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The Precision Medicine Approach in Oncology
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
A companion diagnostic assay kit, the IDH2 Mutation CDxTM kit, has been developed by Abbott Inc. The purpose of this test kit is to identify patients who might benefit from treatment with enasidenib (IdhifaTM), an inhibitor of the mutant R140Q, R172S, and R172K variants of the IDH2 enzyme. This leads to decreased serum 2-HG levels, and an increased rate of myeloid differentiation and reduced blast counts. The assay kit is based on real-time PCR methodology, and detects IDH2 gene mutations in tumor cells from blood or bone marrow samples. In one study based on patients selected for treatment by the kit, it was shown that after six months of treatment with enasidenib (IdhifaTM), 19% of patients experienced complete remission for eight months.
Acute Myeloid Leukemia An Introduction
Published in Wojciech Gorczyca, Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
IDH1 and IDH2 mutations were reported originally to be associated with a poor prognosis [13,71–73]. The complex interactions of IDH1 mutations with other molecular changes in cytogenetically normal AML made their prognostic significance controversial. IDH1 mutations occur in 10%–15% and IDH2 mutations in 5%–10% of AML cases (~19% of cytogenetically normal AML). They are usually associated with normal cytogenetics, occur frequently with NPM1 and MLL-PTD, and are mutually exclusive with TET2 and WT1 mutations. IDH1 mutations predict poor prognosis in NPM1+/FLT3-ITD− patients and CEBPA+/FLT3-ITD− patients. Recent studies showed that the prognosis of IDH1 mutations with AML depends on FLT3-ITD status [74]. Green et al. [74] found no difference in outcome between IDH1+ and IDH1− patients in univariate or multivariate analysis, or if the results were stratified by NPM1 mutational status. However, when stratified by FLT3-ITD status, an IDH1 mutation was an independent adverse factor for relapse in FLT3-ITD− patients and a favorable factor in FLT3-ITD+ patients [74]. Similar to IDH1, the prognostic significance of IDH2 mutations is controversial.
Acute Myeloid Leukaemia
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
It is of interest that despite the extensive genomic and epigenetic data collated from patients with AML, until spring 2017, there was just one genotypic selective therapy, ATRA-ATO, licensed for patients with APL. Since then, several targeted drugs have received US Food and Drug Administration (FDA) approval for selected patients with AML. In April 2017, midostaurin, an N-benzoyl staurosporine analog derived from Streptomyces staurosporeus, was licensed for the treatment of adults with newly diagnosed FLT3ITD AML, in combination with standard chemotherapy, followed in July 2017, by venetoclax, for use in combination with low-dose cytarabine in newly diagnosed older patients with AML. In August 2017, enasidenib, an IDH2 inhibitor, was licensed for adult patients with IDH2R140 or IDH2R172 relapsed or refractory AML, and vyxeos (CPX-351), a novel liposomal cytarabine-daunorubicin formulation, for adult patients with newly diagnosed t-AML or AML with MDS-related changes. This was followed, in September 2017, by an approval for gemtuzumab ozagamicin (mylotarg; GO), and then in July 2018, of ivosidenib, an IDH1 inhibitor, both for patients with relapsed/refractory AML. Clearly these approvals will impact the therapy of AML, and we must continue to use the accumulated enormous genetic data in concert with the new risk stratification tools, such as the ELN 2017 AML Risk Score, to inform the development of rationally designed clinical trials targeting specific mutations and co-mutations to improve the survival of all patients with AML. Notably enasidenib is conceptually novel and is associated with a differentiation syndrome, akin to that observed with ATRA in APL. And since IDH2 and FLT3ITD are expressed in diverse myeloid malignancies, we can anticipate that these drugs may well have activity in other myeloid disorders, such as MDS.
