State of the Art in Low-Grade Glioma Management: Insights From Isocitrate Dehydrogenase and Beyond.

Low-grade gliomas present a formidable challenge in neuro-oncology because of the challenges imposed by the blood-brain barrier, predilection for the young adult population, and propensity for recurrence. In the past two decades, the systematic examination of genomic alterations in adults and children with primary brain tumors has uncovered profound new insights into the pathogenesis of these tumors, resulting in more accurate tumor classification and prognostication. It also identified several common recurrent genomic alterations that now define specific brain tumor subtypes and have provided a new opportunity for molecularly targeted therapeutic intervention. Adult-type diffuse low-grade gliomas are frequently associated with mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2), resulting in production of 2-hydroxyglutarate, an oncometabolite important for tumorigenesis. Recent studies of IDH inhibitors have yielded promising results in patients at early stages of disease with prolonged progression-free survival (PFS) and delayed time to radiation and chemotherapy. Pediatric-type gliomas have high rates of alterations in BRAF, including BRAF V600E point mutations or BRAF-KIAA1549 rearrangements. BRAF inhibitors, often combined with MEK inhibitors, have resulted in radiographic response and improved PFS in these patients. This article reviews emerging approaches to the treatment of low-grade gliomas, including a discussion of targeted therapies and how they integrate with the current treatment modalities of surgical resection, chemotherapy, and radiation.

Bruton's tyrosine kinase (BTK) inhibitors for the treatment of primary central nervous system lymphoma (PCNSL): current progress and latest advances.

The incidence of primary central nervous system lymphoma (PCNSL) has steadily increased, particularly in elderly patients. Although highly responsive to first-line chemotherapy and radiotherapy, approximately 50% of patients relapse or become refractory within 1 year. Prognosis following relapse is dismal and no standard salvage therapy exists. Bruton's tyrosine kinase (BTK), a key regulator of the B-cell receptor (BCR) pathway, has emerged as a promising therapeutic target. The first BTK inhibitor ibrutinib has been evaluated in the relapsed/refractory PCNSL setting, with overall response rates of 51.9%-89.0% and median progression-free survival of 4.6-4.8 months. However, ibrutinib inhibits several kinases in addition to BTK, leading to off-target effects. Second-generation BTK inhibitors have since been developed, which afford greater selectivity for BTK and fewer off-target effects. We review current practices in the diagnosis and evaluation of PCNSL, as well as clinical trials of BTK inhibitors in PCNSL and future developments in PCNSL treatment.

Central Nervous System Lymphoma.

OBJECTIVE: This article reviews the clinical presentation, diagnostic workup, staging, and treatment of primary central nervous system (CNS) lymphoma and common manifestations of secondary CNS lymphoma. LATEST DEVELOPMENTS: Lymphoma can arise in the CNS de novo (primary CNS lymphoma) or as the result of systemic disease (secondary CNS lymphoma). Symptoms may include focal neurologic deficits related to the disease site, cognitive decline, and symptoms of increased intracranial pressure. Standard treatment may differ based on lymphoma subtype and location. A majority of CNS lymphoma is diffuse large B-cell subtype and exhibits aggressive behavior. First-line treatment is generally methotrexate-based polychemotherapy. Response rates to treatment are high, approximately 80% to 90% for primary CNS lymphoma, but relapse is common. Consolidation approaches including myeloablative chemotherapy followed by autologous stem cell rescue, nonmyeloablative chemotherapy, radiation, and medical maintenance regimens reduce rates of relapse. The recent development of targeted agents such as Bruton tyrosine kinase inhibitors and immunomodulatory strategies have shown promise in the treatment of CNS lymphoma. Immunotherapy in the form of checkpoint inhibitors and chimeric antigen receptor T cells is being studied. More indolent forms of lymphoma may be treated with radiation or targeted therapy. ESSENTIAL POINTS: CNS lymphoma is an uncommon but clinically meaningful manifestation of extranodal lymphoma. The diagnosis requires a high level of suspicion for rapid initiation of potentially curative treatment.

Long-term Outcomes in Primary CNS Lymphoma After R-MVP and High-Dose Chemotherapy With Autologous Hematopoietic Stem Cell Transplant.

