Cases Of Primary Central Nervous System Lymphoma Research Articles

10215-ML-7 CLINICAL OUTCOME OF TIRABRUTINIB IN PCNSL REFRACTORY TO R-MPV THERAPY

Abstract In recent years, R-MPV therapy has been widely used for treatment of primary central nervous system lymphoma (PCNSL). Although a high response rate and favorable prognosis have been reported with R-MPV therapy using multiple drugs, the treatment strategy for cases refractory to induction therapy has not been established. High-dose radiotherapy is currently recommended for refractory cases, however, the efficacy and frequency of adverse events such as leukoencephalopathy are not yet clear. Tirabrutinib has been available for recurrent or refractory PCNSL cases since 2020. However, there have been few reports on the results of tilabrutinib in these refractory cases. We have been using tirabrutinib for these refractory cases since its introduction. Here, we compared the results of tirabrutinib with those before the introduction of tirabrutinib. We investigated 30 cases with PCNSL treated with R-MPV at our hospital since 2013. 5 (16.7%) of the 30 cases revealed refractory to R-MPV. Two cases were promptly treated with irradiation (total 40-45 Gy) and both remitted, but one (a 70's male) had extensive white matter changes. One case (40's female) also had white matter changes but maintained CR for 4 years and 8 months. All three patients treated with tirabrutinib achieved CR or PR immediately, and two patients (a 60's woman and a 70's man) received whole brain irradiation of 23.4 Gy at 26 and 28 days after tirabrutinib introduction and remained in remission for 2 years 3 months and 2 years 4 months respectively with no significant white matter changes. The results suggest that tirabrutinib may be useful for cases refractory to R-MPV therapy. Because the long-term results of tirabrutinib are not yet clear, careful consideration should be given to the necessity of radiotherapy for cases who have achieved remission with tirabrutinib.

Single Cell Multi Omics and Spatial Analysis Reveals Plasmablast Signature Malignant Cells As a Key of Intratumor Heterogeneity in Primary Central Nervous System Lymphoma

Background: Primary central nervous system lymphoma (PCNSL) constitutes approximately 5% of extranodal lymphomas. More than 90% of PCNSL are diagnosed as diffuse large B-cell lymphomas (DLBCL), mainly classified as the activated B cell (ABC) subtype. Recent genetic analyses have identified key molecular drivers of PCNSL, including MYD88, CARD11 and CD79B. However, molecular analyses using bulk samples have provided limited insights into the heterogeneity in lymphoma cells of PCNSL. To improve our understanding in the biology of PCNSL, we conducted a multimodal single-cell analyses and integrated single-cell and spatial analyses to characterize the molecular properties of PCNSL tumors. Methods:Our study included seven PCNSL patients and two patients with reactive lymph nodes (RLN). We performed Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) combined with B-cell and T-cell receptor (BCR and TCR) analysis on samples from 3 PCNSL and 2 RLN patients, while the remaining PCNSL patients' samples were subjected to single-cell transcriptomic sequencing. Additionally, six formalin-fixed and paraffin-embedded (FFPE) tissues from the patients analyzed in the single-cell sequencing (except for one patient) were performed with GeoMx digital spatial profiling (DSP). Result: To ensure data quality, we filtered out low-quality cells and doublets, resulting in a dataset of 41,556 single cells. B cells represented the most abundant cluster, followed by T cells and monocytes. Copy number alterations (CNAs) data derived from InferCNV analysis showed distinct CNAs patterns in lymphoma cells of each patient. UMAP plot projection analysis revealed the presence of a distinct subtype of malignant cells within the B-cell population, which was characterized as high expression of plasmablast (PBL)-associated surface proteins, including SLAMF7, CD39, and CD38. Enrichment analysis based on germinal center (GC) gene expression signatures (Holmes AB et al. J Exp Med. 2020) revealed a broader spectrum of B-cell differentiation states in malignant B cells. Single-cell BCR sequencing further demonstrated that different GC signature state cells harbored the same BCR repertoire within each patient, suggesting a common origin of malignant cells. Non-negative matrix factorization (NMF) analysis confirmed the enrichment of PBL signature scores in the distinct malignant cell population observed in the UMAP plot, consistent with DPE analysis (Figure A). Interestingly, the proportion of PBL signature cells varied among patients. Signaling interaction analysis highlighted CD70-CD27 and SPP1-CD44 pathways as enriched in tumor cells. PBL signature cells received TNFSF13B and TNFSF13 signaling through TNFRSF17 (BCMA), whereas other tumor cells expressed TNFRSF13C (BAFF-R) and received TNFSF13B signaling alone. We further analyzed two public bulk RNA-seq data (Bruno A et al. Neuro Oncol 2018, n = 6; Radke J et al. Nat Commun 2022, n=38) in PCNSL to decompose tumor components. Tumor PBL components were identified in most PCNSL cases, although several cases exhibited a low presence of tumor PBL population. Of note, analysis including these public datasets with our single-cell cohort showed that PCNSL samples with high tumor PBL proportion had unfavorable prognosis . Additionally, we performed DSP to integrate the single-cell and spatial multi-omics analyses. We deconvoluted the cell composition by using transcriptomic data derived from each region of interest (ROI) and found that the cell proportions in ROI were consistent with the corresponding single-cell results. However, there were differential profiles of cell composition according to patients rather than ROIs, suggesting that PCNSL tumors may display spatial homogeneity (Figure B). Conclusion: Through the application of single-cell and spatial transcriptomic analysis, we identified a distinct subtype expressing the PBL signature gene. These findings have important therapeutic implications and provide new insights into the mechanisms of relapse in PCNSL.

