title: Pretreatment d-2-hydroxyglutarate serum levels negatively impact on outcome in IDH1-mutated acute myeloid leukemia.
abstract: 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 IDH(mut) 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.
authors.affiliation: Department of Neuropathology, University of Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ) and DKTK, Heidelberg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Balss
authors.affiliation: Department of Internal Medicine I, University of Dresden, Dresden, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Thiede
authors.affiliation: Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Bochtler
authors.affiliation: Department of Pediatrics, University of Heidelberg, Heidelberg, Germany.
authors.forename: J G
authors.initials: JG
authors.lastname: Okun
authors.affiliation: Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Saadati
authors.affiliation: Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Benner
authors.affiliation: Department of Neuropathology, University of Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ) and DKTK, Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Pusch
authors.affiliation: Department of Internal Medicine I, University of Dresden, Dresden, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Ehninger
authors.affiliation: Department of Internal Medicine I, University of Dresden, Dresden, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schaich
authors.affiliation: Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: A D
authors.initials: AD
authors.lastname: Ho
authors.affiliation: Department of Neuropathology, University of Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ) and DKTK, Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: von Deimling
authors.affiliation: Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Krämer
authors.affiliation: Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: C E
authors.initials: CE
authors.lastname: Heilig
mesh_terms: D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor / Q000097:blood*; D020732:Cytogenetic Analysis; D005260:Female; D005500:Follow-Up Studies; D005977:Glutarates / Q000097:blood*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000097:blood* / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D015996:Survival Rate; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D005977:Glutarates; C019417:alpha-hydroxyglutarate; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human