BACKGROUND AND OBJECTIVES: Primary CNS lymphoma (PCNSL), a rare CNS malignancy, is usually treated with high-dose methotrexate in the first-line setting, typically followed by consolidation therapy. Due to the broad range of currently available treatments for PCNSL, comparability in long-term follow-up studies is limited, and data are scattered across small studies. METHODS: In this study, we report the long-term survival of patients with newly diagnosed immunocompetent PCNSL, enrolled in a phase II trial from June 2005 to September 2011. Patients were treated using rituximab, methotrexate, vincristine, and procarbazine (R-MVP) chemotherapy followed by high-dose chemotherapy (HDC) and autologous stem cell transplant (ASCT) in those with partial or complete response to R-MVP. In a post hoc analysis, clinical and imaging features were evaluated in those still alive. RESULTS: 26 of 32 patients underwent HDC-ASCT consolidation. Of them, 3 patients died of treatment-related toxicity and 2 due to disease progression within 1 year of ASCT. None of the remaining 21 patients had disease progression with a median follow-up of 12.1 years and were included in the analysis. Compared with the post-HDC-ASCT assessment, at the last follow-up, there was no significant difference in the median Karnofsky Performance Status (80 [range: 60-100] vs 90 [range: 70-100]), the median Neurologic Assessment in Neuro-Oncology score (1 [range: 0-4] vs 1 [range: 0-5]), and leukoencephalopathy score (1 [range: 0-3] vs 1 [range: 1-4]). DISCUSSION: Long-term follow-up demonstrated that treatment was well tolerated in most patients enrolled in this study, with stable leukoencephalopathy on imaging and stable clinical performance status. Disease recurrence was not observed beyond 2 years after HDC-ASCT consolidation.

Preclinical and clinical evaluation of Buparlisib (BKM120) in recurrent/refractory Central Nervous System Lymphoma.

Central Nervous System (CNS) Lymphomas are aggressive brain tumors with limited treatment options. Targeting the phosphoinositide 3-kinase (PI3K) pathway yields promising responses across B-cell malignancies, but its therapeutic potential in CNS lymphomas remains unexplored. We present pre-clinical and clinical data on the pan-PI3K inhibitor Buparlisib in CNS lymphomas. In a primary CNS lymphoma-patient-derived cell line, we define the EC50. Four patients with recurrent CNS lymphoma were enrolled in a prospective trial. We evaluated Buparlisib plasma and cerebrospinal fluid pharmacokinetics, clinical outcomes, and adverse events. Treatment was well tolerated. Common toxicities include hyperglycemia, thrombocytopenia, and lymphopenia. The presence of Buparlisib in plasma and CSF was confirmed 2h post-treatment with a median CSF concentration below the EC50 defined in the cell line All four patients were evaluated for response and the median time to progression was 39 days. Buparlisib monotherapy did not lead to meaningful responses and the trial was prematurely stopped.Clinical Trial Registration: NCT02301364.

Is more better? Increased doses of high dose methotrexate and addition of rituximab is associated with improved outcomes in a large primary CNS lymphoma cohort.

Background: Primary central nervous system lymphoma (PCNSL) is a rare and aggressive primary brain tumor. While high dose methotrexate (HDMTX) regimens remain standard of care, it remains unclear if optimization of HDMTX doses and the addition of rituximab provide clinical benefit. Over the last 30 years, standard care given at Memorial Sloan Kettering Cancer Center (MSKCC) has evolved, allowing the comparison of patients receiving different numbers of HDMTX doses and those treated with and without rituximab. The purpose of this study was to describe outcomes based on treatment pattern changes. Methods: This single-center, retrospective, IRB-approved study at MSKCC included patients with immunocompetent PCNSL, age ≥18 years and diagnosed between 1/1983-12/2017. Overall survival (OS) was modeled from date of last HDMTX for analyses associating HDMTX and OS. Multivariable Cox regression models estimated hazard ratios (HR) and corresponding 95% confidence intervals (CI). Results: There were 546 patients identified with newly diagnosed PCNSL. Median overall survival (mOS) of the entire population was 4.7 years (95% CI: 3.8-5.7 years); 3.3 years (95% CI: 2.7-3.9 years) in patients diagnosed prior to 2006 and 8.1 years (95% CI: 6.6-11.1 years) in patients diagnosed 2006 onwards. Patients receiving ≥6 doses of HDMTX had improved survival compared to those receiving <6 doses of HDMTX (mOS: 7.8 vs. 4.3 years; P=0.001). Patients receiving induction rituximab had improved OS compared to those who did not receive rituximab (mOS: 10.5 vs. 3.2 years; P<0.0001). Patients receiving ≥6 doses of HDMTX and rituximab had greatest mOS at 13 years, with a 70% reduction in death (HR =0.30; 95% CI: 0.19-0.47) adjusting for treatment era, sex, and recursive partitioning analysis (RPA) classes comprising age and karnofsky performance score (KPS). Conclusions: OS for PCNSL has improved significantly over the last few decades. Patients seem to benefit with ≥6 doses of HDMTX and the addition of rituximab, an effect independent of treatment era, age, and KPS.

