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BIOMARKER:

IDH2 R140Q

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Other names: IDH2, Isocitrate Dehydrogenase (NADP(+)) 2, Isocitrate Dehydrogenase (NADP(+)) 2, Mitochondrial, Isocitrate Dehydrogenase 2 (NADP+), Mitochondrial, Isocitrate Dehydrogenase [NADP], Mitochondrial, Oxalosuccinate Decarboxylase, NADP(+)-Specific ICDH, ICD-M, IDH, IDP, MNADP-IDH, D2HGA2, IDHM, IDPM
Entrez ID:
Related biomarkers:
2ms
FDA Cleared Companion Diagnostics (CDx) Tests (IDH1, IDH2 and FLT3) for Acute Myeloid Leukemia (AML) Patient Care (ASH 2021)
In recent years the US Food and Drug Administration (FDA) has been very active in approving targeted therapeutic drugs for AML patients including Midostaurin (Rydapt; 2017) and Gilteritinib (Xospata;2018) for FLT3 mutations; Enasidenib (Idhifa; 2017) for IDH2 mutations and Ivosidenib (Tibsovo; 2018) for IDH1 mutations. The IDH1 CDx, IDH2 CDx and FLT3 CDx tests are highly sensitive and Versiti provides average turn around time of 3 business days which enable rapid decision making on the recently available drug therapies for AML patients. We strongly recommend that the IDH1 CDx, IDH2 CDx and FLT3 CDx tests should be performed on all AML patients for better care.
Clinical • Companion diagnostic
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FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
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IDH1 mutation • IDH2 mutation • FLT3 mutation • FLT3 D835 • IDH1 R132H • IDH2 R172K • IDH1 R132C • FLT3 I836 • IDH2 R140Q • IDH1 R132 • IDH1 R132G • IDH2 R140 • IDH2 R172 • IDH2 R172G
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LeukoStrat® CDx FLT3 Mutation Assay
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Xospata (gilteritinib) • Rydapt (midostaurin) • Tibsovo (ivosidenib) • Idhifa (enasidenib)
2ms
Properties and Distribution of IDH-1/2 Mutations in Acute Myeloid Leukemia By the Comprehensive Genomic Analysis (ASH 2021)
IDH mutant-specific inhibitors such as ivosidenib and enasidenib were already approved in the US, and combination treatment with venetoclax and Azacitidine was recently approved in Japan...Serial genome profiling analyses were performed to evaluate the time-dependent changes in the genome profiles of patients administered FLT3 inhibitors, gilteritinib, and quizartinib for treating FLT3-mutated AML... In our evaluation of the suitability of F1H for HM-SCREEN-Japan 01, we successfully identified IDH-1/2 mutation that can be used as therapeutic targets in AML, which have rarely been identified thus far.
KRAS (KRAS proto-oncogene GTPase) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • NPM1 (Nucleophosmin 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11)
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KRAS mutation • IDH1 mutation • IDH2 mutation • FLT3 mutation • NPM1 mutation • DNMT3A mutation • RUNX1 mutation • IDH1 R132C • IDH2 R140Q • IDH1 R132
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FoundationOne® Heme CDx
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Venclexta (venetoclax) • Xospata (gilteritinib) • azacitidine • Vanflyta (quizartinib) • Tibsovo (ivosidenib) • Idhifa (enasidenib)
2ms
IDH1/2 Mutations Are Maintained in a Subset of Patients with Acute Myeloid Leukemia in Complete Remission and Do Not Correlate with Residual Disease (ASH 2021)
In these AML patients, the persistence of IDH1/2 mutations may be part of a more complex process involving clonal hematopoiesis. In such setting, further studies on the biological and clinical significance of IDH1/2 mutations persistence are warranted.
