevertheless, we identified several recurrent genetic alterations not described in systemic DLBCL. TOX (a regulator of T-cell development) and TBL1XR1 (a negative regulator of the NF-kB and Wnt pathways) were either deleted or mutated in 30% of PNCSL, something not previously described in systemic DLBCL. Additionally, chromosomal breakpoints either in DLGAP1 or DLGAP2 (play a role in neuronal cell signaling) were found in 18% of PCNSL but not in systemic DLBCL. Moreover, mutations in ATM (master controller of cell cycle checkpoint), BAI3 (inhibitor of brain angiogenesis), BTG2 (cell cycle arrest), KDM6B (histone demethylase), PKC family members PRKCD/PRKCDE, genes from the histone cluster, the protocadherin family and the WD repeat domain were found in 10% to 50% of PCNSL. Pathway analysis including the most commonly affected genes in PCNSL showed an enrichment of networks associated with immune response, NF-kB pathway, proliferation, regulation of the apoptosis and lymphocyte differentiation and activation. In summary, we show evidence of a highly complex genome and identified a subset of genes with potential relevance in PCNSL pathogenesis. The genomic profile described here reinforces the existence of a specific molecular signature in PCNSL, thus helping to genetically differentiate this entity from the nodal DLBCL and related lymphomas. Disclosures: Stewart: Millenium: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Celgene: Consultancy. Fonseca:Medtronic: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Genzyme: Consultancy; BMS: Consultancy; Lilly: Consultancy; Onyx: Consultancy; Binding site: Consultancy; Millenium: Consultancy; AMGEN: Consultancy; Celgene : Research Funding; Onyx: Research Funding; prognostication of MM based on genetic categorization of the disease: Prognostication of MM based on genetic categorization of the disease Patents & Royalties.

scholarly journals Enhanced Expression of FGF Signaling in Primary Central Nervous System Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2847-2847
Author(s):  
Alanna Maguire ◽  
Talal Hilal ◽  
Xianfeng Chen ◽  
Allison C. Rosenthal ◽  
Lisa M. Rimsza
Keyword(s):  
Gene Expression ◽  
Central Nervous System ◽  
Nervous System ◽  
B Cell ◽  
Signaling Pathways ◽  
Central Nervous System Lymphoma ◽  
Fgf Signaling ◽  
Mitogenic Signaling ◽  
Gene Set ◽  
Systemic Dlbcl

Abstract Introduction: Primary central nervous system lymphoma (PCNSL) is a rare intracranial lymphoma that accounts for less than 1% of all non-Hodgkins lymphomas and 3% of all brain tumors. Histopathologically, approximately 90% of PCNSL cases are categorized as a diffuse large B-Cell lymphoma (DLBCL). DLBCL malignancies are subdivided by Cell of Origin (COO), with the vast majority of PCNSL categorized as non-germinal center B cell (non-GCB) by immunohistochemistry. Gene expression profiling (GEP), however, has shown that immunohistochemically defined non-GCB resolves into two distinct subtypes, namely activated B-cell (ABC) and unclassified (UNC) subtypes. Using the Lymph2Cx molecular COO subtyping assay, we have found that 91% of PCNSL are ABC (unpublished data). Unlike systemic-DLBCL, PCNSL is largely confined to and rarely metastasizes outside of the immune privileged central nervous system. Despite this, PCNSL is one of the most aggressive forms of DLBCL. Given the immune privileged milieu in which PCNSL arises, we hypothesized that this milieu elicits a transcriptional profile that contributes to the enhanced aggressive nature of PCNSL compared to systemic-DLBCL. To investigate this hypothesis, this study assessed the gene expression differences between ABC-PCNSL and ABC-systemic-DLBCL, in order to identify novel players in the pathogenesis of ABC-PCNSL. Methods: A total of 35 HIV negative samples, with proven ABC-subtype COO as per the GEP Lymph2Cx assay, were employed; including 10 ABC systemic-DLBCL and 25 primary ABC PCNSL cases with no concurrent or prior history of systemic DLBCL. Samples were reviewed by a hematopathologist to confirm diagnoses and determine tumor content. Samples with <60% tumor content were macro-dissected before nucleic acid extraction, which was performed using the Qiagen AllPrep DNA/RNA FFPE Kit. Extracted DNA and RNA were quantified using the Qubit HS-kit and NanoDrop respectively. Digital gene expression technology was used to perform the PanCancer Pathways panel (NanoString, Seattle, WA). Differential gene expression analysis was performed using the NanoString specific statistical method NanoStringDiff. Identified gene sets were analyzed using the online Gene Set Enrichment Analysis (GSEA) Molecular Signatures Database (MSigDB). Results: Of the 739 cancer related genes targeted by the PanCancer panel, 256 were found to be significantly differentially expressed in the ABC-PCNSL cohort compared to the ABC-DLBCL cohort (p<0.05). Fifty six genes were upregulated and 200 were downregulated. With a 4.9 fold change, the most significantly overexpressed gene was FGF1 (p=4.7E-11). FGF1 encodes a primary ligand for the fibroblast growth factor receptors (FGFR) -1, -2, -3 and -4; of which, FGFR2 (p=1.0E-7) and FGFR3 (p=0.003) were also significantly overexpressed. Moreover, MSigDB identified the FGF signaling pathway as enriched in the upregulated gene set (5 genes, p=7.4E-9, FDR=6.6E-7). FGFRs are a family of receptors that activate known mitogenic signaling pathways including MAPK signaling, which MSigDB identified as the most enriched pathway in the upregulated gene set (14 genes, p=1.65E-19, FDR=2.2E-16). MSigDB analysis of the 200 down regulated genes revealed that 5 of the top 20 enriched signaling pathways were immune related and included Signaling by interleukins (26 genes, p=2.9E-38, FDR=3.2E-36), Immune cytokine signaling (31 genes, p=1.1 E-34, FDR=1.1E-32), chemokine signaling (28 genes, p=1.5E-34, FDR=1.4E-32), T-cell receptor signaling (24 genes, p=2.4E-34, FDR=1.9E-32) and Toll-like receptor signaling (23 genes, p=4.1E-33, FDR=3.0E-31). Conclusions: We show, for the first time, that ABC-PCNSL and ABC-systemic-DLBCL possess significantly different transcriptional profiles despite identical, molecularly determined, COO status. A principle difference between these DLBCL malignancies is their anatomical location related immune privilege status which is reflected as reduced immune related signaling in the CNS-DLBCL cohort and may have important mitogenic signaling implications. Indeed, the results suggest that the enhanced aggressive nature of PCNSL compared to systemic-DLBCL is mediated, at least in part, by enhanced FGF signaling; a pathway with known roles in cell survival and proliferation. Disclosures Rimsza: NanoString: Other: Inventor on the patent for the Lymph2Cx assay.