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

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

PATH-44. INTRA-OPERATIVE ANALYSES OF GENETIC ALTERATIONS IN THE CENTRAL NERVOUS SYSTEM TUMORS USING RAPID QUANTITATIVE PCR DEVICE

Abstract Recent comprehensive molecular analyses of central nervous system (CNS) tumors identified several diagnostic or prognostic markers. IDH mutation, TERT promoter (pTERT) mutation and CDKN2A homozygous deletion in adult-type diffuse gliomas, BRAF p.V600E mutation in circumscribed astrocytic gliomas, histone H3 gene mutations in pediatric-type diffuse high-grade gliomas or MYD88 mutation in primary CNS lymphoma (PCNSL) are quite important markers. Intra-operative identification of these molecular alterations could be effective for decision-making of tumor removal strategy. In this study, we established intra-operative gene analysis method using rapid quantitative PCR device, GeneSoC, by which we could obtain genotype of these important genes for 20 minutes in an operating room. Using GeneSoC, we could perform 50 cycles of quantitative PCR for approximately 12 minutes. We established rapid gene analyses of mutations of IDH1 p.R132H, pTERT C225T, pTERT C250T, H3 K27M, BRAF p.V600E and homozygous deletion of CDKN2A for diffuse gliomas and circumscribed astrocytic tumors and MYD88 p.L265P for PCNSL. For elution of DNA, we incubated at least 1mg of tumor tissue at 95°for 5 minutes. Combined this boiling method with GeneSoC, we could obtain those genetic alterations for 20 minutes after collection of tumor tissue. For 42 glioma cases and 10 PCNSL cases, we could obtain accurate genetic alterations (IDH1 p.R132H, pTERT C225T, pTERT C250T for gliomas or MYD88 p.L265P for PCNSL) in all cases, using this method. For detection of CDKN2A homozygous deletion, sensitivity and specificity are 100% and 83% in analyzed 50 cases, respectively. In this study, we could obtain the genotype of important molecular markers intra-operatively, not only during tumor removal but even during tumor biopsy, using GeneSoC device. This rapid genetic analysis might be effective not only for intra-operative diagnosis but also for detection of boundary between tumor and normal tissue.

Differentiation of glioblastoma and primary central nervous system lymphomas using multiparametric diffusion and perfusion magnetic resonance imaging.

