Prognostic Value of CSF IL-10 at Early Assessment of Induction Chemotherapy in Primary CNS Lymphomas: A LOC Network Study.

OBJECTIVES: Despite a high response rate at the first evaluation during induction chemotherapy, the risk of early relapse remains high and unpredictable in primary CNS lymphomas (PCSNLs). We aimed to assess the prognostic value of early IL-10 levels in CSF (e-IL-10) after 2 months of induction chemotherapy. METHODS: We retrospectively selected from the LOC (Lymphomes Oculo-Cérébraux) network database patients with PCSNLs who had complete or partial response at the 2-month evaluation of a high-dose methotrexate-based first-line chemotherapy for whom e-IL-10 was available. RESULTS: Thirty patients (median age: 62 years, brain involvement in 30/30, CSF involvement in 10/30, median baseline CSF IL-10: 27.5 pg/mL) met the selection criteria. e-IL-10 was undetectable in 22 patients and detectable in 8 patients. At the end of induction treatment, 7 of 8 and 4 of 22 of the patients with detectable and undetectable e-IL-10 had experienced progressive disease, respectively (p = 0.001, OR: 26.8, 95% CI 2-1,478). The median progression-free survival times were 5.8 months (95% CI 2.8-8.8) and 28.7 months (95% CI 13.4-43.9) in the groups with detectable and undetectable e-IL-10, respectively (p < 0.001). DISCUSSION: Our results suggest that despite an objective response, the persistence of detectable e-IL-10 is associated with a high risk of early relapse in PCNSL. A closer follow-up of such patients is warranted.

Real-world experience of commercial relmacabtagene autoleucel (relma-cel) for relapsed/refractory central nervous system lymphoma: a multicenter retrospective analysis of patients in China.

BACKGROUND: Relapsed/refractory (R/R) central nervous system lymphomas (CNSLs) are associated with a poor prognosis. Relmacabtagene autoleucel (relma-cel), expressing the same chimeric antigen receptor (CAR) as lisocabtagene maraleucel, with an optimized commercial-ready process developed in China, demonstrated remarkable efficacy and manageable safety in the pivotal RELIANCE study. However, no published data are available on the "real-world" use of relma-cel, especially for patients with CNS involvement. PATIENTS AND METHODS: Retrospective analyses were conducted for commercial relma-cel used in patients with R/R CNSL at 12 clinics. The primary endpoint was to evaluate the proportion of patients who achieved complete response (CR) at 3 months. Secondary endpoints included best complete response (BCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), and the incidence of adverse events. RESULTS: Among the 22 CNSL patients (12 primary CNSLs; 10 secondary CNSLs), the best overall response rate was 90.9% and the BCR rate was 68.2%. With median follow-up of 316 days (range, 55-618 days), the estimated 1-year PFS rate, DOR, and OS rate were 64.4%, 71.5%, and 79.2%, respectively. Significant clinical benefits were observed in patients who were in durable CR or partial response to the most recent prior therapy preleukapheresis and received relma-cel as consolidation therapy (n=8), with 1-year PFS rate of 100.0% versus 41.7% (p=0.02). In addition, in terms of primary endpoint, non-CR at 3 months postinfusion seemed to be predictive of a worse prognosis, with an estimated 1-year PFS of 83.3% versus 37.0% (p=0.03), respectively. CRS occurred in 72.9% of patients (grade 3: 4.5%) and immune effector cell-associated neurotoxicity syndrome in 36.4% of patients (grade 3: 4.5%). With the add-on agent PD-1 inhibitor (tislelizumab) to the ongoing BTKi, significant re-expansions of CAR T-cell were detected by quantitative PCR or flow cytometry after a median of 2 weeks (range, 12-32 days). CONCLUSIONS: This study was the first and largest real-world study of commercial relma-cel for R/R CNSL, demonstrating promising efficacy and acceptable safety. We reaffirmed the benefit of immuno-agents such as BTKi or PD-1 inhibitor on CAR T-cell re-expansion and hypothesized a dual-agent CAR-T related combinatorial therapies, which warrants further validation. Most importantly, we highlighted the earlier use of CAR T-cell therapy as a consolidative therapy for patients sensitive to salvage therapy, which provided an impetus and inspired-future strategy.

