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Gene | FLT3 |
Variant | D835X |
Impact List | missense |
Protein Effect | unknown |
Gene Variant Descriptions | FLT3 D835X indicates any Flt3 missense mutation that results in the replacement of the aspartic acid (D) at amino acid 835 by a different amino acid. FLT3 codon 835 mutations are hotspot mutations that often result in constitutive phosphorylation of Flt3 and activation of downstream signaling (PMID: 11290608, PMID: 15256420). |
Associated Drug Resistance | |
Category Variants Paths |
FLT3 mutant FLT3 exon20 FLT3 D835X |
Transcript | NM_004119.3 |
gDNA | chr13:g.28018503_28018505 |
cDNA | c.2503_2505 |
Protein | p.D835 |
Source Database | RefSeq |
Genome Build | GRCh38/hg38 |
Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
---|---|---|---|---|---|
NM_004119 | chr13:g.28018503_28018505 | c.2503_2505 | p.D835 | RefSeq | GRCh38/hg38 |
NM_004119.3 | chr13:g.28018503_28018505 | c.2503_2505 | p.D835 | RefSeq | GRCh38/hg38 |
NM_004119.2 | chr13:g.28018503_28018505 | c.2503_2505 | p.D835 | RefSeq | GRCh38/hg38 |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
---|---|---|---|---|---|---|---|
FLT3 D835X | acute myeloid leukemia | sensitive | Crenolanib | Phase I | Actionable | In a Phase I trial, Crenolanib treatment resulted in an overall survival (OS) of 185 days in AML patients harboring FLT3 D835X that received no prior therapy (J Clin Oncol 34, 2016 (suppl; abstr 7008)). | detail... |
FLT3 D835X | 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 D835X | acute myeloid leukemia | sensitive | Cytarabine + Daunorubicin + Midostaurin | FDA approved - On 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 (74.7 mo vs 25.6 mo) in patients with FLT3-mutant (D835X and I836X) or FLT3-ITD (exon 14 insertions) acute myeloid leukemia compared to Cytosar-U (cytarabine) and Daunorubicin with placebo (PMID: 28644114). | detail... 28644114 detail... |
FLT3 D835X | acute myeloid leukemia | sensitive | Gilteritinib | FDA approved - On 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... 31665578 detail... |
FLT3 D835X | myelodysplastic syndrome | not applicable | N/A | Guideline | Prognostic | FLT3 D835 mutations are associated with poor prognosis in patients with myelodysplastic syndromes (NCCN.org). | detail... |
FLT3 D835X | acute myeloid leukemia | predicted - sensitive | LAM-003 | Preclinical - Patient cell culture | Actionable | In a preclinical study, patient-derived acute myeloid leukemia cells harboring FLT3 D835X demonstrated sensitivity to LAM-003 treatment in culture (PMID: 31751472). | 31751472 |
FLT3 D835X | acute myeloid leukemia | sensitive | Azacitidine + Gilteritinib + Venetoclax | Phase Ib/II | Actionable | In a Phase I/II trial, Venclexta (venetoclax), Vidaza (azacitidine), and Xospata (gilteritinib) treatment demonstrated safety in acute myeloid leukemia patients with FLT3-ITD or FLT3 D835 mutations and led to a combined complete remission (CR)/CR with incomplete hematologic recovery (CR/CRi) rate of 96% and a median relapse-free survival and median overall survival not reached in newly diagnosed patients (n=30), and a CR/CRi rate of 27% in relapsed/refractory patients (n=22) (PMID: 38277619; NCT04140487). | 38277619 |