CNS Lymphoma Patients Research Articles

Intraoperative pathologic diagnosis of central nervous system lymphomas: A comparison of frozen and permanent section diagnoses, and the significance of preoperative imaging

BackgroundCentral nervous system (CNS) lymphomas, either primary or secondary in origin, are rare malignant tumors affecting the brain, spinal cord, or leptomeninges. Diagnosis of CNS lymphomas is complicated by their diverse clinical presentations, radiological features, and histopathological characteristics. Although frozen section (FS) analysis is commonly employed for various CNS tumors, its role and accuracy in CNS lymphoma diagnosis are less explored. In this study, we conducted a comparative analysis to assess the impact of knowledge of preoperative imaging on enhancing the accuracy of FS diagnosis in CNS lymphomas. MethodsData collection involved a retrospective review of CNS lymphoma patients from January 2009 to August 2021. Patients who underwent intraoperative consultation were included, excluding those with prior cortisone treatment. The dataset incorporated patient demographics, classification as primary or secondary lymphoma, radiological preliminary diagnoses, FS diagnosis, and permanent section diagnosis. We employed various archived materials, including FSs, touch imprint slides, crush cytology slides, H&E-stained sections, and immunohistochemical stains, and re-evaluated all slides for diagnostic validation. ResultsOur study included 25 patients, of whom 60 % were female and had a mean age of 56.5 years. Preoperative radiology data were available for 80 % of cases, with preliminary diagnoses commonly including lymphoma and/or metastasis. Intraoperative consultation results indicated lymphoma in 18 (72 %) patients, with discordance observed in 28 % of cases when compared to permanent section diagnoses. Most permanent section diagnoses were diffuse large B-cell lymphomas (92 %), with the remainder being T-cell non-Hodgkin lymphoma (4 %) and follicular lymphoma (4 %). Intraoperative misdiagnoses were significantly associated with the absence of knowledge of preoperative imaging. ConclusionOur study demonstrates the reliability of FS diagnosis for CNS lymphomas during surgery, with a favorable complete concordance rate of 72 % when compared to permanent diagnoses. Importantly, lack of knowledge of preoperative imaging significantly impaired diagnostic accuracy in FS, emphasizing the need for close collaboration between pathologists and radiologists.

Diagnostic utility of CSF IL-10:IL-6 ratio in diagnosing primary CNS lymphoma patients- a case series

Diagnostic utility of CSF IL-10:IL-6 ratio in diagnosing primary CNS lymphoma patients- a case series

A Phase I/II Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of BTK Inhibitor HZ-a-018 in Adult Patients with Relapsed and/or Refractory Central Nervous System Lymphoma

Background: HZ-A-018 is a highly selective and potent covalent BTK inhibitor with CNS-penetrating profile, which was previously reported (Abstract 5501, ASH 2022). Phase I/II study is ongoing in China, and here we present preliminary results of HZ-A-018 monotherapy of the phase I part in central nervous system lymphoma. Methods: HZ-A-018-102 is an ongoing phase I/II study (CTR20210181) to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of HZ-A-018 in central nervous system lymphoma. The primary objective for phase I monotherapy was to determine the safety and tolerability and the recommended phase 2 dose (RP2D), and secondary objectives included preliminary antitumor activity and pharmacokinetics in patients with relapsed/refractory primary/secondary CNS lymphoma (R/R PCNSL/SCNSL) and primary vitreoretinal lymphoma (PVRL) who had received ≥1 prior therapy. HZ-A-018 was administered orally once daily in 28-day cycles until disease progression or unacceptable toxicity. Results: At the data cutoff date of 30 May 2023, 21 pts from the phase I monotherapy were analyzed, including 18 R/R PCNSL and 3 R/R SCNSL. 3 pts received 300mg/d, 12 pts received 450mg/d and 6 pts received 600mg/d. 600mg was the highest dose pre-defined in the study and MTD was not reached. Pts were with a median age of 62 years (range: 36-80), median KPS 80 (range: 60-90) and a median of 2 prior systemic therapies (range: 1-5). 20 pts (95.2%) presented with brain parenchyma, and 1 pt (4.8%) presented with intraocular (IO) involvement. All patients had received HD-MTX based chemotherapy, 19 pts (90.5%) had received rituximab and 1 pt had received whole brain radiation therapy (WBRT). 16 of 21 pts (76.2%) experienced a treatment related adverse event (TRAE). The most common TRAEs (≥10%) were thrombocytopenia (42.9%), neutropenia (23.8%), leukopenia (23.8%), and hypokalemia (14.3%), majority of which were grade 1 to 2. DLTs occurred in 1 pt at 450 mg/d and 1 pt at 600 mg/d. 4 pts (19.0%) had dose interruption, no pts had dose reductions, and no pts discontinued from the study due to TRAEs. The plasma and cerebrospinal fluid (CSF) pharmacokinetics showed HZ-A-018 was rapidly absorbed and could cross the blood-brain barrier with CSF HZ-A-018 concentration ranged from 5.94 to 17.5 ng/mL two hours post-dose. Of 19 pts available for tumor assessment (16 PCNSL with brain parenchyma, 1 PCNSL with IO and 2 SCNSL with brain parenchyma) and 2 pts not evaluable (1 PCNSL with brain parenchyma, and 1 SCNSL with brain parenchyma), the overall response rate (ORR) was 52.4% (95%CI: 29.8, 74.3), including 23.8% (5 pts) complete response(CR)/unconfirmed complete response(CRu), 28.6% (6 pts) partial response (PR), and 19.0% (4 pts) stable disease (SD), contributing to an 71.4% (95%CI: 47.8, 88.7) disease control rate (DCR). At 600mg/d, all 6 pts had achieved high and deep responses, contributing to 100% ORR and 50% CRR, with the 3-month duration of response (DOR) rate not reached. Dose expansion was ongoing at 600mg QD. Conclusions: These results demonstrated that HZ-A-018 was efficacious and well-tolerated in CNS lymphoma patients with high CNS penetrating profile. The monotherapy RP2D for R/R PCNSL was determined as 600 mg QD and a phase 2 R/R PCNSL registration study in China is currently planned.