Glioblastoma and Other Primary Brain Malignancies in Adults: A Review.

Importance: Malignant primary brain tumors cause more than 15 000 deaths per year in the United States. The annual incidence of primary malignant brain tumors is approximately 7 per 100 000 individuals and increases with age. Five-year survival is approximately 36%. Observations: Approximately 49% of malignant brain tumors are glioblastomas, and 30% are diffusely infiltrating lower-grade gliomas. Other malignant brain tumors include primary central nervous system (CNS) lymphoma (7%) and malignant forms of ependymomas (3%) and meningiomas (2%). Symptoms of malignant brain tumors include headache (50%), seizures (20%-50%), neurocognitive impairment (30%-40%), and focal neurologic deficits (10%-40%). Magnetic resonance imaging before and after a gadolinium-based contrast agent is the preferred imaging modality for evaluating brain tumors. Diagnosis requires tumor biopsy with consideration of histopathological and molecular characteristics. Treatment varies by tumor type and often includes a combination of surgery, chemotherapy, and radiation. For patients with glioblastoma, the combination of temozolomide with radiotherapy improved survival when compared with radiotherapy alone (2-year survival, 27.2% vs 10.9%; 5-year survival, 9.8% vs 1.9%; hazard ratio [HR], 0.6 [95% CI, 0.5-0.7]; P < .001). In patients with anaplastic oligodendroglial tumors with 1p/19q codeletion, probable 20-year overall survival following radiotherapy without vs with the combination of procarbazine, lomustine, and vincristine was 13.6% vs 37.1% (80 patients; HR, 0.60 [95% CI, 0.35-1.03]; P = .06) in the EORTC 26951 trial and 14.9% vs 37% in the RTOG 9402 trial (125 patients; HR, 0.61 [95% CI, 0.40-0.94]; P = .02). Treatment of primary CNS lymphoma includes high-dose methotrexate-containing regimens, followed by consolidation therapy with myeloablative chemotherapy and autologous stem cell rescue, nonmyeloablative chemotherapy regimens, or whole brain radiation. Conclusions and Relevance: The incidence of primary malignant brain tumors is approximately 7 per 100 000 individuals, and approximately 49% of primary malignant brain tumors are glioblastomas. Most patients die from progressive disease. First-line therapy for glioblastoma is surgery followed by radiation and the alkylating chemotherapeutic agent temozolomide.

Dynamic Mutational Landscape of Cerebrospinal Fluid Circulating Tumor DNA and Predictors of Survival after Proton Craniospinal Irradiation for Leptomeningeal Metastases.

PURPOSE: Proton craniospinal irradiation (pCSI) is a promising treatment for patients with solid tumor leptomeningeal metastasis (LM). We hypothesize that genetic characteristics before and changes resulting after pCSI will reflect clinical response to pCSI. We analyzed the cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) from patients receiving pCSI for LM and explored genetic variations associated with response. EXPERIMENTAL DESIGN: We subjected CSF from 14 patients with LM before and after pCSI to cell-free DNA sequencing using a targeted-sequencing panel. In parallel, plasma ctDNA and primary tumors were subjected to targeted sequencing. Variant allele frequency (VAF) and cancer cell fraction (CCF) were calculated; clonality of observed mutations was determined. Kaplan-Meier analysis was used to associate genomic changes with survival. RESULTS: The median overall survival (OS) for the cohort was 9 months [interquartile range (IQR), 5-21 months]. We showed clonal evolution between tumor and ctDNA of the CSF and plasma with unique mutations identified by compartment. Higher CSF ctDNA mean VAF before pCSI (VAFpre) had worse OS (6 months for VAFpre ≥ 0.32 vs. 9 months for VAFpre < 0.32; P = 0.05). Similarly, increased VAF after pCSI portended worse survival (6 vs. 18 months; P = 0.008). Higher mean CCF of subclonal mutations appearing after pCSI was associated with worse OS (8 vs. 17 months; P = 0.05). CONCLUSIONS: In patients with solid tumor LM undergoing pCSI, we found unique genomic profiles associated with pCSI through CSF ctDNA analyses. Patients with reduced genomic diversity within the leptomeningeal compartment demonstrated improved OS after pCSI suggesting that CSF ctDNA analysis may have use in predicting pCSI response.

