BIOM-08. DNA METHYLATION-BASED SUBGROUPING PREDICTS SURVIVAL BENEFIT FROM LOMUSTINE/TEMOZOLOMID COMBINATION THERAPY IN MGMT PROMOTOR-METHYLATED GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi11-vi11
Author(s):  
Johannes Weller ◽  
Andreas Waha ◽  
Matthias Schneider ◽  
Clemens Seidel ◽  
Joachim Steinbach ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Overall Survival ◽  
Survival Benefit ◽  
Tumor Tissue ◽  
Newly Diagnosed ◽  
Array Analysis ◽  
Logrank Test ◽  
Methylation Array ◽  
Survival Prolongation ◽  
Temozolomide Chemotherapy

Abstract BACKGROUND The CeTeG/NOA-09 trial showed that lomustine/temozolomide chemotherapy prolongs survival for newly diagnosed MGMT-methylated glioblastoma patients. Previous reports on temozolomide monotherapy suggested, that the survival benefit of temozolomide in MGMT-methylated tumors may be restricted to the RTK II methylation subgroup and absent in RTK I and MES subgroups. To identify patients with a particularly strong benefit from CCNU/TMZ, we explored the association of methylation subgroups with outcome after lomustine/temozolomide therapy. METHODS All patients from the CeTeG/NOA-09 trial with sufficiently available tumor tissue (n = 98) underwent 850K methylation array analysis of their tumor and methylation subgroup annotation (Heidelberg brain tumor methylation classifier v11b4; calibrated score > 0.5 required). Overall survival (OS) was compared between a pooled cohort of tumors of the RTK I/MES subgroups and RTK II tumors. RESULTS In the CCNU/TMZ arm of CeTeG/NOA-09, OS was prolonged in RTK I/MES (n = 16; median not reached, 4-year OS 69%) as compared to RTK II patients (n = 14; median 20.6 months, 4-year OS 23%; p = 0.004 logrank test). In the standard temozolomide arm of CeTeG/NOA-09, OS tended to be shorter in RTK I/MES (n = 7; median 23.7 months, 4-year OS 17%) as compared to RTK II patients (n = 17; median 35.2 months; 4-year OS 38%, p = 0.15). CONCLUSION The CCNU/TMZ-dependent survival prolongation in patients with RTK I/MES tumors as opposed to RTK II seen in CeTeG/NOA-09 suggests that methylation-based subgrouping could be predictive for CCNU/TMZ efficacy in newly diagnosed MGMT-methylated glioblastoma.

scholarly journals DNA methylation array analysis identifies breast cancer associated RPTOR, MGRN1 and RAPSN hypomethylation in peripheral blood DNA

Oncotarget ◽  
2016 ◽  
Vol 7 (39) ◽  
pp. 64191-64202 ◽  
Author(s):  
Qiuqiong Tang ◽  
Tim Holland-Letz ◽  
Alla Slynko ◽  
Katarina Cuk ◽  
Frederik Marme ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Peripheral Blood ◽  
Array Analysis ◽  
Methylation Array ◽  
Dna Methylation Array

Bevacizumab plus radiotherapy for elderly patients with glioblastoma (ARTE).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS2105-TPS2105 ◽  
Author(s):  
Ghazaleh Tabatabai ◽  
Michael Weller
Keyword(s):  
Overall Survival ◽  
Elderly Patients ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Combined Modality Treatment ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Biomarker Analysis ◽  
Radiotherapy Alone ◽  
Temozolomide Chemotherapy