Skeletal Muscle Index, As a Measure of Muscle Mass, Is a Significant Prognostic Factor for Newly Diagnosed Diffuse Large B-Cell Primary CNS Lymphoma Patients

Background: Primary cerebral lymphoma (PCNSL) is a rare subtype of diffuse large B-cell lymphoma (DLBCL) with a particularly poor outcome compared to systemic DLBCL. Several prognostic scores have been developed for PCNSL. These include the International Extranodal Lymphoma Study Group (IELSG) score with five prognostic factors (patient age, serum lactate dehydrogenase [LDH] level, Eastern Cooperative Oncology Group performance status [PS], deep brain involvement and cerebrospinal fluid [CSF] protein level), and the Memorial Sloan-Kettering Cancer Center (MSKCC) score, which is based on age and the Karnofsky Performance Score (KPS). However, the reproducibility of these two scoring systems is low, and the IESLG score requires CSF protein and LDH levels evaluation, which are not often available. None of these scores incorporate data on nutritional status, in particular albumin, which has been shown to be an important prognostic factor in systemic DLBCL. In addition, a recent study demonstrated that the muscle density and mass determined by imaging segmentation, were strong prognostic factors for newly diagnosed systemic DLBCL patients (Jullien et al. Cancers 2021). Our aim was to determine whether these imaging data were also predictive factors for outcome in newly diagnosed diffuse large B-cell PCNSL patients. Methods: For each patient included in the study, muscle mass and density were estimated using skeletal muscle index (SMI) and mean skeletal muscle radiation attenuation (SMRA), respectively. SMI and SMRA were computed at L3 level using the whole-body scan (WBS) performed at the diagnosis of PCNSL, by the mean of an automated segmenting algorithm. Muscle characteristics were then classified as normal or low using already validated cut-off according to patients' age and body mass index (Westenberg et al. Sci Rep 2023). Patients' outcomes were then compared based on their muscle quality, albumin level at diagnosis and other clinical variables commonly included in PCNSL prognostic scores. Results: Between 2015 and 2022, 98 consecutive diffuse large B-cell PCNSL patients were newly diagnosed at Hematology Department of Hospital Lyon Sud, France. Among them, 77 had WBS at diagnosis with available data for this study. The median age was 69 years (range 24-87) and 22 patients (29%) presented an altered ECOG PS (PS 3-4 score). All patients were treated with first-line high-dose methotrexate-based chemotherapy in combination with rituximab. SMI was normal in 64 patients (83%) and 17 patients (17%) had low SMI. Patients with low SMI had more frequently an altered PS (p=0.07) and had lower albumin level (mean 36.7 g/L vs 32.0 g/L, p=0.007). SMRA was normal in 30 patients (39%) and 47 patients (61%) had low SMRA. Patients with low SMRA were older (60 vs 70 years old, p=0.001). In univariate analysis, patients with low SMI had worse outcome with significantly shorter overall survival (p=0.002, median OS, 21.4 months vs not reached) and a trend towards shorter event-free survival (p=0.055, median EFS, 11.9 months vs 42.3 months, Figure 1). No significant prognostic difference was seen for SMRA for EFS or OS. The multivariate analysis showed that SMI (Hazard ratio [HR]=3.33, 95% confidence interval [95%CI]= 1.21-9.20, p=0.02) and age (HR =1.86, 95%CI =1.15-3.0, p=0.012) were strongly associated with OS but not tumor localization (HR =1.46, 95%CI =0.60-3.55, p=0.4), PS (HR = 1.54, 95%CI =0.65-3.65, p=0.32) and albumin level (HR =1.05, 95%CI =0.47-2.32, p=0.91). Age was significantly associated with EFS (HR=1.4, p = 0.04) with a more limited association of SMI with EFS (HR=2.03, p=0.095). In exploratory subgroup analyses, we showed that SMI still influenced OS in patients with PS 4 (10 months vs not reached, p= 0.002), suggesting that SMI may be a more appropriate prognostic factor than PS, especially for patients with motor deficit for whom PS is difficult to estimate. Conclusions: This retrospective analysis of newly diagnosed PCNSL patients showed a significant association between decreased muscle mass, measured by SMI and overall survival, after controlling for other prognostic variables. These findings warrant confirmative analyses to explore the relationship between muscle mass/density and diffuse large B-cell PCNSL patient's outcome and integrate SMI in PCNSL prognostic scores.

