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Acute myeloid leukemia

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

Leukemia volume 30, pages 782–788 (2016)Cite this article

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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 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.

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Acknowledgements

Written on behalf of the Study Alliance Leukemia (SAL). We are thankful to all physicians and patients of the SAL study group.

Author contributions

Study design: AK, AD, JGO, CEH. D2HG measurement: JB, JGO. Molecular genetic analysis: CT. Statistical analysis: MS, AB. Data analysis and interpretation: CEH, JB, TB, AD, SP, ADH, GE, MSch, AK. Manuscript writing: all authors. Final approval of manuscript: all authors.

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Authors and Affiliations

  1. Department of Neuropathology, University of Heidelberg, Heidelberg, Germany

    J Balss, S Pusch & A von Deimling

  2. Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ) and DKTK, Heidelberg, Germany

    J Balss, S Pusch & A von Deimling

  3. Department of Internal Medicine I, University of Dresden, Dresden, Germany

    C Thiede, G Ehninger & M Schaich

  4. Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany

    T Bochtler, A D Ho, A Krämer & C E Heilig

  5. German Cancer Research Center (DKFZ) and Department of Internal Medicine V, Clinical Cooperation Unit Molecular Hematology/Oncology, University of Heidelberg, Heidelberg, Germany

    T Bochtler, A Krämer & C E Heilig

  6. Department of Pediatrics, University of Heidelberg, Heidelberg, Germany

    J G Okun

  7. Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany

    M Saadati & A Benner

Authors
  1. J Balss
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  9. M Schaich
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  10. A D Ho
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Corresponding author

Correspondence to A Krämer.

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Competing interests

JB: DKFZ (patent/intellectual property), Bayer Healthcare (research funding). CT: AgenDix Diagnostics GmbH (stock/other ownership), Bayer (research funding). TB: TEVA (travel, accomodations). SP: DKFZ (patent/intellectual property). GE: Celgene (research funding), GEMoaB Monoclonals (patent/intellectual property, stock/other ownership), Rhön-Klinikum AG (leadership role, stock/other ownership), Cellex GmbH (stock/other ownership), GEMoaB Monoclonals (stock/other ownership), AgenDix Diagnostics GmbH (stock/other ownership), Novartis (travel, accomodations, expenses). AD: Dianova/Roche (patent/intellectual property). AK: Novartis (consulting/advisory role), Roche (research funding), Bayer (research funding), DKFZ (patent/intellectual property), TEVA (travel, accomodations). CEH: Gilead, TEVA, Pharmamar, Shire, MSD (travel, accomodations). The remaining authors declare no conflict of interest.

Additional information

Preliminary data were presented at the Annual Meeting of the European Hematology Association, Milan, Italy, June 2014.

Supplementary Information accompanies this paper on the Leukemia website

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Balss, J., Thiede, C., Bochtler, T. et al. Pretreatment d-2-hydroxyglutarate serum levels negatively impact on outcome in IDH1-mutated acute myeloid leukemia. Leukemia 30, 782–788 (2016). https://doi.org/10.1038/leu.2015.317

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