TPS2105 Background: The standard of care for patients with newly diagnosed glioblastomas after surgical resection is radiotherapy with concomitant and adjuvant temozolomide chemotherapy. Yet, inclusion into the pivotal trial was limited to patients up to the age of 70, and subgroup analyses suggested that older patients did not gain benefit from combined modality treatment. Further, the efficacy of radiotherapy has been confirmed in a randomized trial comparing best supportive care versus radiotherapy alone. Of note, hypofractionated radiotherapy is equieffective in patients aged 65-70 years and more. Two randomized trials in elderly patients (NOA-08, Nordic Trial) indicated smilar efficacy of primary temozolomide chemotherapy alone compared with radiotherapy alone. Combined radiochemotherapy is compared with radiotherapy alone in an ongoing NCIC-CTG EORTC TROG Japanese group trial 26062-22061. Thus, radiotherapy alone is the standard of care for newly diagnosed glioblastoma of elderly patients. These clinical data justify the exploration of new, temozolomide-free first-line treatment strategies in elderly patients. Methods: The ARTE trial will therefore investigate bevacizumab when added to a short course of radiotherapy and bevacizumab maintenance therapy until progression. The translational research program shall include blood and urine biomarker analysis and FET-PET in addition to MRI for monitoring the course of the disease. This trial is an explorative randomized, non-comparative phase II trial aiming at recruiting 60 patients in Switzerland. Elderly patients (> 65) will be randomized 2:1 either to the experimental arm (bevacizumab plus radiotherapy) or the standard arm (radiotherapy). The primary endpoint is median overall survival. Secondary endpoints include overall survival at 6 months, overall survival at 12 months, median progression-free survival, progression-free survival at 6 months, median time to treatment failure.

Body mass index (BMI) influence on survival in adult patients with newly diagnosed acute myeloid leukemia (AML)/high-risk MDS: Retrospective study of 130 patients from a single institution.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e18011-e18011
Author(s):  
Mohamed Abdelfatah ◽  
Ali Al-Ameri ◽  
Zeyad Kanaan ◽  
Ahmed Malkawi ◽  
Nairmeen Awad Haller
Keyword(s):  
Body Mass Index ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Median Survival ◽  
Survival Benefit ◽  
Myeloid Leukemia ◽  
Normal Weight ◽  
Adult Patients ◽  
Newly Diagnosed ◽  
Acute Myeloid

e18011 Background: The incidence of obesity is increasing worldwide and is associated with numerous adverse health outcomes. In AML high body mass index (BMI) is associated with increased risk of treatment-related complications; the overall survival in patients with acute myeloid leukemia is inferior, with most studies conducted in the pediatric population. Aim: To evaluate the effect of increasing (BMI) in the overall survival (OS) of adult patients with AML/High risk MDS. Methods: After obtaining IRB approval, all adult patients with AML diagnosed and treated at our institution (2002–2010) were studied. Data collection included patient demographics, laboratory tests, bone marrow biopsies, BMI, and survival information. We classified the AML patients into two groups according to BMI (kg/m2) classification by WHO; normal Weight 18-25 kg/m2, overweight and obese >25 kg/m2. Chi-Square and T-test were used for between group comparisons and Kaplan-Meier test was applied for survival estimates. Results: Adult patients with newly diagnosed AML (n = 130) had a median age of 55 years (range: 19-90), and 43 (56%) patients were older than 75 years. Seventy-two patients (55%) were male and 58 (45%) were female. 45 patients (35%) in total had complex cytogenetics, 20 patients (15%) had AML arise from MDS.Forty-four patients (34%) were considered normal weight; Eighty-six patients (66%) were classified as overweight or obese. Overall median survival was 28 weeks; patients with BMI 18-25 kg/m2 had a 36-week median survival, while patients with BMI <25 kg/m2 had a 25-week median survival (p<0.499). Conclusions: Overall survival was low in the study population; survival in obese and overweight patients (BMI>25) was slightly lower than normal weight group (18-25 kg/m2), although this did not translate into a survival benefit. Future large scale studies may be needed to further define the role of BMI in survival benefit for these patients.