Trial in Progress: A Phase I/II Study of Tafasitamab Plus Lenalidomide in Patients with Relapsed CNS Lymphoma

Background and Significance The development of novel, more effective biological strategies to prevent secondary CNS lymphoma (CNSL) and to treat primary and secondary CNSL would have significant impact. It is well established that the CD19 transmembrane glycoprotein is expressed by B-cells throughout differentiation, by the majority of B cell malignancies, and by follicular dendritic cells. Given the high incidence of neurotoxicity associated with blood-brain barrier disruption with CD19-directed CAR-T cells and bi-specific T-cell engager antibodies, Parker et al. recently investigated the possibility of CD19 expression by previously unrecognized cell population(s) in the brain. Single-cell RNA sequencing data demonstrated CD19 expression in brain mural cells, an integral component of the neurovascular unit that regulates integrity of the blood-brain barrier.(Cell, 2020; 183:126-42). Given these observations and the compelling problem of relapsed primary and secondary CNS lymphoma, we are evaluating tafasitamab, an anti-CD19 humanized monoclonal antibody, as a novel therapeutic for refractory CNS lymphomas. We hypothesize that tafasitamab may modulate blood-brain barrier integrity by perturbation of CD19 expressed on mural cells; but without recruitment of cytotoxic T cells and resultant cytokine release syndrome. Our rationale is supported by the Phase II L-MIND study, in which tafasitamab plus lenalidomide exhibited synergistic efficacy against relapsed/refractory aggressive non-Hodgkin lymphoma, with overall response rate of 60%, complete response rate of 43%, and a favorable toxicity profile compared to CAR-T without neurotoxicity. Notably, the L-MIND trial excluded patients previously treated with immunomodulatory drugs as well as CNS lymphoma. (Lancet Oncology 2020: 21:978-88). We also recently reported that tafasitamab plus lenalidomide induced brain parenchymal regressions in two consecutive CNS lymphoma patients with disease refractory to lenalidomide, pomalidomide and rituximab. (British Journal of Haematology 2023 201(1):154-157). Study Design and Methods This single-arm, open-label, multicenter Phase I/II study (NCT05351593) assesses safety, CNS pharmacokinetics and preliminary efficacy of tafasitamab plus lenalidomide in patients with relapsed primary and secondary CNSL. The Phase I portion of the study will determine tolerated dose (MTD) and recommended Phase II dose (RP2D) of lenalidomide in combination with tafasitamab. We are applying 3+3 dose escalation rules to examine lenalidomide 10mg, 15mg and 20 mg plus tafasitamab at 12 mg/kg. After the RP2D is identified, the Phase II portion of the study will begin. The primary objective of the Phase II expansion is to evaluate the clinical benefit rate (stable disease or better) via Simon's minimax two-stage design. Exploratory endpoints include assessment of effect of tafasitamab on blood-brain barrier permeability, correlation of the relationships between tumor response or resistance with tumor mutational profile, and changes in CSF and blood immune cell phenotypes. The study plans to enroll up to 35 patients. Eligibility mandates age ≥ 18 years, anticipated survival >2 months, ECOG PS 0-1, and receipt of at least one prior systemic therapy. Patients with prior exposure to lenalidomide or pomalidomide or concomitant systemic lymphoma are allowed. Patients with HIV infection, CNS PTLD, and those who previously received a CD19-targeting CAR-T product are ineligible. The study is currently enrolling at the University of California San Francisco, with plans to expand enrollment to other institutions within the United States.

