In Vivo 2-Hydroxyglutarate Monitoring with Edited MR Spectroscopy for the Follow-up of IDH -Mutant Diffuse Gliomas: The IDASPE Prospective Study

Anna Luisa Di Stefano; Lucia Nichelli; Giulia Berzero; Romain Valabregue; Mehdi Touat; Laurent Capelle; Clément Pontoizeau; Franck Bielle; Julie Lerond; Marine Giry; Chiara Villa; Bertrand Baussart; Caroline Dehais; Damien Galanaud; Capucine Baldini; Julien Savatovsky; Frédéric Dhermain; Dinesh K. Deelchand; Chris Ottolenghi; Stéphane Lehéricy; Małgorzata Marjańska; Francesca Branzoli; Marc Sanson

doi:10.1212/wnl.0000000000201137

In Vivo 2-Hydroxyglutarate Monitoring with Edited MR Spectroscopy for the Follow-up of IDH -Mutant Diffuse Gliomas: The IDASPE Prospective Study

Anna Luisa Di Stefano, Lucia Nichelli, Giulia Berzero, Romain Valabregue, Mehdi Touat, Laurent Capelle, Clément Pontoizeau, Franck Bielle, Julie Lerond, Marine Giry, Chiara Villa, Bertrand Baussart, Caroline Dehais, Damien Galanaud, Capucine Baldini, Julien Savatovsky, Frédéric Dhermain, Dinesh K. Deelchand, Chris Ottolenghi, Stéphane LehéricyMałgorzata Marjańska, Francesca Branzoli, Marc Sanson

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18 Scopus citations

Abstract

Background and ObjectivesD-2-hydroxyglutarate (2HG) characterizes IDH-mutant gliomas and can be detected and quantified with edited MRS (MEGA-PRESS). In this study, we investigated the clinical, radiologic, and molecular parameters affecting 2HG levels.MethodsMEGA-PRESS data were acquired in 71 patients with glioma (24 untreated, 47 treated) on a 3 T system. Eighteen patients were followed during cytotoxic (n = 12) or targeted (n = 6) therapy. 2HG was measured in tumor samples using gas chromatography coupled to mass spectrometry (GCMS).ResultsMEGA-PRESS detected 2HG with a sensitivity of 95% in untreated patients and 62% in treated patients. Sensitivity depended on tumor volume (>27 cm3; p = 0.02), voxel coverage (>75%; p = 0.002), and expansive presentation (defined by equal size of T1 and FLAIR abnormalities, p = 0.04). 2HG levels were positively correlated with IDH-mutant allelic fraction (p = 0.03) and total choline levels (p < 0.001) and were higher in IDH2-mutant compared with IDH1R132H-mutant and non-R132H IDH1-mutant patients (p = 0.002). In patients receiving IDH inhibitors, 2HG levels decreased within a few days, demonstrating the on-target effect of the drug, but 2HG level decrease did not predict tumor response. Patients receiving cytotoxic treatments showed a slower decrease in 2HG levels, consistent with tumor response and occurring before any tumor volume change on conventional MRI. At progression, 1p/19q codeleted gliomas, but not the non-codeleted, showed detectable in vivo 2HG levels, pointing out to different modes of progression characterizing these 2 entities.DiscussionMEGA-PRESS edited MRS allows in vivo monitoring of 2-hydroxyglutarate, confirming efficacy of IDH inhibition and suggests different patterns of tumor progression in astrocytomas compared with oligodendrogliomas.

