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| Gene | IDH2 |
| Variant | R140L |
| Impact List | missense |
| Protein Effect | unknown |
| Gene Variant Descriptions | IDH2 R140L lies within the substrate binding region of the Idh2 protein (UniProt.org). R140L has been identified in the scientific literature (PMID: 29448963, PMID: 38980314, PMID: 36064577), but has not been biochemically characterized and therefore, its effect on Idh2 protein function is unknown (PubMed, Aug 2024). |
| Associated Drug Resistance | |
| Category Variants Paths |
IDH2 mutant IDH2 R140X IDH2 R140L |
| Transcript | NM_002168.4 |
| gDNA | chr15:g.90088702C>A |
| cDNA | c.419G>T |
| Protein | p.R140L |
| Source Database | RefSeq |
| Genome Build | GRCh38/hg38 |
| Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
|---|---|---|---|---|---|
| NM_002168 | chr15:g.90088702C>A | c.419G>T | p.R140L | RefSeq | GRCh38/hg38 |
| NM_002168.4 | chr15:g.90088702C>A | c.419G>T | p.R140L | RefSeq | GRCh38/hg38 |
| NM_002168.3 | chr15:g.90088702C>A | c.419G>T | p.R140L | RefSeq | GRCh38/hg38 |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| IDH2 R140X | myelodysplastic syndrome | predicted - sensitive | Azacitidine + Enasidenib | Phase II | Actionable | In a Phase II trial, Idhifa (enasidenib) and Vidaza (azacitidine) combination treatment was well tolerated and resulted in an overall response rate of 68% (30/46, 11 complete remission (CR), 3 partial remission, 12 marrow CR, 4 hematological improvement only) in patients with higher-risk myelodysplastic syndrome harboring IDH2 R140 or R172 mutations who were naive to hypomethylating agents, with a median overall survival of 21.3 months (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 7010-7010; NCT03383575). | detail... |
| IDH2 R140X | acute myeloid leukemia | predicted - sensitive | LY3410738 | Phase I | Actionable | In a Phase I trial, LY3410738 demonstrated safety and inhibited D-2-HG in patients with relapsed or refractory IDH-mutant acute myeloid leukemia, resulting in a composite complete remission (CRc) rate of 9% (2/23, 2 CR) in IDH inhibitor-naive patients harbor IDH2 R140 mutations (Cancer Res (2023) 83 (8_Supplement): CT026; NCT04603001). | detail... |
| IDH2 R140X | myelodysplastic syndrome | predicted - sensitive | Enasidenib | Phase II | Actionable | In a Phase II trial, Idhifa (enasidenib) treatment was well tolerated and resulted in an overall response rate of 43% (9/21, 5 complete remission (CR), 1 partial remission, 1 marrow CR, 2 hematological improvement only) in patients with higher-risk myelodysplastic syndrome harboring IDH2 R140 or R172 mutations who were refractory to or progressed on hypomethylating agents, with a median overall survival of 21.3 months (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 7010-7010; NCT03383575). | detail... |
| IDH2 mutant | acute myeloid leukemia | predicted - sensitive | Talazoparib | Preclinical - Patient cell culture | Actionable | In a preclinical study, cells from a patient with acute myeloid leukemia harboring an IDH2 mutation were sensitive to treatment with Talzenna (talazoparib) in culture, demonstrating decreased colony formation (PMID: 29339439). | 29339439 |
| IDH2 mutant | polycythemia vera | not applicable | N/A | Guideline | Prognostic | IDH2 mutations are associated with inferior overall survival and leukemia-free survival in patients with polycythemia vera (NCCN.org). | detail... |
| IDH2 mutant | acute myeloid leukemia | sensitive | Decitabine + Venetoclax | Guideline | Actionable | Venclexta (venetoclax) in combination with Dacogen (decitabine) is included in guidelines for adult patients with acute myeloid leukemia harboring an IDH2 mutation (NCCN.org). | detail... |