QLTI-13. RETROSPECTIVE REVIEW OF THE DIAGNOSTIC YIELD OF CEREBROSPINAL FLUID (CSF) ANALYSIS IN DIAGNOSIS OF CENTRAL NERVOUS SYSTEM (CNS) LYMPHOMA IN A COMMUNITY NEURO ONCOLOGY CENTER

Abstract Central nervous system (CNS) lymphoma can be a challenging disease to diagnose. Both primary and secondary CNS lymphoma often result in poor outcomes rendering early diagnosis and treatment essential. Traditionally, diagnostic modalities include surgery, cerebral spinal fluid (CSF) cytologic analysis, vitrectomy, and chorioretinal biopsy. Radiographic and clinical presentation can widely vary between patients, further enhancing diagnostic dilemma. We present a retrospective study from a community neuro oncology center analyzing the utility of CSF analysis in the diagnosis of CNS lymphoma. Between 2018-2022, 26 CNS lymphoma patients were identified of which 22 (85%) were primary CNS lymphoma patients. Median age of diagnosis was 68.5 years, and 21 (81%) of the patients were immunocompetent. 13 (50%) of the patients underwent CSF analysis, including cytology and flow cytometry), prior to biopsy and none (0%) yielded a positive diagnosis of CNS lymphoma. While mean CSF volume for cytology was slightly more than 3 cc of fluid, patients who had 5-10 cc of fluid sent for cytology also yielded a negative result for CNS lymphoma. For all patients, median duration from presentation of symptoms to surgery was 10.5 days. However, when divided between patients who proceeded straight to biopsy (CSFsecond) versus those who underwent CSF analysis prior to biopsy (CSFfirst), the duration from presentation of symptoms to surgery was 6 days versus 11 days, respectively. 10 patients in the CSFfirst group were not on steroids at the time of lumbar puncture whereas only 4 patients in the CSFsecond group were not on steroids at time of biopsy suggesting that steroid use did not seem to influence the yield of either diagnostic modalities. Our experience suggests that CSF analysis in community settings should be reserved only for staging and that surgical biopsy should be pursued as soon as the diagnosis of CNS lymphoma is considered.

Age-adjusted high-dose chemotherapy followed by autologous stem cell transplantation or conventional chemotherapy with R-MP as first-line treatment in elderly primary CNS lymphoma patients – the randomized phase III PRIMA-CNS trial

BackgroundOlder primary central nervous system lymphoma (PCNSL) patients have an inferior prognosis compared to younger patients because available evidence on best treatment is scarce and treatment delivery is challenging due to comorbidities and reduced performance status. High-dose chemotherapy and autologous stem cell transplantation (HCT-ASCT) after high-dose methotrexate (MTX)-based immuno-chemotherapy has become an increasingly used treatment approach in eligible elderly PCNSL patients with promising feasibility and efficacy, but has not been compared with conventional chemotherapy approaches. In addition, eligibility for HCT-ASCT in elderly PCNSL is not well defined. Geriatric assessment (GA) may be helpful in selecting patients for the best individual treatment choice, but no standardized GA exists to date. A randomized controlled trial, incorporating a GA and comparing age-adapted HCT-ASCT treatment with conventional chemotherapy is needed.MethodsThis open-label, multicenter, randomized phase III trial with two parallel arms will recruit 310 patients with newly diagnosed PCNSL > 65 years of age in 40 centers in Germany and Austria. The primary objective is to demonstrate that intensified chemotherapy followed by consolidating HCT-ASCT is superior to conventional chemotherapy with rituximab, MTX, procarbazine (R-MP) followed by maintenance with procarbazine in terms of progression free survival (PFS). Secondary endpoints include overall survival (OS), event free survival (EFS), (neuro-)toxicity and quality of life (QoL). GA will be conducted at specific time points during the course of the study. All patients will be treated with a pre-phase rituximab-MTX (R-MTX) cycle followed by re-assessment of transplant eligibility. Patients judged transplant eligible will be randomized (1:1). Patients in arm A will be treated with 3 cycles of R-MP followed by maintenance therapy with procarbazine for 6 months. Patients in arm B will be treated with 2 cycles of MARTA (R-MTX/AraC) followed by busulfan- and thiotepa-based HCT-ASCT.DiscussionThe best treatment strategy for elderly PCNSL patients remains unknown. Treatments range from palliative to curative but more toxic therapies, and there is no standardized measure to select patients for the right treatment. This randomized controlled trial will create evidence for the best treatment strategy with the focus on developing a standardized GA to help define eligibility for an intensive treatment approach.Trial registrationGerman clinical trials registry DRKS00024085 registered March 29, 2023.

