Primary Central Nervous System Lymphoma Patients Research Articles

MTHFR polymorphisms and neurotoxicity and overall survival after methotrexate-based therapy in primary CNS lymphoma.

2079 Background: The folate-antagonist methotrexate (HD-MTX) is an integral to induction chemotherapy for primary CNS lymphoma (PCNSL); however, it can be associated with toxicities, including injury to cerebral white matter known as leukoencephalopathy. Methylenetetrahydrofolate Reductase (MTHFR) is involved in intracellular folate metabolism, and MTHFR polymorphisms may affect CNS-specific side effects of HD-MTX. Here, we evaluated the possible association of MTHFR polymorphisms an HD-MTX related CNS toxicity. Methods: We retrospectively searched our institutional database at the Massachusetts General Hospital for newly diagnosed PCNSL patients treated with HD-MTX (without use of radiotherapy or intrathecal chemotherapy). MTHFR polymorphisms were correlated with evolution of leukoencephalopathy over a time period of five years and patient outcomes. ROC curves were generated to estimate the diagnostic ability of specific MTHFR genotypes. Survival was calculated using Kaplan-Meier survival analysis and log-rank test. The significance level was set at p ≤ 0.05. Results: Among 68 PCNSL patients, MTHFR polymorphisms were found in 60 individuals (88.2%; 677C>T: 29 patients, 1298A>C: 18 patients, combined 677C>T & 1298A>C: 13 patients). Neither MTX clearance nor disease response to HD-MTX was affected by specific genotypes, and complete response was achieved in 72.1% of patients by induction with HD-MTX-based therapy. However, the 1298A>C genotype was associated with increased frequency and severity of leukoencephalopathy over time (χ2 = 7.43). Such genotype predicted treatment-induced leukoencephalopathy with a sensitivity of 71.0%% and a specificity of 62.2% (ROC: p = 0.019). While progression-free survival did not differ in genotype-based subgroups, overall survival was significantly lower when the 1298A>C genotype was present. Conclusions: The MTHFR 1298A>C genotype may serve to identify PCNSL patients at elevated risk for HD-MTX-induced leukoencephalopathy. This was associated with reduced overall survival, potentially due to decreased functional status in patients less suitable for aggressive subsequent therapies.

IDENTIFICATION OF GENOMIC BIOMARKERS OF DISEASE PROGRESSION AND SURVIVAL IN NEWLY‐DIAGNOSED PRIMARY CNS LYMPHOMA

Introduction: There is a significant unmet need for robust genomic biomarkers that identify patients with newly-diagnosed primary CNS lymphoma (PCNSL) at high risk of progression, both during standard methotrexate-based induction as well as after dose-intensive consolidation. Methods: We performed targeted next-generation sequencing of 529 cancer genes of formalin-fixed, paraffin-embedded tumors from 74 patients with newly diagnosed primary CNS diffuse large B-cell lymphoma using the UCSF500 Cancer Panel and the Institute for Human Genetics CLIA Laboratory. The assay detects structural variants including single nucleotide variants, small insertions and deletions, and copy-number alterations (CNAs). Sixty-four EBV-negative PCNSL patients treated with a standard methotrexate, temozolomide, rituximab (MTR) induction were available for complete analysis. Results: We identified frequent mutations involving MYD88 (77%), CD79B (41.9%), ETV6 (27%) and BTG1 (25.7%) as well as frequent CNA involving 6q loss (62.5%), 9p loss (34.4%) and 12 gain (31.3%). Three genomic alterations were most significantly associated with early disease progression in PCNSL: (1) Alterations at 6p21.3, predominantly copy neutral loss of heterozygosity (CN-LOH) at the HLA Class I (HLA-A, B, C) and Class II loci (HLA-DR, DP, DQ, TAP1) as well as homozygous deletion of HLA Class II; (2) Mutations of tumor suppressor genes BTG1 and ETV6. Overall, these genomic alterations were detected in 28 out of 31 progression events in the cohort. The subgroup with either CN-LOH or homozygous deletion at 6p had the earliest progression, followed by the subgroup with mutations at either BTG1/ETV6 and no 6p CN-LOH or homozygous deletion, compared to no alterations at these 3 loci. 10 of 18 tumors with these alterations at 6p also contained BTG1 and/or ETV6 mutations. Survival analysis demonstrates that the subgroup with 6p CN-LOH or homozygous deletion had the earliest progression, followed by the subgroup with BTG1/ETV6 mutations compared to no alterations at these 3 loci (PFS p = 3.7e-5, OS p = 0.0017, logrank test, Figure 1). Multivariate Cox proportional hazard analysis demonstrated a significant 3.24-fold increased risk of progression with 6p CN-LOH/homozygous deletion or BTG1/ETV6 mutations (p = 3.5e-5, adjusted by Age, KPS, IELSG, MSKCC, IOL, Maintenance, and Consolidation). The research was funded by: National Cancer Institute NIH R01CA139-83-01A1 Keywords: aggressive B-cell non-Hodgkin lymphoma, diagnostic and prognostic biomarkers, genomics, epigenomics, and other-omics No conflicts of interests pertinent to the abstract.

