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• W1855948267 abstract "Isocitrate dehydrogenase (IDH) is an enzyme of the citric acid cycle whose encoding gene is mutated in various malignancies, including acute myeloid leukaemia (AML) (Mardis et al, 2009). Two isoforms, IDH1 and IDH2, have been implicated in tumourigenesis; both catalyse the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG). Approximately one-third of cytogenetically normal AML patients have a mutation in IDH1 or IDH2 (Abbas et al, 2010). Mutant IDH and wild-type IDH form a novel heterodimer that possesses the neomorphic ability to catalyse the reduction of α-KG to the D-stereoisomer of 2-hydroxyglutarate (D-2HG) (Dang et al, 2009; Ward et al, 2010). D-2HG is a putative oncometabolite shown to disrupt metabolic regulation of the cell epigenome and thereby promote tumourigenesis. Mutant IDH is thus under investigation as a drug therapy target. Mutant IDH inhibitors have been shown to decrease D-2HG production and inhibit leukaemia cell growth (Wang et al, 2013; Stein et al, 2014a,b). Thus, accurate identification of IDH mutations in patients with AML may have significant clinical impact. A variety of assays have been developed for the detection of mutated IDH, including polymerase chain reaction (PCR)-based Sanger sequencing, liquid chromatography with direct sequencing and next generation sequencing (Ward et al, 2010; Chotirat et al, 2012). These testing methods have variable sensitivity thresholds, and false negative results are possible when the mutant IDH is present in a percentage of cells below the detection threshold. Plasma D-2HG is a useful biomarker in this setting. Elevated D-2HG levels may direct further laboratory workup to confirm the definitive presence or absence of an IDH mutation. Such was the case in an AML patient who falsely tested negative when screened for IDH mutations. An elevated D-2HG level prompted additional testing, revealing the presence of an IDH2 R140Q mutation. This led to the patient's participation in a clinical trial of a drug targeting the mutant enzyme. A 78-year-old patient was being symptomatically managed for chronic myelomonocytic leukaemia (CMML) when he developed 13% circulating myeloblasts. A peripheral blood sample was analysed for IDH1 and IDH2 mutations by a reference laboratory using PCR to amplify segments of exon 4 of IDH1 and IDH2 followed by Sanger sequencing. With an analytical sensitivity of 20% tumour cells (10% mutant alleles, the IDH mutation is heterozygous in tumours), the test failed to detect any mutations. However, our centre has routinely assayed D-2HG levels in patients being considered for IDH inhibitor studies. In this patient, the liquid chromatography-tandem mass spectrometry (LC/MS-MS)-based assay for D-2HG showed a markedly elevated plasma D-2HG of 1114·50 ng/ml (reference range 18–263 ng/ml), suggestive of an oncogenic IDH mutation (See Fig 1) (Rakheja et al, 2011). A second sample was submitted for IDH1 and IDH2 mutation analysis. Unlike the first analysis, this sample was taken from a marrow aspirate, which showed 35% myeloblasts. The aspirate was analysed using PCR amplification and Sequenom mass spectrometry, which had the same analytic sensitivity as the initial test using PCR-based Sanger sequencing. This second assay detected an IDH2 R140Q mutation (see Fig 2). The presence of mutant IDH2 led to the patient's enrolment in a clinical trial of the mutant IDH2 inhibitor, AG-221. Our patient tolerated the drug well and achieved a partial remission. However, he developed progressive disease 6 months after beginning the drug and was removed from the study. Given targeted drug therapies’ promising results, prompt identification of IDH mutations is essential in providing comprehensive treatment options to patients with AML. Conventional molecular assays for IDH mutation identification include PCR followed by Sanger sequencing or Sequenom mass spectrometry. These assays have an analytical sensitivity of approximately 20% tumour cells and therefore give false-negative results for IDH mutations in AML with low myeloblast percentage. A potentially more sensitive screening tool for IDH mutations is measurement of the mutant enzyme's oncometabolite, D-2HG, by LC/MS-MS. Our patient's elevated plasma D-2HG prompted testing to confirm an IDH mutation, allowing him to benefit from a clinical trial targeting mutant IDH2. We propose a measurement of plasma/serum D-2HG as a rapid assay to screen for IDH mutation in AML patients who may benefit from clinical trials with IDH inhibitors. EM wrote the paper. DR, WC and RC contributed revisions and edits to the paper. WC and DR analysed the data. DO ran the repeated IDH assay. RB ran the D-2HG assay. The authors have no financial conflicts of interest with regard to the publication of this case report." @default.
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• W1855948267 date "2015-07-20" @default.
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• W1855948267 title "The importance of plasma D-2HG measurement in screening for<i>IDH</i>mutations in acute myeloid leukaemia" @default.
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• W1855948267 doi "https://doi.org/10.1111/bjh.13598" @default.
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