The role of upfront lenalidomide maintenance for primary central nervous system lymphoma following first-line methotrexate treatment: A retrospective study.

BACKGROUND: Consolidation therapy improves the duration of response among patients with primary central nervous system lymphoma (PCNSL). Lenalidomide maintenance has shown encouraging results in older patients with PCNSL. Herein, we performed a retrospective, single-center analysis to evaluate the effect of lenalidomide maintenance on the duration of response in patients with newly-diagnosed PCNSL. METHODS: Sixty-nine adult patients with PCNSL who achieved complete remission or partial remission (PR) after induction therapy were enrolled. The median age of patients was 58.0 years. The maintenance group (n = 35) received oral lenalidomide (25 mg/day) for 21 days, every 28 days for 24 months; the observation group did not undergo any further treatment. RESULTS: After a median follow-up of 32.6 months, the maintenance group experienced fewer relapse events. However, the median progression-free survival (PFS) was similar between groups (36.1 vs. 30.6 months; hazard ratio, 0.78; 95% confidence interval, 0.446). Lenalidomide maintenance significantly improved PFS and overall survival (OS) only among patients who experienced PR after induction. The median duration of lenalidomide maintenance was 18 months; lenalidomide was well tolerated and minimally impacted the quality of life. CONCLUSIONS: The present study was the first to evaluate lenalidomide maintenance as a frontline treatment among patients with PCNSL, PFS and OS did not improve, although the safety profile was satisfactory.

Impact of HMGB1 on cancer development and therapeutic insights focused on CNS malignancy.

The present study explores the complex roles of High Mobility Group Box 1 (HMGB1) in the context of cancer development, emphasizing glioblastoma (GBM) and other central nervous system (CNS) cancers. HMGB1, primarily known for its involvement in inflammation and angiogenesis, emerges as a multifaceted player in the tumorigenesis of GBM. The overexpression of HMGB1 correlates with glioma malignancy, influencing key pathways like RAGE/MEK/ERK and RAGE/Rac1. Additionally, HMGB1 secretion is linked to the maintenance of glioma stem cells (GSCs) and contributes to the tumor microenvironment's (TME) vascular leakiness. Henceforth, our review discusses the bidirectional impact of HMGB1, acting as both a promoter of tumor progression and a mediator of anti-tumor immune responses. Notably, HMGB1 exhibits tumor-suppressive roles by inducing apoptosis, limiting cellular proliferation, and enhancing the sensitivity of GBM to therapeutic interventions. This dualistic nature of HMGB1 calls for a nuanced understanding of its implications in GBM pathogenesis, offering potential avenues for more effective and personalized treatment strategies. The findings underscore the need to explore HMGB1 as a prognostic marker, therapeutic target, and a promising tool for stimulating anti-tumor immunity in GBM.

[Clinical study of 15 cases of primary non-immunodeficient central nervous system lymphoma in children].

Clinical data of 15 primary central nervous system lymphoma (PCNSL) children aged ≤18 years admitted to our hospital between May 2013 to May 2023 were retrospectively analyzed. Our goal was to summarize the clinical features of children and investigate the therapeutic effect of a high-dose methotrexate (HD-MTX) based chemotherapy regimen on this disease. The male-to-female ratio was 2.7∶1, and the median age was 7.2 (2.3-16.4) years at diagnosis. The initial clinical symptoms were primarily cranial hypertension, with imaging findings revealing multiple lesions. Pediatric PCNSL with normal immune function has a favorable prognosis with HD-MTX-based chemotherapy. Patients with a stable disease can be treated with minimal or no maintenance. HD-MTX-based chemotherapy remains effective when the disease progresses or recurs after an initial course of non-HD-MTX-based chemotherapy.

Comparative analysis of bevacizumab and LITT for treating radiation necrosis in previously radiated CNS neoplasms: a systematic review and meta-analysis.