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

Detecting Double Expression Status in Primary Central Nervous System Lymphoma Using Multiparametric MRI Based Machine Learning.

Double expression lymphoma (DEL) is a subtype of primary central nervous system lymphoma (PCNSL) that often has a poor prognosis. Currently, there are limited noninvasive ways to detect protein expression. To detect DEL in PCNSL using multiparametric MRI-based machine learning. Retrospective. Forty PCNSL patients were enrolled in the study among whom 17 were DEL (9 males and 8 females, 61.29 ± 14.14 years) and 23 were non-DEL (14 males and 9 females, 55.57 ± 14.16 years) with 59 lesions (28 DEL and 31 non-DEL). ADC map derived from DWI (b = 0/1000 s/mm2 ), fast spin echo T2WI, T2FLAIR, and contrast-enhanced T1 weighted imaging (T1CE) were collected at 3.0 T. Two raters manually segmented lesions by ITK-SNAP on ADC, T2WI, T2FLAIR and T1CE. A total of 2234 radiomics features from the tumor segmentation area were extracted. The t-test was conducted to filter the features, and elastic net regression algorithm combined with recursive feature elimination was used to calculate the essential features. Finally, 12 groups with combinations of different sequences were fitted to 6 classifiers, and the optimal models were selected. Continuous variables were assessed by the t-test, while categorical variables were assessed by the non-parametric test. Interclass correlation coefficient tested variables' consistency. Sensitivity, specificity, accuracy F1-score, and area under the curve (AUC) were used to evaluate model performance. DEL status could be identified to varying degrees with 72 models based on radiomics, and model performance could be improved by combining different sequences and classifiers. Both SVMlinear and logistic regression (LR) combined with four sequence group had similar largest AUCmean (0.92 ± 0.09 vs. 0.92 ± 0.05), and SVMlinear was considered as the optimal model in this study since the F1-score of SVMlinear (0.88) was higher than that of LR (0.83). Multiparametric MRI-based machine learning is promising in DEL detection. 4 TECHNICAL EFFICACY STAGE: 2.

Comparison of differing dose levels of methotrexate for patients with primary central nervous system lymphoma.

It has long been established that high-dose methotrexate is an essential part of therapy for primary central nervous system lymphoma. When regimens utilizing high-dose methotrexate were first studied, a dose of 8 g/m2 was used. More recently, reduced dosing strategies have been studied and adopted in attempts to reduce rates of adverse events. Studies utilizing 3.5 g/m2 of methotrexate have shown promising outcomes and improved rates of adverse events but there have never been any randomized head-to-head studies of differing dose levels of high-dose methotrexate. The purpose of this study was to compare efficacy and safety of different dosing strategies of high-dose methotrexate (HD-MTX) for primary central nervous system lymphoma (PCNSL). This single center retrospective review was conducted between 07/01/2013 to 6/3/2020. The patient population was separated into two arms based upon dose of methotrexate. The high intensity (HiHD) arm was defined as patients who received doses > 3.5 g/m2, while the low intensity (LiHD) arm received ≤ 3.5 g/m2. The primary endpoint was overall response rate (ORR) and secondary endpoints include efficacy via 2-year overall survival (OS), progression to transplant, and utilization of consolidation or salvage therapy. Safety was assessed through monitoring of relevant laboratory studies. A total of 92 patients were included in this analysis. Baseline demographics were similar between groups, with the LiHD group trending toward older age. There were 78 patients eligible for assessment for ORR; there was no significant difference between the two groups (42.0% LiHD vs. 44.4% HiHD; p = 1.0). Rates of OS, progression to transplant and progression to consolidation chemotherapy were not different between groups. There were statistically significantly higher rates of renal and/or hepatic dysfunction with the first dose in the HiHD group compared with the LiHD group (11.5% LiHD vs. 64.3% HiHD; p ≤ 0.01). In this PCNSL patient cohort, there is no difference in terms of efficacy between HiHD LiHD methotrexate, but patients in the HiHD group had higher rates of renal and hepatic dysfunction. Limitations include small sample size and disparity between group sizes.

