IDH2 R172

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.

Significant differences in GA and immune biomarkers are noted between IDH1/2+ and IDHwt iCCA. IDH1-/2-mutated tumors appear immunologically cold without gLOH. These immunogenomic data provide insight for precision targeting of iCCA with IDH alterations.

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, N=75, Recruiting, Hutchmed | Trial completion date: Sep 2023 --> Jun 2025 | Trial primary completion date: Sep 2023 --> Sep 2024

P1/2, N=60, Completed, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Suspended --> Completed

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

P1/2, N=27, Terminated, University Health Network, Toronto | Trial completion date: Jul 2023 --> Oct 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Jul 2023 --> Oct 2023; Insufficient Funding

The rat gliomas appear to share some genetic alterations with IDH1 wildtype human gliomas and rat cardiac schwannomas also harbor mutations in some of the queried cancer genes. These data demonstrate that targeted NGS panels based on tumor specific orthologous human cancer driver genes are an important tool to examine the translational relevance of rodent tumors resulting from chronic/life-time rodent bioassays.

We found that IDH1 R132 mutations were negatively associated with the prognosis of patients with bone chondrosarcomas. Nevertheless, more extensive studies (such as multicenter international studies) are needed and advisable to confirm our observations in this preliminary small series. Moreover, evaluating mutational status in fresh samples instead of in paraffin-embedded sections could help to increase the number of patients with adequate DNA for analysis. If our findings will be confirmed, the evaluation of IDH mutational status in biopsy samples or resection specimens could be considered when stratifying patients, highlighting those who may benefit from more aggressive treatment (such as adjuvant chemotherapy) or closer follow-up.

We described a series of 15 well-characterized TFHL patients with an indolent outcome, suggesting that a watch-and-wait approach can be proposed in selected patients. Identifying factors predicting such evolution is warranted.

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

P1/2, N=60, Suspended, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Oct 2023 --> Dec 2023 | Trial primary completion date: Oct 2023 --> Dec 2023

P2, N=94, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

In conclusion, post-HCT maintenance therapy with enasidenib is safe and feasible with highly favorable survival outcomes in mIDH2 AML. Treatment delays and dose reductions were commonly seen; however, most patients completed their 2-years maintenance.

P3, N=331, Active, not recruiting, Institut de Recherches Internationales Servier

Aside from bringing about more knowledge of PTCL biology, these mutations were shown to increase the sensitivity of PTCLs to certain epigenetic therapies, like hypomethylating agents (HMAs) and histone deacetylase inhibitors (HDACis). Thus, to answer the question from the title of this review: We found the Achilles heel, but only for one of the Achilles.

Concurrent nodal involvement by AITL and KS is rare and identification of both neoplastic components may pose diagnostic challenges. The question of whether the association between AITL and KS may be fortuitous or could reflect the underlying immune dysfunction in AITL remains open.

In the first randomized Phase 3 study of a targeted therapy in grade 2 mIDH1/2 glioma, vorasidenib prolonged median PFS by BIRC, relative to placebo, irrespective of IDH1/2 VAF.

Introduction: Recent phase III trial presented by Mellinghoff at 2023 ASCO demonstrated successful treatment of Isocitrate dehydrogenase (IDH)–mutant grade 2 gliomas with Vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes. Ivosidenib and enasidenib are separate inhibitors of mutant IDH1 and IDH2, which have shown single-agent activity for the treatment of IDH1- or IDH2-mutant acute myeloid leukemia but the effect in the treatment of glioma is uncertain...The patient underwent surgery resection, radiation and Temozolomide (TMZ), and 4 cycles of adjuvant TMZ...Clinically, the patient has no symptoms from tumor. Our case review found post-surgery therapy with IDH2 inhibitor Enasidenib for IDH2 mutant recurrent AO is tolerated and could postpone next intervention such as re-radiation or re-challenge with TMZ.

This case report aims to warn of the possibility that other driver mutations may be associated with the diagnosis of TCCRP, such as IDH1 R132 and not just IDH2 R172, and that a comprehensive testing approach of the IDH1/2 genes might be more accurate in these cases.