Association of MTHFR Polymorphisms With Leukoencephalopathy Risk in Patients With Primary CNS Lymphoma Treated With Methotrexate-Based Regimens.

The folate antagonist high-dose methotrexate (HD-MTX) is integral to induction chemotherapy for primary CNS lymphoma (PCNSL); however, it can be associated with leukoencephalopathy. Methylenetetrahydrofolate reductase (MTHFR) is involved in intracellular folate depletion. We assessed whether MTHFR polymorphisms affect the risk of leukoencephalopathy. We retrospectively searched our database at the Massachusetts General Hospital for newly diagnosed PCNSL treated with HD-MTX (without radiotherapy nor intrathecal chemotherapy). Among 68 patients with PCNSL, MTHFR polymorphisms were found in 60 individuals (88.2%) including a 677C→T genotype, a 1298A→C genotype, or a combined 677C→T/1298A→C genotype. Neither MTX clearance nor response to induction therapy was affected by specific genotypes, and complete response was achieved in 72.1% of patients by HD-MTX-based induction. However, the 1298A→C genotype was associated with increased frequency and severity of leukoencephalopathy over time (odds ratio 4.0, CI 1.5-11.4). Such genotype predicted treatment-induced leukoencephalopathy with a sensitivity of 71.0% and a specificity of 62.2% (area under the curve 0.67, CI 0.5-0.8; p = 0.019). While progression-free survival did not differ in genotype-based subgroups, overall survival was lower for the 1298A→C genotype. The MTHFR 1298A→C genotype may serve to identify patients with PCNSL at elevated risk of HD-MTX-induced leukoencephalopathy. This seems to translate into reduced survival, potentially due to decreased functional status.

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

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

OC-0439 Consolidation patterns and associated outcomes for a large cohort of primary CNS lymphoma patients

OC-0439 Consolidation patterns and associated outcomes for a large cohort of primary CNS lymphoma patients

EBV-positive PCNSL in older patients: incidence, characteristics, tumor pathology, and outcomes across a large multicenter cohort

The objective of this multicenter retrospective study was to examine the incidence, patient characteristics, pathology, and outcomes associated with Epstein-Barr virus (EBV)-related CNS lymphoma (CNSL) in older patients. Among 309 CNSL patients aged ≥60, 11.7% had EBV + tumors of which 72.2% were solid organ transplant (SOT)-related post-transplant lymphoproliferative disorders (PTLD). Younger age, SOT or autoimmune disease, and immunosuppressive treatment correlated highly with EBV-positivity. EBV + tumors were associated with absent C-MYC and BCL6 expression. EBV + PTLD was more likely to be associated with the absence of CD5 expression. EBV + non-PTLD had better median OS (not reached) compared to EBV + PTLD (10.8 months) and EBV-negative patients (43 months). Multivariable Cox regression analysis showed that age, performance status, and PTLD were negative predictors of OS. EBV status and immunosuppressive treatment were not correlated with OS. Our findings merit further investigation of EBV + PCNSL tumors and EBV-directed therapies.

Radiomics-Based Machine Learning Model for Predicting Overall and Progression-Free Survival in Rare Cancer: A Case Study for Primary CNS Lymphoma Patients

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.

522 - Methotrexate-Based Induction Regimen Followed By Autologous Stem Cell Transplantation Provided Survival Advantage to Primary CNS Lymphoma Patients Which Is Not Improved Further By Adding Procarbazine in an Ethnically Diverse, Socioeconomically Disadvantaged Cohort in the Real-World Setting

522 - Methotrexate-Based Induction Regimen Followed By Autologous Stem Cell Transplantation Provided Survival Advantage to Primary CNS Lymphoma Patients Which Is Not Improved Further By Adding Procarbazine in an Ethnically Diverse, Socioeconomically Disadvantaged Cohort in the Real-World Setting

High-Dose Chemotherapy and Autologous Stem Cell Transplant in Elderly and Fit Primary CNS Lymphoma Patients - a Multicenter Study By the Cooperative PCNSL Study Group (MARTA study)