PURPOSE: Radiation necrosis (RN) is a local inflammatory reaction that arises in response to radiation injury and may cause significant morbidity. This study aims to evaluate and compare the efficacy of bevacizumab and laser interstitial thermal therapy (LITT) in treating RN in patients with previously radiated central nervous system (CNS) neoplasms. METHODS: PubMed, Cochrane, Scopus, and EMBASE databases were screened. Studies of patients with radiation necrosis from primary or secondary brain tumors were included. Indirect meta-analysis with random-effect modeling was performed to compare clinical and radiological outcomes. RESULTS: Twenty-four studies were included with 210 patients in the bevacizumab group and 337 patients in the LITT group. Bevacizumab demonstrated symptomatic improvement/stability in 87.7% of cases, radiological improvement/stability in 86.2%, and steroid wean-off in 45%. LITT exhibited symptomatic improvement/stability in 71.2%, radiological improvement/stability in 64.7%, and steroid wean-off in 62.4%. Comparative analysis revealed statistically significant differences favoring bevacizumab in symptomatic improvement/stability (p = 0.02), while no significant differences were observed in radiological improvement/stability (p = 0.27) or steroid wean-off (p = 0.90). The rates of adverse reactions were 11.2% for bevacizumab and 14.9% for LITT (p = 0.66), with the majority being grade 2 or lower (72.2% for bevacizumab and 62.5% for LITT). CONCLUSION: Both bevacizumab and LITT exhibited favorable clinical and radiological outcomes in managing RN. Bevacizumab was found to be associated with better symptomatic control compared to LITT. Patient-, diagnosis- and lesion-related factors should be considered when choosing the ideal treatment modality for RN to enhance overall patient outcomes.

A review of natural products and small-molecule therapeutics acting on central nervous system malignancies: Approaches for drug development, targeting pathways, clinical trials, and challenges.

In 2021, the World Health Organization released the fifth edition of the central nervous system (CNS) tumor classification. This classification uses histopathology and molecular pathogenesis to group tumors into more biologically and molecularly defined entities. The prognosis of brain cancer, particularly malignant tumors, has remained poor worldwide, approximately 308,102 new cases of brain and other CNS tumors were diagnosed in the year 2020, with an estimated 251,329 deaths. The cost and time-consuming nature of studies to find new anticancer agents makes it necessary to have well-designed studies. In the present study, the pathways that can be targeted for drug development are discussed in detail. Some of the important cellular origins, signaling, and pathways involved in the efficacy of bioactive molecules against CNS tumorigenesis or progression, as well as prognosis and common approaches for treatment of different types of brain tumors, are reviewed. Moreover, different study tools, including cell lines, in vitro, in vivo, and clinical trial challenges, are discussed. In addition, in this article, natural products as one of the most important sources for finding new chemotherapeutics were reviewed and over 700 reported molecules with efficacy against CNS cancer cells are gathered and classified according to their structure. Based on the clinical trials that have been registered, very few of these natural or semi-synthetic derivatives have been studied in humans. The review can help researchers understand the involved mechanisms and design new goal-oriented studies for drug development against CNS malignancies.

Development of combination therapies with BTK inhibitors and dasatinib to treat CNS-infiltrating E2A-PBX1+/preBCR+ ALL.

ABSTRACT: The t(1;19) translocation, encoding the oncogenic fusion protein E2A (TCF3)-PBX1, is involved in acute lymphoblastic leukemia (ALL) and associated with a pre-B-cell receptor (preBCR+) phenotype. Relapse in patients with E2A-PBX1+ ALL frequently occurs in the central nervous system (CNS). Therefore, there is a medical need for the identification of CNS active regimens for the treatment of E2A-PBX1+/preBCR+ ALL. Using unbiased short hairpin RNA (shRNA) library screening approaches, we identified Bruton tyrosine kinase (BTK) as a key gene involved in both proliferation and dasatinib sensitivity of E2A-PBX1+/preBCR+ ALL. Depletion of BTK by shRNAs resulted in decreased proliferation of dasatinib-treated E2A-PBX1+/preBCR+ cells compared with control-transduced cells. Moreover, the combination of dasatinib with BTK inhibitors (BTKi; ibrutinib, acalabrutinib, or zanubrutinib) significantly decreased E2A-PBX1+/preBCR+ human and murine cell proliferation, reduced phospholipase C gamma 2 (PLCG2) and BTK phosphorylation and total protein levels and increased disease-free survival of mice in secondary transplantation assays, particularly reducing CNS-leukemic infiltration. Hence, dasatinib with ibrutinib reduced pPLCG2 and pBTK in primary ALL patient samples, including E2A-PBX1+ ALLs. In summary, genetic depletion and pharmacological inhibition of BTK increase dasatinib effects in human and mouse with E2A-PBX1+/preBCR+ ALL across most of performed assays, with the combination of dasatinib and BTKi proving effective in reducing CNS infiltration of E2A-PBX1+/preBCR+ ALL cells in vivo.