Survival benefit from bevacizumab in newly diagnosed glioblastoma (GBM) according to transcriptional subclasses.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2057-2057 ◽  
Author(s):  
Jason T. Huse ◽  
Kathryn Beal ◽  
Jianan Zhang ◽  
Edward R. Kastenhuber ◽  
Thomas Joseph Kaley ◽  
...  
Keyword(s):  
Overall Survival ◽  
Survival Benefit ◽  
Newly Diagnosed ◽  
Therapeutic Implications ◽  
Invasion Mechanisms ◽  
Formalin Fixed Paraffin ◽  
Bevacizumab Treatment ◽  
Formalin Fixed Paraffin Embedded ◽  
Newly Diagnosed Glioblastoma ◽  
New Treatment

2057 Background: Genome-wide transcriptional studies (TCGA and others) have identified distinct GBM molecular subtypes, but to date this has not translated into prognostic or therapeutic implications. Bevacizumab has emerged as a new treatment option for GBMs, although a survival benefit has yet to be demonstrated in unselected patients (pts). We analyzed outcomes from a prospective phase II trial in newly diagnosed GBM treated with hypofractionated stereotactic radiotherapy (HFSRT) combined with temozolomide and bevacizumab, and correlated with GBM transcriptional subclasses. Methods: Pts with newly diagnosed GBM with tumor volume < 60cc were eligible. Treatment consisted of HFSRT (6x6 Gy to contrast-enhancing tumor and 6x4 Gy to FLAIR hypersignal with dose painting), concomitant with bevacizumab (10 mg/kg Q2 weeks) and temozolomide (75mg/m2 daily), followed by standard adjuvant bevacizumab/ temozolomide. Primary endpoint was 1-y overall survival (OS). To establish TCGA transcriptional subclasses, mRNA from formalin-fixed paraffin-embedded tissue blocks was analyzed with a validated, 151-probe Nanostring gene expression assay. Results: A total of 40 evaluable pts were accrued, achieving a 1-y OS of 90% (95% CI 76-96), 2-y OS of 32% (95%CI 19-47) and median OS of 17.4m. The molecular subclass could be defined in 31 pts, as follows: Mesenchymal: 14 (45%) pts, pro-neural: 8 (26%), classical: 7 (23%), neural: 2 (6%). The pro-neural phenotype was associated with reduced overall survival: median OS of 13.5m vs 21.2m for non pro-neural tumors (univariate: p = 0.015; multivariate: p = 0.003). MGMT promoter methylation did not predict survival (p = 0.13). Conclusions: We provide proof-of-principle that GBM transcriptional classification is biologically and therapeutically relevant, identifying non pro-neural GBMs as the best candidates for bevacizumab treatment. Our findings imply that angiogenesis and tumor invasion mechanisms in proneural tumors may be distinct from other subtypes, and we suggest such pts should not be offered bevacizumab treatment upfront. Future randomized trials focusing on non-proneural tumors may finally demonstrate a survival advantage for bevacizumab in GBM. Clinical trial information: NCT01392209.

Rituximab Does Not Improve Progression Free (PFS) or Overall Survival (OS) in Patients with Limited Stage Diffuse Large B Cell Lymphoma (DLBCL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3755-3755
Author(s):  
Ephraim P. Hochberg ◽  
Nicole Birrer ◽  
Christiana E. Toomey ◽  
Jeffrey A. Barnes ◽  
Alfred Ian Lee ◽  
...  
Keyword(s):  
Overall Survival ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Newly Diagnosed ◽  
Logrank Test ◽  
Limited Stage ◽  
Large B Cell Lymphoma ◽  
The Impact ◽  
Large B Cell