Combination Olaparib and Temozolomide for the Treatment of Glioma: A Retrospective Case Series.

OBJECTIVES: To report on the tolerability and efficacy of olaparib with temozolomide (TMZ) for glioma METHODS: Single-center retrospective series of glioma patients treated with olaparib/TMZ September 2018-December 2021 RESULTS: Twenty patients (median age: 42, median Karnofsky Performance Status: 90) received olaparib/TMZ for diagnoses of IDH-mutant oligodendroglioma (n=5), IDH-mutant astrocytoma grade 2-3 (n=4), IDH-mutant astrocytoma grade 4 (n=7), or IDH-wildtype glioma (n=4). One patient was treated upfront and 19 at recurrence (median=3). Olaparib 150mg was administered three times/week concurrent with TMZ 50-75mg/m2 daily. Fatigue, gastrointestinal symptoms, and hematologic toxicity were common. 6/20 patients required dose reduction (n=4) or discontinuation (n=2) due to toxicity. Radiographic response was evaluable in 16 and observed (complete + partial) in 4/8 with IDH-mutant grade 2-3 glioma. No responses were seen in patients with grade 4 IDH-mutant astrocytomas (0/5) or IDH-wildtype gliomas (0/3). Progression-free survival was 7.8, 1.3, and 2.0 months, respectively. DISCUSSION: Olaparib/TMZ resulted in objective radiographic response in 50% of evaluable patients with recurrent IDH-mutant grade 2-3 gliomas with encouraging PFS and manageable toxicity. This supports a prospective trial of olaparib/TMZ for this population. CLASSIFICATION OF EVIDENCE: This case series provides Class IV evidence that treatment with olaparib/TMZ may result in radiographic response in patients with glioma.

Routine use of low-dose glucarpidase following high-dose methotrexate in adult patients with CNS lymphoma: an open-label, multi-center phase I study.

BACKGROUND: High-dose methotrexate (HD-MTX) has broad use in the treatment of central nervous system (CNS) malignancies but confers significant toxicity without inpatient hydration and monitoring. Glucarpidase is a bacterial recombinant enzyme dosed at 50 units (u)/kg, resulting in rapid systemic MTX clearance. The aim of this study was to demonstrate feasibility of low-dose glucarpidase to facilitate MTX clearance in patients with CNS lymphoma (CNSL). METHODS: Eight CNSL patients received HD-MTX 3 or 6 g/m2 and glucarpidase 2000 or 1000u 24 h later. Treatments repeated every 2 weeks up to 8 cycles. RESULTS: Fifty-five treatments were administered. Glucarpidase 2000u yielded > 95% reduction in plasma MTX within 15 min following 33/34 doses (97.1%) and glucarpidase 1000u yielded > 95% reduction following 15/20 doses (75%). Anti-glucarpidase antibodies developed in 4 patients and were associated with MTX rebound. In CSF, glucarpidase was not detected and MTX levels remained cytotoxic after 1 (3299.5 nmol/L, n = 8) and 6 h (1254.7 nmol/L, n = 7). Treatment was safe and well-tolerated. Radiographic responses in 6 of 8 patients (75%) were as expected following MTX-based therapy. CONCLUSIONS: This study demonstrates feasibility of planned-use low-dose glucarpidase for MTX clearance and supports the hypothesis that glucarpidase does not impact MTX efficacy in the CNS. CLINICAL TRIAL REGISTRATION: NCT03684980 (Registration date 26/09/2018).

Primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare extranodal lymphomatous malignancy that affects the brain, spinal cord, leptomeninges, or vitreoretinal space, without evidence of systemic involvement. The diagnosis of PCNSL requires a high level of suspicion because clinical presentation varies depending upon involved structures. Initiation of treatment is time sensitive for optimal neurologic recovery and disease control. In general, the prognosis of PCNSL has improved significantly over the past few decades, largely as a result of the introduction and widespread use of high-dose methotrexate (MTX) chemotherapy, which is considered the backbone of first-line polychemotherapy treatment. Upon completion of MTX-based treatment, a consolidation strategy is often required to prolong duration of response. Consolidation can consist of radiation, maintenance therapy, nonmyeloablative chemotherapy, or myeloablative treatment followed by autologous stem cell transplant. Unfortunately, even with consolidation, relapse is common, and 5-year survival rates stand at only 30% to 40%. Novel insights into the pathophysiology of PCNSL have identified key mechanisms in tumor pathogenesis, including activation of the B-cell receptor pathway, immune evasion, and a suppressed tumor immune microenvironment. These insights have led to the identification of novel small molecules targeting these aberrant pathways. The Bruton tyrosine kinase inhibitor ibrutinib and immunomodulatory drugs (lenalidomide or pomalidomide) have shown promising clinical response rates for relapsed/refractory PCNSL and are increasingly used for the treatment of recurrent disease. This review provides a discussion of the clinical presentation of PCNSL, the approach to work-up and staging, and an overview of recent advancements in the understanding of the pathophysiology and current treatment strategies for immunocompetent patients.

Update on Novel Therapeutics for Primary CNS Lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare lymphoma isolated to the central nervous system or vitreoretinal space. Standard treatment consists of cytotoxic methotrexate-based chemotherapy, with or without radiation. Despite high rates of response, relapse is common, highlighting the need for novel therapeutic approaches. Recent advances in the understanding of PCNSL have elucidated mechanisms of pathogenesis and resistance including activation of the B-cell receptor and mammalian target of rapamycin pathways. Novel treatment strategies such as the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, phosphatidylinositol-3 kinase (PI3K) inhibitors, and immunomodulatory drugs are promising. Increasingly, evidence suggests immune evasion plays a role in PCNSL pathogenesis and several immunotherapeutic strategies including checkpoint inhibition and targeted chimeric antigen receptor T (CAR-T) cells are under investigation. This review provides a discussion on the challenges in development of targeted therapeutic strategies, an update on recent treatment advances, and offers a look toward ongoing clinical studies.

DNA Repair Mechanisms and Therapeutic Targets in Glioma.

PURPOSE OF REVIEW: This review discusses current and investigative strategies for targeting DNA repair in the management of glioma. RECENT FINDINGS: Recent strategies in glioma treatment rely on the production of overwhelming DNA damage and inhibition of repair mechanisms, resulting in lethal cytotoxicity. Many strategies are effective in preclinical glioma models while clinical feasibility remains under investigation. The presence of glioma biomarkers, including IDH mutation and/or MGMT promoter methylation, may confer particular susceptibility to DNA damage and inhibition of repair. These biomarkers have been adopted as eligibility criteria in the design of multiple ongoing clinical trials. Targeting DNA repair mechanisms with novel agents or therapeutic combinations is a promising approach to the treatment of glioma. Further investigations are underway to optimize this approach in the clinical setting.

Prognostic value of [18F]FDG PET/CT in patients with CNS lymphoma receiving ibrutinib-based therapies.

