scholarly journals Immunotherapeutic early-phase clinical trials and malignant gliomas: a single-center experience and comprehensive immunophenotyping of circulating leukocytes

2021 ◽  
Author(s):  
Matteo Simonelli ◽  
Pasquale Persico ◽  
Arianna Capucetti ◽  
Claudia Carenza ◽  
Sara Franzese ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Promoter Methylation ◽  
Early Phase ◽  
Univariate Analysis ◽  
Malignant Gliomas ◽  
Mgmt Promoter Methylation ◽  
Control Group ◽  
Large Expansion ◽  
Mgmt Promoter ◽  
Early Phase Clinical Trials

Abstract Background Immunotherapeutic early-phase clinical trials (ieCTs) increasingly adopt large expansion cohorts exploring novel agents across different tumor types. High-grade glioma (HGG) patients are usually excluded from these trials. Methods Data of patients with recurrent HGGs treated within multicohort ieCTs between February 2014 and August 2019 (experimental group, EG) at our Phase I Unit were retrospectively reviewed and compared to a matched control group (CG) of patients treated with standard therapies. We retrospectively evaluated clinical, laboratory, and molecular parameters through univariate and multivariate analysis. A prospective characterization of circulating leukocyte subpopulations was performed in the latest twenty patients enrolled in the EG, with a statistical significance cutoff of p <0.1. Results Thirty HGG patients were treated into six ieCTs. Fifteen patients received monotherapies (anti PD-1, anti CSF-1R, anti TGFβ, anti cereblon), fifteen patients combination regimens (anti PD-L1 + anti CD38, anti PD-1 + anti CSF-1R). In the EG, median progression-free survival and overall survival (OS) from treatment initiation were 1.8 and 8.6 months; twelve patients survived more than 12 months, and two of them more than six years. Univariate analysis identified O 6-methylguanine DNA methyltransferase (MGMT) promoter methylation and total protein value at six weeks as significantly correlated with a better outcome. Decreased circulating neutrophils and increased conventional dendritic cells levels lead to significantly better OS. Conclusions A subgroup of EG patients achieved remarkably durable disease control. MGMT promoter methylation identifies patients who benefit more from immunotherapy. Monitoring dynamic changes of innate immune cell populations may help to predict clinical outcomes.

scholarly journals MGMT-Methylation in Non-Neoplastic Diseases of the Central Nervous System

2021 ◽  
Vol 22 (8) ◽  
pp. 3845
Author(s):  
Sarah Teuber-Hanselmann ◽  
Karl Worm ◽  
Nicole Macha ◽  
Andreas Junker
Keyword(s):  
Promoter Methylation ◽  
Dna Methyltransferase ◽  
Alkylating Agents ◽  
Malignant Gliomas ◽  
Mgmt Promoter Methylation ◽  
Demyelinating Diseases ◽  
Brain Diseases ◽  
Tumor Biomarker ◽  
Mgmt Promoter ◽  
First Time

Quantifying O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation plays an essential role in assessing the potential efficacy of alkylating agents in the chemotherapy of malignant gliomas. MGMT promoter methylation is considered to be a characteristic of subgroups of certain malignancies but has also been described in various peripheral inflammatory diseases. However, MGMT promoter methylation levels have not yet been investigated in non-neoplastic brain diseases. This study demonstrates for the first time that one can indeed detect slightly enhanced MGMT promoter methylation in individual cases of inflammatory demyelinating CNS diseases such as multiple sclerosis and progressive multifocal leucencephalopathy (PML), as well as in other demyelinating diseases such as central pontine and exptrapontine myelinolysis, and diseases with myelin damage such as Wallerian degeneration. In this context, we identified a reduction in the expression of the demethylase TET1 as a possible cause for the enhanced MGMT promoter methylation. Hence, we show for the first time that MGMT hypermethylation occurs in chronic diseases that are not strictly associated to distinct pathogens, oncogenic viruses or neoplasms but that lead to damage of the myelin sheath in various ways. While this gives new insights into epigenetic and pathophysiological processes involved in de- and remyelination, which might offer new therapeutic opportunities for demyelinating diseases in the future, it also reduces the specificity of MGMT hypermethylation as a tumor biomarker.

scholarly journals Treatment of recurrent malignant gliomas with fotemustine monotherapy: impact of dose and correlation with MGMT promoter methylation

BMC Cancer ◽  
2009 ◽  
Vol 9 (1) ◽  
Author(s):  
Alessandra Fabi ◽  
Giulio Metro ◽  
Michelangelo Russillo ◽  
Antonello Vidiri ◽  
Carmine Maria Carapella ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Malignant Gliomas ◽  
Mgmt Promoter Methylation ◽  
Mgmt Promoter

