IDH1 mutation status and outcome in clinical trials for recurrent glioblastoma.

Abstract INTRODUCTION Vaccination with dendritic cells (DCs) fares poorly in primary and recurrent glioblastoma (GBM). Moreover, GBM vaccine trials are often underpowered due to limited sample size. METHODS To address these limitations, we conducted three sequential clinical trials utilizing Cytomegalovirus (CMV)-specific DC vaccines in patients with primary GBM. Autologous DCs were generated and electroporated with mRNA encoding for the CMV protein pp65. Serial vaccination was given throughout adjuvant temozolomide cycles, and 111Indium radiolabeling was implemented to assess migration efficiency of DC vaccines. Patients were followed for median overall survival (mOS) and OS. RESULTS Our initial study was the phase II ATTAC study (NCT00639639; total n=12) with 6 patients randomized to vaccine site preconditioning with tetanus-diphtheria (Td) toxoid. This led to an expanded cohort trial (ATTAC-GM; NCT00639639) of 11 patients receiving CMV DC vaccines containing granulocyte-macrophage colony-stimulating factor (GM-CSF). Follow-up data from ATTAC and ATTAC-GM revealed 5-year OS rates of 33.3% (mOS 38.3 months; CI95 17.5-undefined) and 36.4% (mOS 37.7 months; CI95 18.2-109.1), respectively. ATTAC additionally revealed a significant increase in DC migration to draining lymph nodes following Td preconditioning (P=0.049). Increased DC migration was associated with OS (Cox proportional hazards model, HR=0.820, P=0.023). Td-mediated increased migration has been recapitulated in our larger confirmatory trial ELEVATE (NCT02366728) of 43 patients randomized to preconditioning (Wilcoxon rank sum, Td n=24, unpulsed DC n=19; 24h, P=0.031 and 48h, P=0.0195). In ELEVATE, median follow-up of 42.2 months revealed significantly longer OS in patients randomized to Td (P=0.026). The 3-year OS for Td-treated patients in ELEVATE was 34% (CI95 19-63%) compared to 6% given unpulsed DCs (CI95 1-42%). CONCLUSION We report reproducibility of our findings across three sequential clinical trials using CMV pp65 DCs. Despite their small numbers, these successive trials demonstrate consistent survival outcomes, thus supporting the efficacy of CMV DC vaccine therapy in GBM.

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The Relationship Between IDH1 Mutation Status and Metabolic Imaging in Nonenhancing Supratentorial Diffuse Gliomas: A 11C-MET PET Study

Molecular Imaging ◽

10.1177/1536012119894087 ◽

2019 ◽

Vol 18 ◽

pp. 153601211989408

Author(s):

Nijiati Kudulaiti ◽

Huiwei Zhang ◽

Tianming Qiu ◽

Junfeng Lu ◽

Abudumijiti Aibaidula ◽

...

Keyword(s):

Standardized Uptake Value ◽

Idh1 Mutation ◽

Metabolic Imaging ◽

Wild Type ◽

Isocitrate Dehydrogenase 1 ◽

Mutation Status ◽

Positron Emission ◽

Diffuse Gliomas ◽

The Relationship ◽

Met Pet

Purpose: We evaluated the relationship between isocitrate dehydrogenase 1 (IDH1) mutation status and metabolic imaging in patients with nonenhancing supratentorial diffuse gliomas using 11C-methionine positron emission tomography (11C-MET PET). Materials and Methods: Between June 2012 and November 2017, we enrolled 86 (38 women and 48 men; mean age, 41.9 ± 13.1 years [range, 8-67 years]) patients with newly diagnosed supratentorial diffuse gliomas. All patients underwent preoperative 11C-MET PET. Tumor samples were obtained and immunohistochemically analyzed for IDH1 mutation status. Results: The mutant and wild-type IDH1 diffuse gliomas had significantly different mean maximum standardized uptake value values (2.73 [95% confidence interval, CI: 2.32-3.16] vs 3.85 [95% CI: 3.22-4.51], respectively; P = .004) and mean tumor-to-background ratio (1.90 [95% CI: 1.65-2.16] vs 2.59 [95% CI: 2.17-3.04], respectively; P = .007). Conclusions: 11C-methionine PET can noninvasively evaluate the IDH1 mutation status of patients with nonenhancing supratentorial diffuse gliomas.

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Morphologic patterns of noncontrast-enhancing tumor in glioblastoma correlate with IDH1 mutation status and patient survival

Journal of Clinical Neuroscience ◽

10.1016/j.jocn.2017.09.007 ◽

2018 ◽

Vol 47 ◽

pp. 168-173 ◽

Cited By ~ 7

Author(s):

Arian Lasocki ◽

Frank Gaillard ◽

Mark Tacey ◽

Katharine Drummond ◽

Stephen Stuckey

Keyword(s):

Patient Survival ◽

Idh1 Mutation ◽

Mutation Status

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PHASE II TRIAL OF THE PHOSPHATIDYINOSITOL-3 KINASE (PI3K) INHIBITOR BUPARLISIB (BKM120) IN RECURRENT GLIOBLASTOMA CONDUCTED BY THE IVY FOUNDATION EARLY PHASE CLINICAL TRIALS CONSORTIUM

Neuro-Oncology ◽

10.1093/neuonc/nou209.20 ◽

2014 ◽

Vol 16 (suppl 3) ◽

pp. iii47-iii47 ◽

Cited By ~ 7

Author(s):

P. Y. Wen ◽

W. K. A. Yung ◽

I. K. Mellinghoff ◽

S. Ramkissoon ◽

...