Clinical
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FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • NPM1 (Nucleophosmin 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
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FLT3-ITD mutation • IDH1 mutation • IDH2 mutation • NPM1 mutation • IDH1 R132H • IDH2 R172K • IDH2 R140Q • IDH1 R132 • IDH1 R132G • IDH2 R172
3ms
Synergistic Combination Activity of the Novel GSPT1 Degrader CC-90009 in Acute Myeloid Leukemia Models (ASH 2021)
Based on these results, the combination activity of CC-90009 with venetoclax (VEN)/azacitidine (AZA) is being evaluated in a phase 1/2 trial in patients with AML (NCT04336982)...Synergy between the isocitrate dehydrogenase 2 (IDH2) inhibitor enasidenib and CC-90009 was evaluated in a TF‑1 erythroleukemia cell line overexpressing IDH2 R140Q mutant, and an IDH2 R140Q PDX model, AM7577...FLT3 inhibitors, including sunitinib, pexidartinib, midostaurin, lestaurtinib, crenolanib, and gilteritinib, synergized with CC-90009 to reduce viability in FLT3-ITD AML cell lines MV4-11 and MOLM-13...The FLT3 inhibitor quizartinib significantly prolonged survival when combined with CC‑90009 compared with either agent alone ( P < 0.001)... Using a high-throughput combination screen, we identified rational combination partners that synergize with CC-90009 in in vitro and in vivo AML models. Collectively, these results support the clinical evaluation of CC-90009 in combination with FLT3, BCL2, and IDH2 inhibitors to further improve treatment outcomes for patients with AML.
IO biomarker
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FLT3 (Fms-related tyrosine kinase 3) • MCL1 (Myeloid cell leukemia 1) • CRBN (Cereblon) • CD34 (CD34 molecule) • CD14 • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • GSPT1 (G1 To S Phase Transition 1)
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IDH2 mutation • IDH2 R140Q • IDH2 overexpression
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Venclexta (venetoclax) • Sutent (sunitinib) • Xospata (gilteritinib) • azacitidine • Vanflyta (quizartinib) • Rydapt (midostaurin) • crenolanib besylate (ARO-002) • Idhifa (enasidenib) • Turalio (pexidartinib) • CC-90009 • lestaurtinib (CEP-701)
3ms
Intronic Architecture Links DNA Methylation to Gene Expression and Helps Drive Subtype-Specific Transcriptional Landscapes in DNMT3A- and IDH1/2-Mutant Acute Myeloid Leukemias (AML) (ASH 2021)
This mechanism seems to also be active in normal hematopoiesis and thus, is hijacked by leukemic cells. Therefore, our findings identify retrotransposons as a missing link in the understanding of epigenetic regulation of gene expression, reveal a previously uncharacterized role for these elements in leukemogenesis, and point to different cells of origin for each AML subtype.
Epigenetic controller
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IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • DNMT3A (DNA methyltransferase 1)
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DNMT3A mutation • IDH2 R140Q
3ms
Differential Prognostic Impact of IDH1 and IDH2 Mutations in Chronic Myelomonocytic Leukemia (ASH 2021)
Five (11%) IDH2 mutant patients were treated with enasidenib (IDH2 inhibitor), none with a durable response, while none of the IDH1 mutant patients received targeted therapy...IDH mutations negatively impacting AML-FS without a significant impact on OS. Prospective clinical trials testing the safety and efficacy of IDH1/2 inhibitors in CMML are much needed.
IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • TET2 (Tet Methylcytosine Dioxygenase 2) • SRSF2 (Serine and arginine rich splicing factor 2)
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IDH1 mutation • IDH2 mutation • TET2 mutation • IDH1 R132H • SRSF2 mutation • IDH2 R140Q • IDH1 R132 • IDH2 R140
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Idhifa (enasidenib)
3ms
Adverse Prognostic Role of IDH2 Mutations at Diagnosis and during Follow-up in Patients with Acute Myeloid Leukemia and Normal Karyotype (ASH 2021)
In this retrospective monocentric study, the presence at diagnosis of IDH2m correlated with relapse risk and with survival, suggesting that additional treatment with targeted agents and or consolidation with allogeneic transplant should be considered. In addition, in AML without NPM1m or FLT3m, the persistence of genes mutation detected by NGS monitoring after consolidation had a significant prognostic value to predict subsequent relapse.
