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| Gene | FLT3 |
| Variant | F590_Y591delinsGD |
| Impact List | indel |
| Protein Effect | gain of function |
| Gene Variant Descriptions | FLT3 F590_Y591delinsGD results in a deletion of 2 amino acids in the juxtamembrane domain of the Flt3 protein from amino acids 590 to 591, combined with the insertion of a glycine (G) and an aspartic acid (D) at the same site (PMID: 11756186). F590_Y591delinsGD results in constitutive phosphorylation of Flt3, activation of Stat5 signaling, and transformation of cells in culture (PMID: 16410449). |
| Associated Drug Resistance | |
| Category Variants Paths |
FLT3 mutant FLT3 act mut FLT3 F590_Y591delinsGD FLT3 mutant FLT3 exon14 FLT3 F590_Y591delinsGD |
| Transcript | NM_004119.3 |
| gDNA | chr13:g.28034146_28034151delinsGTCACC |
| cDNA | c.1768_1773delinsGGTGAC |
| Protein | p.F590_Y591delinsGD |
| Source Database | RefSeq |
| Genome Build | GRCh38/hg38 |
| Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
|---|---|---|---|---|---|
| NM_004119 | chr13:g.28034146_28034151delinsGTCACC | c.1768_1773delinsGGTGAC | p.F590_Y591delinsGD | RefSeq | GRCh38/hg38 |
| NM_004119.3 | chr13:g.28034146_28034151delinsGTCACC | c.1768_1773delinsGGTGAC | p.F590_Y591delinsGD | RefSeq | GRCh38/hg38 |
| NM_004119.2 | chr13:g.28034146_28034151delinsGTCACC | c.1768_1773delinsGGTGAC | p.F590_Y591delinsGD | RefSeq | GRCh38/hg38 |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| FLT3 exon14 | acute myeloid leukemia | sensitive | Midostaurin | Guideline | Actionable | Rydapt (midostaurin) is included in guidelines as maintenance therapy for patients with acute myeloid leukemia harboring a mutation in the FLT3 tyrosine kinase domain (exons 14-23) (NCCN.org). | detail... |
| FLT3 exon14 | acute myeloid leukemia | sensitive | Cytarabine + Daunorubicin + Midostaurin | Guideline | Actionable | Rydapt (midostaurin), in combination with Cerubidine (daunorubicin) and Cytosar-U (cytarabine), is included in guidelines for patients with acute myeloid leukemia harboring a mutation in the FLT3 tyrosine kinase domain (exons 14-23) (NCCN.org). | detail... |
| FLT3 exon14 | acute myeloid leukemia | sensitive | Cytarabine + Daunorubicin + Midostaurin | Guideline | Actionable | Rydapt (midostaurin), in combination with Cerubidine (daunorubicin) and Cytosar-U (cytarabine), is included in guidelines as first-line treatment for patients with acute myeloid leukemia harboring a mutation in the FLT3 tyrosine kinase domain (exons 14-23) (PMID: 32171751; ESMO.org). | 32171751 detail... |
| FLT3 exon14 | acute myeloid leukemia | sensitive | Gilteritinib | Guideline | Actionable | Xospata (gilteritinib) is included in guidelines for patients with relapsed or refractory acute myeloid leukemia harboring a mutation in the FLT3 tyrosine kinase domain (exons 14-23) (PMID: 32171751; ESMO.org). | detail... 32171751 |
| FLT3 exon14 | acute myeloid leukemia | sensitive | Gilteritinib | Guideline | Actionable | Xospata (gilteritinib) is included in guidelines for patients with relapsed or refractory acute myeloid leukemia harboring a mutation in the FLT3 tyrosine kinase domain (exons 14-23) (NCCN.org). | detail... |
| FLT3 exon14 | acute myeloid leukemia | sensitive | Cytarabine + Midostaurin | Guideline | Actionable | Rydapt (midostaurin) in combination with Cytosar-U (cytarabine) is included in guidelines as consolidation therapy for patients with acute myeloid leukemia harboring a mutation in the FLT3 tyrosine kinase domain (exons 14-23) (NCCN.org). | detail... |