Original language	English (US)
Pages (from-to)	E94-E106
Journal	Neurology
Volume	100
Issue number	1
DOIs	https://doi.org/10.1212/wnl.0000000000201137
State	Published - Jan 3 2023

Bibliographical note

Funding Information:
The authors would like to thank Edward J. Auerbach, PhD, for implementing MRS sequences on the Siemens platform. The MRS sequences used in this study are part of the MRS package developed by Edward J. Auerbach, Ph.D., and Małgorzata Marjańska, Ph.D., and provided by the University of Minnesota under a C2P agreement. Lucia Nichelli acknowledges support from the scholarship “Bourse de Recherche Alain Rahmouni SFR-CERF 2019”. Małgorzata Marjańska acknowledges support from National Institutes of Health grants BTRC P41 EB027061 and P30 NS076408. The authors would like to thank Edward J. Auerbach, PhD, for implementing MRS sequences on the Siemens platform. The MRS sequences used in this study are part of the MRS package developed by Edward J. Auerbach, Ph.D., and Małgorzata Marjańska, Ph.D., and provided by the University of Minnesota under a C2P agreement.

Funding Information:
L. Nichelli has received support from the scholarship “Bourses de Recherche Alain Rahmouni 2019.” M. Touat reports consulting or advisory role from Agios Pharmaceutical, Integragen, and Taiho Oncology, outside the submitted work; research funding from Sanofi, outside the submitted work. S. Lehéricy reports research funding from ANR-11-INBS-0006 (France Life Imaging–FLI), and Biogen outside the submitted work M. Marjańska has received support from National Institutes of Health grants BTRC P41 EB027061 and P30 NS076408. M. Sanson reports consulting or advisory role from Genenta, Abbvie, Taiho Oncology, Orion Pharma, Mundipharma outside the submitted work and research funding from Astra-Zeneca, outside the submitted work. The other authors report no relevant disclosures. Go to Neurology.org/N for full disclosures.

Funding Information:
This study (NCT02597335) was funded by the INCa- Institut National du Cancer (PHRC Cancer 2012, sponsor Assistance Publique Hôpitaux de Paris), by the grant INCa-DGOS-Inserm_12560 of the SiRIC CURAMUS, by funding from the program “investissements d'avenir” ANR-10-IAIHU-06, and by a grant from the Ligue Nationale contre le Cancer (LNCC; équipe labellisée).

Publisher Copyright:
© American Academy of Neurology.

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Di Stefano, A. L., Nichelli, L., Berzero, G., Valabregue, R., Touat, M., Capelle, L., Pontoizeau, C., Bielle, F., Lerond, J., Giry, M., Villa, C., Baussart, B., Dehais, C., Galanaud, D., Baldini, C., Savatovsky, J., Dhermain, F., Deelchand, D. K., Ottolenghi, C., ... Sanson, M. (2023). In Vivo 2-Hydroxyglutarate Monitoring with Edited MR Spectroscopy for the Follow-up of IDH -Mutant Diffuse Gliomas: The IDASPE Prospective Study. Neurology, 100(1), E94-E106. https://doi.org/10.1212/wnl.0000000000201137

Di Stefano, AL, Nichelli, L, Berzero, G, Valabregue, R, Touat, M, Capelle, L, Pontoizeau, C, Bielle, F, Lerond, J, Giry, M, Villa, C, Baussart, B, Dehais, C, Galanaud, D, Baldini, C, Savatovsky, J, Dhermain, F, Deelchand, DK, Ottolenghi, C, Lehéricy, S, Marjańska, M, Branzoli, F & Sanson, M 2023, 'In Vivo 2-Hydroxyglutarate Monitoring with Edited MR Spectroscopy for the Follow-up of IDH -Mutant Diffuse Gliomas: The IDASPE Prospective Study', Neurology, vol. 100, no. 1, pp. E94-E106. https://doi.org/10.1212/wnl.0000000000201137

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title = "In Vivo 2-Hydroxyglutarate Monitoring with Edited MR Spectroscopy for the Follow-up of IDH -Mutant Diffuse Gliomas: The IDASPE Prospective Study",