Clinical outcomes of etoposide and cytarabine as consolidation in elderly patients with primary CNS lymphoma.

BACKGROUND: A consolidation strategy has not been established for transplant-ineligible elderly patients with primary central nervous system lymphoma (PCNSL). In this study, we aimed to retrospectively evaluate the clinical outcomes of etoposide and cytarabine (EA) as consolidation chemotherapy for transplant-ineligible patients with PCNSL following high-dose methotrexate (MTX)-based induction chemotherapy. MATERIALS AND METHODS: Between 2015 and 2021, newly diagnosed transplant-ineligible patients with PCNSL with diffuse large B-cell lymphoma were consecutively enrolled. All enrolled patients were over 60 years old and received EA consolidation after achieving a complete or partial response following induction chemotherapy. RESULTS: Of the 85 patients who achieved a complete or partial response to MTX-based induction chemotherapy, 51 received EA consolidation chemotherapy. Among the 25 (49.0%, 25/51) patients in partial remission before EA consolidation, 56% (n = 14) achieved complete remission after EA consolidation. The median overall survival and progression-free survival were 43 and 13 months, respectively. Hematological toxicities were most common, and all patients experienced grade 4 neutropenia and thrombocytopenia. Forty-eight patients experienced febrile neutropenia during consolidation chemotherapy, and 4 patients died owing to treatment-related complications. CONCLUSION: EA consolidation chemotherapy for transplant-ineligible, elderly patients with PCNSL improved response rates but showed a high relapse rate and short progression-free survival. The incidences of treatment-related mortality caused by hematologic toxicities and severe infections were very high, even after dose modification. Therefore, the use of EA consolidation should be reconsidered in elderly patients with PCNSL.

Repurposing mebendazole against triple-negative breast cancer CNS metastasis.

PURPOSE: Triple-negative breast cancer (TNBC) often metastasizes to the central nervous system (CNS) and has the highest propensity among breast cancer subtypes to develop leptomeningeal disease (LMD). LMD is a spread of cancer into leptomeningeal space that speeds up the disease progression and severely aggravates the prognosis. LMD has limited treatment options. We sought to test whether the common anti-helminthic drug mebendazole (MBZ) may be effective against murine TNBC LMD. METHODS: A small-molecule screen involving TNBC cell lines identified benzimidazoles as potential therapeutic agents for further study. In vitro migration assays were used to evaluate cell migration capacity and the effect of MBZ. For in vivo testing, CNS metastasis was introduced into BALB/c athymic nude mice through internal carotid artery injections of brain-tropic MDA-MB-231-BR or MCF7-BR cells. Tumor growth and spread was monitored by bioluminescence imaging and immunohistochemistry. MBZ was given orally at 50 and 100 mg/kg doses. MBZ bioavailability was assayed by mass spectrometry. RESULTS: Bioinformatic analysis and migration assays revealed higher migratory capacity of TNBC compared to other breast cancer subtypes. MBZ effectively slowed down migration of TNBC cell line MDA-MB-231 and its brain tropic derivative MDA-MB-231-BR. In animal studies, MBZ reduced leptomeningeal spread, and extended survival in brain metastasis model produced by MDA-MB-231-BR cells. MBZ did not have an effect in the non-migratory MCF7-BR model. CONCLUSIONS: We demonstrated that MBZ is a safe and effective oral agent in an animal model of TNBC CNS metastasis. Our findings are concordant with previous efforts involving MBZ and CNS pathology and support the drug's potential utility to slow down leptomeningeal spread.

[Acute myeloid leukemia with central nervous system involvement successfully treated with gilteritinib].