The present study aimed to determine whether combining diffusion-weighted (DWI) and dynamic susceptibility contrast-enhanced perfusion-weighted (DSC-PWI) magnetic resonance imaging (MRI) could differentiate between primary central nervous system lymphoma (PCNSL) and glioblastoma (GBM). The present retrospective study evaluated 45 patients with histologically confirmed brain tumors, of which 18 had PCNSLs and 27 had GBMs. All patients underwent conventional, DWI, and DSC-PWI MRIs before the surgical removal of the lesion or stereotactic biopsy. The solid tumor component, peritumoral edema, and abnormal white matter were measured in three regions of interest to evaluate relative cerebral blood volume (rCBV), apparent diffusion coefficient (ADC) and DWI. In conventional MRI, there were significant differences in tumor numbers, tumor enhancement type, tumor necrosis, hemorrhage and open-ring sign between GBM and PCNSL. Solid tumor ADC and rCBV values (ADCt and rCBVt, respectively) and their ratios with abnormal white matter amounts were significantly higher in GBM cases than in PCNSL cases (P<0.05). The rCBV value for peritumoral edema (rCBVe) and its ratio with abnormal white matter amount (rCBVe/n) were significantly higher in GBM cases than in PCNSL cases (P<0.05). However, ADC values did not differ significantly for peritumoral edema. DWI values did not differ significantly. Combining rCBVt and rCBVe/n provided a perfect area under the receiver operating characteristic curve of 1.00, with 100% sensitivity and 100% specificity for distinguishing GBM from PCNSL. In the results of the present study, the major criterion in the decision-making process distinguishing PCNSL from GBM was the combined rCBVt and rCBVe/n parameter. A minor criterion was the ADCt value of the lesion.

Study on primary central nervous system lymphoma in pediatric patients.

Primary central nervous system lymphoma (PCNSL) in pediatric patients presents diagnostic and treatment challenges, leading to delays and suboptimal strategies. Moreover, PCNSL in immunocompetent pediatric patients is rarely reported. This retrospective study aimed to describe the demographic and clinical features, as well as outcomes, of pediatric PCNSL cases. A retrospective review was conducted on 11 immunocompetent pediatric patients diagnosed with PCNSL between January 2012 and April 2020. Data regarding age, gender, initial presenting symptoms, tumor location, and radiological characteristics were collected. Treatment strategies and analyzed prognosis were documented. Survival curves were generated using the Kaplan-Meir method, and data were analyzed using SPSS (version 23.0, IBM Corp.). The study cohort comprised 11 patients, including 10 males and 1 female. The age at diagnosis ranged from 4 to 15 years, with a median age of 10.6 years. Headache was the most common presenting symptom, observed in 81.8% (9/11) of patients. Tumor locations in the supratentorial and infratentorial regions exhibited a similar occurrence rate. All tumors showed strong contrast enhancement on T1-weighted images. The average survival time for the 11 patients was 44.4 months. Among them, 5 patients died by the last follow-up visit, with a mean survival time of 8.8 months (one patient died in a car accident). Headache is the predominant manifestation of PCNSL in pediatric patients. PCNSL demonstrates imaging characteristics resembling various intracranial tumors and is associated with a poor prognosis. Therefore, pediatric neurosurgeons should exercise caution in diagnosing and treating intracranial lymphoma.

Whole-Exome Sequencing Revealed the Mutational Profiles of Primary Central Nervous System Lymphoma.

Primary central nervous system lymphoma (PCNSL) is a highly aggressive type of extranodal non-Hodgkin lymphoma, of which approximately 90% of the cases are diffuse large B-cell lymphoma (DLBCL). In recent years, the incidence of PCNSL has significantly increased in women and older men. Although advanced treatments such as high-dose methotrexate (HD-MTX) and targeted agents have been introduced, the prognosis of these patients remains poorer than those with other forms of non-Hodgkin's lymphoma. Twelve cases of Chinese PCNSL were analyzed to detect their genetic alterations using whole-exome sequencing (WES). We identified 448 potential somatic single nucleotide variants (SNVs) with a median of 12 SNVs per PCNSL sample and 35 small indels with potentially protein-changing features in 9 PCNSL samples. We found that myeloid differentiation factor 88 (MYD88) had the highest mutation frequency, which affected the activity of the nuclear factor-κB (NF-κB) pathway. PCNSL samples with low-density lipoprotein receptor-related protein 1B (LRP1B) mutations had a higher mutation rate than samples with wild-type LRP1B. Polycystic kidney and hepatic disease 1 (PKHD1), the causal gene of autosomal recessive polycystic kidney disease (ARPKD), was identified in 2 PCNSL cases and exhibited missense mutations. Pathway analysis revealed enrichment in pathways associated with central carbon metabolism in cancer, renal cell carcinoma, nicotine addiction, bladder cancer, and long-term depression. WES revealed significantly mutated genes associated with the molecular mechanisms of PCNSL, which could serve as therapeutic targets to improve patient outcomes.

