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IDH1R132, IDH2R140 and IDH2R172 in AML: different genetic landscapes correlate with outcome and may influence targeted treatment strategies

Leukemia volume 32, pages 1249–1253 (2018)Cite this article

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Acute myeloid leukemia (AML) is characterized by impaired hematopoiesis and bone marrow failure caused by clonal expansion of undifferentiated myeloid precursors. The classification of AML is mainly driven by cytomorphology, cytogenetics and single gene mutations like NPM1, CEBPA or RUNX1. Precision medicine aims at specifically targeting different gene mutations. In AML, five targeted therapies are used or under clinical investigation. The well-established therapy with all-trans retinoic acid (ATRA) targets PML-RARA-mutated AML, midostaurin targets FLT3-mutated AML, while the still investigated PARP and DOT1L inhibitors target RUNX1-RUNX1T1 and MLL translocated AML, respectively. Finally, novel drugs, which inhibit IDH mutant activity, such as AG-120 (IDH1), AG-221 (IDH2) or AG-881 (both IDH1 and 2) are currently tested in clinical trials to assess whether they confer better prognosis and overall survival to patients that carry these mutations. Mutated IDH1 and IDH2 lead to a novel enzyme activity, accumulating a oncometabolite in the cell that is suggested to alter the genetic, epigenetic and metabolic profile of the IDH mutant cell [1, 2]. In AML, IDH mutations occur at a frequency of 7% for IDH1 and 14% for IDH2 [3]. Although recent studies indicate to classify IDH2R172-mutated AML separately due to their rare overlap with other genetic AML classes [4], no comprehensive study addressing the genetic background of IDH-mutated AML is available. Therefore, the aim of this study was to comprehensively investigate the genetics and prognosis of de novo AML with IDH1R132, IDH2R140 and IDH2R172 mutations.

We investigated 306 de novo AML patients, all IDH1 or IDH2 mutated, diagnosed by cytomorphology, immunophenotyping and genetic studies strictly following WHO criteria [5]. The cohort comprised 141 females and 165 males, the median age was 65 years (range: 21–90 years). In all patients, a 26-gene panel was investigated by next-generation sequencing: ASXL1, BCOR, CALR, CBL, CEBPA, CSNK1A1, DNMT3A, ETV6, EZH2, FLT3-TKD, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NPM1, NRAS, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53, U2AF1 and ZRSR2. Additionally, FLT3-ITD and KMT2A-PTD were analyzed by gene scan and quantitative PCR, respectively. Variants of uncertain significance were excluded from statistical analyses. Chromosome banding analysis was performed for all patients according to standard procedures. All patients were treated with intensive standard chemotherapy. Overall survival (OS) analyses were performed in comparison to a FAB and MRC-matched IDH wild-type reference cohort (n = 540) [6, 7]. For detailed cohort characteristics and methods see Supplementary Information.

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Acknowledgements

We thank all clinicians for sending samples to our laboratory for diagnostic purposes and for providing clinical information and follow-up data. In addition, we would like to thank all the co-workers at the MLL Munich Leukemia Laboratory for approaching together many aspects in the field of leukemia diagnostics and research. Furthermore we would like to acknowledge the Italian Association for Cancer Research (AIRC) that is supporting the research activities of B. Falini.

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Author notes

  1. These authors contributed equally: Manja Meggendorfer, Luca Vincenzo Cappelli.

Authors and Affiliations

  1. MLL Munich Leukemia Laboratory, Munich, Germany

    Manja Meggendorfer, Wencke Walter, Claudia Haferlach, Wolfgang Kern & Torsten Haferlach

  2. Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy

    Luca Vincenzo Cappelli

  3. Institute of Hematology and Center for Hemato-Oncology Research, University and Hospital of Perugia, Perugia, Italy

    Brunangelo Falini

Authors
  1. Manja Meggendorfer
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  2. Luca Vincenzo Cappelli
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  6. Brunangelo Falini
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Correspondence to Manja Meggendorfer.

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WK, CH, and TH declare part ownership of the MLL Munich Leukemia Laboratory. MM and WW are employed by the MLL Munich Leukemia Laboratory.

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Meggendorfer, M., Cappelli, L.V., Walter, W. et al. IDH1R132, IDH2R140 and IDH2R172 in AML: different genetic landscapes correlate with outcome and may influence targeted treatment strategies. Leukemia 32, 1249–1253 (2018). https://doi.org/10.1038/s41375-018-0026-z

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