Abstract Abstract 3755 Poster Board III-691 Introduction Diffuse Large B Cell Lymphoma (DLBCL) is the most common lymphoid malignancy accounting for approximately 33% of all newly diagnosed NHLs. Three randomized trials and multiple retrospective analyses have demonstrated both progression-free (PFS) and overall survival (OS) benefit to the addition of the anti-CD20 monoclonal antibody rituximab to anthracycline-containing chemotherapy in older advanced-stage patients, and in young low-risk patients with DLBCL. Approximately half of newly diagnosed patients with DLBCL present in limited stage and the benefit of rituximab containing chemotherapy regimens for these patients remains uncertain. Methods We used an IRB-approved clinicopathologic database, derived from comprehensive tumor registry data at the Massachusetts General Hospital, Dana Farber Cancer Institute and Brigham and Women's Hospital, to identify all patients 18 years or older diagnosed with limited stage DLBCL between 2000 and 2006. We included all patients treated with 3 or more cycles of anthracycline containing chemotherapy with curative intent. We excluded primary DLBCL of the CNS. We determined the impact of the use of rituximab on OS and PFS. PFS and OS were calculated from the date of initial diagnosis. Results A total of 138 patients met eligibility criteria and are included in the analysis. Median age was 51 years (range 18-89 years). 30% of patients were above 60 years of age, and less than 3% had an IPI score of 3 or higher. One hundred and six patients received CHOP + rituximab (RCHOP) and 32 received CHOP alone. Of the 106 patients receiving RCHOP, 48 were irradiated and 58 were not. Of the 32 patients receiving CHOP, 20 received radiation and 12 did not. At a median follow-up of 35 months (range 3-109 months), PFS and OS for the entire cohort are 86.2% and 90.6%, respectively. On univariate analysis of outcome, the addition of rituximab to CHOP did not improve PFS (81.3% vs. 87.7%,p=0.817, Logrank Test) or OS (84.4% vs. 92.5%, p=0.411, Logrank Test). Conclusion The outcome of an unselected series of patients with limited stage DLBCL is excellent. In this retrospective cohort of patients with limited stage DLBCL, the use of rituximab in conjunction with standard chemotherapy did not improve PFS or OS. The results we obtained are very similar to those reported by SWOG (Persky et al. JCO 2008). The overlapping confidence intervals for PFS and OS between SWOG 0014 and 8736 patients and our data suggest that a large multicenter trial will be needed to show a benefit of rituxan in this extremely good prognosis population. Disclosures: Hochberg: Genentech: Speakers Bureau; Biogen-Idec: Speakers Bureau; Enzon: Speakers Bureau; Amgen: Speakers Bureau.

No Improvement Of Overall Survival After Extended Follow-Up Of Donor Versus No Donor Analysis Of Newly Diagnosed Myeloma Patients Included In The HOVON 50/54 Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2132-2132 ◽  
Author(s):  
Henk Lokhorst ◽  
Bronno van der Holt ◽  
Jan Cornelissen ◽  
Marie José Kersten ◽  
Marinus H.J. Van Oers ◽  
...  
Keyword(s):  
Overall Survival ◽  
Maintenance Therapy ◽  
Survival Benefit ◽  
Research Funding ◽  
Phase Iii ◽  
High Dose ◽  
Newly Diagnosed ◽  
Donor Group ◽  
No Donor