Detection of MGMT promoter methylation in malignant gliomas.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. e23131-e23131
Author(s):  
Michelle Afkhami ◽  
Vandana Sharma ◽  
Maria Cuellar ◽  
Massimo D'Apuzzo ◽  
Behnam Badie ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Malignant Gliomas ◽  
Mgmt Promoter Methylation ◽  
Mgmt Promoter

Impact of predictive impact of MGMT promoter methylation in malignant astrocytomas depends on the methylation subgroup.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2013-2013
Author(s):  
Wolfgang Wick ◽  
Tobias Kessler ◽  
Michael Platten ◽  
Christoph Meisner ◽  
Michael Bamberg ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Malignant Gliomas ◽  
Predictive Biomarker ◽  
Copy Number Variations ◽  
Mgmt Promoter Methylation ◽  
Published Data ◽  
Global Methylation ◽  
Methyl Transferase ◽  
Mgmt Promoter

2013 Background: O6-methylguanine DNA-methyl transferase (MGMT) status is predictive for alkylating chemotherapy in most series, but there are non-benefitting subgroups. Despite multiple attempts, MGMT has not been unambiguously established as a predictive biomarker for patients with malignant gliomas. Further, these tumors are to be better classified according to global methylation profiles. Methods: Long-term efficacy data of the NOA-08 trial (NCT01502241) that compared efficacy and safety of radiotherapy (RT, n= 176) to temozolomide (TMZ, n= 193) in patients > 65 years with anaplastic astrocytoma (AA) or GB as well as genome-wide DNA methylation patterns and copy number variations assessed by methylation arrays in a biomarker subset ( n= 104) and an independent cohort ( n= 380) have been used to assess the interaction between MGMT status and methylation subgroups. Results: In the long-term update of NOA-08 patients with MGMT methylated tumors had longer OS and EFS when treated with TMZ (18.4 [13.9-24.4] months and 8.5 [6.9-13.3] months) versus RT (9.6 [6.4-13.7] months and 4.8 [4.3-6.2] months, HR 0.44 [0.27-0.70], p < 0.001 for OS and 0.46 [0.29-0.73], p = 0.001 for EFS). These data compared favorably with recently published data from patients treated with chemoradiation (Perry et al. NEJM 2017). Importantly, only patients with glioblastomas of the methylation class receptor tyrosine kinase II (RTKII) and mesenchymal but not RTK I demonstrated the predictive impact of MGMT in the NOA and the independent validation cohort. Conclusions: MGMT promoter methylation as a strong but methylation subclass-dependent predictive biomarker for the use of alkylating chemotherapy in malignant gliomas. The data call for embedding of MGMT tests into global methylation analyses for all patients with malignant gliomas potentially treated with alkylating chemotherapy.

The prognostic value of MGMT promoter methylation in glioblastoma: A meta-analysis of clinical trials

2017 ◽  
Vol 233 (1) ◽  
pp. 378-386 ◽  
Author(s):  
Maryam Moradi Binabaj ◽  
Afsane Bahrami ◽  
Soodabeh ShahidSales ◽  
Marjan Joodi ◽  
Mona Joudi Mashhad ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Promoter Methylation ◽  
Prognostic Value ◽  
Meta Analysis ◽  
Mgmt Promoter Methylation ◽  
Mgmt Promoter

MGMT promoter methylation in malignant gliomas

2010 ◽  
Vol 5 (3) ◽  
pp. 161-165 ◽  
Author(s):  
Markus J. Riemenschneider ◽  
Monika E. Hegi ◽  
Guido Reifenberger
Keyword(s):  
Promoter Methylation ◽  
Malignant Gliomas ◽  
Mgmt Promoter Methylation ◽  
Mgmt Promoter

scholarly journals MGMT promoter methylation in malignant gliomas: ready for personalized medicine?

2009 ◽  
Vol 6 (1) ◽  
pp. 39-51 ◽  
Author(s):  
Michael Weller ◽  
Roger Stupp ◽  
Guido Reifenberger ◽  
Alba A. Brandes ◽  
Martin J. van den Bent ◽  
...  
Keyword(s):  
Personalized Medicine ◽  
Promoter Methylation ◽  
Malignant Gliomas ◽  
Mgmt Promoter Methylation ◽  
Mgmt Promoter

scholarly journals P05.08 High-grade gliomas and immunotherapeutic early phase clinical trials: a single-center experience

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii35-iii36
Author(s):  
M Simonelli ◽  
P Persico ◽  
A Dipasquale ◽  
E Lorenzi ◽  
L Giordano ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Early Phase ◽  
Univariate Analysis ◽  
Methylation Status ◽  
High Grade ◽  
Clinical Factors ◽  
Lymphocyte Ratio ◽  
High Grade Gliomas ◽  
Early Phase Clinical Trials