| IDH2 mutant | acute myeloid leukemia | sensitive | Azacitidine + Venetoclax | Guideline | Actionable | Venclexta (venetoclax) in combination with Vidaza (azacitidine) is included in guidelines for adult patients with acute myeloid leukemia harboring an IDH2 mutation (NCCN.org). | detail... |
| IDH2 mutant | malignant astrocytoma | not applicable | N/A | Guideline | Diagnostic | IDH2 mutations aid in the diagnosis of grade II and grade III astrocytomas (NCCN.org). | detail... |
| IDH2 mutant | low grade glioma | predicted - sensitive | Vorasidenib | Case Reports/Case Series | Actionable | In a Phase I trial, Voranigo (vorasidenib) treatment resulted in an objective response in 13.6% (3/22, 1 partial response, 2 minor response) and stable disease in 72.7% (16/22) of patients with non-enhancing low-grade glioma harboring mutations in IDH1 (n=20) or IDH2 (n=1), with a median progression-free survival of 36.8 months, and resulted in stable disease as best response in 56.7% (17/30) of patients with enhancing tumors harboring mutations in IDH1 (n=28) or IDH2 (n=2) (PMID: 34078652; NCT02481154). | 34078652 |
| IDH2 mutant | anaplastic astrocytoma | not applicable | N/A | Guideline | Diagnostic | IDH2 mutations aid in the diagnosis of grade III astrocytomas (NCCN.org). | detail... |
| IDH2 mutant | oligodendroglioma | not applicable | N/A | Guideline | Diagnostic | IDH2 mutations aid in the diagnosis of oligodendrogliomas (NCCN.org). | detail... |
| IDH2 mutant | hematologic cancer | sensitive | Enasidenib | Phase I | Actionable | In a Phase I study, Enasidenib (AG-221) demonstrated safety and efficacy in patients with hematological cancer harboring IDH2 mutations and included 8 CR, 1 CRp, 3 CRi, and 8 PR (ASH Meeting, Dec 2014, abstract #115). | detail... |
| IDH2 mutant | essential thrombocythemia | not applicable | N/A | Guideline | Prognostic | The presence of at least one mutation in either SH2B3, IDH2, U2AF1, SRSF2, SF3B1, EZH2, TP53, or RUNX1 is associated with inferior overall survival in patients with essential thrombocythemia (NCCN.org). | detail... |
| IDH2 mutant | acute myeloid leukemia | sensitive | Azacitidine + Enasidenib | Guideline | Actionable | Idhifa (enasidenib) in combination with Vidaza (azacitidine) is included in guidelines (category 2B) for patients with acute myeloid leukemia harboring an IDH2 mutation (NCCN.org). | detail... |
| IDH2 mutant | acute myeloid leukemia | predicted - sensitive | Olaparib | Preclinical - Patient cell culture | Actionable | In a preclinical study, cells from a patient with acute myeloid leukemia harboring an IDH2 mutation were sensitive to treatment with Lynparza (olaparib) in culture, demonstrating decreased colony formation (PMID: 29339439). | 29339439 |
| IDH2 mutant | high grade glioma | not applicable | N/A | Guideline | Prognostic | IDH2 mutations are associated with a favorable prognosis in patients with glioma, and are associated with a survival benefit for patients treated with radiation or alkylator therapy (NCCN.org). | detail... |
| IDH2 mutant | high grade glioma | not applicable | N/A | Guideline | Diagnostic | IDH2 mutations aid in the diagnosis of gliomas (NCCN.org). | detail... |
| IDH2 mutant | acute myeloid leukemia | sensitive | Enasidenib | FDA approved - Has Companion Diagnostic | Actionable | In a Phase I/II trial that supported FDA approval, Idhifa (enasidenib) treatment resulted in an overall response rate of 40.3% (71/176) with a median response duration of 5.8 months, complete remission in 19.3% (34/176), and stable disease in 48.3% (85/176) of acute myeloid leukemia patients harboring IDH2 mutations (R140Q/L/G/W, R172K/M/G/S/W) (PMID: 28588020; NCT01915498). | 28588020 detail... detail... |