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

Spatial single cell analysis of tumor microenvironment remodeling pattern in primary central nervous system lymphoma

To determine the overall tumor microenvironment (TME), characteristics, and transition mechanisms in primary central nervous system lymphoma (PCNSL), we performed spatial transcriptomics and matched the corresponding single-cell sequencing data of PCNSL patients. We found that tumor cells may achieve a “TME remodeling pattern” through an “immune pressure-sensing model”, in which they could choose to reshape the TME into a barrier environment or a cold environment according to the immune pressure. A key FKBP5+ tumor subgroup was found to be responsible for pushing tumors into the barrier environment, which provides a possible way to evaluate the stage of PCNSL. The specific mechanism of the TME remodeling pattern and the key molecules of the immune pressure-sensing model were identified through the spatial communication analysis. Finally, we discovered the spatial and temporal distributions and variation characteristics of immune checkpoint molecules and CAR-T target molecules in immunotherapy. These data clarified the TME remodeling pattern of PCNSL, provided a reference for its immunotherapy, and provided suggestions for the TME remodeling mechanism of other cancers.

Clues on Optical Coherence Tomography Leading to Diagnosis of Primary CNS Lymphoma (P2-9.012)

<h3>Objective:</h3> NA <h3>Background:</h3> Vitreoretinal lymphoma is a rare variant of primary central nervous system lymphoma (PCNSL). Around 20% of the PCNSL patients develop concurrent ocular involvement in the retina, vitreous, or optic nerve head. However, only 50% of these patients report visual symptoms, thus making a detailed ophthalmic examination a necessity. <h3>Design/Methods:</h3> NA <h3>Results:</h3> A 65-year-old man with history of hypertension and hyperlipidemia, presented with progressive hypersomnia, confusion, intermittent horizontal binocular diplopia, tremors, and blood pressure fluctuations over a course of 9 months. A magnetic resonance imaging of the brain with and without gadolinium contrast showed multifocal confluent cerebral and cerebellar enhancing and non-enhancing white matter abnormalities. Lumbar puncture revealed borderline pleocytosis (WBC 5) with negative cytology. The patient was referred to neuro-ophthalmology to be evaluated for ocular signs that may help with the diagnosis. At that visit, he was noted to have severe vision loss (visual acuity of 7/200) in the left eye that was not noticed by the patient until the time of examination. There was a left relative afferent pupillary defect. Further exam was notable for vitreous cells and yellow retinal placoid deposits. The optic nerve was normal. Optical coherence tomography (OCT) revealed multiple, hyper-reflective foci in the outer layers of the left macula with patchy discontinuity in the ellipsoid and photoreceptor layers. A vitreous biopsy detected CD20+, MYD88+ large B-cell lymphoma, and patient was initiated on systemic chemotherapy. <h3>Conclusions:</h3> High-resolution OCT has enabled physicians to recognize unique features of different neoplasms such as PCNSL. Our case emphasizes the importance of detailed neuro-ophthalmologic examination and utilization of adjunct tests such as OCT in cases of progressive subacute leukoencephalopathy of unknown etiology. This would also lead to use of less invasive diagnostic methods such as vitreous biopsy instead of brain biopsy, earlier diagnosis, and treatment of patients with PCNSL. <b>Disclosure:</b> Dr. Moheb has nothing to disclose. Dr. Olsen has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for American Academy of Ophthalmology. Dr. Olsen has stock in Non-Medical, unrelated. The institution of Dr. Olsen has received research support from National Eye Institute (NEI). The institution of Dr. Olsen has received research support from Novartis. Dr. Olsen has received intellectual property interests from a discovery or technology relating to health care. The institution of Dr. Tobin has received research support from Mallinckrodt. Dr. Tobin has received personal compensation in the range of $500-$4,999 for serving as a Speaker with NeurologyLive. John J. Chen has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for UCB. John J. Chen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. John J. Chen has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Horizon.