PURPOSE: Current clinical and imaging tools remain suboptimal for predicting treatment response and prognosis in CNS lymphomas. We investigated the prognostic value of baseline [18F]FDG PET in patients with CNS lymphoma receiving ibrutinib-based treatments. METHODS: Fifty-three patients enrolled in a prospective clinical trial and underwent brain PET before receiving single-agent ibrutinib or ibrutinib in combination with methotrexate with or without rituximab. [18F]FDG uptake in these lesions was quantified by drawing PET volumes of interest around up to five [18F]FDG-avid lesions per patient (with uptake greater than surrounding brain). We measured standardized uptake values (SUVmax), metabolic tumor volumes, total lesion glycolysis (TLG), and the sum thereof in these lesions. We analyzed the relationship between PET parameters and mutation status, overall response rates, and progression-free survival (PFS). RESULTS: Thirty-eight patients underwent single-agent therapy and 15 received combination therapy. On PET, 15/53 patients had no measurable disease. In the other 38 patients, a total of 71 lesions were identified on PET. High-intensity [18F]FDG uptake and a larger volume of [18F]FDG-avid disease were inversely related to treatment outcome (p ≤ 0.005). In univariable analysis, PFS was linearly correlated with all PET parameters, with stronger association when sum-values were used. A multivariable model showed that risk of progression increased by 9% for every 5-unit increase in sumSUVmax (hazard ratio = 1.09 [95% CI: 1.04 to 1.14]). CONCLUSION: Higher lesional metabolic parameters are inversely related to outcome in patients undergoing ibrutinib-based therapies, and sumSUVmax emerged as a strong independent prognostic factor. TRIAL REGISTRATION: NCT02315326; https://clinicaltrials.gov/ct2/show/NCT02315326?term=NCT02315326&draw=2&rank=1.

Primary central nervous system lymphoma: a narrative review of ongoing clinical trials and goals for future studies.

Primary central nervous system lymphoma (PCNSL) is a rare disease of the brain, spine, cerebrospinal fluid (CSF) and/or vitreoretinal space. PCNSL is chemo and radiosensitive but relapse is common even years after initial treatment. Outside of consensus regarding the use of high-dose methotrexate (HD-MTX) for first line treatment, there is little uniformity in the management of newly diagnosed or relapsed PCNSL. The lack of consensus is driven by a paucity of randomized trials in this disease. Prospective studies are troubled by low enrollment, the lack of a standard induction regimen, and a varied approach to consolidation strategies. Moreover, the PCNSL patient population is heterogeneous and includes a high proportion of elderly or frail patients and consists of patients manifesting disease in varied compartments of the central nervous system (CNS). As a result, current treatment strategies vary widely and are often dictated by physician and institutional preference or regional practice. This review provides an overview of recently completed and ongoing therapeutic studies for patients with newly diagnosed and recurrent or refractory PCNSL. It discusses the existing evidence behind common approaches to induction and consolidation or maintenance regimens as well as the recent data regarding management of recurrent disease. Finally, it highlights the complexity of trial design in this disease and provides a framework for the design of future studies, which are needed to identify patient populations likely to benefit from specific induction, consolidation, or maintenance therapies.

Clinical trial of proton craniospinal irradiation for leptomeningeal metastases.

BACKGROUND: Leptomeningeal metastases (LM) are associated with limited survival and treatment options. While involved-field radiotherapy is effective for local palliation, it lacks durability. We evaluated the toxicities of proton craniospinal irradiation (CSI), a treatment encompassing the entire central nervous system (CNS) compartment, for patients with LM from solid tumors. METHODS: We enrolled patients with LM to receive hypofractionated proton CSI in this phase I prospective trial. The primary endpoint was to describe treatment-related toxicity, with dose-limiting toxicity (DLT) defined as any radiation-related grade 3 non-hematologic toxicity or grade 4 hematologic toxicity according to the Common Terminology Criteria for Adverse Events that occurred during or within 4 weeks of completion of proton CSI. Secondary endpoints included CNS progression-free survival (PFS) and overall survival (OS). RESULTS: We enrolled 24 patients between June 2018 and April 2019. Their median follow-up was 11 months. Twenty patients were evaluable for protocol treatment-related toxicities and 21 for CNS PFS and OS. Two patients in the dose expansion cohort experienced DLTs consisted of grade 4 lymphopenia, grade 4 thrombocytopenia, and/or grade 3 fatigue. All DLTs resolved without medical intervention. The median CNS PFS was 7 months (95% CI: 5-13) and the median OS was 8 months (95% CI: 6 to not reached). Four patients (19%) were progression-free in the CNS for more than 12 months. CONCLUSION: Hypofractionated proton CSI using proton therapy is a safe treatment for patients with LM from solid tumors. We saw durable disease control in some patients.

Central Nervous System Lymphoma: Approach to Diagnosis and Treatment.