The Genomic Landscape Of Primary Central Nervous System Lymphomas

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 504-504 ◽  
Author(s):  
Esteban Braggio ◽  
Brian Patrick O'Neill ◽  
Scott Van Wier ◽  
Juhi Ojha ◽  
Jackline ayres-Silva ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Copy Number ◽  
Research Funding ◽  
Central Nervous System Lymphoma ◽  
Genetic Alterations ◽  
Activating Mutations ◽  
Genomic Study ◽  
Recurrent Mutations ◽  
Systemic Dlbcl

Abstract Primary central nervous system lymphoma (PCNSL) is an aggressive and incurable variant of non-Hodgkin lymphoma (NHL) that is confined to the central nervous system. Most PCNSL (90%) are part of the immune-privileged site-associated diffuse large B-cell lymphomas (DLBCL). Unlike nodal DLBCL, only a limited number of genetic studies have been performed in PCNSL, partly due to lack of available tissue specimens. Because of the fragmented knowledge of the genomic basis, it is still a matter of debate whether they differ from systemic DLBCL with respect to their molecular features and pathogenesis and also if there is a CNS specific signature. We performed a comprehensive genomic study in a cohort of 22 immunocompetent (HIV- and EBV-) PCNSL. DNA was extracted from FFPE tissues (N=15) and frozen tissue (N=7). Samples were analyzed using a combination of aCGH (N=18), exome sequencing (N=10), mate-pair genome sequencing (N=2) and targeted sequencing (N=8). We found a complex karyotype with a median of 21 copy-number abnormalities (range 10–47), 6 structural abnormalities, 6 frameshift indels and 67 nonsynonymous mutations. By integrating mutation and copy number data we found a group of genes recurrently mutated and/or deleted in PNCSL. Remarkable findings were the high prevalence of MYD88 activating mutations (L265P/M232T/V217F), found in 69% of cases and the biallelic loss of CDKN2A (60%). A subset of recurrent abnormalities was exclusively found in PCNSL, and not being previously identified in systemic DLBCL. Thus, 11% of PCNSL have biallelic inactivation of TOX (a regulator of T-cell development) and PRKCD (protein kinase C delta), while another 17% of cases show focal monoallelic deletions/mutations in these genes. Finally, recurrent mutations have been identified in ATM, which have not been found in nodal DLBCL. Several other genes affected have been previously identified in nodal DLBCL, such as biallelic loss of TNFAIP3 (16%), PRDM1 (16%), GNA13, TMEM30A, B2M and CD58 (11% each), activating mutations of CD79B (28%) and CARD11 (19%) and translocations of BCL6 (22%). Components of the NF-kB pathways were altered in >90% of PNCSL. Pathway analysis also showed an enrichment of networks associated with immune response, proliferation, regulation of apoptosis and lymphocyte differentiation and activation. Finally, we searched for associations between genetic alterations and clinical outcome. We showed that deletions of 6q21 (PRDM1) and 6q23 (TNFAIP3) were both associated with shorter overall survival (p=0.007 and p=0.03, respectively). In summary, we report a genomic background in PCNSL similar to post-GC DLBCL but reinforcing the existence of a subset of abnormalities specific to PCNSL, suggesting their potential relevance in the disease pathogenesis. Additionally, the results obtained from FFPE samples are encouraging and larger archival tissue collections can now be analyzed in order to complement the still fragmented knowledge we have of the genetic basis of the disease. Disclosures: Stewart: Onyx: Consultancy, Research Funding; Millenium: Honoraria, Research Funding; Celgene: Honoraria; BMS: Honoraria. Fonseca:Medtronic: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Genzyme: Consultancy; BMS: Consultancy; Lilly: Consultancy; Onyx: Consultancy, Research Funding; Binding Site: Consultancy; Millennium: Consultancy; AMGEN: Consultancy; Cylene: Research Funding; Prognostication of MM based on genetic categorization of the disease: Patents & Royalties.