Use of rituximab, temozolomide, and radiation in recurrent and refractory primary central nervous system lymphoma in the Philippines: a retrospective analysis (P13-13.006)

<h3>Objective:</h3> This study aimed to present the clinical course and outcomes of patients with recurrent or refractory disease who were given a combination of radiation, temozolomide, and rituximab. <h3>Background:</h3> Refractory disease in primary central nervous system lymphoma (PCNSL) may occur despite adequate initial treatment. There is currently no standard of care for relapsed and recurrent PCSNL. No study to date documents using a combined regimen of radiotherapy, temozolomide, and rituximab. <h3>Design/Methods:</h3> Retrospective analysis was employed to evaluate data from recurrent or refractory PCNSL patients who were treated with radiation, temozolomide, and rituximab in two tertiary hospitals in the Philippines. Baseline demographics, treatment regimen, and outcomes were analyzed. <h3>Results:</h3> Fifteen patients with a median age of 56 years were included, 11 with refractory disease and 4 with recurrent disease. Patients with bulky disease received either whole brain radiotherapy or partial field radiotherapy with rituximab and temozolomide given during radiation and for 6 months after radiation. Overall response rate to salvage therapy was 93.3% (14/15). Median overall survival from initial diagnosis was not reached (median follow-up: 84 months). Mortality rate was 33.3% (5/15), but only 2 out of 5 mortalities were from disease progression. There were only two reported cases of mild allergic reactions to rituximab, which did not result in treatment interruption. <h3>Conclusions:</h3> Rituximab, temozolomide, and radiotherapy can be considered as an effective and safe salvage therapy for relapsed and recurrent central nervous system lymphoma. <b>Disclosure:</b> Dr. Apor has nothing to disclose. Dr. Batara has nothing to disclose. Christianne Mojica has nothing to disclose. Mark Willy Mondia has nothing to disclose.

A single-center, retrospective analysis of relapse and progression patterns of primary central nervous system lymphoma: can whole brain radiotherapy be replaced?

To analyze recurrence and progression patterns of primary central nervous system lymphoma (PCNSL) in patients without whole brain radiotherapy (WBRT) and assess the value of WBRT in PCNSL treatment. This retrospective single-center study included 27 patients with PCNSL, who experienced recurrence/progression after achieving complete remission (CR), partial remission, or stable disease following initial treatments with chemotherapy but without WBRT. The patients were followed up regularly after the treatment for treatment efficacy assessment. By comparing the anatomical location of the lesions on magnetic resonance images (MRI) at the initial diagnosis and at recurrence/progression, we analyzed the patterns of relapse/progression in patients with different treatment responses and different initial status of the lesions. MRI data showed that in 16 (59.26%) of the 27 patients, recurrence/progression occurred in out-field area (outside the simulated clinical target volume [CTV]) but within the simulated WBRT target area in 16 (59.26%) patients, and within the CTV (in-field) in 11 (40.74%) patients. None of the patients had extracranial recurrence of the tumor. Of the 11 patients who achieved CR after the initial treatments, 9 (81.82%) had PCNSL recurrences in the out-field area but within WBRT target area; of the 13 patients with a single lesion at the initial treatment, 11 (84.62%) experienced PCNSL recurrence in the out-field area but within WBRT target area. Systemic therapy combined with WBRT still remains the standard treatment for PCNSL patients, especially those who achieve CR after treatment or have a single initial lesion. Future prospective studies with larger sample sizes are needed to further explore the role of low-dose WBRT in PCNSL treatment.

Older patients with primary central nervous system lymphoma: Survival and prognostication across 20 U.S. cancer centers.