Central nervous system lymphoma (CNSL) is a rare form of extranodal non-Hodgkin lymphoma. Central nervous system lymphoma can be primary (isolated to the central nervous space) or secondary in the setting of systemic disease. Treatment of CNSL has improved since the introduction of high-dose methotrexate and aggressive consolidation regimens. However, results after treatment are durable in only half of patients, and long-term survivors may experience late neurotoxicity, impacting quality of life. Given the rarity of this disease, few randomized prospective trials exist. This leaves many questions unanswered regarding optimal first-line and salvage treatments. Recent advances in the knowledge of pathophysiology of CNSL will hopefully help the development of future treatments. This review gives an overview of the epidemiology, pathophysiology, clinical presentation, diagnosis, and treatment of immunocompetent patients with CNSL.

Prognostic and radiographic correlates of a prospectively collected molecularly profiled cohort of IDH1/2-wildtype astrocytomas.

BACKGROUND: In the molecular era, the relevance of tumor grade for prognostication of IDH1/2-wildtype (WT) gliomas has been debated. It has been suggested that histologic grade II and III astrocytomas with molecular features of glioblastoma, IDH1/2-WT have a similar prognosis to glioblastoma and should be considered for the same clinical trials. METHODS: We integrated prospective clinical sequencing from 564 patients with IDH1/2-WT gliomas (26 grade II, 71 grade III and 467 grade IV) with clinical and radiographic data to assess associations between molecular features, grade and outcome. RESULTS: Compared to histologic grade IV IDH1/2-WT astrocytomas, histologic grade II astrocytomas harbor fewer chromosome 7/10 alterations (P = 0.04), EGFR amplifications (P = 0.022) and alterations in cell-cycle effectors (P = 1.9e-11), but a similar frequency of TERT promoter mutations. In contrast, there is no difference in the frequency of these canonical molecular features in histologic grade III vs. IV IDH1/2-WT disease. Progression-free (PFS) and overall survival (OS) for histologic grade II tumors were significantly longer than grade III tumors (P = 0.02 and P = 0.008, respectively), whereas there was no difference in PFS and OS for histologic grade III compared to grade IV tumors. Median PFS for histologic grade II, III and IV tumors was 19, 11 and 9 months, respectively. Median OS for the same tumors was 44, 23 and 23 months, respectively. In histologic grade II and III IDH1/2 WT tumors, gliomatosis is associated with the absence of cell-cycle alterations (P = 0.008) and enriched in grade II features (P = 0.1) and alterations in the PI3K-AKT pathway (P = 0.09). CONCLUSIONS: Grade II histology has genotypic and phenotypic associations with prognostic implications in IDH1/2-WT astrocytomas.

Characterization of MGMT and EGFR protein expression in glioblastoma and association with survival.

PURPOSE: Understanding the molecular landscape of glioblastoma (GBM) is increasingly important in the age of targeted therapy. O-6-Methylguanine-DNA methyltransferase (MGMT) promoter methylation and EGFR amplification are markers that may play a role in prognostication, treatment, and/or clinical trial eligibility. Quantification of MGMT and EGFR protein expression may offer an alternative strategy towards understanding GBM. Here, we quantify baseline expression of MGMT and EGFR protein in newly diagnosed GBM samples using mass spectrometry. We correlate findings with MGMT methylation and EGFR amplification statuses and survival. METHODS: We retrospectively identified adult patients with newly diagnosed resected GBM. MGMT and EGFR protein expression were quantified using a selected reaction monitoring mass spectrometry assay. Protein levels were correlated with MGMT methylation and EGFR amplification and survival data. RESULTS: We found a statistically significant association between MGMT protein expression and promoter methylation status (p = 0.02) as well as between EGFR protein expression and EGFR amplification (p < 0.0001). EGFR protein expression and amplification were more tightly associated than MGMT protein expression and methylation. Only MGMT promoter methylation was statistically significantly associated with progression-free and overall survival. CONCLUSIONS: Unlike EGFR protein expression and EGFR amplification which are strongly associated, only a weak association was seen between MGMT protein expression and promoter methylation. Quantification of MGMT protein expression was inferior to MGMT methylation for prognostication in GBM. Discordance was observed between EGFR amplification and EGFR protein expression; additional study is warranted to determine whether EGFR protein expression is a better biomarker than EGFR amplification for clinical decisions and trial enrollment.