Clinical
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KRAS (KRAS proto-oncogene GTPase) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • NPM1 (Nucleophosmin 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • DNMT3A (DNA methyltransferase 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • SRSF2 (Serine and arginine rich splicing factor 2)
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FLT3-ITD mutation • IDH2 mutation • NPM1 mutation • DNMT3A mutation • TET2 mutation • IDH2 R172K • SRSF2 mutation • IDH2 R140Q • IDH2 R172
3ms
Enasidenib in Combination with Venetoclax in IDH2-Mutated Myeloid Malignancies: Preliminary Results of the Phase Ib/II Enaven-AML Trial (ASH 2021)
The MDS patient experienced secondary azacitidine failure. VEN in combination with ENA is a well-tolerated regimen with no dose-limiting toxicities observed at the current dose level. The preliminary efficacy of this combination is encouraging with an ORR of 55% in evaluable R/R AML patients, with some responders achieving deep molecular remissions. Patient enrollment in dose-escalation cohorts is ongoing.
P1/2 data • Combination therapy • IO biomarker
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IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
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IDH2 mutation • IDH2 R172K • IDH2 R140Q • IDH2 R172
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Venclexta (venetoclax) • azacitidine • Idhifa (enasidenib)
3ms
Two novel high-risk adult B-cell acute lymphoblastic leukemia subtypes with high expression of CDX2 and IDH1/2 mutations. (PubMed, Blood)
We delineated the genetic and transcriptomic landscape of adult B-ALL and identified two novel subtypes that predict poor disease outcomes. Our findings highlight the age-dependent distribution of subtypes, which partially accounts for the prognostic differences between adult and pediatric B-ALL.
Clinical • Journal
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IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • CDX-2
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IDH1 R132C • IDH2 R140Q
4ms
Comprehensive analysis of mutations and clonal evolution patterns in a cohort of patients with cytogenetically normal acute myeloid leukemia. (PubMed, Mol Cytogenet)
The findings of this study suggest that the relapse-initiating clones may pre-exist prior to therapy, which harbor or acquire mutations that confer selective advantage during chemotherapy, resulting in clonal expansion and eventually leading to relapse.
Clinical • Journal
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FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • NPM1 (Nucleophosmin 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
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FLT3-ITD mutation • NPM1 mutation • NRAS G12D • NRAS G12 • IDH2 R140Q • NPM1 W288
4ms
The biological and clinical relevance of SRSF2 mutations in patients with acute myeloid leukemia (AML) receiving allogeneic stem cell transplantation (HSCT) (DGHO 2021)
Following allogeneic HSCT SRSF2 mut AML pts did not have dismal outcomes with a 77% 2-year OS, indicating that SRSF2 mut AML pts may benefit from HSCT consolidation. Importantly, the VAF levels of SRSF2 mutations in remission at HSCT did not correlate with outcomes following HSCT consolidation, limiting the applicability of SRSF2 mutations as MRD marker in AML.
Clinical
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NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • ASXL1 (ASXL Transcriptional Regulator 1) • RUNX1 (RUNX Family Transcription Factor 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • SRSF2 (Serine and arginine rich splicing factor 2)
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SRSF2 mutation • IDH2 R140Q • SRSF2 P95H
5ms
Olaparib in Treating Patients With Advanced Glioma, Cholangiocarcinoma, or Solid Tumors With IDH1 or IDH2 Mutations (clinicaltrials.gov)
P2, N=145, Recruiting, National Cancer Institute (NCI) | Trial completion date: Jul 2021 --> Jul 2022 | Trial primary completion date: Jul 2021 --> Jul 2022
Clinical • Trial completion date • Trial primary completion date
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IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
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IDH2 mutation • IDH1 R132H • IDH2 R172K • IDH1 R132C • IDH2 R140Q • IDH1 R132 • IDH1 R132G • IDH1 R132V • IDH2 R172 • IDH2 R172G
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Lynparza (olaparib)
6ms
Mutant Idh2 cooperates with a NUP98-HOXD13 fusion to induce early immature thymocyte precursor ALL. (PubMed, Cancer Res)
In vitro treatment of Idh2R140Q/NHD13 thymocytes with enasidenib, a selective inhibitor of mutant IDH2, led to a marked decrease in leukemic cell proliferation. These findings demonstrate that Idh2R140Q/NHD13 mice can serve as a useful in vivo model for the study of EITP ALL development and therapy.