There is a paucity of large-scale data delineating outcomes and prognostication of older patients with primary central nervous system lymphoma (PCNSL). We retrospectively analyzed 539 newly-diagnosed PCNSL patients ages ≥60 years across 20 U.S. academic centers. The median age was 70 years (range 60-88); at least one geriatric syndrome was present in 46%; the median Cumulative Index Ratings Scale-Geriatrics (CIRS-G) score was 6 (range, 0-27); and 36% had impairment in activities of daily living (ADL). The most common induction regimens were high-dose methotrexate (HD-MTX) ± rituximab; methotrexate, temozolomide, rituximab (MTR); and rituximab, methotrexate, procarbazine, vincristine (R-MPV). Overall, 70% of patients achieved remission, with 14% undergoing consolidative autologous stem cell transplant (ASCT) and 24% receiving maintenance. With 58-month median follow-up, median progression-free survival (PFS) and overall survival (OS) were 17 months (95% CI 13-22 months) and 43 months (95% CI 31-56 months), respectively. Three-year PFS and OS were highest with MTR (55% and 74%, respectively). With single-agent methotrexate ± rituximab, 3-year PFS and OS were 30% (p=.0002) and 47% (p=.0072). On multivariate analysis, increasing age at diagnosis and Cooperative Oncology Group (ECOG) performance status (PS) was associated with inferior PFS; age, hypoalbuminemia, higher CIRS-G score, and ECOG PS adversely affected OS. Among patients receiving maintenance, 3-year PFS was 65% versus 45% without maintenance (p=0.02), with 3-year OS of 84% versus 61%, respectively (p=.0003). Altogether, outcomes in older PCNSL patients appeared optimized with HD-MTX combination induction regimens and maintenance therapy. Furthermore, several prognostic factors, including geriatric measures, were associated with inferior outcomes.

Germline genetic variations in methotrexate pathway are associated with pharmacokinetics, outcome, and toxicity in patients with primary central nervous system lymphoma

ABSTRACT Background High-dose methotrexate (HD-MTX)–based regimens are the standard treatment for patients with primary central nervous system lymphoma (PCNSL); however, MTX has extensive interpatient variability in pharmacokinetics and clinical outcomes, with genetic variation an important factor involved in the variability in drug response. Methods 123 PCNSL patients who received 524 courses of chemotherapy were genotyped for 42 single nucleotide polymorphisms in MTX pathway. The relationship between these polymorphisms and the pharmacokinetics, clinical outcomes, and toxicity of MTX was explored using both univariate and multivariate analyses. Results We found ABCB1 rs2032582 and GGH rs2305558 were substantially associated with the pharmacokinetics of MTX. Patients with GGH rs2305558 T and ABCB1 rs2032582 non-G allele had a higher Cmax increased by 20.5%, area under the concentration-time curve (AUC0-48h) increased by 19.6% and lower clearance decreased by 19.6%. ABCB1 rs1045642 and rs2032582 might be independent predictors of progression-free survival. Patients with ABCB1 rs1045642 non-A and rs2032582 G allele correlated with higher progression risk of the disease. Furthermore, ATIC rs3821353 was associated with MTX-induced hepatotoxicity (Grade ≥ 2). Conclusion These variants may serve as biomarkers to predict the pharmacokinetics, clinical outcomes, and hepatotoxicity of MTX and contribute to personalized therapy for PCNSL patients.

Usefulness of Serum Soluble Interleukin-2 Receptor Levels for Differentiating between PCNSL and SCNSL.

Serum soluble interleukin-2 receptor (sIL-2R) is a practical tumor marker that is elevated in hematogenous tumors. The purpose of this study was to determine the usefulness of serum sIL-2R for differentiating among malignant brain tumors, including primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL). This study retrospectively investigated the sIL-2R levels in 130 patients with various types of malignant brain tumors, including PCNSL patients (n = 48) and SCNSL (n = 8); metastatic brain tumors (MTs, n = 16); and glioblastoma (GBM, n = 58). The median sIL-2R level (U/mL) of the PCNSL, SCNSL, MTs, and GBM groups were 489.7, 1024.8, 413.3, and 332.7 respectively. The sIL-2R level was significantly higher in the SCNSL group than in the PCNSL or other groups. The area under the ROC curve generated from the sIL-2R level was 0.826 (sensitivity: 0.875, specificity: 0.667, cutoff value: 521 U/mL) for differentiating SCNSL from PCNSL and 0.685 (sensitivity: 0.667, specificity: 0.707, cutoff value: 342 U/mL) for differentiating PCNSL from GBM. Measurement of sIL-2R level was convenient and useful to differentiate between SCNSL and PCSNL, both of which demand different treatment strategies.

