IDH2 mutation

P2, N=68, Active, not recruiting, Groupe Francophone des Myelodysplasies | Recruiting --> Active, not recruiting | Trial completion date: Feb 2023 --> Mar 2026

The constructed core regulatory network and outcomes of in-silico network perturbations are supported by survival data from AML patients. We expect that the combined bioinformatics and systems-biology modeling approach will be generally applicable to elucidate the gene regulation of disease progression.

The emergence of these novel agents in AML offers patients a new modality of therapy, and shifts treatment paradigms toward individualized medicine. In this review, we outline the role of IDH mutations in malignant transformation, focus in on a novel group of targeted therapeutic agents directed toward IDH1- and IDH2-mutant AML, and explore their impact on prognosis in patients with AML.

P2, N=80, Recruiting, Mayo Clinic | N=55 --> 80

In multivariable analyses, RAS and RTK pathway mutations were significantly associated with decreased overall survival, after adjusting for treatment arm, IDH2 variant, and mutational burden. Importantly, enasidenib-mediated survival benefit was more pronounced in patients with IDH2-R172 variants.

This current investigation aimed to assess enasidenib on the pharmacokinetics (PKs) of CYP substrates, including dextromethorphan (CYP2D6 probe drug), flurbiprofen (CYP2C9 probe drug), midazolam (CYP3A4 probe drug), omeprazole (CYP2C19 probe drug), and pioglitazone (CYP2C8 probe drug), in patients with AML or myelodysplastic syndrome. The parameters for omeprazole increased by 1.86 (90% CI: 1.33, 2.60) and 1.47 (0.93, 2.31)-fold, respectively, compared to omeprazole alone, while those for pioglitazone decreased to 0.80 (90% CI: 0.62, 1.03) and 0.87 (90% CI: 0.65, 1.16)-fold, respectively, in comparison to pioglitazone alone. These findings provide valuable insights into dose recommendations concerning drugs acting as substrates of CYP2D6, CYP2C9, CYP3A4, CYP2C19, and CYP2C8 when administered concurrently with enasidenib.

The patient with skin nodules and the pathology diagnosed BPDCN, the next generation sequencing of skin nodules showed mutations of IDH2 and ASXL1. DVT (decitabine combined with Venetoclax and thalidomide) has significant efficacy with rapid and deep remission for BPDCN, and the adverse effects is less, especially suitable for elderly patients who cannot tolerate intense chemotherapy.

P1, N=18, Recruiting, Massachusetts General Hospital | Trial completion date: May 2024 --> May 2025 | Trial primary completion date: May 2022 --> May 2024

Overall, this work provides preclinical evidence for the use of enasidenib to treat mIDH2 chondrosarcomas.

P1, N=95, Active, not recruiting, Institut de Recherches Internationales Servier | Trial completion date: Dec 2023 --> Mar 2024

This case suggests that dose capping of anthracyclines in the treatment of newly diagnosed AML may be an effective and safe treatment alternative in those with extreme BMI elevations beyond what has been studied in the literature. Given the increasing incidence of morbid obesity, further studies are needed to confirm appropriate dosing of anthracycline-based regimens at upper BMI extremes (>60 kg/m2).

This meta-analysis sheds light on the prevalence of genetic mutations in AML patients with MS, providing insights into the unique characteristics of the mutations and their frequencies. These discoveries are crucial in informing therapeutic and prognostic decisions for individuals with myeloid sarcoma.

P2, N=55, Recruiting, Mayo Clinic | Trial completion date: Mar 2024 --> Mar 2026 | Trial primary completion date: Mar 2024 --> Dec 2025

Oligosarcoma is a prognostically unfavorable CNS neoplasm with characteristic imaging and pathologic features, and a strong association with previously resected oligodendroglioma. Aggressive treatment is recommended, including gross total resection and adjuvant chemoradiation. Further study is required to define optimal treatment protocol for this CNS malignancy.

This finding led to a specific recommendation in the package insert to avoid the concurrent use of certain CYP1A2 substrates with enasidenib, unless directed otherwise in the prescribing information. Furthermore, this research underlines the technical benefits of integrating full Bayesian inference and incorporating Student's t-distribution for residual error modeling in the PK field.

P1/2, N=48, Recruiting, Stanford University | Trial completion date: Jan 2024 --> Aug 2024 | Trial primary completion date: Jan 2024 --> Aug 2024

P1, N=9, Active, not recruiting, Washington University School of Medicine | Trial completion date: Dec 2023 --> Dec 2024

P2, N=50, Suspended, National Cancer Institute (NCI) | Trial completion date: Mar 2024 --> Mar 2025 | Trial primary completion date: Mar 2024 --> Mar 2025

With advancements in molecular diagnostics and precision therapy, IDH inhibitors such as ivosidenib, vorasidenib and enasidenib are now mainstay in management of patients with a susceptible mutation. The Idyllaâ„¢ IDH1-2 Mutation Assay Kit (RUO) is a fully automated qPCR assay for the qualitative detection of 15 common mutations in IDH1 (R132C/H/G/S/L) and IDH2 (R140Q/L/G/W, R172K/M/G/W/S) at codon level. The Idyllaâ„¢ IDH1-2 Mutation Assay Kit demonstrates a high concordance with established reference methods across a range of different specimen types.