Abstract Background The value of Allo-SCT in myeloma is heavily disputed. In our previous Donor versus No Donor (DvND) comparison we found no survival benefit of Allo-RIC in newly diagnosed myeloma. (Lokhorst et al:Blood 2012119: 6219-6225). However, a recent update of the EBMT-NMA 2000 trial (Gahrton el al:Blood 2013121: 5055-506) suggested that extended follow-up (> 5 years) may be necessary for a correct interpretation of a potential survival benefit for Allo-RIC. Here we present the extended follow-up of our trial, in which the median follow-up of patients now exceeds over 7.5 years since the first autologous SCT. Methods Patients with an HLA–identical sibling donor included in the phase III HOVON-50 study, that was designed to assess the role of thalidomide in induction treatment and maintenance after high-dose therapy (HDM 200 mg/m2), could proceed to the Hovon 54 study in which an Allo-SCT was performed after conditioning with low dose TBI only, between 2-6 months after HDM. Among the 536 eligible patients randomized in the HOVON-50 trial, ultimately 260 patients were eligible to be included into the DvND analysis: 122 patients with a donor, of whom 99 patients received an Allo-RIC and 138 without a donor, of whom 115 patients started maintenance therapy with thalidomide. Groups were comparable with regard to age, myeloma stage, and prognostic factors including cytogenetics and ISS stage. Results 93% of the patients in the no donor group achieved at least a PR (38% CR, 71% at least VGPR ), versus 96% of the patients in the donor group (43% CR, 73% at least VGPR). After a median follow-up of 91 months after HDM, PFS and OS were comparable between the two groups. In the intention to treat analysis median PFS was 29 months for the no donor group and 30 months the no donor group (P=0.25). Median OS was 76 for the donor group and 81 months for the no donor group (P=0.61). For the patients who actually received their allocated treatment (Allo-RIC or maintenance), PFS curves started to diverge after 3 years, however no statistical difference was observed (P=0.07). Allo-RIC improved the median overall survival from 73 to 94 months compared to patients receiving maintenance. However, due to frequent late mortality (> after 96 months) in the Allo-RIC group the benefit was not statistically significant (P=0.54). No subgroup including those achieving CR or those with high risk features (ISS, deletion of chromosome 13) did benefit from Allo-RIC. Conclusion This analysis failed to show improvement of tandem Auto Allo-RIC as part of first line therapy in myeloma as compared to Auto-SCT followed by maintenance therapy, even after extended follow-up. Disclosures: Lokhorst: Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria. Minnema:Janssen Cilag: Consultancy, Honoraria. Sonneveld:Janssen-Cilag: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen-Cilag: Research Funding; Millenium: Research Funding; Onyx: Research Funding; Celgene: Research Funding.

Alternate Splicing Is a Frequent Event and Impacts Clinical Outcome in Myeloma: A High-Density Exon Array Analysis of Uniformly Treated Newly-Diagnosed Myeloma Patients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 498-498 ◽  
Author(s):  
Nikhil C. Munshi ◽  
Cheng Li ◽  
Stephane Minvielle ◽  
Samir B Amin ◽  
Philippe Moreau ◽  
...  
Keyword(s):  
Overall Survival ◽  
Amyloid Beta ◽  
Exon Array ◽  
Newly Diagnosed ◽  
Alternate Splicing ◽  
Array Analysis ◽  
Exon 2 ◽  
Array Data ◽  
Human Exon ◽  
Exon 10

Abstract Alternate splicing is an important post translational change that alters specificity of gene function. Misregulation of alternative splicing has been implicated in number of disease processes including cancer. We have here analyzed alternate splicing in myeloma using high throughput exon array analysis. The GeneChip Human Exon 1.0 ST Arrays used in this investigation not only provides information on expression levels for genes, but as the probe sets are spread evenly over each exon, the array data also provides information on presence of each exon and identify recurrent alternately spliced genes. We conducted a study in series of 170 newly-diagnosed patients with multiple myeloma treated homogeneously in tandem transplantation IFM trials. RNA isolated from CD138 purified MM cells collected at the time of diagnosis were analyzed using the GeneChip Human Exon 1.0 ST Arrays. The dChip software was modified to analyze exon array data. We first normalized gene-level expression values across samples, and then identified differentially expressed exons between two sample groups. These exons are candidates for alternatively splicing events. We observed over 100 genes with candidate alternate splicing events, which have up or down-regulation of an exon relative to the baseline group in more than 20% patients. Dividing the group based on response, 52 alternately spliced exons were identified as influencing response to therapy. The genes and their exons with highest frequency of alternate splicing were CD79A exon 5 and 6, EDNRB exon 2, RASSF1 exon 8, CD1d exon9, TGFBetaRII exon 1, Calmin exon2, CEACAM1 exon 7, MADH1 exon 7, TBX5 exon 2, Amyloid beta exon 14, Nit protein 2 exon 10, Thymidylate synthetase exon 7. Amongst these genes, 32 genes had the most influence on response with over 50% differential frequency in patients achieving CR. Similarly we have identified 85 alternately spliced genes as influencing overall survival between groups divided by less than or more than 48 month survival. The genes with highest frequency of alternate splicing were NOTCH2 exon 18, CXCL3 exon 8, CD9 exon 3 Calmin exon 2, TIMELESS exon 12, SPOUTY homolog 1 exon 4, Amyloid beta exon 14, Nit protein 2 exon 10, Cyclin A2 exon7, lymphocyte antigen 6 exon 7. Forty-nine genes within this group had the most influence on overall survival. Number of spliced variants were shared between both response and survival groups suggesting their biological and functional significance. Further validation of these alternate splicing is under investigations. This study highlights significant frequency of alternate splicing and points to the need for evaluation of not only the expression level of genes but also post translational modifications. The genes identified here are important target for therapy as well as possible immune modulation.