A 69-year-old woman was referred to our hospital due to hyperleukocytosis. We diagnosed acute myeloid leukemia and started induction therapy with the CAG regimen (aclarubicin, cytarabine and filgrastim). However, the patient was refractory to the initial treatment and developed quadriplegia, and a cerebrospinal fluid (CSF) test showed elevated blasts. We then performed intrathecal chemotherapy, and the number of blasts in CSF gradually decreased. But only two cycles of intrathecal therapy were possible due to severe methotrexate-induced mucositis. The leukemia cells had fms-like kinase 3-internal tandem duplication (FLT3-ITD), so we started treatment with oral gilteritinib. The patient then achieved hematological complete remission. Her paralysis was also resolving, and the CSF was clear of blasts for more than 6 months. Some reports show that gilteritinib may penetrate the CNS, and this case also supports the effectiveness of gilteritinib on CNS leukemia.

Bifunctional iRGD-Exo-DOX crosses the blood-brain barrier to target central nervous system lymphoma.

Central nervous system lymphoma (CNSL) is a type of hematological tumor. Treatment of CNSL is difficult due to the existence of the blood-brain barrier (BBB). Here, we used exosomes (Exos), a type of extracellular vesicle, and iRGD to construct a new drug carrier system and use it to load doxorubicin (DOX). The results of in vitro and in vivo experiments showed that the iRGD-Exo-DOX system can efficiently and securely transport DOX through the BBB and target tumor cells. The results suggest that iRGD-Exo-DOX may cross the BBB through brain microvascular endothelial cell-mediated endocytosis. Together, our study indicates an impactful treatment of central nervous system tumors.

A Phase 1 Study of Intravenous EGFR-ErbituxEDVsMIT in Children with Solid or CNS Tumours Expressing Epidermal Growth Factor Receptor.

BACKGROUND: Recurrent or refractory solid and central nervous system (CNS) tumours in paediatric patients have limited treatment options and carry a poor prognosis. The EnGeneIC Dream Vector (EDV) is a novel nanocell designed to deliver cytotoxic medication directly to the tumour. The epidermal growth factor receptor is expressed in several CNS and solid tumours and is the target for bispecific antibodies attached to the EDV. OBJECTIVE: To assess the safety and tolerability of EGFR-Erbitux receptor EnGeneIC Dream Vector with mitoxantrone (EEDVsMit) in children with recurrent / refractory solid or CNS tumours expressing EGFR. PATIENTS AND METHODS: Patients aged 2-21 years with relapsed or refractory CNS and solid tumours, or radiologically diagnosed diffuse intrinsic pontine glioma (DIPG), were treated in this phase I open-label study of single agent EEDVsMit. Thirty-seven patients' tumours were screened for EGFR expression. EEDVsMit was administered twice weekly in the first cycle and weekly thereafter. Standard dose escalation with a rolling 6 design was employed. Dosing commenced at 5 × 108 EEDVsMit per dose and escalated to 5 × 109 EEDVsMit per dose. RESULTS: EGFR expression was detected in 12 (32%) of the paediatric tumours tested. Nine patients were enrolled and treated on the trial, including three patients with diffuse midline glioma. Overall, EEDVsMit was well tolerated, with no dose-limiting toxicities observed. The most common drug-related adverse events were grade 1-2 fever, nausea and vomiting, rash, lymphopaenia, and mildly deranged liver function tests. All patients had disease progression, including one patient who achieved a mixed response as the best response. CONCLUSIONS: EGFR-Erbitux receptor targeted EnGeneIC Dream Vector with mitoxantrone can be safely delivered in paediatric patients aged 2-21 years with solid or CNS tumours harbouring EGFR expression. The discovery of EGFR expression in a high proportion of paediatric gliomas means that EGFR may be useful as a target for other treatment strategies. Targeted therapeutic-loaded EDVs may be worth exploring further for their role in stimulating an anti-tumour immune response. GOV IDENTIFIER: NCT02687386.

Efficiency and tolerance of second-line triple BRAF inhibitor/MEK inhibitor/anti-PD1 combined therapy in BRAF mutated melanoma patients with central nervous system metastases occurring during first-line combined targeted therapy: a real-life survey.