abstract = "Background and ObjectivesD-2-hydroxyglutarate (2HG) characterizes IDH-mutant gliomas and can be detected and quantified with edited MRS (MEGA-PRESS). In this study, we investigated the clinical, radiologic, and molecular parameters affecting 2HG levels.MethodsMEGA-PRESS data were acquired in 71 patients with glioma (24 untreated, 47 treated) on a 3 T system. Eighteen patients were followed during cytotoxic (n = 12) or targeted (n = 6) therapy. 2HG was measured in tumor samples using gas chromatography coupled to mass spectrometry (GCMS).ResultsMEGA-PRESS detected 2HG with a sensitivity of 95% in untreated patients and 62% in treated patients. Sensitivity depended on tumor volume (>27 cm3; p = 0.02), voxel coverage (>75%; p = 0.002), and expansive presentation (defined by equal size of T1 and FLAIR abnormalities, p = 0.04). 2HG levels were positively correlated with IDH-mutant allelic fraction (p = 0.03) and total choline levels (p < 0.001) and were higher in IDH2-mutant compared with IDH1R132H-mutant and non-R132H IDH1-mutant patients (p = 0.002). In patients receiving IDH inhibitors, 2HG levels decreased within a few days, demonstrating the on-target effect of the drug, but 2HG level decrease did not predict tumor response. Patients receiving cytotoxic treatments showed a slower decrease in 2HG levels, consistent with tumor response and occurring before any tumor volume change on conventional MRI. At progression, 1p/19q codeleted gliomas, but not the non-codeleted, showed detectable in vivo 2HG levels, pointing out to different modes of progression characterizing these 2 entities.DiscussionMEGA-PRESS edited MRS allows in vivo monitoring of 2-hydroxyglutarate, confirming efficacy of IDH inhibition and suggests different patterns of tumor progression in astrocytomas compared with oligodendrogliomas.",

author = "{Di Stefano}, {Anna Luisa} and Lucia Nichelli and Giulia Berzero and Romain Valabregue and Mehdi Touat and Laurent Capelle and Cl{\'e}ment Pontoizeau and Franck Bielle and Julie Lerond and Marine Giry and Chiara Villa and Bertrand Baussart and Caroline Dehais and Damien Galanaud and Capucine Baldini and Julien Savatovsky and Fr{\'e}d{\'e}ric Dhermain and Deelchand, {Dinesh K.} and Chris Ottolenghi and St{\'e}phane Leh{\'e}ricy and Ma{\l}gorzata Marja{\'n}ska and Francesca Branzoli and Marc Sanson",

note = "Funding Information: The authors would like to thank Edward J. Auerbach, PhD, for implementing MRS sequences on the Siemens platform. The MRS sequences used in this study are part of the MRS package developed by Edward J. Auerbach, Ph.D., and Ma{\l}gorzata Marja{\'n}ska, Ph.D., and provided by the University of Minnesota under a C2P agreement. Lucia Nichelli acknowledges support from the scholarship “Bourse de Recherche Alain Rahmouni SFR-CERF 2019”. Ma{\l}gorzata Marja{\'n}ska acknowledges support from National Institutes of Health grants BTRC P41 EB027061 and P30 NS076408. The authors would like to thank Edward J. Auerbach, PhD, for implementing MRS sequences on the Siemens platform. The MRS sequences used in this study are part of the MRS package developed by Edward J. Auerbach, Ph.D., and Ma{\l}gorzata Marja{\'n}ska, Ph.D., and provided by the University of Minnesota under a C2P agreement. Funding Information: L. Nichelli has received support from the scholarship “Bourses de Recherche Alain Rahmouni 2019.” M. Touat reports consulting or advisory role from Agios Pharmaceutical, Integragen, and Taiho Oncology, outside the submitted work; research funding from Sanofi, outside the submitted work. S. Leh{\'e}ricy reports research funding from ANR-11-INBS-0006 (France Life Imaging–FLI), and Biogen outside the submitted work M. Marja{\'n}ska has received support from National Institutes of Health grants BTRC P41 EB027061 and P30 NS076408. M. Sanson reports consulting or advisory role from Genenta, Abbvie, Taiho Oncology, Orion Pharma, Mundipharma outside the submitted work and research funding from Astra-Zeneca, outside the submitted work. The other authors report no relevant disclosures. Go to Neurology.org/N for full disclosures. Funding Information: This study (NCT02597335) was funded by the INCa- Institut National du Cancer (PHRC Cancer 2012, sponsor Assistance Publique H{\^o}pitaux de Paris), by the grant INCa-DGOS-Inserm_12560 of the SiRIC CURAMUS, by funding from the program “investissements d'avenir” ANR-10-IAIHU-06, and by a grant from the Ligue Nationale contre le Cancer (LNCC; {\'e}quipe labellis{\'e}e). Publisher Copyright: {\textcopyright} American Academy of Neurology.",