| FLT3 exon14 | acute myeloid leukemia | sensitive | Cytarabine + Idarubicin + Midostaurin | Guideline | Actionable | Rydapt (midostaurin) in combination with Idamycin (idarubicin) and Cytosar-U (cytarabine) is included in guidelines for patients with acute myeloid leukemia harboring a mutation in the FLT3 tyrosine kinase domain (exons 14-23) (NCCN.org). | detail... |
| FLT3 mutant | acute myeloid leukemia | sensitive | Azacitidine + Midostaurin | Phase Ib/II | Actionable | In a Phase Ib/II trial, acute myeloid leukemia patients harboring a FLT3 mutation demonstrated an improved remission duration when treated with the combination therapy, Rydapt (midostaurin) and Vidaza (azacitidine) (PMID: 25530214). | 25530214 |
| FLT3 mutant | acute myeloid leukemia | sensitive | Cytarabine + Daunorubicin + Midostaurin | Phase Ib/II | Actionable | In a Phase Ib clinical trial, Rydapt (midostaurin) treatment after Daunorubicin and Cytosar-U (cytarabine) induction resulted in complete remission in 92% (12/13) of acute myeloid leukemia patients carrying FLT3 mutations, although overall survival rate was similar to patients with wild-type FLT3 (PMID: 22627678). | 22627678 |
| FLT3 mutant | acute myeloid leukemia | sensitive | Cytarabine + Daunorubicin + Midostaurin | FDA approved - Has Companion Diagnostic | Actionable | In a Phase III trial that supported FDA approval, treatment with Rydapt (midostaurin), combined with Cytosar-U (cytarabine) and Daunorubicin, improved overall survival (HR=0.78, p=0.009) and event-free survival (HR=0.78, p=0.002) in patients with FLT3-mutant (ITD, D835X, and I836X mutations) acute myeloid leukemia compared to Cytosar-U (cytarabine) and Daunorubicin with placebo (PMID: 28644114; NCT00651261). | 28644114 detail... detail... |
| FLT3 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 a FLT3 mutation (NCCN.org). | detail... |
| FLT3 mutant | acute myeloid leukemia | sensitive | UNC2025 | Preclinical | Actionable | In a preclinical study, UNC2025 inhibited FLT3 activation and growth of acute myeloid leukemia cells harboring a FLT3-ITD mutation in culture (PMID: 25068800). | 25068800 |
| FLT3 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 44% (7/16) of patients with acute myeloid leukemia harboring FLT3 mutations who were ineligible for intensive chemotherapy (ASH Annual Meeting, Dec 2018, Abstract 284; NCT02287233). | detail... |
| FLT3 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 a FLT3 mutation (NCCN.org). | detail... |
| FLT3 mutant | acute myeloid leukemia | sensitive | Crenolanib | Phase I | Actionable | In a Phase I trial, Crenolanib treatment resulted in complete response (CR) in 39% (7/18), partial response (PR) in 11% (2/18), and an overall survival (OS) of 234 days in AML patients harboring FLT3 mutations (D835X, ITD, or both) that received no prior therapy, and CR in 17% (6/36), PR in 14% (5/36), and OS of 94 days in those progressed on TKIs (J Clin Oncol 34, 2016 (suppl; abstr 7008)). | detail... |
| FLT3 mutant | acute myeloid leukemia | sensitive | Zotiraciclib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Zotiraciclib (TG02) inhibited growth of FLT3-mutated acute myeloid leukemia cells in culture, resulted in complete tumor regression in cell line xenograft animal models (PMID: 21860433). | 21860433 |
| FLT3 mutant | acute myeloid leukemia | sensitive | Gilteritinib | Phase Ib/II | Actionable | In a Phase I/II trial, treatment with Gilteritinib (ASP2215) resulted in an overall response rate of 49% (93/191) in patients with relapsed or refractory acute myeloid leukemia harboring FLT3 mutations, compared to 12% (7/58) in patients with wild-type FLT3 (PMID: 28645776; NCT02014558). | detail... 28645776 |