Crosstalk Between Insulin and Toll-like Receptor Signaling Pathways in the Central Nervous system

2014 ◽  
Vol 50 (3) ◽  
pp. 797-810 ◽  
Author(s):  
Fatemeh Hemmati ◽  
Rasoul Ghasemi ◽  
Norlinah Mohamed Ibrahim ◽  
Leila Dargahi ◽  
Zahurin Mohamed ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Signaling Pathways ◽  
Receptor Signaling ◽  
Toll Like Receptor ◽  
The Central Nervous System

Cerebrospinal Fluid Cytology of Lyme Neuroborreliosis: A Report of 3 Cases with Literature Review

2015 ◽  
Vol 59 (4) ◽  
pp. 339-344 ◽  
Author(s):  
Juan Xing ◽  
Lisa Radkay ◽  
Sara E. Monaco ◽  
Christine G. Roth ◽  
Liron Pantanowitz
Keyword(s):  
Central Nervous System ◽  
Flow Cytometry ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Lyme Disease ◽  
B Cell ◽  
Plasma Cells ◽  
Lyme Neuroborreliosis ◽  
Chain Analysis ◽  
The Central Nervous System

Lyme disease can affect the central nervous system causing a B-cell-predominant lymphocytic pleocytosis. Since most reactions to infection in the cerebrospinal fluid (CSF) are typically T-cell predominant, a B-cell-predominant lymphocytosis raises concern for lymphoma. We present 3 Lyme neuroborreliosis cases in order to illustrate the challenging cytomorphological and immunophenotypic features of their CSF specimens. Three male patients who presented with central nervous system manifestations were diagnosed with Lyme disease. The clinical presentation, laboratory tests, CSF cytological examination and flow-cytometric studies were described for each case. CSF cytology showed lymphocytic pleocytosis with increased plasmacytoid cells and/or plasma cells. Flow cytometry showed the presence of polytypic B lymphocytes with evidence of plasmacytic differentiation in 2 cases. In all cases, Lyme disease was confirmed by the Lyme screening test and Western blotting. In such cases of Lyme neuroborreliosis, flow cytometry of CSF samples employing plasmacytic markers and cytoplasmic light-chain analysis is diagnostically helpful to exclude lymphoma.

scholarly journals Challenges in the Treatment of Newly Diagnosed and Recurrent Primary Central Nervous System Lymphoma

2020 ◽  
Vol 18 (11) ◽  
pp. 1571-1578
Author(s):  
Matthias Holdhoff ◽  
Maciej M. Mrugala ◽  
Christian Grommes ◽  
Thomas J. Kaley ◽  
Lode J. Swinnen ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
B Cell ◽  
Central Nervous System Lymphoma ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Newly Diagnosed ◽  
Phase Ii Trials ◽  
Whole Brain Radiation ◽  
The Central Nervous System

Primary central nervous system lymphomas (PCNSLs) are rare cancers of the central nervous system (CNS) and are predominantly diffuse large B-cell lymphomas of the activated B-cell (ABC) subtype. They typically present in the sixth and seventh decade of life, with the highest incidence among patients aged >75 years. Although many different regimens have demonstrated efficacy in newly diagnosed and relapsed or refractory PCNSL, there have been few randomized prospective trials, and most recommendations and treatment decisions are based on single-arm phase II trials or even retrospective studies. High-dose methotrexate (HD-MTX; 3–8 g/m2) is the backbone of preferred standard induction regimens. Various effective regimens with different toxicity profiles can be considered that combine other chemotherapies and/or rituximab with HD-MTX, but there is currently no consensus for a single preferred regimen. There is controversy about the role of various consolidation therapies for patients who respond to HD-MTX–based induction therapy. For patients with relapsed or refractory PCNSL who previously experienced response to HD-MTX, repeat treatment with HD-MTX–based therapy can be considered depending on the timing of recurrence. Other more novel and less toxic regimens have been developed that show efficacy in recurrent disease, including ibrutinib, or lenalidomide ± rituximab. There is uniform agreement to delay or avoid whole-brain radiation therapy due to concerns for significant neurotoxicity if a reasonable systemic treatment option exists. This article aims to provide a clinically practical approach to PCNSL, including special considerations for older patients and those with impaired renal function. The benefits and risks of HD-MTX or high-dose chemotherapy with autologous stem cell transplantation versus other, better tolerated strategies are also discussed. In all settings, the preferred treatment is always enrollment in a clinical trial if one is available.

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