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    BIOMARKER:

    FLT3 D835

    i
    Other names: FLT3, Fms Related Tyrosine Kinase 3, Receptor-Type Tyrosine-Protein Kinase FLT3, Stem Cell Tyrosine Kinase 1, Fms-Like Tyrosine Kinase 3, CD135, FLK-2, STK1, Growth Factor Receptor Tyrosine Kinase Type III, Fetal Liver Kinase 2
    Entrez ID:
    2322
    Related biomarkers:
    Expression
    Mutation
    CNA
    Fusion
    Others
    Related tests:
    10d
    Target-Capture Next-Generation Sequencing (NGS) for Use in Molecular-Based Research of Myeloid Measurable Residual Disease (MRD) (AMP 2024)
    Target-capture NGS provides the opportunity to evaluate many genes in a single assay. Suitability for MRD requires highly uniform and sensitive target enrichment. Our study demonstrated reliable and accurate detection of variants down to 0.05% VAF, providing researchers with the capability to use capture-based NGS for myeloid MRD monitoring.
    Next-generation sequencing
    |
    FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • JAK2 (Janus kinase 2)
    |
    FLT3-ITD mutation • NPM1 mutation • FLT3 D835Y • FLT3 D835 • IDH2 R172K • KIT D816V • IDH1 R132C • JAK2 V617F • IDH1 R132 • IDH2 R172
    |
    SureSeq™ Myeloid MRD Panel
    2ms
    ADMIRAL: A Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation (clinicaltrials.gov)
    P3, N=371, Active, not recruiting, Astellas Pharma Global Development, Inc. | Trial completion date: Aug 2024 --> Dec 2024
    Trial completion date
    |
    FLT3 (Fms-related tyrosine kinase 3)
    |
    FLT3-ITD mutation • FLT3 mutation • FLT3 D835 • FLT3 I836
    |
    cytarabine • Xospata (gilteritinib) • azacitidine • etoposide IV • idarubicin hydrochloride • mitoxantrone • fludarabine IV
    6ms
    Structure-Based Optimization of Pyrazinamide-Containing Macrocyclic Derivatives as Fms-like Tyrosine Kinase 3 (FLT3) Inhibitors to Overcome Clinical Mutations. (PubMed, ACS Pharmacol Transl Sci)
    Furthermore, 8v demonstrated ideal anticancer efficacy in a Ba/F3-FLT3-ITD-D835Y xenograft model. The results suggested that 8v can serve as a promising macrocycle-based FLT3 inhibitor for the treatment of AML.
    Journal
    |
    FLT3 (Fms-related tyrosine kinase 3)
    |
    FLT3 mutation • FLT3 D835Y • FLT3 F691L • FLT3 D835 • FLT3-ITD mutation + FLT3 D835Y + FLT3 F691L
    8ms
    NCI-2019-04959: Azacitidine, Venetoclax, and Gilteritinib in Treating Patients With Recurrent/Refractory FLT3-Mutated Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia, or High-Risk Myelodysplastic Syndrome/Myeloproliferative Neoplasm (clinicaltrials.gov)
    P1/2, N=55, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=42 --> 55
    Enrollment closed • Enrollment change
    |
    FLT3 (Fms-related tyrosine kinase 3)
    |
    FLT3-ITD mutation • FLT3 mutation • FLT3 D835
    |
    Venclexta (venetoclax) • Xospata (gilteritinib)
    9ms
    FRIDA: Study of Iadademstat and Gilteritinib in Patients With R/R AML With FMS-like Tyrosine Kinase Mutation (FLT3 Mut+) (clinicaltrials.gov)
    P1, N=50, Recruiting, Oryzon Genomics S.A. | Trial primary completion date: Jan 2024 --> Jan 2025
    Trial primary completion date
    |
    FLT3 (Fms-related tyrosine kinase 3)
    |
    FLT3 mutation • FLT3 D835 • FLT3 I836
    |
    Xospata (gilteritinib) • iadademstat (ORY-1001)
    10ms
    OGILAR: Study Investigating the Efficacy and Safety of the Addition of Oral-azacitidine to Salvage Treatment by Gilteritinib in Subjects ≥18 Years of Age With Relapsed/Refractory FLT3-mutated Acute Myeloid Leukemia (clinicaltrials.gov)
    P2, N=33, Recruiting, French Innovative Leukemia Organisation | Not yet recruiting --> Recruiting
    Enrollment open
    |
    FLT3 (Fms-related tyrosine kinase 3)
    |
    FLT3 mutation • FLT3 D835 • FLT3 I836
    |
    Xospata (gilteritinib) • Onureg (azacitidine oral)
    11ms
    Crenolanib Maintenance Following Allogeneic Stem Cell Transplantation in FLT3-positive Acute Myeloid Leukemia Patients (clinicaltrials.gov)
    P2, N=30, Completed, Arog Pharmaceuticals, Inc. | Active, not recruiting --> Completed | N=48 --> 30
    Trial completion • Enrollment change
    |
    HLA-DRB1 (Major Histocompatibility Complex, Class II, DR Beta 1)
    |
    FLT3 D835
    |
    crenolanib (ARO-002)
    12ms
    An imidazo[1,2-a]pyridine-pyridine derivative potently inhibits FLT3-ITD and FLT3-ITD secondary mutants, including gilteritinib-resistant FLT3-ITD/F691L. (PubMed, Eur J Med Chem)
    Recently, several FLT3 inhibitors have demonstrated clinical activity and three are currently approved - midostaurin, quizartinib, and gilteritinib. In summary, compound 24 has inhibition potency on FLT3 comparable to gilteritinib, but a more balanced inhibition on FLT3 secondary mutations, especially FLT3-ITD/F691L which is gilteritinib resistant. Compound 24 may serve as a promising lead for the drug development of either primary or relapsed AML with FLT3 secondary mutations.