Journal
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KRAS (KRAS proto-oncogene GTPase) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • NUP98 (Nucleoporin 98 And 96 Precursor 2) • JAK3 (Janus Kinase 3) • SH2B3 (SH2B Adaptor Protein 3)
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KRAS mutation • IDH2 mutation • JAK3 mutation • IDH2 R140Q
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Idhifa (enasidenib)
6ms
Lysine acetylation restricts mutant IDH2 activity to optimize transformation in AML cells. (PubMed, Mol Cell)
Mechanistically, K413 acetylation of mitochondrial mIDH2 is achieved through a series of hierarchical phosphorylation events mediated by tyrosine kinase FLT3, which phosphorylates mIDH2 to recruit upstream mitochondrial acetyltransferase ACAT1 and simultaneously activates ACAT1 and inhibits upstream mitochondrial deacetylase SIRT3 through tyrosine phosphorylation. Moreover, we found that the intrinsic enzyme activity of mIDH2 is much higher than mIDH1, thus the inhibitory K413 acetylation optimizes leukemogenic ability of mIDH2 in AML cells by both producing sufficient 2-HG for transformation and avoiding cytotoxic accumulation of intracellular 2-HG.
Journal
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FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • SIRT3 (Sirtuin 3) • ACAT1 (Acetyl-CoA Acetyltransferase 1)
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IDH2 mutation • IDH1 R132H • IDH2 R140Q
7ms
Nucleophosmin1 and isocitrate dehydrogenase 1 and 2 as measurable residual disease markers in acute myeloid leukemia. (PubMed, PLoS One)
While NPM1 variant allele frequency decreased below 2.5% in remission in all patients, IDH1/2 mutations (typically IDH2 R140Q) persisted in 24% of cases. Our results support that NPM1 MRD even at DNA level is a reliable prognostic factor, while IDH1/2 mutations may represent pre-leukemic, founder or subclonal drivers.
Journal
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FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • NPM1 (Nucleophosmin 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
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IDH2 mutation • NPM1 mutation • IDH2 R140Q
9ms
[VIRTUAL] PREVALENCE AND PROGNOSTIC IMPACT OF IDH MUTATIONS IN THE REAL-WORLD SETTING: RESULTS FROM THE PROSPECTIVE IDH SCREENING COHORT OF THE SAL AML REGISTRY (EHA 2021)
Our results confirm the favorable prognosis of the IDH2-R172K subgroup. Furthermore, the results from this real-world cohort including r/r AMLs and pts ineligible for intensive treatment match the results of previously published newly diagnosed and fit patient groups from clinical trials.
Clinical • Real-world evidence
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IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
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IDH1 mutation • IDH2 mutation • IDH1 R132H • IDH2 R172K • IDH1 R132C • IDH2 R140Q • IDH2 R172
9ms
IDH2 mutations in patients with normal karyotype AML predict favorable responses to daunorubicin, cytarabine and cladribine regimen. (PubMed, Sci Rep)
We assessed the prognostic significance of IDH1/2 mutations (IDH1/2) in 398 AML patients with normal karyotype (NK-AML), treated with daunorubicine + cytarabine (DA), DA + cladribine (DAC), or DA + fludarabine. Altogether, DAC regimen produces better outcomes in IDH2 NK-AML patients than DA, and this likely results from the hypomethylating activity of cladribine. Our observations warrant further investigations of induction protocols combining cladribine with IDH1/2 inhibitors in IDH2-mutant.
Clinical • Journal
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IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
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IDH1 mutation • IDH2 mutation • IDH2 R172K • IDH2 R140Q • IDH2 R172
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cytarabine • cladribine • fludarabine IV
10ms
Combination of azacitidine and enasidenib enhances leukemic cell differentiation and cooperatively hypomethylates DNA. (PubMed, Exp Hematol)
Combination treatment reduced 5mC levels at greater numbers of sites and these loci were significantly enriched in regions with increased 5hMC, compared to azacitidine alone (25.8% vs. 7.4%). Results are consistent with a model in which enasidenib-mediated reactivation of TET enzymes cooperates with azacitidine-mediated inhibition of DNA methyltransferase enzymes, leading to greater reductions in DNA methylation and enhanced erythroid differentiation.