Introduction: High-dose methotrexate (HD-MTX) based induction chemo-immunotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (HCT-ASCT) has been shown to be feasible and effective in younger and in selected elderly PCNSL patients. We aimed to investigate this treatment approach in patients > 65 years with newly diagnosed PCNSL in a multicentre study. Methods: This open-label, multicentre, single arm phase II study was conducted at 15 German centres (DRKS 00011932). Main eligibility criteria included newly diagnosed PCNSL, immunocompetence, age > 65 years, Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤ 2, and adequate organ function. Induction treatment consisted of two 21-day cycles of HD-MTX 3.5 g/m² (day 1), cytarabine 2 g/m² twice daily (days 2, 3) and rituximab 375 mg/m² before and after each chemotherapy with stem cell harvest after the 1st cycle. Patients not suffering disease progression subsequently received consolidation treatment with HCT-ASCT with rituximab 375 mg/m² (day -8), busulfan 3.2 mg/kg (days -7, -6), thiotepa 5 mg/kg/d (days -5, -4) and reinfusion of stem cells (day 0). Primary endpoint was progression-free survival (PFS) at 1 year by intention-to-treat (ITT). Secondary endpoints included overall survival (OS), treatment response and toxicities. Results: Between Nov 2017 and Sept 2020, we registered 57 patients. Five patients were excluded because of systemic lymphoma manifestation, absence of measurable radiologic lesion(s), inadequate renal function, ECOG PS >2 and deterioration before the start of study treatment. Finally, 52 eligible patients were included in the ITT population. Mean age was 72 years (range 65-80 years), 27/52 (51.9%) patients initially presented with an ECOG PS > 1. All patients started induction chemo-immunotherapy, 45 of 52 (86.5%) patients completed induction treatment. Thirty-seven of 52 (71.2%) patients proceeded to HCT-ASCT. Most common serious adverse events were infections, renal failure and (cerebro)vascular events, which mainly occurred during induction treatment. Overall, 22 (42.3%) patients died, 12 of whom (23.1%) without evidence of disease progression or relapse. Three (5.8%) patients died because of treatment-related complications, all of them during induction treatment. An additional patient died within 30 days after HCT-ASCT due to fatal viral pneumonia, main other non treatment-related causes of deaths were late infections and (cerebro)vascular events. Forty-one of 52 (78.8%) patients responded to induction treatment; 23 (44.2%) patients achieved a (unconfirmed) complete response and 11 (21.2%) patients a partial response 30 days after HCT-ASCT. After an estimated median follow-up of 23 months, PFS at 12 and 24 months was 57.7% (95% CI 43.2-69.7%) and 54.8% (40-67.4%), respectively; median PFS was 41.1 months (95% CI 6.7 to not calculable). Overall survival at 12 and 24 months was 63.1% (95% CI 48.4-74.7%) and 60.5% (95% CI 45.5-72.5%), respectively; median OS was 41.1 months (95% CI 10.3 to not calculable). Of those 37 patients undergoing HCT-ASCT, 2-year PFS and OS rates were 71.7% (95% CI 53.4-83.8%) and 80.8% (95% CI 63.8-90.3%), respectively. Conclusions: Feasibility and efficacy of HCT-ASCT in selected elderly patients with newly diagnosed PCNSL are confirmed in a multicenter setting with survival rates comparable to those of younger cohorts. Nevertheless, non-relapse mortality remains a major challenge in this vulnerable patient population emphasizing that standardized assessment of eligibility for intensive treatment is of utmost importance. This will be addressed in the upcoming randomized phase III PRIMA-CNS trial (DRKS00022768). Final data analysis is currently ongoing and will be presented in detail at the meeting.

ABCL-161 Reasons for Non-Referral for Autologous Stem Cell Transplantation in Central Nervous System Lymphoma (CNSL) Patients in a Minority-Rich, Multiracial, and Underprivileged Population at Montefiore Medical Center, Albert Einstein College of Medicine