| IDH2 mutant | acute myeloid leukemia | sensitive | Enasidenib | Guideline | Actionable | Idhifa (enasidenib) is included in guidelines for patients with relapsed or refractory acute myeloid leukemia harboring an IDH2 mutation (NCCN.org). | detail... |
| IDH2 mutant | acute myeloid leukemia | sensitive | Azacitidine | Guideline | Actionable | Vidaza (azacitidine) is included in guidelines for adult patients with acute myeloid leukemia harboring an IDH2 mutation (NCCN.org). | detail... |
| IDH2 mutant | myelofibrosis | not applicable | N/A | Guideline | Diagnostic | IDH2 mutations aid in the diagnosis of primary myelofibrosis in the absence of JAK2, CALR, or MPL mutations (NCCN.org). | detail... |
| IDH2 mutant | myelofibrosis | not applicable | N/A | Guideline | Prognostic | IDH2 mutations are associated with inferior leukemia-free survival in patients with myelofibrosis (NCCN.org). | detail... |
| IDH2 mutant | acute myeloid leukemia | predicted - sensitive | Venetoclax | Phase II | Actionable | In a Phase II trial, 33% (4/12) of acute myeloid leukemia patients harboring either IDH1 or IDH2 mutations responded to treatment with Venclexta (venetoclax), demonstrating a complete response or complete response with incomplete blood count recovery (PMID: 27520294). | 27520294 |
| IDH2 mutant | acute myeloid leukemia | predicted - sensitive | Daunorubicin + Talazoparib | Preclinical - Patient cell culture | Actionable | In a preclinical study, the combination therapy of Talzenna (talazoparib) and Cerubidine (daunoruibicin) resulted in an additive effect in cells from a patient with acute myeloid leukemia harboring an IDH2 mutation, demonstrating decreased colony formation in culture (PMID: 29339439). | 29339439 |
| IDH2 mutant | acute myeloid leukemia | sensitive | Decitabine | Guideline | Actionable | Dacogen (decitabine) is included in guidelines for adult patients with acute myeloid leukemia harboring an IDH2 mutation (NCCN.org). | detail... |
| IDH2 mutant | angioimmunoblastic T-cell lymphoma | not applicable | N/A | Guideline | Diagnostic | IDH2 mutations aid in the diagnosis of angioimmunoblastic T-cell lymphoma (NCCN.org). | detail... |
| IDH2 mutant | acute myeloid leukemia | sensitive | Cytarabine + Venetoclax | Guideline | Actionable | Venclexta (venetoclax) in combination with Cytosar-U (cytarabine) is included in guidelines for adult patients with acute myeloid leukemia harboring an IDH2 mutation (NCCN.org). | detail... |
| IDH2 mutant | acute myeloid leukemia | sensitive | Cytarabine + Venetoclax | Phase Ib/II | Actionable | In a Phase I/II trial, Venclexta (venetoclax) in combination with low-dose cytarabine resulted in complete remission or complete remission with incomplete count recovery in 72% (13/18) of patients with acute myeloid leukemia harboring IDH1 or IDH2 mutations who were ineligible for intensive chemotherapy (ASH Annual Meeting, Dec 2018, Abstract 284; NCT02287233). | detail... |
| IDH2 mutant | acute myeloid leukemia | predicted - sensitive | Daunorubicin + Olaparib | Preclinical - Patient cell culture | Actionable | In a preclinical study, the combination therapy of Lynparza (olaparib) and Cerubidine (daunoruibicin) resulted in an additive effect in cells from a patient with acute myeloid leukemia harboring an IDH2 mutation, demonstrating decreased colony formation in culture (PMID: 29339439). | 29339439 |