Keyword(s):

Clinical Trials ◽

Phase Ii ◽

Early Phase ◽

Phase Ii Trial ◽

Recurrent Glioblastoma ◽

Pi3k Inhibitor ◽

Early Phase Clinical Trials

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New prognostic factors and calculators for outcome prediction in patients with recurrent glioblastoma: A pooled analysis of EORTC Brain Tumour Group phase I and II clinical trials

European Journal of Cancer ◽

10.1016/j.ejca.2012.02.004 ◽

2012 ◽

Vol 48 (8) ◽

pp. 1176-1184 ◽

Cited By ~ 115

Author(s):

Thierry Gorlia ◽

Roger Stupp ◽

Alba A. Brandes ◽

Roy R. Rampling ◽

Pierre Fumoleau ◽

...

Keyword(s):

Clinical Trials ◽

Prognostic Factors ◽

Phase I ◽

Brain Tumour ◽

Outcome Prediction ◽

Pooled Analysis ◽

Recurrent Glioblastoma ◽

Tumour Group ◽

Phase I And Ii

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Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy Foundation Early Phase Clinical Trials Consortium phase II study

Neuro-Oncology ◽

10.1093/neuonc/nov245 ◽

2015 ◽

Vol 18 (4) ◽

pp. 557-564 ◽

Cited By ~ 174

Author(s):

Nicholas Butowski ◽

Howard Colman ◽

John F. De Groot ◽

Antonio M. Omuro ◽

Lakshmi Nayak ◽

...

Keyword(s):

Clinical Trials ◽

Phase Ii ◽

Early Phase ◽

Phase Ii Study ◽

Recurrent Glioblastoma ◽

Colony Stimulating Factor ◽

Early Phase Clinical Trials ◽

Stimulating Factor ◽

Receptor Inhibitor

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Use of DNA copy number analysis of grade 2-4 gliomas to reveal differences in molecular ontogeny associated with IDH mutation status.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.2026 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 2026-2026

Author(s):

Mariko Sato ◽

Kenneth D. Aldape ◽

Clinton C Mason ◽

Kristin Diefes ◽

Lindsey Heathcock ◽

...

Keyword(s):

Copy Number ◽

Genetic Alterations ◽

Idh1 Mutation ◽

Low Grade ◽

Copy Number Alterations ◽

Copy Number Analysis ◽

Mutation Status ◽

Younger Age ◽

Ffpe Samples ◽

Molecular Inversion Probes

2026 Background: The genetic alterations of glioma have been studied extensively. IDH1 mutation is associated with younger age and better survival. However, differences in molecular ontogeny within glioma related to IDH1 mutation remain unknown. Here we describe a detailed analysis of copy number alterations (CNA) between IDH1mut vs IDH1wt gliomas of grade 2-3 and 4. Methods: CNA were detected by molecular inversion probes (Affymetrix) and analyzed with Nexus Copy Number Software (BioDiscovery). DNA was extracted from 94 patient FFPE samples including grade 2-3: IDH1wt (n = 17) and IDH1mut (n = 28), and grade IV: IDH1wt ( n = 25) and IDH1mut(n = 24). Chromothripsis was detected using a stringent criteria of at least ten switches of CNA in individual chromosomes. Results: We validated prior findings that IDH1wt GBM have higher frequency of Chr7 amplification (including EGFR) and loss of Chr10 (including PTEN). Other CNA across all grades were: gain of 19q12 and loss of 14q11 in IDH1wt, and gain of 11q21, 10p11, 8q21 and loss of 11p15, 19q13 in IDH1mut. Within grade 2-3 samples, few CNA were associated with mutation status: 2-3wt demonstrated higher frequencies of gain of 7q and loss of 10q, 14q11, and 22q13, while 2-3mut demonstrated higher frequencies of 11q21 gain and 19q13 loss. Grade 4 tumors demonstrated more CNA that differed by mutation status, with 4wt tumors demonstrating gain of 7 and loss of 10 and 14q11, while 4mut demonstrated gains of 8q, 10p, 12p13, 1q23, and loss of 11p15, 3p, 19q13, among others. Comparison of grade 2-3mut vs grade 4mut tumors demonstrated larger number of CNA in the grade 4mut tumors including gain of 1p, 14q, 13q33, 9p, 8q and loss of 22q, 11p15, 10q, and 3p, among others. A significantly higher incidence of chromothripsis events was observed in grade 4mut compared to grade 4wt (p = 0.0374). Conclusions: CNA analysis showed significant differences in molecular ontogeny between IDH1wt and IDH1mut, some of which may further elucidate pathogenesis. Significant CNA increases and increased chromthripsis in grade 4mut support malignant transformation of low grade gliomas through accumulation of genomic instability and genomic catastrophe.

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