The outcome of ibrutinib-based regimens in relapsed/refractory central nervous system lymphoma and the potential impact of genomic variants.

Relapsed/refractory (r/r) central nervous system lymphoma (CNSL) exhibits aggressive behavior and poor outcomes. As an effective bruton tyrosine kinase (BTK) inhibitor, ibrutinib yields benefits in B-cell malignancies. We aimed to explore the efficacy of ibrutinib in treating r/r CNSL patients, and whether genomic variants impact treatment outcomes. The ibrutinib-based regimens in 12 r/r primary CNSL (PCNSL) and 2 secondary CNSL (SCNSL) patients were analyzed retrospectively. The impact of genetic variants on the effects of treatments was examined using whole-exome sequencing (WES) technology. In PCNSL, the overall response rate was 75%, with median overall survival (OS) not reached (NR) and progression-free survival (PFS) of 4 months. Both SCNSL patients responded to ibrutinib, with median OS NR and PFS of 0.5-1.5 months. Infections were common during ibrutinib therapy (42.86%). The PCNSL patients harboring gene mutations in PIM1, MYD88 and CD79B, and the proximal BCR and nuclear factor kappa B (NF-κB) pathways responded to ibrutinib. Patients who harbored simple genetic variants and those with a low tumor mutation burden (TMB; 2.39-5.56/Mb) responded swiftly and maintained remission for more than 10 months. A patient with a TMB of 11/Mb responded to ibrutinib but continued to experience disease progression. In contrast, patients with complex genomic features, especially extremely high TMB (58.39/Mb), responded poorly to ibrutinib. Our study demonstrates that ibrutinib-based therapy is effective and relatively safe for the treatment of r/r CNSL. Patients with less genomic complexity, especially with regard to TMB, might benefit more from ibrutinib regimens.

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.

Hepatotoxicity from high-dose methotrexate in primary central nervous system lymphoma.

High-dose methotrexate (HDMTX) is a mainstay of primary central nervous system lymphoma (PCNSL) treatment. Transient hepatotoxicity from HDMTX has been characterized in pediatric patients but not in adults. We sought to characterize hepatotoxicity in adult PCNSL patients undergoing HDMTX treatment. Retrospective study of 65 PCNSL patients treated at the University of Virginia from 02/01/2002 to 04/01/2020 was performed. Hepatotoxicity was defined using National Cancer Institute Common Toxicity Criteria (CTC) for adverse events, fifth version. High-grade hepatotoxicity was defined as a bilirubin or aminotransferase CTC grade of 3 or 4. Relationships between clinical factors and hepatotoxicity were assessed with logistic regression. Most patients (90.8%) had a rise of at least one aminotransferase CTC grade during HDMTX treatment. 46.2% had high-grade hepatotoxicity based on aminotransferase CTC grade. No patients developed high-grade bilirubin CTC grades during chemotherapy. Liver enzyme test values decreased to low CTC grade or normal in 93.8% of patients after the conclusion of HDMTX treatment without treatment regimen changes. Prior ALT elevation (P = .0120) was a statistically significant predictor of high-grade hepatotoxicity during treatment. Prior history of hypertension was associated with increased risk of toxic serum methotrexate levels during any cycle (P = .0036). Hepatotoxicity develops in the majority of HDMTX-treated PCNSL patients. Transaminase values decreased to low or normal CTC grades in almost all patients after treatment, without modification of MTX dosage. Prior ALT elevation may predict patients' increased hepatotoxicity risk, and hypertension history may be a risk factor for delayed MTX excretion.

Non-cancer-specific survival in patients with primary central nervous system lymphoma: A multi-center cohort study.

