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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 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.
A review of FDA-approved acute myeloid leukemia therapies beyond ‘7 + 3’
Published in Expert Review of Hematology, 2021
Alexandre Bazinet, Sarit Assouline
Enasidenib is a small molecule inhibitor of IDH2 that is active against the IDH2 R140 and IDH2 R172 variants [68]. In a phase I/II trial in relapsed/refractory IDH2-mutated AML, enasidenib (100 mg orally once daily) produced a 40.3% ORR (including 19.3% CR) [79]. A median OS of 9.3 months compared favorably to standard therapies in this difficult-to-treat population. Enasidenib was well tolerated. As with IDH1 inhibitors, this treatment can induce an IDH differentiation syndrome. In addition, elevations of unconjugated bilirubin (without transaminitis) are common and likely related to off-target inhibition of UGT1A1, mimicking Gilbert syndrome [79]. QT prolongation is not seen with enasidenib [80]. FDA approval for enasidenib was granted in 2017 for relapsed/refractory IDH2-mutated AML [81]. Unfortunately, the phase III trial (IDHENTIFY) comparing enasidenib to CCRs in relapsed/refractory IDH2-mutated AML in older patients did not meet its OS primary endpoint [82]. As with ivosidenib, enasidenib combined with ICT and AZA backbones in the first-line setting is safe and has shown promising response rates [75,76]. It is also being combined with ICT in the phase III HOVON150AML trial (NCT03839771).
In vitro inhibition of human nucleoside transporters and uptake of azacitidine by an isocitrate dehydrogenase-2 inhibitor enasidenib and its metabolite AGI-16903
Published in Xenobiotica, 2019
Zeen Tong, Usha Yerramilli, Sylvia Yao, James D. Young, Matthew Hoffmann, Sekhar Surapaneni
Mutations of isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) enzymes have been identified in several tumors, including AML (Dang et al., 2009, 2010; Yen et al., 2010). The resulting mutant IDH proteins convert α-ketoglutarate (α-KG) to the oncometabolite 2 hydroxyglutarate (2-HG). The resulting elevated levels of 2-HG have been shown to cause DNA hypermethylation by inhibition of methylcytosine dioxygenase TET2 (Figueroa et al., 2010; Turcan et al., 2012) and histone hypermethylation through competitive inhibition of α-KG-dependent Jumonji-C histone demethylases (Tsukada et al., 2006; Turcan et al., 2012; Yamane et al., 2006), thereby leading to broad epigenetic changes and a block in myeloid differentiation (Chowdhury et al., 2011). Enasidenib is a specific inhibitor of IDH2 mutant protein, and has been recently approved by the FDA for the treatment of relapsed or refractory AML in adult patients with an IDH2 mutation. Nonclinical studies have demonstrated that enasidenib effectively inhibits the activity of IDH mutant protein leading to the reduction of 2-HG in tumors and the reversal of IDH mutation-induced histone and DNA hypermethylation (Kernytsky et al., 2015; Yen et al., 2017). Clinical data have shown that treatment with enasidenib is safe and results in reductions in plasma 2-HG concentrations as well as durable clinical responses (Amatangelo et al., 2017; Stein et al., 2017).
Absorption, distribution, metabolism and excretion of an isocitrate dehydrogenase-2 inhibitor enasidenib in rats and humans
Published in Xenobiotica, 2019
Zeen Tong, Christian Atsriku, Usha Yerramilli, Xiaomin Wang, Yan Li, Josephine Reyes, Bin Fan, Hua Yang, Matthew Hoffmann, Sekhar Surapaneni
Enasidenib is a first-in-class, selective, potent oral inhibitor of the IDH2 mutant protein that has been approved by FDA for the treatment of relapsed or refractory AML adult patients with an IDH2 mutation. Direct inhibition of the gain-of-function activity of the IDH2 mutated protein is intended to inhibit the production of the oncogenic metabolite 2-HG. Enasidenib is also being developed for the treatment of patients with solid tumors (including glioma) and AITL that are IDH2 mutant-positive.