Combining MYD88 L265P mutation detection and clonality determination on CSF cellular and cell-free DNA improves diagnosis of primary CNS lymphoma.

Diagnosis of primary central nervous system lymphoma (PCNSL) is challenging, and although brain biopsy remains the gold standard, cerebrospinal fluid (CSF) constitutes a less invasive source of lymphomatous biomarkers. In a retrospective cohort of 54 PCNSL cases tested at diagnosis or relapse, we evaluated the contribution of immunoglobulin heavy chain (IGH) gene clonality and MYD88 L265P detection on both CSF cell pellets and supernatants, in comparison with cytology, flow cytometry, interleukin (IL)-10 and IL-6 quantification. Clonality assessment included a new assay to detect partial IGH-DJ rearrangements. Clonal IGH rearrangements and/or MYD88 L265P mutation were detected in 27 (50%) cell pellets and 24 (44%) supernatant cell-free (cf) DNA. Combining analyses on both compartments, 36 (66%) cases had at least one detectable molecular marker, present only in cfDNA for 9 (16%) of them. While cytology and flow cytometry were positive in only 7 (13.0%) and 9 (17.3%) cases respectively, high IL-10 levels were observed in 36 (66.7%) cases. Overall, taking into account molecular and cytokine results, 46/54 (85%) cases had at least one lymphomatous biomarker detectable in the CSF. These results show that this combination of biomarkers evaluated on both cell pellet and supernatant CSF fractions improves significantly the biological diagnosis of PCNSL.

Rapid detection of the MYD88 L265P mutation for pre- and intra-operative diagnosis of primary central nervous system lymphoma.

The myeloid differentiation primary response gene 88 (MYD88) L265P mutation is a disease-specific mutation of primary central nervous system lymphoma (PCNSL) among the central nervous system tumors. Accordingly, this mutation is considered a reliable diagnostic molecular marker of PCNSL. As the intra-operative diagnosis of PCNSL is sometimes difficult to achieve using histological examinations alone, intra-operative detection of the MYD88 L265P mutation could be effective for the accurate diagnosis of PCNSL. Herein, we aimed to develop a novel rapid genotyping system (GeneSoC) using real-time polymerase chain reaction (PCR) based on microfluidic thermal cycling technology. This real-time PCR system shortened the analysis time, which enabled the detection of the MYD88 L265P mutation within 15 min. Rapid detection of the MYD88 L265P mutation was performed intra-operatively using GeneSoC in 24 consecutive cases with suspected malignant brain tumors, including 10 cases with suspected PCNSL before surgery. The MYD88 L265P mutation was detected in eight cases in which tumors were pathologically diagnosed as PCNSL after the operation, while wild-type MYD88 was detected in 16 cases. Although two of the 16 cases with wild-type MYD88 were pathologically diagnosed as PCNSL after the operation, MYD88 L265P could be detected in all eight PCNSL cases harboring MYD88 L265P. The MYD88 L265P mutation could also be detected using cell-free DNA derived from the cerebrospinal fluid of two PCNSL cases. Detection of the MYD88 L265P mutation using GeneSoC might not only improve the accuracy of intra-operative diagnosis of PCNSL but also help the future pre-operative diagnosis through liquid biopsy of cerebrospinal fluid.