    Journal
    |
    FLT3 (Fms-related tyrosine kinase 3)
    |
    FLT3-ITD mutation • FLT3 mutation • FLT3 D835Y • FLT3 F691L • FLT3 D835
    |
    Xospata (gilteritinib) • Rydapt (midostaurin) • Vanflyta (quizartinib)
    12ms
    Discovery of benzimidazole-indazole derivatives as potent FLT3-tyrosine kinase domain mutant kinase inhibitors for acute myeloid leukemia. (PubMed, Eur J Med Chem)
    More importantly, 22f showed single-digit nanomolar GI values in the mutant FLT kinase expressed Ba/F3 cell lines including FLT-D835Y (GI = 0.29 nM) and FLT3-F691L (GI = 2.87 nM). Molecular docking studies indicated that the compound exhibits a well-fitted binding mode as a type 1 inhibitor in the homology model of active conformation of FLT3 kinase.
    Journal
    |
    FLT3 (Fms-related tyrosine kinase 3)
    |
    FLT3 mutation • FLT3 D835Y • FLT3 F691L • FLT3 D835
    almost1year
    N-(3-Methoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine is an inhibitor of the FLT3-ITD and BCR-ABL pathways, and potently inhibits FLT3-ITD/D835Y and FLT3-ITD/F691L secondary mutants. (PubMed, Bioorg Chem)
    Studies indicate that it mediates proapoptotic effects on cells by inhibiting FLT3 and BCR-ABL pathways, and other possible targets. Compound 1 is more potent against FLT3-ITD than BCR-ABL, and it may have other possible targets; however, compound 1 is first step for further optimization for the development of a balanced FLT3-ITD/BCR-ABL dual inhibitor for the treatment of relapsed FLT3-ITD mutated AML with multiple secondary clinical resistant subtypes such as FLT3-ITD/D835Y, FLT3-ITD/F691L, and cells co-expressing FLT3-ITD and BCR-ABL.
    Journal
    |
    FLT3 (Fms-related tyrosine kinase 3) • ABL1 (ABL proto-oncogene 1) • BCR (BCR Activator Of RhoGEF And GTPase)
    |
    FLT3-ITD mutation • FLT3 mutation • FLT3 D835Y • FLT3 F691L • FLT3 D835 • FLT3 expression • FLT3-ITD expression
    1year
    Design, synthesis and biological evaluation of 2-aminopyrimidine derivatives as potent FLT3 inhibitors. (PubMed, Bioorg Med Chem Lett)
    Compound 15 also possessed potent antiproliferative activities against BaF3 cells carrying various FLT3-TKD and FLT3-ITD-TKD mutations, indicating its potential to overcome on-target resistance caused by FLT3 mutations. In summary, compound 15 showed promising potential for further exploration as a treatment of AML.
    Journal
    |
    FLT3 (Fms-related tyrosine kinase 3)
    |
    FLT3-ITD mutation • FLT3 mutation • FLT3 D835Y • FLT3 D835 • FLT3-ITD mutation + FLT3-TKD mutation
    1year
    A Phase 2 Study of Ponatinib for Prevention of Relapse after Allotransplantation in FLT3-ITD + AML Patients : The Ponallo Trial (ASH 2023)
    (Table 2) Conclusion : Ponatinib administration after allo-SCT is associated with toxicity and do not reduce relapse or improve survival in this small cohort of FLT3+ AML patients. Other FLT3 inhibitors have to be considered in FLT3+ AML patients for maintenance after allo-SCT.