Journal
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CD34 (CD34 molecule)
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IDH2 R172K • IDH2 R140Q
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azacitidine • Idhifa (enasidenib)
1year
[VIRTUAL] Whole genome profiling of adult B‐other acute lymphoblastic leukaemia on the UKALL14 trial (BSH-I 2020)
Distinct classes of genomic instability are identified in B‐other ALL this include a RAG mutation phenotype, high SV burden and MMR hypermutator. This approach sets the premise to design an extended genotype‐clinical correlative study on B‐ALL cases enrolled in UKALL14 and 60+ trials.
Clinical • Tumor Mutational Burden
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ABL1 (ABL proto-oncogene 1) • TMB (Tumor Mutational Burden) • FGFR1 (Fibroblast growth factor receptor 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • CDKN2A (Cyclin-dependent kinase inhibitor 2A) • JAK2 (Janus kinase 2) • ASXL1 (ASXL Transcriptional Regulator 1) • PDGFRB (Platelet Derived Growth Factor Receptor Beta) • ETV6 (ETS Variant Transcription Factor 6) • IKZF1 (IKAROS Family Zinc Finger 1) • CRLF2 (Cytokine Receptor Like Factor 2) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • PAX5 (Paired Box 5) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • P2RY8 (P2Y Receptor Family Member 8) • ABL2 (ABL Proto-Oncogene 2, Non-Receptor Tyrosine Kinase)
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IDH2 mutation • ASXL1 mutation • IDH2 R140Q
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PDGFRB FISH Assay
1year
[VIRTUAL] Outcomes of Molecular Characteristics in East Asian IDH2-mutant Non-Small Cell Lung Cancer Patients (IASLC-WCLC 2020)
IDH2-mutated NSCLC can exhibit other driver gene alterations. RB1 accompanied mutations might play a good prognosis in IDH2 gene mutation patients.
Clinical
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EGFR (Epidermal growth factor receptor) • TP53 (Tumor protein P53) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • CDKN2A (Cyclin-dependent kinase inhibitor 2A) • RB1 (RB Transcriptional Corepressor 1)
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TP53 mutation • EGFR mutation • IDH2 mutation • CDKN2A mutation • RB1 mutation • IDH2 R140Q • IDH2 R172
1year
[VIRTUAL] Assessment of NTRK Alterations and TRK Inhibitor Therapy: A Single Center Experience (AMP 2020)
Our cohort displayed occurrence of NTRK fusions in a spectrum ranging from rare solid tumors (infantile fibrosarcoma >75% incidence) to AML (<5% incidence). Demonstration of the remarkable efficacy of larotrectinib and entrectinib in clinical trials led to their accelerated tissue-agnostic US Food and Drug Administration (FDA) approval for adult and pediatric patients with NTRK gene fusion solid tumors. Thus, it appears beneficial to screen all solid tumors without any known oncogenic driver for NTRK fusions.
Clinical
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KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • NPM1 (Nucleophosmin 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • DNMT3A (DNA methyltransferase 1) • CDKN2A (Cyclin-dependent kinase inhibitor 2A) • ETV6 (ETS Variant Transcription Factor 6) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • TPM3 (Tropomyosin 3) • NTRK (Neurotrophic receptor tyrosine kinase)
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TP53 mutation • NTRK1 fusion • NTRK3 fusion • NPM1 mutation • KRAS G13D • ETV6-NTRK3 fusion • KRAS G13 • TPM3-NTRK1 fusion • IDH2 R140Q • NPM1 W288 • PIK3CA Q546R • miR138 underexpression + miR497 overexpression • NTRK fusion • NTRK positive
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Vitrakvi (larotrectinib) • Rozlytrek (entrectinib)
1year
[VIRTUAL] Persistent IDH Mutations in AML Patients in Remission on IDH Inhibitors (AMP 2020)
Ivosidenib and enasidenib, the IDH1 and IDH2 inhibitors, have been approved by the FDA for the treatment of adult relapsed or refractory (R/R) AML with IDH1 and IDH2 mutations, respectively. More than 70% of AML patients on IDH inhibitor therapies had detectable IDH mutations at the time of remission, indicating that IDH inhibitors induce blast differentiation/maturation rather than cell death. For AML patients with IDH2 mutations on enasidenib, the patients with R140Q mutations are more likely to have persistent mutation at the time of remission than those with R172K mutations.