Is CD19-directed chimeric antigen receptor T cell therapy a smart strategy to combat central nervous system lymphoma?

Primary central nervous system lymphoma (PCNSL) is a rare form and aggressive type of diffuse large B-cell lymphoma (DLBCL) that occurs in both immunocompetent and immunocompromised adults. While adding rituximab to chemotherapeutic regimens resulted in dramatic improvement in both progression-free survival and overall survival in patients with non-central nervous system (CNS) DLBCL, the outcomes of PCNSL are generally poor due to the immune-privileged tumor microenvironment or suboptimal delivery of systemic agents into tumor tissues. Therefore, more effective therapy for PCNSL generally requires systemic therapy with sufficient CNS penetration, including high-dose intravenous methotrexate with rituximab or high-dose chemotherapy followed by autologous stem cell transplantation. However, overall survival is usually inferior in comparison to non-CNS lymphomas, and treatment options are limited for elderly patients or patients with relapsed/refractory disease. Chimeric antigen receptor T (CAR-T) cell therapy has emerged as a cutting-edge cancer therapy, which led to recent FDA approvals for patients with B-cell malignancies and multiple myeloma. Although CAR-T cell therapy in patients with PCNSL demonstrated promising results without significant toxicities in some small cohorts, most cases of PCNSL are excluded from the pivotal CAR-T cell trials due to the concerns of neurotoxicity after CAR-T cell infusion. In this review, we will provide an overview of PCNSL and highlight current approaches, resistance mechanisms, and future perspectives of CAR-T cell therapy in patients with PCNSL.

The Profile of P63 Expression and Epstein-Barr-Encoded RNA (EBER) Distribution in Primary Central Nervous System Lymphoma: A Retrospective Bi-center Study

Background and Aims: Primary central nervous system lymphoma (PCNSL) is a type of lymphoma occurring around 0.5 – 1.2% of all intracranial neoplasms. However, recent epidemiological research shows a threefold increase in cases. The Epstein-Barr virus (EBV) and PCNSL are both associated with immunosuppression or immunodeficiency, which are often found to have a significant relationship. Moreover, the TP63 mutation is associated with a poor prognosis. Settings and Design: This is a descriptive study to assess the expression of TP63 and EBER on PCNSL and present the characteristics of the disease. The study was conducted on 25 cases from two health centers with the most cases of brain tumors in Indonesia (Siloam Hospital Lippo Village and Cipto Mangunkusumo National General Hospital) from 2014 to 2018. Four pathologists performed the P63 expression and EBER-1 examinations. Statistical Analysis: Descriptive analyses were done using frequencies and percentages for the data. Potential association of antibody expression and lymphoma subtypes were analyzed using Chi-square. Results: Of a total of 25 patients, 13 (52.0%) were male, ranging from age 30 – 79, with an average of 57.6 years old, located mainly in the frontal lobe in 8 patients (32.0%). Further analysis revealed positive P63 results in 20 cases (80.0%), while the EBER test was negative for all 25 patients. Further analysis with the software SPSS 25 proves that P63 expression is not associated with germinal center B-cell type (GCB) or non-GCB type (p-value 0,87). Neither P63 have any association with Ki67 with a p-value of 1.00. Conclusions: There is a possibility that PCNSL cases in Indonesia are not associated with Epstein-Barr virus infection, but most patients will have a poor prognosis as indicated by P63 expression.

Primary central nervous system lymphoma: Comprehension of cell-of-origin subtypes.