Abstract BACKGROUND Patients with high-grade gliomas (HGGs) have historically been excluded from immunotherapeutic early-phase clinical trials (ieCTs) due to unavailability of serial bioptic sampling, the frequent need of corticosteroids, concerns regarding activity of immunotherapy in central nervous system, and rapid clinical deterioration. MATERIAL AND METHODS We retrospectively reviewed data of all recurrent HGG patients enrolled in ieCTs at Humanitas Cancer Center Phase I Unit between 2014 and 2019. Disease control rate (DCR) according to RANO criteria, six-months progression-free and overall survival (PFS-6; OS-6), and treatment-related adverse events (TRAEs), were evaluated. A control-cohort (CC) of patients treated with standard treatments (temozolomide, fotemustine, lomustine and procarbazine, bevacizumab) matched (1:1) for sex, age, line of treatment, MGMT methylation status, and IDH mutational status, was selected for comparison. A series of clinical parameters with an established prognostic value for patients with solid tumors treated into ieCTs were correlated with survivals through an univariate analysis. These include: use of steroids, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, lactate dehydrogenase, albumin, total protein. RESULTS Five among the 23 ieCTs conducted at our Phase I Unit allowed inclusion of HGG patients. 25 patients were enrolled in the experimental cohort (EC): 22 (88%) glioblastoma, 3 (12%) anaplastic astrocytoma. Median age was 50 years (range 25–71); 16 patients (64%) were men, 9 (36%) women; 17 pts (68%) required steroid therapy, with a median baseline dexamethasone dose of 2 mg (range 1–6). The median number of prior systemic therapies was 1 (range 1–2). Twelve patients (48%) received monotherapies (anti PD-1, anti CSFR-1, anti TGF-ß, anti cereblon), 13 (52%) combination regimens (anti PD-L1 + anti CD38, anti PD-1 + anti CSFR-1). DCR was 40% (1 CR + 2 PR + 7 SD) and 37% (9 SD), in EC and CC, respectively. Four patients (16%) in EC had grade ≥3 TRAEs (1 neutropenia, 1 pneumonia, 2 hepatitis). With a median follow-up of 14 months PFS-6 were 35% and 16% (p=0.075), in EC and CC respectively, while OS-6 was significantly improved in the EC (82% vs 44%, p=0.004). In our small series, none of clinical factors resulted prognostic. CONCLUSION Survival outcomes of ourHGG patients treated into ieCTs compared very favorably with a matched CC. Inclusion of HGGs patients into ieCTs should be strongly encouraged. Identification of clinical factors to select who may benefit from ieCTs still remains crucial.

scholarly journals ACT-10 TREATMENT FOR GLIOBLASTOMA RECURRED AFTER CONCOMITANT CHEMORADIATION THERAPY WITH TEMOZOLOMIDE AND THEIR PROGNOSIS

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii14-ii14
Author(s):  
Kanji Mori ◽  
Tomoko Shofuda ◽  
Masayuki Mano ◽  
Yoshinori Kodama ◽  
Manabu Kinoshita ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Performance Status ◽  
Univariate Analysis ◽  
Young Patients ◽  
Clinical Information ◽  
Primary Diagnosis ◽  
Chemoradiation Therapy ◽  
Mgmt Promoter Methylation ◽  
Mgmt Promoter ◽  
Concomitant Chemoradiation

Abstract There are few data about treatment for glioblastoma recurred after concomitant chemoradiation therapy with temozolomide (TMZ). We retrospectively examined treatment and prognosis of recurred glioblastoma patients who registered Kansai molecular diagnosis network for central nervous system tumors, and whose clinical information were available. One hundred and fifty-seven patients that were clinically diagnosed as recurrence between November 2007 and April 2019 were included. Their median age at primary diagnosis was 52 years old and median KPS was 80%. Proportion of methylated MGMT promoter was 43.3% (65 patients), and mutated IDH was 5.4% (8 patients). Median overall survival after recurrence (mSAR) was 8.2 months. One hundred and sixteen patients (73.9%) were received any anticancer treatment and their mSAR was 10.5m. Combination of TMZ and bevacizumab (Bev) were most frequently used for 33 patients, followed by Bev monotherapy for 17 patients, surgery + TMZ + Bev for 15 patients, surgery + TMZ for 12 patients, and TMZ monotherapy for ten. Their mSAR were 8.0m, 7.5m, 10.5m, 13.0m, and 8.0m, respectively. Using univariate analysis, MGMT promoter methylation (p=0.0007), TMZ (p=0.00933), surgery (p=0.0126), re-radiation (p=0.0367), and surgery+TMZ+Bev (p=0.0493) significantly affected prognosis. By multivariate analysis, MGMT promoter methylation, TMZ, and re-radiation were statistically significant (p=0.000138, 0.00161, 0.00403, respectively). These data showed that relatively young patients with good performance status would receive anti-cancer treatment beyond progression and MGMT promoter methylation might be one of prognostic factor for longer survival. In this cohort, re-radiation was performed for few patients and nitrosourea such as nimustine was almost not used. Further study would be needed whether these treatments have any positive effect or not.

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