| FLT3 mutant | acute myeloid leukemia | sensitive | Gilteritinib | FDA approved - Has Companion Diagnostic | Actionable | In a Phase III trial (ADMIRAL) that supported FDA approval, Xospata (gilteritinib) improved median overall survival (9.3 vs 5.6 mo, HR. 0.64, p<0.001) compared to chemotherapy, resulted in superior median event-free survival (2.8 vs 0.7 mo, HR 0.79) and rate of complete remission with full or partial hematologic recovery (34.0% vs 15.3%) in patients with relapsed or refractory acute myeloid leukemia harboring a FLT3 internal tandem duplication (ITD), D835, or I836 mutation (PMID: 31665578; NCT02421939). | detail... detail... 31665578 |
| FLT3 mutant | acute myeloid leukemia | sensitive | Selinexor + Sorafenib | Phase Ib/II | Actionable | In a Phase I/II trial, combination of Selinexor and Nexavar (sorafenib) treatment resulted in complete remission in 29% (4/14) and more than 50% blast reduction in 14% (2/14) of patients with acute myeloid leukemia harboring FLT3 ITD and/or D835 mutations (ASH, 59th Annual Meeting and Exposition, Dec 2017, Abstract 1344; NCT01607892). | detail... |
| FLT3 mutant | acute myeloid leukemia | sensitive | E6201 | Preclinical | Actionable | In a preclinical study, acute myeloid leukemia cell lines harboring FLT3 mutations demonstrated increased sensitivity to E6201 induced growth inhibition and apoptosis in culture compared to FLT3 wild-type cells (PMID: 26822154). | 26822154 |
| FLT3 mutant | acute myeloid leukemia | predicted - sensitive | ERAS-601 + Gilteritinib | Preclinical | Actionable | In a preclinical study, the combination of ERAS-601 and Xospata (gilteritinib) demonstrated synergy, resulting in decreased viability of acute myeloid leukemia cells harboring FLT3 mutations in culture and inhibition of tumor growth in in vivo models (Cancer Res (2022) 82 (12_Supplement): 3345). | detail... |
| FLT3 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 a FLT3 mutation (NCCN.org). | detail... |
| FLT3 act mut | leukemia | sensitive | Pexidartinib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, PLX3397 inhibited FLT3 autophosphorylation in leukemia cells overexpressing FLT3 or harboring FLT3 activating mutations, and inhibited growth of leukemia cells harboring FLT3-ITD mutations in culture and in cell line xenograft models (ASH Annual Meeting Abstracts 2011 118: 3632). | detail... |
| FLT3 act mut | acute myeloid leukemia | sensitive | TCS 359 | Preclinical | Actionable | In a preclinical study, TCS-359 inhibited growth of FLT3-ITD positive acute myeloid leukemia cell lines in culture (PMID: 27099147). | 27099147 |
| FLT3 act mut | acute myeloid leukemia | sensitive | VS-5584 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, VS-5584 inhibited PI3K/mTOR signaling and cell proliferation in a FLT3-ITD positive human acute myeloid leukemia cell line in culture, and inhibited tumor growth in xenograft models (PMID: 23270925). | 23270925 |
| FLT3 act mut | acute myeloid leukemia | sensitive | Palbociclib + SGI-1776 | Preclinical | Actionable | In a preclinical study, Ibrance (palbociclib) and SGI-1776 were synergistic towards growth inhibition of FLT3-ITD positive acute myeloid leukemia cell lines in culture (PMID: 27099147). | 27099147 |
| FLT3 act mut | acute myeloid leukemia | sensitive | Cytarabine + Daunorubicin + Sunitinib | Phase Ib/II | Actionable | In a Phase Ib/II trial, 59% (13/22) of acute myeloid leukemia patients harboring FLT3 activating mutations achieved complete remission following treatment with Sutent (sunitinib) in combination with Cytarabine and Daunorubicin (PMID: 25818407). | 25818407 |