To classify PCNS-DLBCL into COO-subtypes based on immunohistochemical algorithms by Hans and Choi and evaluate concordance between the two. A further aim is to investigate the clinicoradiological and histomorphological parameters of the subtypes thus obtained. As many as 143 cases of primary CNS lymphoma were evaluated by immunohistochemistry for CD10, BCL6, MUM1, GCET, and FOXP1 and based on which the said 143 cases were further classified into COO subtypes using Hans and Choi algorithms. Mean age was 53.8 years with marginal male preponderance and predominantly centroblastic morphology (75.5%). CD 10 was positive in 8.9% of the cases, BCL6 in 58.6%, MUM1 in 89.9%, GCET in 32.9%, and FOXP1 in 79.5%. As much as 84.9% cases were of non-germinal center B-cell (GCB) subtype and 15.1% cases were of GCB subtype as determined based on Hans algorithm. Furthermore, 90.7% cases were of activated B-cell (ABC) subtype and 9.3% cases were of GCB subtype according to Choi algorithm. A 91.8% concordance was observed between Hans and Choi algorithms. Among the 6 discordant cases, 5 cases were subtyped as GCB by Hans and ABC by Choi and 1 case as ABC by Hans and GCB by Choi. Most of PCNS-DLBCLs are of non-GCB/ABC COO subtype, but inconsistences abound in the utility of IHC algorithms in PCNS-DLBCL COO subtypes.

ML-9 TREATMENT OUTCOMES OF TIRABRUTINIB FOR RELAPSED AND REFRACTORY PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA IN A SINGLE INSTITUTE

Abstract Recent clinical studies improved prognosis of primary central nervous system lymphoma (PCNSL) using multiple treatment reagents combined with radiation therapy. However, for recurrent and refractory cases after treatment with regimen consisting of multiple reagents, potent effective treatment has not been established yet. Tirabrutinib, Bruton's tyrosine kinase inhibitor was introduced for treatment of recurrent and refractory PCNSL in Japan. However, case series study investigating the clinical outcome of PCNSL cases treated with tirabrutinib have not been reported yet excepting for phase I/II study of tirabrutinib. We treated nine recurrent and two refractory cases. In all of these cases, except for one case exhibiting severe skin rash in spite of cessation of administration of tirabrutinib, we obtained favorable overall response rate (CR or Cru=5 and PR=5) together with favorable progression free survival (median; 339 days). Five cases exhibited skin rash (CTCAE grade 3; n=2 and grade 2; n=3). Grade 3 or 2 skin rash were found on day 9 or 75 of tirabrutinib treatment, respectively. In one case, MYD88 mutations in ctDNA derived from blood plasma were turned to be negative after one week administration of tirabrutinib. Although adverse effects such as skin rash was frequently found, tirabrutinib is effective for recurrent or refractory PCNSL cases. Our data suggested that treatment response of tirabrutinib could be evaluated via evaluation of copy number analysis of MYD88 mutations in ctDNA of blood plasma.

ML-5 THE TRANSITION OF THE TREATMENT OF 60 PCNSL CASES AT OUR INSTITUTION AND CLINICAL CONSIDERATIONS

Abstract The efficacy of RMPV-A (rituximab, methotrexate, procarbazine, vincristine, and cytarabine) and whole brain irradiation for primary central nervous system lymphoma (PCNSL) have recently been reported. Our institution also introduced RMPV therapy in 2020 after an era of conventional HD-MTX to cytarabine and rituximab combination. In this report, we analyzed 60 PCNSL cases treated from 2013 to 2021.There were 32 female patients (53%) with a median age of 70 years (30-87). Five patients (8%) received radiotherapy alone as initial treatment, 30 (50%) received HD-MTX (including radiation), 17 (28%) received HD-MTX plus rituximab or cytarabine, and 9 (13%) received RMPV therapy. The response rate (CR, CRu, PR) in the HD-MTX group was 88%, and the complete response rate (CR, CRu) was 51%. In contrast, the RMPV arm had a response rate of 100% and a complete response rate of 6 patients (66.7%). 7 patients (14%) in the HD-MTX arm and 2 patients (22%) in the RMPV arm were unable to continue treatment due to adverse events. The treatment of PCNSL has undergone significant changes in recent years, with the availability of RMPV-A, thiotepa, and tirabrutinib, and it is now possible to construct treatment that avoids leukoencephalopathy caused by radiation therapy as much as possible, which had been a major problem of conventional therapy. However, because of the use of strong drugs, caution must be exercised when treating patients in poor general conditions, especially the elderly. However, the present analysis indicates that many elderly patients can be successfully treated with careful observation. In the future, it is essential to accumulate cases treated with RMPV therapy and tilabrutinib and conduct further data analysis to establish a new generation of treatment for PCNSL.