P2, N=94, Recruiting, National Cancer Institute (NCI) | Active, not recruiting --> Recruiting

Conclusion Allogeneic HCT in CR1 could bring some survival benefit on RFS in AML pts with IDH1/2 mutation, but not confirmed in MVA. Further study is warranted to reach a clearer conclusion with larger number of

Both PBCs and B-LPDs in TFH-LPD patients are commonly EBV+ and share TET2/DNMT3A mutations with TFH-LPDs, consistent with common origin from CH. B-LPDs more often harbor additional unique mutations than PBCs. Thus, CH mutations and EBV activation in B-cells may predispose TFH-LPD patients to B-LPDs, which may develop with additional private genomic aberrations aiding transformation (Figure 1B).

Additionally, several IDH1/IDH2 inhibitors such as ivosidenib and enasidenib have been approved by the FDA for treatment of AML patients with IDH1 and IDH2 mutations respectively. We have prototyped 18-plex assay designed to detect 7 IDH1 and 10 IDH2 mutations and call out its corresponding codon in EDTA whole blood samples using a single cartridge at an estimated LoD of 1%.

Low mRNA expression of PHLPP2 predicted poor prognosis (p=.03) and engineered PHLPP2 loss showed enhanced PI(3)K activation and FOXO1 inactivation in CD4+ T-cells in-vitro. Thus, we defined the genomic landscape for AITL, which is largely characterized by epigenetic alterations, TCR signaling and PI3K/AKT dysregulation, which may be amenable for therapeutic targeting.

Particularly, we identified the molecular subgroup with unfavorable prognosis (A53) for which different clinical approach should be warranted. This classification will refine the patient prognostication and stratification in nTFHL.

Almost all pts had AML, except one with MDS who progressed on treatment with azacitidine. The combination of ENA and VEN is safe and well tolerated in pts with R/R mIDH2 myeloid malignancies. The ENA-VEN combination compares favorably to ENA single-agent in this patient population. Further studies of targeted combination therapies using IDH2 and BCL2 inhibitors are warranted.

The Idylla Rapid IDH1/2 Mutation Assay had 92% concordance with NGS for FFPE sections. Compared with Idylla EGFR and KRAS assays (previously published) both control and target Cqs were considerably higher using the same number of sections or amount of DNA. A large DNA input requires stewardship for effective tissue utilization for molecular testing, especially in glioma biopsy samples, which may be limited.

P1, N=23, Completed, Massachusetts General Hospital | Active, not recruiting --> Completed

P2, N=94, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

P2, N=63, Recruiting, M.D. Anderson Cancer Center | N=105 --> 63

P1/2, N=60, Suspended, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Active, not recruiting --> Suspended

The efficiency of mutation introduction with our methodology was similar to that of ribonucleoprotein strategies, and no off-target events were detected. Overall, our strategy represents a valid and intuitive alternative for introducing desired mutations into hard-to-transfect leukemic cells without viral transduction.

P=N/A, N=334, Completed, Chang Gung Memorial Hospital | Enrolling by invitation --> Completed | Trial completion date: Nov 2023 --> Jul 2023

P2, N=145, Recruiting, National Cancer Institute (NCI) | Trial completion date: Jul 2023 --> Jul 2024 | Trial primary completion date: Jul 2023 --> Jul 2024

P1/2, N=27, Active, not recruiting, University Health Network, Toronto | Trial primary completion date: Apr 2023 --> Jul 2023

"The IDH1/IDH2 cartridge-based assay for the Idylla system allows ultra-rapid, sensitive, and robust screening for recurrent mutations at residues R132 in IDH1 and R140 or R172 in IDH2. The system provides reliable analysis of both extracted and pre- extraction tumor tissue from numerous sources beyond FFPE, including direct blood and bone marrow samples. It markedly simplifies the workflows in the lab and enables rapid treatment decisions."

Practical implementation of routine molecular work-up of CNS tumors is compromised by impractically long turnaround times and economic restraints. Based on our results, we advocate a stepwise approach, providing fast-track results obtained by MLPA for first-line therapy decisions within a week after surgery.

This meta-analysis demonstrates that IDH2R140 mutation improves OS in younger AML patients and that the prognostic value of IDH2R172 mutation is significantly heterogeneous. Differences in region and data type have a significant impact on the prognosis of AML patients with IDH2R140 and/or IDH2R172 mutations. Additionally, AML patients with IDH2R140 mutation have a better prognosis than those with IDH2R172 mutations, albeit with some degree of heterogeneity.