year = "2023",

month = jan,

day = "3",

doi = "10.1212/wnl.0000000000201137",

language = "English (US)",

volume = "100",

pages = "E94--E106",

journal = "Neurology",

issn = "0028-3878",

publisher = "Lippincott Williams and Wilkins",

number = "1",

}

TY - JOUR

T1 - In Vivo 2-Hydroxyglutarate Monitoring with Edited MR Spectroscopy for the Follow-up of IDH -Mutant Diffuse Gliomas

T2 - The IDASPE Prospective Study

AU - Di Stefano, Anna Luisa

AU - Nichelli, Lucia

AU - Berzero, Giulia

AU - Valabregue, Romain

AU - Touat, Mehdi

AU - Capelle, Laurent

AU - Pontoizeau, Clément

AU - Bielle, Franck

AU - Lerond, Julie

AU - Giry, Marine

AU - Villa, Chiara

AU - Baussart, Bertrand

AU - Dehais, Caroline

AU - Galanaud, Damien

AU - Baldini, Capucine

AU - Savatovsky, Julien

AU - Dhermain, Frédéric

AU - Deelchand, Dinesh K.

AU - Ottolenghi, Chris

AU - Lehéricy, Stéphane

AU - Marjańska, Małgorzata

AU - Branzoli, Francesca

AU - Sanson, Marc

N1 - Funding Information: The authors would like to thank Edward J. Auerbach, PhD, for implementing MRS sequences on the Siemens platform. The MRS sequences used in this study are part of the MRS package developed by Edward J. Auerbach, Ph.D., and Małgorzata Marjańska, Ph.D., and provided by the University of Minnesota under a C2P agreement. Lucia Nichelli acknowledges support from the scholarship “Bourse de Recherche Alain Rahmouni SFR-CERF 2019”. Małgorzata Marjańska acknowledges support from National Institutes of Health grants BTRC P41 EB027061 and P30 NS076408. The authors would like to thank Edward J. Auerbach, PhD, for implementing MRS sequences on the Siemens platform. The MRS sequences used in this study are part of the MRS package developed by Edward J. Auerbach, Ph.D., and Małgorzata Marjańska, Ph.D., and provided by the University of Minnesota under a C2P agreement. Funding Information: L. Nichelli has received support from the scholarship “Bourses de Recherche Alain Rahmouni 2019.” M. Touat reports consulting or advisory role from Agios Pharmaceutical, Integragen, and Taiho Oncology, outside the submitted work; research funding from Sanofi, outside the submitted work. S. Lehéricy reports research funding from ANR-11-INBS-0006 (France Life Imaging–FLI), and Biogen outside the submitted work M. Marjańska has received support from National Institutes of Health grants BTRC P41 EB027061 and P30 NS076408. M. Sanson reports consulting or advisory role from Genenta, Abbvie, Taiho Oncology, Orion Pharma, Mundipharma outside the submitted work and research funding from Astra-Zeneca, outside the submitted work. The other authors report no relevant disclosures. Go to Neurology.org/N for full disclosures. Funding Information: This study (NCT02597335) was funded by the INCa- Institut National du Cancer (PHRC Cancer 2012, sponsor Assistance Publique Hôpitaux de Paris), by the grant INCa-DGOS-Inserm_12560 of the SiRIC CURAMUS, by funding from the program “investissements d'avenir” ANR-10-IAIHU-06, and by a grant from the Ligue Nationale contre le Cancer (LNCC; équipe labellisée). Publisher Copyright: © American Academy of Neurology.