Clinical
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IDH1 (Isocitrate dehydrogenase (NADP(+)) 1)
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IDH1 mutation • IDH2 mutation • IDH1 R132H • IDH2 R172K • IDH1 R132C • IDH2 R140Q • IDH1 R132G • IDH2 R172
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Tibsovo (ivosidenib) • Idhifa (enasidenib)
1year
[VIRTUAL] Inhibition of Critical DNA Dioxygenase Activity in IDH1/2 Mutant Myeloid Neoplasms (ASH 2020)
Neomorphic mutations in IDH1/2 producing R-2-Hydroxyglutrate (R-2HG), are common in myeloid malignancies and in various solid cancers...To explore this hypothesis we conducted a series of in vitro experiments in different isogenic cell lines expressing either mutant or wild type IDH1 or IDH2, that were simultaneously mutant, wild type (WT) or knock down (KD) for TET2 (TF1-IDH2R140Q, K562-IDH1R132C both WT for TET2 gene, and K18-IDH1R132C TET2KD and SIGM5-IDH1R132C TET2MT, both with a doxycycline inducible promoter for mutant IDH1)...In summary, results shown here represent an important proof of concept that the increased inhibition of DNA dioxygenase activity, instead of being more leukemogenic, can be synthetically lethal. Our observations may have implications with regard to the therapy of IDH1/2 mutated neoplasms including AML and MDS
IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • TET2 (Tet Methylcytosine Dioxygenase 2)
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IDH1 mutation • IDH2 mutation • TET2 mutation • IDH1 R132C • IDH2 R140Q
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Lutrate (leuprorelin depot) • doxycycline
1year
[VIRTUAL] Elucidating Mechanisms of Acquired Resistance to IDH Inhibition By Saturation Variant Screening of Base-Edited Leukemia Cells (ASH 2020)
Small molecule inhibitors ivosidenib and enasidenib, which specifically target mutant IDH1 and IDH2 respectively, are now approved for the treatment of newly diagnosed and/or relapsed/refractory acute myeloid leukemia (AML) patients with IDH1/2 mutations. We integrated the results with targeted sequencing of IDH1/2 mutations in AML patients, structural modeling, and functional studies. Our findings not only uncover de novo pathogenic mutations associated with resistance to IDH inhibition, but also provide new insights into the molecular mechanisms for acquired resistance to a targeted therapy in AML.
IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
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IDH1 mutation • IDH2 mutation • IDH1 R132H • IDH2 R140Q
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Tibsovo (ivosidenib) • Idhifa (enasidenib)
over1year
Enrollment change • PARP Biomarker
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IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
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IDH2 mutation • IDH1 R132H • IDH2 R172K • IDH1 R132C • IDH2 R140Q • IDH1 R132G • IDH1 R132V • IDH2 R172 • IDH2 R172G
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Lynparza (olaparib)
over1year
Olaparib in Treating Patients With Advanced Glioma, Cholangiocarcinoma, or Solid Tumors With IDH1 or IDH2 Mutations (clinicaltrials.gov)
P2, N=145, Recruiting, National Cancer Institute (NCI) | Trial completion date: Jul 2020 --> Jul 2021 | Trial primary completion date: Jul 2020 --> Jul 2021
Clinical • Trial completion date • Trial primary completion date • PARP Biomarker
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IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
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IDH2 mutation • IDH1 R132H • IDH2 R172K • IDH1 R132C • IDH2 R140Q • IDH1 R132G • IDH1 R132V • IDH2 R172 • IDH2 R172G
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Lynparza (olaparib)
over1year
Using the Anticancer Drug Olaparib to Treat Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome With an Isocitrate Dehydrogenase (IDH) Mutation (clinicaltrials.gov)
P2, N=46, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | Trial completion date: Dec 2020 --> Dec 2022 | Trial primary completion date: Dec 2020 --> Dec 2022
Enrollment open • Trial completion date • Trial primary completion date • PARP Biomarker
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IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
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IDH2 mutation • IDH1 R132H • IDH2 R172K • IDH1 R132C • IDH2 R140Q • IDH1 R132G • IDH1 R132V • IDH2 R172 • IDH2 R172G
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Lynparza (olaparib)