The study aimed to evaluate the non-cancer-specific death risk and identify the risk factors affecting the non-cancer-specific survival (NCSS) in patients with primary central nervous system lymphoma (PCNSL). This multi-center cohort study included 2497 patients with PCNSL in the Surveillance, Epidemiology and End Results (SEER) database from 2007 to 2016, with a mean follow-up of 4.54 years. The non-cancer-specific death risk in patients with PCNSL and primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL) was evaluated using the proportion of deaths, standardized mortality ratio (SMR), and absolute excess risk (AER). Univariate and multivariate competing risk regression models were utilized to identify the risk factors of NCSS. PCNSL was the most frequent cause of death in PCNSL patients (75.03%). Non-cancer-specific causes constituted a non-negligible portion of death (20.61%). Compared with the general population, PCNSL patients had higher risks of death from cardiovascular disease (CVD) (SMR, 2.55; AER, 77.29), Alzheimer's disease (SMR, 2.71; AER, 8.79), respiratory disease (SMR, 2.12; AER, 15.63), and other non-cancer-specific diseases (SMR, 4.12; AER, 83.12). Male sex, Black race, earlier year of diagnosis (2007-2011), being unmarried, and a lack of chemotherapy were risk factors for NCSS in patients with PCNSL and PCNS-DLBCL (all P < 0.05). Non-cancer-specific causes were important competing causes of death in PCNSL patients. More attention is recommended to non-cancer-specific causes of death in the management of PCNSL patients.

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

Pretreatment findings on magnetic resonance imaging in primary central nervous system lymphoma may predict overall survival duration.

and purpose: Primary central nervous system lymphoma (PCNSL) lesions often show avid contrast enhancement on T1-weighted contrast-enhanced MRI sequences. However, several case reports and a clinical study have described PCNSL in patients with no contrast enhancement on MRI. We assessed whether overall survival (OS) time was related to any tumor characteristics (lesion location, volume, and number; contrast enhancement; necrosis; proximity to the subarachnoid space; and edema) on MRI in patients with PCNSL. We retrospectively reviewed records (MRI features, pathology, and survival data) of all patients at our institution with PCNSL who had been seen from, 2007 through 2017, and had undergone pretreatment MRI. We identified 79 patients (42 men, 37 women) with a mean age at diagnosis of 61.7 ± 10.4years. The mean OS duration was 44.6 ± 41.7months. The most common pathological diagnosis (74 patients) was diffuse large B-cell lymphoma. No associations were found between OS time and lesion location, volume, and number; contrast enhancement; necrosis; proximity to the subarachnoid space; or edema. However, a sole patient with non-enhancing PCNSL on MRI was found to have low-grade disease, with prolonged survival (>83months). Several other patients with leptomeningeal disease had a mean OS time of 80 months. Patients with hemorrhagic lesions had a mean OS of 25.5months. The survival time for patients with PCNSL may be longer than previously thought, especially for patients with leptomeningeal seeding and lesions with hemorrhagic components Also, non-enhancing tumors may be less aggressive than enhancing tumors.

Patient Reported and Clinical Outcomes after High-Dose Chemotherapy and Autologous Stem Cell Transplantation in Primary Central Nervous System Lymphoma.

Primary central nervous system lymphomas (PCNSL) are rare and associated with an adverse prognosis. High-dose chemotherapy followed by autologous stem cell transplantation (HDC/ASCT) improves progression free (PFS) and overall survival (OS) but neurocognition, performance status and quality of life (QoL) in patient-reported outcome (PRO) after HDC/ASCT remains underexplored. Especially elderly patients may insufficiently recover from this demanding therapy. Therefore, this single-center analysis investigated all PCNSL patients who received HDC/ASCT at the University Hospital Tübingen from 2006-2021 (n = 40, median age 60.5 years) in a retrospective manner. The 2-year PFS/OS was 78.7%/77.3%, respectively, without significant differences between the tested age-groups (≤60 vs. >60 years, p = 0.531/p = 0.334). Higher Thiotepa dosage was an independent predictor for better OS (p = 0.018). Additionally, a one-time prospective, cross-sectional analysis after HDC/ASCT in the same cohort was performed (n = 31; median follow-up 45 months). Here, the median ECOG improved by HDC/ASCT from 1 to 0 and mini-mental state examinations revealed unimpaired neurocognitive functioning (median 28 pts.). PRO data collected by EORTC QLQ-C30 showed a good QoL in both age groups with an average global health status (GHS) of 68.82% (≤60y: 64.72%, >60y: 74.14%). Together, our data indicate that HDC/ASCT is an effective therapy with respect to disease control, overall health status and quality of life, irrespective of patient age.