PY - 2023/1/3

Y1 - 2023/1/3

N2 - Background and ObjectivesD-2-hydroxyglutarate (2HG) characterizes IDH-mutant gliomas and can be detected and quantified with edited MRS (MEGA-PRESS). In this study, we investigated the clinical, radiologic, and molecular parameters affecting 2HG levels.MethodsMEGA-PRESS data were acquired in 71 patients with glioma (24 untreated, 47 treated) on a 3 T system. Eighteen patients were followed during cytotoxic (n = 12) or targeted (n = 6) therapy. 2HG was measured in tumor samples using gas chromatography coupled to mass spectrometry (GCMS).ResultsMEGA-PRESS detected 2HG with a sensitivity of 95% in untreated patients and 62% in treated patients. Sensitivity depended on tumor volume (>27 cm3; p = 0.02), voxel coverage (>75%; p = 0.002), and expansive presentation (defined by equal size of T1 and FLAIR abnormalities, p = 0.04). 2HG levels were positively correlated with IDH-mutant allelic fraction (p = 0.03) and total choline levels (p < 0.001) and were higher in IDH2-mutant compared with IDH1R132H-mutant and non-R132H IDH1-mutant patients (p = 0.002). In patients receiving IDH inhibitors, 2HG levels decreased within a few days, demonstrating the on-target effect of the drug, but 2HG level decrease did not predict tumor response. Patients receiving cytotoxic treatments showed a slower decrease in 2HG levels, consistent with tumor response and occurring before any tumor volume change on conventional MRI. At progression, 1p/19q codeleted gliomas, but not the non-codeleted, showed detectable in vivo 2HG levels, pointing out to different modes of progression characterizing these 2 entities.DiscussionMEGA-PRESS edited MRS allows in vivo monitoring of 2-hydroxyglutarate, confirming efficacy of IDH inhibition and suggests different patterns of tumor progression in astrocytomas compared with oligodendrogliomas.

AB - Background and ObjectivesD-2-hydroxyglutarate (2HG) characterizes IDH-mutant gliomas and can be detected and quantified with edited MRS (MEGA-PRESS). In this study, we investigated the clinical, radiologic, and molecular parameters affecting 2HG levels.MethodsMEGA-PRESS data were acquired in 71 patients with glioma (24 untreated, 47 treated) on a 3 T system. Eighteen patients were followed during cytotoxic (n = 12) or targeted (n = 6) therapy. 2HG was measured in tumor samples using gas chromatography coupled to mass spectrometry (GCMS).ResultsMEGA-PRESS detected 2HG with a sensitivity of 95% in untreated patients and 62% in treated patients. Sensitivity depended on tumor volume (>27 cm3; p = 0.02), voxel coverage (>75%; p = 0.002), and expansive presentation (defined by equal size of T1 and FLAIR abnormalities, p = 0.04). 2HG levels were positively correlated with IDH-mutant allelic fraction (p = 0.03) and total choline levels (p < 0.001) and were higher in IDH2-mutant compared with IDH1R132H-mutant and non-R132H IDH1-mutant patients (p = 0.002). In patients receiving IDH inhibitors, 2HG levels decreased within a few days, demonstrating the on-target effect of the drug, but 2HG level decrease did not predict tumor response. Patients receiving cytotoxic treatments showed a slower decrease in 2HG levels, consistent with tumor response and occurring before any tumor volume change on conventional MRI. At progression, 1p/19q codeleted gliomas, but not the non-codeleted, showed detectable in vivo 2HG levels, pointing out to different modes of progression characterizing these 2 entities.DiscussionMEGA-PRESS edited MRS allows in vivo monitoring of 2-hydroxyglutarate, confirming efficacy of IDH inhibition and suggests different patterns of tumor progression in astrocytomas compared with oligodendrogliomas.

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DO - 10.1212/wnl.0000000000201137

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VL - 100

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JF - Neurology

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ER -

In Vivo 2-Hydroxyglutarate Monitoring with Edited MR Spectroscopy for the Follow-up of IDH -Mutant Diffuse Gliomas: The IDASPE Prospective Study

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