Although current systemic therapies significantly improved the outcome of advanced melanoma, the prognosis of patient with central nervous system (CNS) metastases remains poor especially when clinically symptomatic. We aimed to investigate the efficiency of CNS targets and tolerance of second-line combined anti-PD1/dual-targeted anti-BRAF/anti-MEK therapy implemented in patients with CNS progression after initially efficient first-line combined targeted therapy in patients with BRAF-mutated melanoma in a real-life setting. A monocentric retrospective analysis including all such patients treated from January 2017 to January 2022 was conducted in our tertiary referral center. The response of CNS lesions to second-line triple therapy was assessed through monthly clinical and at least quarterly morphological (according to RECIST criteria) evaluation. Tolerance data were also collected. Seventeen patients were included with a mean follow-up of 2.59 (±2.43) months. Only 1 patient displayed a significant clinical and morphological response. No statistically significant difference was observed between patients receiving or not additional local therapy (mainly radiotherapy) as to response achievement. Immunotherapy was permanently discontinued in 1 patient owing to grade 4 toxicity. Mean PFS and OS after CNS progression were 2.59 and 4.12 months, respectively. In this real-life survey, the subsequent addition of anti-PD1 to combined targeted therapy in melanoma patients with upfront CNS metastases did not result in significant response of CNS targets in most BRAF mutated melanoma patients with secondary CNS progression after initially successful first-line combined targeted therapy.

Treatment outcomes and prognostic factors in patients with driver mutant non-small cell lung cancer and de novo brain metastases.

Central nervous system (CNS) metastases can be seen at a rate of 30% in advanced stages for patients with non-small cell lung cancer (NSCLC). Growing evidence indicates the predictive roles of driver gene mutations in the development of brain metastases (BM) in recent years, meaning that oncogene-driven NSCLC have a high incidence of BM at diagnosis. Today, 3rd generation targeted drugs with high intracranial efficacy, which can cross the blood-brain barrier, have made a positive contribution to survival for these patients with an increased propensity to BM. It is important to update the clinical and pathological factors reflected in the survival with real-life data. A multi-center, retrospective database of 306 patients diagnosed with driver mutant NSCLC and initially presented with BM between between November 2008 and September 2022 were analyzed. The median progression-free survival (mPFS) was 12.25 months (95% CI, 10-14.5). While 254 of the patients received tyrosine kinase inhibitor (TKI), 51 patients received chemotherapy as first line treatment. The median intracranial PFS (iPFS) was 18.5 months (95% CI, 14.8-22.2). The median overall survival (OS) was 29 months (95% CI, 25.2-33.0). It was found that having 3 or less BM and absence of extracranial metastases were significantly associated with better mOS and iPFS. The relationship between the size of BM and survival was found to be non-significant. Among patients with advanced NSCLC with de novo BM carrying a driver mutation, long-term progression-free and overall survival can be achieved with the advent of targeted agents with high CNS efficacy with more conservative and localized radiotherapy modalities.

Osimertinib readministration for central nervous system metastases in non-small cell lung cancer positive for EGFR activating mutations.

BACKGROUND: Osimertinib shows pronounced efficacy for EGFR mutation-positive non-small cell lung cancer (NSCLC) including associated central nervous system (CNS) metastases. Tumors inevitably develop resistance to the drug, however. Osimertinib is sometimes readministered after completion of standard chemotherapy. To clarify which patients might receive benefit from osimertinib readministration, we have retrospectively assessed its efficacy with a focus on CNS metastases. METHODS: A retrospective analysis of medical records was performed for 21 patients who underwent osimertinib readministration at Kyushu University Hospital between March 2016 and April 2023. CNS metastases were evaluated according to modified Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: Among the 21 enrolled patients, 16 individuals had target lesions on the basis of RECIST. One (6.3%) of these 16 patients achieved a partial response to osimertinib readministration, with the remaining 15 patients showing stable or progressive disease. The median overall progression-free survival (PFS) and median overall survival for all 21 patients were 3.8 and 13.9 months, respectively. The efficacy of osimertinib readministration for CNS metastases was evaluable in eight patients including five individuals with leptomeningeal metastases. The objective response rate for CNS metastases and the improvement rate for leptomeningeal metastases were both 100%. The median PFS with regard to CNS or non-CNS lesions for these eight patients was 24.7 and 10.5 months, respectively. CONCLUSIONS: Osimertinib readministration showed limited efficacy for non-CNS lesions but excellent efficacy for CNS metastases, suggesting that such treatment is an option for EGFR-mutated NSCLC patients with CNS metastases.