We determined the reasons limiting access to autologous stem cell transplantation (ASCT) in CNS lymphoma patients. Disparities in access to ASCT have been reported but studies analyzing the reasons are sparse. We found only one such study done by Hyun D et al at Grady Memorial hospital where established clinical criteria and poor functional status were the leading causes of non-referral for ASCT. To analyze reasons limiting access to ASCT in CNSL. Retrospective cohort including patients from 06/15/1999-04/05/2022. Tertiary oncologic center. 71 CNSL patients, median age at diagnosis 63 years, Asians 5.7%, Blacks 32.8%, Hispanic 37%, White 12.8%, American Indians 0.1% and Others 10%. 17.1% of the patients were HIV positive. Electronic chart review. 32.8% (23/70) of CNSL patients received ASCT. HIV-positive status was associated with poor ECOG performance status at diagnosis (p=0.03). 47/70 patients were not offered ASCT because 14 (29.7%) had poor baseline functional status at diagnosis, functional status of 5 (10.6%) patients deteriorated after induction therapy, 6 (12.7%) refused ASCT, 3 (6.3%) were non-compliant with treatment, and for 2 (4.2%) patients provider chose different consolidation treatment, 1 died before ASCT could be done and 4 (8.5%) lost to follow-up and unknown reason for 12 (25.5%) patients. HIV-positive status was significantly associated with decreased access to ASCT in the logistic regression model (p=0.01). Majority of HIV-positive patients did not receive ASCT due to poor performance status (41.7%). 62.5% of HIV-positive patients with uncontrolled disease didn't receive ASCT due to poor performance status. Those with controlled HIV refused ASCT (50%) or were not offered ASCT (50%) due to non-compliance. Access to ASCT was not affected by socioeconomic status or race/ethnicity. In our population, ASCT was not offered to patients for medical reasons like poor functional status rather than socioeconomic reasons. However socioeconomic factors could be responsible for poor functional status. HIV status was also a significant factor for limited access to ASCT. Further evaluations are needed to identify modifiable factors that can improve referral and assess the impact of ASCT in CNSL.

Improvements in Quality Control and Library Preparation for Targeted Sequencing Allowed Detection of Potentially Pathogenic Alterations in Circulating Cell-Free DNA Derived from Plasma of Brain Tumor Patients.

Simple SummaryMalignant brain tumors present an enormous challenge due to their genetic heterogeneity, and the difficulties in accessing them impede a precise diagnosis. Numerous genetic alterations have been described, and some of them can assist in personalized therapy for glioma patients. Brain biopsy is an invasive procedure with potentially deleterious complications. Liquid biopsy from a patient’s plasma may provide a less invasive method for diagnosis and personalized therapy selection. We performed targeted next-generation sequencing of tumors and circulating cell-free DNA (ccfDNA) from 84 brain tumor patients. We detected tumor-specific genetic alterations in ccfDNA in 5 out of 80 glioma patients and potentially pathogenic alterations in ccfDNA from the plasma of 29 out of 80 glioma patients. Despite a low efficacy, with further improvements, the detection of genetic alterations in ccfDNA holds promise for noninvasive diagnosis, which may revolutionize personalized therapy for these deadly tumors.Malignant gliomas are the most frequent primary brain tumors in adults. They are genetically heterogenous and invariably recur due to incomplete surgery and therapy resistance. Circulating tumor DNA (ctDNA) is a component of circulating cell-free DNA (ccfDNA) and represents genetic material that originates from the primary tumor or metastasis. Brain tumors are frequently located in the eloquent brain regions, which makes biopsy difficult or impossible due to severe postoperative complications. The analysis of ccfDNA from a patient’s blood presents a plausible and noninvasive alternative. In this study, freshly frozen tumors and corresponding blood samples were collected from 84 brain tumor patients and analyzed by targeted next-generation sequencing (NGS). The cohort included 80 glioma patients, 2 metastatic cancer patients, and 2 primary CNS lymphoma (PCNSL) patients. We compared the pattern of genetic alterations in the tumor DNA (tDNA) with that of ccfDNA. The implemented technical improvements in quality control and library preparation allowed for the detection of ctDNA in 8 out of 84 patients, including 5 out of 80 glioma patients. In 32 out of 84 patients, we found potentially pathogenic genetic alterations in ccfDNA that were not detectable in tDNA. While sequencing ccfDNA from plasma has a low efficacy as a diagnostic tool for glioma patients, we concluded that further improvements in sample processing and library preparation can make liquid biopsy a valuable diagnostic tool for glioma patients.

Outcome and prognostic factors of very old patients with primary CNS lymphoma: a retrospective analysis of patients ≥80 years treated with high-dose methotrexate-based chemotherapy

Although >10% of primary CNS lymphoma (PCNSL) patients are ≥80 years, data on this population are limited. We analyzed 19 consecutive octogenarians with PCNSL treated with high-dose methotrexate (HD-MTX)-based chemotherapy at our institution concerning outcome, prognostic factors and living conditions at six-month follow-up for 11 patients alive and in remission. Seven patients received intracerebroventricular (ICV) treatment additional to systemic therapy. Median follow-up was 27.3 months. Median overall survival was 16.3 months. Positive prognosticators of survival were application of ICV treatment (p = 0.033) and female gender (p = 0.015). All 11 patients alive and in remission at 6-month follow-up were living at home with a median Karnofsky performance score of 60 (range 50–90) and a median instrumental activities of daily living score of 3 (range 1–8). HD-MTX-based polychemotherapy including ICV treatment was feasible in this population, patients in remission needed moderate support in everyday live.