P1/2, N=84, Recruiting, M.D. Anderson Cancer Center | Phase classification: P1b/2 --> P1/2

P1, N=40, Completed, Celgene | Active, not recruiting --> Completed

P1, N=42, Recruiting, Nader Sanai | Trial completion date: Oct 2024 --> Feb 2025 | Trial primary completion date: Oct 2023 --> Aug 2024

A small subset of neuroepithelial tumors might better fit into the superseding molecular category of IDH2-mutant sinonasal carcinoma. At this point, sinonasal neuroendocrine and neuroepithelial tumors may best be regarded as a histologic and molecular spectrum that includes core groups of ONB, olfactory carcinoma, neuroendocrine carcinoma, and IDH2-mutant sinonasal carcinoma.

Our results showed significant differences in gene expression between IDH-mutant and IDH-wildtype diffuse gliomas, including higher levels of MAPT (Tau) in IDH-mutant tumors. We are in the process of incorporating the results of mass spectrometry and genome-wide methylation analysis in the context of gene expression data. We anticipate that this analysis will yield new insights into how the metabolic alterations in diffuse gliomas are influenced by epigenetic and gene expression changes.

P1, N=15, Active, not recruiting, City of Hope Medical Center | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P3; Trial completion date: Dec 2023 --> Mar 2024

Notably, none of the patients received oral azacitidine as maintenance therapy... The results indicated that NPM1-/FLT3-ITD- and NPM1+/FLT3-ITD- subgroups in DNMT3A mutated AML benefit from allo-HSCT in CR1. Larger cohorts are warranted to validate these findings.

Notably, none of the patients received oral azacitidine as maintenance therapy... The results indicated that NPM1-/FLT3-ITD- and NPM1+/FLT3-ITD- subgroups in DNMT3A mutated AML benefit from allo-HSCT in CR1. Larger cohorts are warranted to validate these findings.

The autocrine cytokines, including GM-CSF, LIF, and OSM, contribute to constitutive STAT3/5 activation in TF-1(R140Q) cells, thereby modulating IDH2/R140Q-mediated malignant proliferation in TF-1 cells. Targeting STAT3/5 phosphorylation may be a novel strategy for the treatment of AML in patients harboring the IDH2/R140Q mutation. Video Abstract.

The median OS was inferior to that reported in the VIALE-A trial. Outcomes are dismal after failure of HMAs plus VEN, representing an area of urgent unmet clinical need.

P1/2, N=345, Completed, Celgene | Active, not recruiting --> Completed

Isocitrate dehydrogenase (IDH)-mutant acute myeloid leukemia (AML) is treatable with inhibitors of mutant IDH and also responds well to combination therapies including venetoclax, but most patients with IDH-mutant AML either never achieve complete remission or relapse because mutant hematopoietic stem cells persist despite treatment...See related article by Landberg et al. (10).

P2, N=145, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

Using single-cell sequencing, metabolic assessment, and gene-edited human models, we find human pHSCs with IDH1 mutations to be metabolically vulnerable and sensitive to eradication by complex I inhibition. See related commentary by Steensma.

Grade 2, 3 and dedifferentiated chondrosarcomas are further characterized by IDH status, which in turn informs transcriptomic phenotype and overall survival. The transcriptome is distinct depending on IDH status, and implies different treatment targets.

No IDH2 mutations were found. The use of independent diagnostic methods may improve the detection of IDH-mutant specimens in chondroid tumors.

Basal and neural subtypes display distinct TIIC involvement, which may impact their difference in outcome. These findings provide the framework for further investigation in novel immunomodulation strategies for ENB.

There were significant co-occurrence relationships between TET2 and RHOA, TET2 and IDH2, and RHOA and IDH2 gene mutations (P<0.05), respectively, while TET2 and KDM6B gene mutations were mutually exclusive (P<0.05). The study reveals the mutational characteristics of AITL patients using NGS technology, which would provide insights for molecular diagnosis and targeted therapy of AITL.

However, (R)-2HG has many other effects in IDH-mutant cells, some that promote transformation and others that induce metabolic dependencies. Herein, we review how cancer-associated IDH mutations impact epigenetic regulation and cellular metabolism and discuss how these effects can potentially be leveraged to therapeutically target IDH-mutant tumors.

No abstract available

P2, N=6, Completed, John Mascarenhas | Trial completion date: Dec 2022 --> May 2023 | Trial primary completion date: Dec 2022 --> May 2023

P1, N=15, Recruiting, City of Hope Medical Center | Phase classification: P1b --> P1 | Trial completion date: Mar 2024 --> May 2025 | Trial primary completion date: Mar 2024 --> May 2025