Preliminary clinical application of multimodal imaging combined with frameless robotic stereotactic biopsy in the diagnosis of primary central nervous system lymphoma

ObjectiveTo evaluate the clinical application of multimodal imaging combined with frameless robotic stereotactic biopsy in the diagnosis of primary central nervous system lymphoma (PCNSL). MethodsWe retrospectively reviewed the clinical data of 8 patients who were considered suspected cases of PCNSL by multimodal imaging techniques. The final pathologic diagnosis were determined by the frameless robotic stereotactic biopsy. The postoperative related complications and pathological results were analyzed. ResultsAll patients underwent biopsies under general anesthesia with an average surgery time of 29.5 ± 4.5 min. The final pathological diagnostic accordant rate with the preoperative ones was 100%, and the pathologic examination of our patients showed features of diffuse large B-cell lymphoma. During the surgery, one patient suffered intratumoral hemorrhage without leading to serious cerebral edema, and conservative treatment was given. There was no death occurring during the study, and there were no significant differences in the Karnofsky Performance Scale Scores of all patients before and after surgery. Finally, they were transferred to the hematology department for standardized chemoradiotherapy according to the pathological results of PCNSL. ConclusionThis study shows that it may play a vital role in the early diagnosis of PCNSL with the technique of multimodal imaging. The technique of frameless robotic stereotactic biopsy for obtaining the pathology outcomes in suspected PCNSL patients has the advantages of safety, efficiency, and minimally invasiveness.

P11.48.A Primary CNS lymphoma after CLIPPERS: a case series

Abstract Background Few cases of primary CNS lymphoma(PCNSL) following a diagnosis of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) are reported in the literature. Here we explore implications of this sequel for CLIPPERS follow-up and PCNSL outcome. Material and Methods A systematic review and meta-analysis of previously described cases in the MEDLINE database was performed in compliance with PRISMA guidelines. Clinical, radiological and pathological characteristics were summarized. Overall survival was estimated using the Kaplan-Meier method. Results In addition to a case from our institution, nine cases were previously described in the literature. Eight patients fulfilled diagnostic criteria for ‘definite’ CLIPPERS whereas two cases were diagnosed with ‘probable’ CLIPPERS. Male-to-female ratio was 9:1. Median interval from CLIPPERS to PCNSL diagnosis was 4.5 months. All patients had received immunosuppressive therapy including methylprednisone in all and azathioprine or cyclophosphamide in most cases. On MRI, appearance of a larger lesion (&amp;gt;3mm) with peripheral contrast enhancement was noted in the most cases upon PCNSLdiagnosis. Whereas Epstein-Barr virus was not detected in biopsy specimen upon CLIPPERS diagnosis, it was identified in the majority of samples upon PCNSL diagnosis. Treatmentfor PCNSL included high-dose methotrexate basedchemotherapy in most cases, however median overall survival was poor (5.5 months). Conclusion Interval from CLIPPERS to PCNSL diagnosis was short and may mandate close clinical and radiological follow-up, specifically within the first two years after CLIPPERS diagnosis. Characteristics of PCNSL following CLIPPERS resemble other immunodeficiency-related PCNSL. Outcome was inferior and may reflect late diagnosis or brainstem localization.

Cerebellar primary central nervous system lymphoma: Case series report.

Introduction and importancePrimary central nervous system lymphoma (PCNSL) is a rare cranial malignant haematological tumour. PCNSL in the cerebellar region is less common than PCNSL in other encephalic regions. A diagnosis of cerebellar PCNSL is relatively difficult to make due to its diverse imaging manifestations. The aim of this case series report is to determine whether surgery could be used to confirm the diagnosis of cerebellar PCNSL and the effect of surgical treatment.MethodsWe report 3 cases of cerebellar PCNSL that underwent neuronavigation microsurgery under general anaesthesia. The operation was performed by author 3 and author 5. One patient underwent left lateral ventricular drainage on the fourth and tenth days after the operation due to postoperative obstructive hydrocephalus. All patients received chemotherapy or radiotherapy after histological confirmation.OutcomesAll patients' tumours were completely removed. One patient developed obstructive hydrocephalus twice during the perioperative period after the operation, was given drainage, and then recovered from the hospital. The other two patients recovered and were discharged smoothly without complications. One patient died 9 months after the operation, and the other two patients survived. The prognosis of 3 patients was related to tumour size and timely follow-up chemo-radiation therapy.ConclusionThe histology of all patients showed diffuse large B-cell lymphoma (GCB phenotype). Suspicious cerebellar PCNSL patients should undergo surgery to confirm the diagnosis, followed by radiotherapy and chemotherapy.

