Pretreatment D-2-hydroxyglutarate serum levels negatively impact on outcome in IDH1-mutated acute myeloid leukemia

被引：21

作者：

Balss, J. ^{[1
,2
,3
]}

Thiede, C. ^{[4
]}

Bochtler, T. ^{[5
,6
]}

Okun, J. G. ^{[7
]}

Saadati, M. ^{[8
]}

Benner, A. ^{[8
]}

Pusch, S. ^{[1
,2
,3
]}

Ehninger, G. ^{[4
]}

Schaich, M. ^{[4
]}

Ho, A. D. ^{[5
]}

von Deimling, A. ^{[1
,2
,3
]}

Kraemer, A. ^{[5
,6
]}

Heilig, C. E. ^{[5
,6
]}

机构：

[1] Heidelberg Univ, Dept Neuropathol, D-69120 Heidelberg, Germany

[2] German Canc Res Ctr, Clin Cooperat Unit Neuropathol, D-69120 Heidelberg, Germany

[3] DKTK, Heidelberg, Germany

[4] Univ Dresden, Dept Internal Med 1, Dresden, Germany

[5] Heidelberg Univ, Dept Internal Med 5, Neuenheimer Feld 280, D-69120 Heidelberg, Germany

[6] German Canc Res Ctr, Clin Cooperat Unit Mol Hematol Oncol, Neuenheimer Feld 280, D-69120 Heidelberg, Germany

[7] Heidelberg Univ, Dept Pediat, D-69120 Heidelberg, Germany

[8] German Canc Res Ctr, Div Biostat, D-69120 Heidelberg, Germany

来源：

LEUKEMIA | 2016年 / 30卷 / 04期

关键词：

ACUTE MYELOGENOUS LEUKEMIA; ISOCITRATE-DEHYDROGENASE; PROGNOSTIC IMPACT; IDH2; MUTATIONS; 2-HYDROXYGLUTARATE LEVELS; (R)-2-HYDROXYGLUTARATE; ASSOCIATION;

D O I：

10.1038/leu.2015.317

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Mutations in isocitrate dehydrogenases (IDHs) 1 and 2 frequently occur in acute myeloid leukemia (AML) and result in the production of the oncometabolite D-2-hydroxyglutarate (D2HG). D2HG has been shown to promote leukemogenesis even in the absence of mutated IDH, but the prognostic significance of pretreatment serum D2HG levels in patients with IDH-mutated AML is unclear. We measured D2HG serum levels in 84 patients with IDH-mutated AML treated in the prospective, randomized multicenter AML2003 trial of the German Study Alliance Leukemia. Multivariate Cox regression showed D2HG levels to negatively impact on event-free survival (EFS) as a continuous variable in the entire IDHmut cohort (P = 0.04), with no effect on overall survival (OS). In a subgroup analysis, the negative impact of D2HG on EFS was found to be restricted to patients with mutations in IDH1 (P = 0.003), adjusted for age, leukocyte count, serum lactate dehydrogenase and European LeukemiaNet risk score. We thus conclude that pretreatment D2HG serum levels may yield prognostic information in patients with IDH1-mutated, but not in IDH2-mutated AML, possibly due to different subcellular localizations of IDH1 and IDH2.

引用

页码：782 / 788

页数：7

共 35 条

[1] Enzymatic assay for quantitative analysis of (D)-2-hydroxyglutarate [J].

Balss, Joerg ;

Pusch, Stefan ;

Beck, Ann-Christin ;

Herold-Mende, Christel ;

Kraemer, Alwin ;

Thiede, Christian ;

Buckel, Wolfgang ;

Langhans, Claus-Dieter ;

Okun, Juergen G. ;

von Deimling, Andreas .

ACTA NEUROPATHOLOGICA, 2012, 124 (06) :883-891

[2] Prognostic Impact of Isocitrate Dehydrogenase Enzyme Isoforms 1 and 2 Mutations in Acute Myeloid Leukemia: A Study by the Acute Leukemia French Association Group [J].

Boissel, Nicolas ;

Nibourel, Olivier ;

Renneville, Aline ;

Gardin, Claude ;

Reman, Oumedaly ;

Contentin, Nathalie ;

Bordessoule, Dominique ;

Pautas, Cecile ;

de Revel, Thierry ;

Quesnel, Bruno ;

Huchette, Pascal ;

Philippe, Nathalie ;

Geffroy, Sandrine ;

Terre, Christine ;

Thomas, Xavier ;

Castaigne, Sylvie ;

Dombret, Herve ;

Preudhomme, Claude .

JOURNAL OF CLINICAL ONCOLOGY, 2010, 28 (23) :3717-3723

[3] The prognostic impact and stability of Isocitrate dehydrogenase 2 mutation in adult patients with acute myeloid leukemia [J].