Developments in FGFR and IDH inhibitors for cholangiocarcinoma therapy
Published in Expert Review of Anticancer Therapy, 2023
Zachary J Brown, Samantha M. Ruff, Timothy M Pawlik
IDH is an enzyme involved in the Kreb cycle existing in two isoforms IDH1 and IDH2. IDH 1/2 mutations are identified in approximately 20% and 5% of patients with ICC, respectively. In contrast, IDH1/2 mutations are generally not present in patients with ECC [12,13]. Under normal conditions, IDH1/2 converts isocitrate to α-ketoglutarate to produce nicotinamide adenine dinucleotide (NADH) (Figure 1). When IDH is mutated, isocitrate is instead converted to 2-hydroxyglutarate (2-HG), which is an oncometabolite that prevents differentiation of hepatic progenitor cells and is associated with hypermethylation of DNA [14]. Additionally, 2-HG inhibits the activity of multiple α-ketoglutarate dependentα-ketoglutarate-dependent dioxygenases and suppression of hepatocyte nuclear factor 4α (HNF-4α), resulting in alterations in cell differentiation, survival, and extracellular matrix maturation [14,15]. However, the full impact of 2-HG on carcinogenesis is not known. In addition, when IDH mutations occur, there is a lower expression of the ARID1A gene, which is involved in chromatin remodeling [16,17]. IDH mutations have also been demonstrated to alter the tumor microenvironment, with less T cell infiltration and lower T cell cytotoxicity [18,19].
An evaluation of ivosidenib for the treatment of IDH1-mutant cholangiocarcinoma
Published in Expert Opinion on Pharmacotherapy, 2022
Sri Harsha Tella, Amit Mahipal
Isocitrate dehydrogenase (IDH) enzyme is a key metabolic enzyme in tricarboxylic acid (Krebs) cycle located in cytoplasm and mitochondrial matrix. IDH1 is predominantly located in cytoplasm, whereas mitochondria harbors IDH2 and IDH3 subtypes. In unaltered cellular physiology, IDH enzymes catalyze the conversion of isocitrate to α-ketoglutarate (αKG) in Krebs cycles. Mutations in IDH1 and IDH2 genes have been identified in several malignancies, including acute myeloid leukemia (AML), myelodysplastic syndrome and myeloproliferative neoplasms, glioblastomas, chondrosarcomas, thyroid malignancies, and cholangiocarcinoma. These mutated IDH enzymes acquire gain-of-function activity, converting αKG to the oncometabolite D-2-hydroxyglutarate (2-HG) [30]. Elevated 2-HG levels interfere with cellular metabolism, augment reactive oxygen species, induce hypoxia-inducible factor, and modify epigenetic regulation by causing hypermethylation of DNA and histones, thereby contributing to oncogenesis (Figure 1) [30]. Patients with cholangiocarcinoma harboring IDH1 mutation may have a prolonged clinical course compared to patients without IDH mutations [31].
Advances in the pharmacological management of acute myeloid leukemia in adults
Published in Expert Opinion on Pharmacotherapy, 2022
Yazan Numan, Yasmin Abaza, Jessica K Altman, Leonidas C Platanias
Approximately 10% of patients with AML harbor IDH1 or IDH2 mutations [62]. These mutations affect the arginine residues in the active enzymatic site [63] and impair the normal citric acid cycle, resulting in alpha-ketoglutarate being converted to 2-hydroxyglutarate – a metabolite that inhibits TET family enzymes and lysin de-methylators [64,65]. In addition, 2-hydroxyglutarate accumulation blocks the cytochrome C oxidase [66]. IDH1 mutations have an inferior outcome while IDH2 mutations have a better prognosis, particularly IDH2 (R172K) mutated AML treated with intensive chemotherapy [62]. Better understanding of the functional implications and relevance of such mutations allowed a rapid development of small molecules that target these enzymes which selectively inhibit 2HG, resulting in reversal of its effects and restoration of the activity of TET enzymes and lysin de-methylators which results in normal myeloid differentiation [67].