DIPG-21. DIPG cells alter the permeability of the blood-brain barrier in the brainstem leading to treatment failure.

Diffuse Intrinsic Pontine Glioma (DIPG) is an aggressive paediatric high-grade glioma with no effective therapies. The blood-brain barrier (BBB) presents a significant obstacle for delivery of therapeutics into the brain, especially in the brainstem. This study aims to investigate the effect of DIPG cells on the BBB in the brainstem. We hypothesized that the location of DIPG may result in a less permeable BBB than other brain regions. We compared two independent orthotopic models with the same DIPG cells injected in the cortical region or brainstem. We found that treatment with mTOR inhibitor, temsirolimus, significantly extended survival for cortical tumors compared with the same tumor in the brainstem (p=0.0097). Immunohistochemical analysis showed significant reduction of mTOR target, P-p70S6K, in the cortical region compared to brainstem in treated animals, with pharmacokinetic analysis confirming significantly higher temsirolimus levels in the cortical region. These findings suggest that cortical tumors respond better than brainstem tumors, and that a less permeable BBB in brainstem tumors contributes to treatment failure. To understand whether DIPG cells affect the BBB in the brainstem, single-cell RNA sequencing experiments were conducted on vasculature isolated from DIPG and matrigel-injected mice. Gene-ontology overrepresentation analyses identified downregulation in the P38MAPK pathway in endothelial cells from DIPG-injected mice, suggesting the potential for therapeutic manipulation with cytokines. Treatment with SNGR-TNFα, a derivative of an agent successfully used in improving drug penetration in CNS lymphoma patients, in an in vitro BBB/DIPG model significantly reduced transendothelial resistance, and further exploration into the effects on the BBB in vivo is currently being undertaken. Our studies indicate that the intact BBB in the brainstem in DIPG is a major reason for treatment failure, and DIPG cells directly influence the vasculature and response to treatment. This may lead to a novel DIPG treatment strategy and for other brain tumors.

NIMG-68. SARCOPENIA AS MEASURED BY TEMPORALIS MUSCLE WIDTH IS A PREDICTOR OF SURVIVAL IN PRIMARY CNS LYMPHOMA

Abstract Sarcopenia refers to a loss of skeletal muscle mass, which has been associated with increased risk of injury and decreased ability to perform activities of daily living. In multiple cancers including systemic lymphomas, sarcopenia has been strongly associated with survival and may be an important way to risk stratify patients in clinical trials as well as routine practice. Temporalis muscle width has been reported as an indicator of sarcopenia and independent predictor of outcomes in multiple settings including glioblastoma, brain metastases and subarachnoid hemorrhage. We evaluated temporalis width in primary CNS lymphoma (PCNSL) patients at presentation and outcomes. Using an institutional database of immunocompetent PCNSL patients treated at the University of Washington, two independent readers reviewed the initial MRIs for 104 patients who presented from 2011-2021 and measured the width of the temporalis muscle on axial T1 images. Median duration of follow up was 42.2 months (range 0.59-125.9 months). Median age at diagnosis was 65 (range 19-90 years), and patients were 42.8% male, 57.2% female. Interrater variability was acceptable with an average intraclass correlation coefficient of 0.934. Temporalis measurements were normally distributed, with mean 0.79 cm and standard deviation 0.18 cm. We divided patients into two groups, those with temporalis width less than or greater than 1 standard deviation below the mean (absolute value 0.60 cm). Temporalis width was strongly associated with survival among all patients (χ2=15.5, p&amp;lt; 0.001) as well as patients 65 years or older (χ2=4.5, p=0.03). We conclude that sarcopenia as measured by temporalis muscle thickness is associated with survival in PCNSL and may be an important variable to consider in clinical trials and routine practice.

Phase I Dose-Escalation Study of Venetoclax Plus BEAM Followed By Autologous Stem Cell Transplant (ASCT) for Chemoresistant or High-Risk Relapsed/Refractory Non-Hodgkin Lymphoma (NHL)

Phase I Dose-Escalation Study of Venetoclax Plus BEAM Followed By Autologous Stem Cell Transplant (ASCT) for Chemoresistant or High-Risk Relapsed/Refractory Non-Hodgkin Lymphoma (NHL)