Chou, W-C ;

Lei, W-C ;

Ko, B-S ;

Hou, H-A ;

Chen, C-Y ;

Tang, J-L ;

Yao, M. ;

Tsay, W. ;

Wu, S-J ;

Huang, S-Y ;

Hsu, S-C ;

Chen, Y-C ;

Chang, Y-C ;

Kuo, K-T ;

Lee, F-Y ;

Liu, M-C ;

Liu, C-W ;

Tseng, M-H ;

Huang, C-F ;

Tien, H-F .

LEUKEMIA, 2011, 25 (02) :246-253

[4] Distinct clinical and biologic characteristics in adult acute myeloid leukemia bearing the isocitrate dehydrogenase 1 mutation [J].

Chou, Wen-Chien ;

Hou, Hsin-An ;

Chen, Chien-Yuan ;

Tang, Jih-Luh ;

Yao, Ming ;

Tsay, Woei ;

Ko, Bor-Shen ;

Wu, Shang-Ju ;

Huang, Shang-Yi ;

Hsu, Szu-Chun ;

Chen, Yao-Chang ;

Huang, Yen-Ning ;

Chang, Yi-Chang ;

Lee, Fen-Yu ;

Liu, Ming-Chi ;

Liu, Chia-Wen ;

Tseng, Mei-Hsuan ;

Huang, Chi-Fei ;

Tien, Hwei-Fang .

BLOOD, 2010, 115 (14) :2749-2754

[5] Cancer-associated IDH1 mutations produce 2-hydroxyglutarate [J].

Dang, Lenny ;

White, David W. ;

Gross, Stefan ;

Bennett, Bryson D. ;

Bittinger, Mark A. ;

Driggers, Edward M. ;

Fantin, Valeria R. ;

Jang, Hyun Gyung ;

Jin, Shengfang ;

Keenan, Marie C. ;

Marks, Kevin M. ;

Prins, Robert M. ;

Ward, Patrick S. ;

Yen, Katharine E. ;

Liau, Linda M. ;

Rabinowitz, Joshua D. ;

Cantley, Lewis C. ;

Thompson, Craig B. ;

Heiden, Matthew G. Vander ;

Su, Shinsan M. .

NATURE, 2009, 462 (7274) :739-U52

[6] Serum 2-hydroxyglutarate levels predict isocitrate dehydrogenase mutations and clinical outcome in acute myeloid leukemia [J].

DiNardo, Courtney D. ;

Propert, Kathleen J. ;

Loren, Alison W. ;

Paietta, Elisabeth ;

Sun, Zhuoxin ;

Levine, Ross L. ;

Straley, Kimberly S. ;

Yen, Katharine ;

Patel, Jay P. ;

Agresta, Samuel ;

Abdel-Wahab, Omar ;

Perl, Alexander E. ;

Litzow, Mark R. ;

Rowe, Jacob M. ;

Lazarus, Hillard M. ;

Fernandez, Hugo F. ;

Margolis, David J. ;

Tallman, Martin S. ;

Luger, Selina M. ;

Carroll, Martin .

BLOOD, 2013, 121 (24) :4917-4924

[7] Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet [J].

Doehner, Hartmut ;

Estey, Elihu H. ;

Amadori, Sergio ;

Appelbaum, Frederick R. ;

Buechner, Thomas ;

Burnett, Alan K. ;

Dombret, Herve ;

Fenaux, Pierre ;

Grimwade, David ;

Larson, Richard A. ;

Lo-Coco, Francesco ;

Naoe, Tomoki ;

Niederwieser, Dietger ;

Ossenkoppele, Gert J. ;

Sanz, Miguel A. ;

Sierra, Jorge ;

Tallman, Martin S. ;

Loewenberg, Bob ;

Bloomfield, Clara D. .

BLOOD, 2010, 115 (03) :453-474

[8] Prospective serial evaluation of 2-hydroxyglutarate, during treatment of newly diagnosed acute myeloid leukemia, to assess disease activity and therapeutic response [J].

Fathi, Amir T. ;

Sadrzadeh, Hossein ;

Borger, Darrell R. ;

Ballen, Karen K. ;

Amrein, Philip C. ;

Attar, Eyal C. ;

Foster, Julia ;

Burke, Meghan ;

Lopez, Hector U. ;

Matulis, Christina R. ;

Edmonds, Katherine M. ;

Iafrate, A. John ;

Straley, Kimberly S. ;

Yen, Katharine E. ;

Agresta, Samuel ;

Schenkein, David P. ;

Hill, Cedric ;

Emadi, Ashkan ;

Neuberg, Donna S. ;

Stone, Richard M. ;

Chen, Yi-Bin .

BLOOD, 2012, 120 (23) :4649-4652

[9] BIPLOT GRAPHIC DISPLAY OF MATRICES WITH APPLICATION TO PRINCIPAL COMPONENT ANALYSIS [J].

GABRIEL, KR .

BIOMETRIKA, 1971, 58 (03) :453-+

[10] PROPORTIONAL HAZARDS TESTS AND DIAGNOSTICS BASED ON WEIGHTED RESIDUALS (VOL 81, PG 551, 1994) [J].

GRAMBSCH, PM ;

THERNEAU, TM .

BIOMETRIKA, 1995, 82 (03) :668-668

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