Serum 2-hydroxyglutarate levels predict isocitrate dehydrogenase mutations and clinical outcome in acute myeloid leukemia

Courtney D. DiNardo, Kathleen J. Propert, Alison W. Loren, Elisabeth Paietta, Zhuoxin Sun, Ross L. Levine, Kimberly S. Straley, Katharine Yen, Jay P. Patel, Samuel Agresta, Omar Abdel-Wahab, Alexander E. Perl, Mark R Litzow, Jacob M. Rowe, Hillard M. Lazarus, Hugo F. Fernandez, David J. Margolis, Martin S. Tallman, Selina M. Luger, Martin Carroll

Research output: Contribution to journalArticle

101 Citations (Scopus)

Abstract

Cancer-associated isocitrate dehydrogenase (IDH) mutations produce the metabolite 2-hydroxyglutarate (2HG), but the clinical utility of 2HG has not been established. We studied whether 2HG measurements in acute myeloid leukemia (AML) patients correlate with IDH mutations, and whether diagnostic or remission 2HG measurements predict survival. Sera from 223 de novo AML patients were analyzed for 2HG concentration by reverse-phase liquid chromatography-mass spectrometry. Pretreatment 2HG levels ranged from 10 to 30 000 ng/mL and were elevated in IDH-mutants (median, 3004 ng/mL), compared to wild-type IDH (median, 61 ng/mL) (P < .0005). 2HG levels did not differ among IDH1 or IDH2 allelic variants. In receiver operating characteristic analysis, a discriminatory level of 700 ng/mL optimally segregated patients with and without IDH mutations, and on subsequent mutational analysis of the 13 IDH wild-type samples with 2HG levels >700 ng/mL, 9 were identified to have IDH mutations. IDH-mutant patients with 2HG levels >200 at complete remission had shorter overall survival compared to 2HG ≤200 ng/mL (hazard ratio, 3.9; P 5 .02). We establish a firm association between IDH mutations and serum 2HG concentration in AML, and confirm that serum oncometabolite measurements provide useful diagnostic and prognostic information that can improve patient selection for IDH-targeted therapies.

Original languageEnglish (US)
Pages (from-to)4917-4924
Number of pages8
JournalBlood
Volume121
Issue number24
DOIs
StatePublished - Jun 13 2013

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Isocitrate Dehydrogenase
Acute Myeloid Leukemia
Mutation
Serum
alpha-hydroxyglutarate
Survival
Liquid chromatography
Reverse-Phase Chromatography
Metabolites
Patient Selection
Mass spectrometry
Mass Spectrometry
Hazards
Association reactions

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

DiNardo, C. D., Propert, K. J., Loren, A. W., Paietta, E., Sun, Z., Levine, R. L., ... Carroll, M. (2013). Serum 2-hydroxyglutarate levels predict isocitrate dehydrogenase mutations and clinical outcome in acute myeloid leukemia. Blood, 121(24), 4917-4924. https://doi.org/10.1182/blood-2013-03-493197

Serum 2-hydroxyglutarate levels predict isocitrate dehydrogenase mutations and clinical outcome in acute myeloid leukemia. / 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.

In: Blood, Vol. 121, No. 24, 13.06.2013, p. 4917-4924.

Research output: Contribution to journalArticle

DiNardo, CD, Propert, KJ, Loren, AW, Paietta, E, Sun, Z, Levine, RL, Straley, KS, Yen, K, Patel, JP, Agresta, S, Abdel-Wahab, O, Perl, AE, Litzow, MR, Rowe, JM, Lazarus, HM, Fernandez, HF, Margolis, DJ, Tallman, MS, Luger, SM & Carroll, M 2013, 'Serum 2-hydroxyglutarate levels predict isocitrate dehydrogenase mutations and clinical outcome in acute myeloid leukemia', Blood, vol. 121, no. 24, pp. 4917-4924. https://doi.org/10.1182/blood-2013-03-493197
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. / Serum 2-hydroxyglutarate levels predict isocitrate dehydrogenase mutations and clinical outcome in acute myeloid leukemia. In: Blood. 2013 ; Vol. 121, No. 24. pp. 4917-4924.
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AU - Sun, Zhuoxin

AU - Levine, Ross L.

AU - Straley, Kimberly S.

AU - Yen, Katharine

AU - Patel, Jay P.

AU - Agresta, Samuel

AU - Abdel-Wahab, Omar

AU - Perl, Alexander E.

AU - Litzow, Mark R

AU - Rowe, Jacob M.

AU - Lazarus, Hillard M.

AU - Fernandez, Hugo F.

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AU - Carroll, Martin

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