| FLT3 act mut | acute myeloid leukemia | sensitive | Palbociclib + Tandutinib | Preclinical | Actionable | In a preclinical study, Ibrance (palbociclib) and tandutinib (MLN518) were synergistic towards growth inhibition of FLT3-ITD positive acute myeloid leukemia cell lines in culture (PMID: 27099147). | 27099147 |
| FLT3 act mut | acute myeloid leukemia | sensitive | Palbociclib + Quizartinib | Preclinical | Actionable | In a preclinical study, Ibrance (palbociclib) and Vanflyta (quizartinib) were synergistic towards growth inhibition of FLT3-ITD positive acute myeloid leukemia cell lines in culture (PMID: 27099147). | 27099147 |
| FLT3 act mut | acute myeloid leukemia | sensitive | Palbociclib + TCS 359 | Preclinical | Actionable | In a preclinical study, Ibrance (palbociclib) following TCS-359 treatment enhanced growth inhibition of FLT3-ITD positive acute myeloid leukemia cell lines in culture (PMID: 27099147). | 27099147 |
| FLT3 act mut | acute myeloid leukemia | predicted - sensitive | NMS-P088 | Phase I | Actionable | In a Phase I trial, NMS-P088 demonstrated manageable safety and preliminary efficacy with responses in 5 of 12 patients with acute myeloid leukemia harboring FLT3 mutations (Cancer Res (2023) 83 (8_Supplement): CT025; NCT03922100). | detail... |
| FLT3 act mut | acute myeloid leukemia | sensitive | Crenolanib | Phase II | Actionable | In a Phase II trial, relapsed or refractory acute myeloid leukemia patients harboring FLT3 activating mutations without a history of FLT3 therapy demonstrated a significantly greater overall survival and event free survival compared to those that had prior FLT3 therapy when treated with Crenolanib (ASH meeting, Dec 2014, abstract #389). | detail... |
| FLT3 act mut | acute myeloid leukemia | sensitive | Gilteritinib + Venetoclax | Phase I | Actionable | In a Phase Ib trial, combination treatment with Venclexta (venetoclax) and Xospata (gilteritinib) demonstrated clinical activity in patients with acute myeloid leukemia harboring FLT3 internal tandem duplication or tyrosine kinase domain mutations, leading to a a modified composite complete response (mCRc) rate of 75% (42/56), duration of response of 4.9 mo., and median overall survival of 10 mo., with a mCRc rate of 56% (5/9) in patients with tyrosine kinase domain mutations (PMID: 35849791; NCT03625505). | 35849791 |
| FLT3 act mut | acute myeloid leukemia | sensitive | Palbociclib | Preclinical | Actionable | In a preclinical study, Ibrance (palbociclib) blocked growth, induced apoptosis, and inhibited STAT activation in human FLT3-ITD positive human acute myeloid leukemia cells in culture (PMID: 27099147). | 27099147 |
| FLT3 act mut | acute myeloid leukemia | predicted - sensitive | Azacitidine + Glasdegib | Case Reports/Case Series | Emerging | In a Phase Ib trial, the combination of Daurismo (glasdegib) and Vidaza (azacitidine) resulted in an improved overall survival in acute myeloid leukemia patients harboring FLT3 mutations compared to those with wild-type FLT3 (P=0.039) (PMID: 35488900; NCT02367456). | 35488900 |
| FLT3 act mut | acute myeloid leukemia | predicted - sensitive | BMF-500 | Preclinical | Actionable | In a preclinical study, BMF-500 inhibited Flt3 phosphorylation and downstream signaling and decreased viability of acute myeloid leukemia cell lines harboring FLT3 activating mutations in culture and induced tumor regression and improved survival in xenograft models (Blood (2022) 140 (Supplement 1): 6191-6192). | detail... |