The imaging substudy of the randomized ARTE trial: MRI and 18FET PET associations with overall survival benefit from bevacizumab in elderly patients with newly diagnosed IDH wildtype glioblastoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2520-2520
Author(s):  
Hans-Georg Wirsching ◽  
Ulrich Roelcke ◽  
Jonathan Weller ◽  
Thomas Hundsberger ◽  
Andreas Felix Hottinger ◽  
...  
Keyword(s):  
Overall Survival ◽  
Amino Acid ◽  
Survival Benefit ◽  
Delayed Diagnosis ◽  
Time Dependent ◽  
Newly Diagnosed ◽  
Open Label ◽  
Fet Pet ◽  
Amino Acid Pet ◽  
Overall Survival Benefit

2520 Background: Bevacizumab failed to demonstrate overall survival benefit despite markedly prolonged progression-free survival in glioblastoma patients. Reasons for this divergence may include suboptimal patient selection and delayed diagnosis of progression on MRI scans under bevacizumab. Imaging analyses of retrospective and uncontrolled clinical trial cohorts suggest MRI diffusion mapping as a predictor of benefit from bevacizumab. Moreover, amino acid PET has been proposed by the RANO working group for the differentiation of tumor versus edema or gliosis based on proof-of-principle studies demonstrating earlier detection of progression with PET compared to MRI. Methods: ARTE (NCT01443676) was a 2:1 randomized, multi-center, open-label trial of hypofractionated radiotherapy in combination with intravenous bevacizumab every 2 weeks (BEV/RT) versus RT alone in patients with newly diagnosed glioblastoma aged 65 years or older. Patients with histologically and molecularly confirmed IDH wildtype glioblastoma aged 65 years or older were analyzed. MRI was available from 67 and serial 18FET PET from 30 patients in this post hoc analysis. 18FET PET intensity ratios and herein reported MRI parameters including tumor volumetric analyses and ADC were analyzed blinded for outcome and study arm. Results: Demographic, clinical and molecular parameters were balanced between treatment arms. Overall survival benefit from bevacizumab was observed for larger contrast-enhancing tumor volumes (hazard ratio [HR] per cm3 0.94, 95% CI 0.89-0.99, p = 0.032) and higher ADC (HR 0.18, 95% CI 0.05-0.66, p = 0.025) on pre-treatment MRI. Response in the BEV/RT arm by the standard MRI-based RANO criteria was associated with overall survival by trend (HR 0.56, 95% CI 0.30-1.10, time-dependent p = 0.094). In a multivariate model controlling for established risk factors, 18FET tumor-to-brain uptake ratios (TBR) of non-contrast-enhancing tumor portions predicted inferior overall survival specifically in the BEV/RT arm (HR [per 0.1 18FET TBR] 1.50, 95% CI 1.05-2.13, time-dependent p = 0.025). Controlling for 18FET TBR at first follow-up identified benefit from BEV/RT by trend (HR 0.41, 95% CI 0.16-1.07, p = 0.069). Conclusions: Large contrast-enhancing tumor mass and high ADC identify patients with overall survival benefit from bevacizumab. Under bevacizumab, non-contrast enhancing tumor portions can be adequately monitored by amino acid PET.

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