Differencial diagnosis of primary central nervous system lymphomas based on multiparametric MRT mapping

INTRODUCTION: Primary central nervous system lymphoma (PCNSL) represent a rare and aggressive form of extranodal NonHodgkin’s lymphoma, which is in most cases confined to the brain. Prompt diagnosis and starting treatment are vital. According to imaging, the tumor is characterized by low MR signal in T1, isointense in T2, pronounced and homogeneous uptake of contrast agent and restricted diffusion.OBJECTIVE: to study the effectiveness of MR-/CT perfusion techniques, underlying the multiparametric MRT mapping with the differential diagnosis of primary CNS lymphomas in comparison with poorly differentiated gliomas (grade 3–4 WHO 2021) and solitary metastatic brain injury.МATERIALS AND METODS: The study includes 80 patients with newly identified CNS tumors, later having check-up/neurosurgery treatment in Federal Centre of Neurosurgery (Tyumen, Russia) with histological verification within the period from 2018 to 2021. Depending on histological conclusion, 4 groups of patients were identified: 1–33 cases with PCNSL (out of which 10 cases with not typical manifestation based on the data of perfusion parameters and 23 cases of classical PCNSL), 2 — with anaplastic astrocytomas — 14 cases, 3–23 cases with glioblastomas and 4–10 cases with solitary metastatic lesion. The research was held on magnetic resonance tomography General Electric Discovery W750 3Т, multispiral x-ray computer tomography Canon Aquilion One before and after the contrast enhancement.RESULTS: During the study it was established that MR-/CT perfusion is a limited imaging method, possessing ambiguous sensitivity and specificity with PCNSL diagnosis, as they are characterized by not typical manifestation considered as exception. Nevertheless, the method has some undeniable advantages being indispensable in the algorithm of complex multiparametric diagnostic approach for this type of neoplasm.CONCLUSION: The capacity of neuroimaging PCNSL, even applying improved techniques of MR-/CT data collection, is rather limited and it doesn’t always allow to differentiate this tumor with other neoplasms accurately.

A multicenter, real-world analysis of primary central nervous system lymphoma in those with and without human immunodeficiency virus.

A multicenter, real-world analysis of primary central nervous system lymphoma in those with and without human immunodeficiency virus.

Primary central nervous system lymphoma high incidence and poor survival in Finnish population-based analysis

BackgroundWe report here the first population-based incidence rates and prognosis of primary central nervous system lymphoma (PCNSL) in Finland.MethodsFinnish Cancer Registry data by histological diagnosis and tumor location (2007–2017) for cases with diffuse large B-cell lymphoma.ResultsDuring 2007–2017, 392 new cases of PCNSL were reported (195 males, 197 females). The average age-adjusted incidence was 0.68/100,000 person-years. Incidence for males was 0.74/100,000 and for females 0.63/100,000, respectively. The incidence was highest, 2.93/100,000, among people aged 75–79 years. Concerning all cases in 2007–2017 the 2-year age-adjusted relative survival rate was 33% and the corresponding 5-year survival rate was 26%. Among patients under the age of 70, the age-adjusted 5-year relative survival rate increased from 36% in 2007–2012 to 43% for 2013–2017. Among patients aged 70+ the corresponding survival rates were poor, 7 and 9%.ConclusionsPCNSL incidence in Finland is among the highest reported in the world. The annual increase in incidence was 2.4%. The prognosis is still dismal, especially in elderly patients.