    Clinical • P2 data
    |
    FLT3 (Fms-related tyrosine kinase 3)
    |
    FLT3 mutation • FLT3 D835
    |
    Iclusig (ponatinib)
    1year
    Kme-0584, a Highly Potent IRAK1/IRAK4/panFLT3 Inhibitor, Is a Promising Clinical Candidate for Hypomethylating Agent Plus Venetoclax Resistant AML/MDS Patients (ASH 2023)
    In primary patient cell lines from FLT3 wildtype (WT) patients, KME-0584 inhibits leukemia stem cell progenitor function as measured by the colony formation assay in methylcellulose with higher potency than IRAK4 inhibitor compounds that lack IRAK1 activity such as CA-4948 (Emavusertib)...Given that monocytic-like subtypes of AML are resistant to Venetoclax plus Azacitidine (VEN/AZA) (S Pei et...KME-0584 exhibits superior potency and efficacy to gilteritinib in the FLT3-ITD (D835Y) xenograft model after QD oral dosing, with sufficient PK and oral bioavailability across multiple species to support QD or BID dosing in the clinic. KME-0584 does not inhibit any of the major or minor cytochrome P450 enzymes at anticipated clinical concentrations and early indication from ongoing GLP toxicology studies suggest that it could be safely administered in humans. A clinical study of KME-0584 in relapsed/refractory AML and HR-MDS is currently planned to start in 1H 2024.
    Clinical
    |
    FLT3 (Fms-related tyrosine kinase 3) • SF3B1 (Splicing Factor 3b Subunit 1) • PDGFRB (Platelet Derived Growth Factor Receptor Beta) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • GLI2 (GLI Family Zinc Finger 2) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
    |
    FLT3 mutation • FLT3 D835Y • FLT3 D835 • U2AF1 mutation • FLT3 wild-type
    |
    Venclexta (venetoclax) • Xospata (gilteritinib) • azacitidine • emavusertib (CA-4948)
    1year
    Clonal Medicine Targeting DNA Damage Response Eradicates AML (ASH 2023)
    The "clonal attack" by DDR inhibitors shifts the paradigm of genotoxic therapies from those using non-discriminative cytotoxic drugs to those selectively attacking DDR vulnerabilities in AML clones with minimal harm to normal cells. Since clonal heterogeneity and DNA damage are hallmarks of cancer, the "clonal attack" may be broadly applicable to the quest for cancer cure.
    PARP Biomarker
    |
    FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • RAD51 (RAD51 Homolog A) • PML (Promyelocytic Leukemia) • CD34 (CD34 molecule) • PARP1 (Poly(ADP-Ribose) Polymerase 1) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • RAD52 (RAD52 Homolog DNA Repair Protein)
    |
    FLT3-ITD mutation • FLT3 mutation • DNMT3A mutation • FLT3 D835Y • FLT3 D835 • NRAS G13 • NRAS G13R
    1year
    PHI-101 As a Potent Next-Generation FLT3 Inhibitor, Overcome Resistances in Previously Treated Patients with FLT3-ITD or TKD Acute Myeloid Leukemia: Results of a Phase Ia/Ib Clinical Trial (ASH 2023)
    Ten pts were R/R following previous treatment with other FLT3 inhibitors (gilteritinib, quizartinib, midostaurin, or HM43239). In dose-escalating phase Ia clinical trials, PHI-101 was well tolerated at all dose levels with no DLTs. Phase Ib dose-expansion trials with 160 mg daily dosing are currently ongoing. PHI-101 has delivered CRcs at 120 mg and 160 mg.
    Clinical • P1 data
    |
    FLT3 (Fms-related tyrosine kinase 3)
    |
    FLT3-ITD mutation • FLT3 mutation • FLT3 D835 • FLT3 N676K • FLT3 wild-type • FLT3 D835E
    |
    Xospata (gilteritinib) • Rydapt (midostaurin) • Vanflyta (quizartinib) • PHI-101 • tuspetinib (HM43239)
    1year
    The Shifting Prognosis of FLT3 Mutations in Acute Myeloid Leukemia in the Era of Targeted Therapy: A Real-World Study Using Large-Scale Electronic Health Record Data (ASH 2023)
    Patients were excluded if they received gilteritinib, sorafenib, or midostaurin but were diagnosed before midostaurin's approval...In a Cox regression, the interaction term was similar (HR 0.54, p = 0.021), with a HR that compared favorably to 0.78, the HR seen in phase III clinical trials studying midostaurin or quizartinib at diagnosis (Stone et al., NEJM, 2017; Erba et al., Lancet, 2023)... The relative prognosis of FLT3 mutations in AML has improved, including in older patients, likely due to the approval of FLT3 inhibitors, and the relative survival is more favorable than what was described in major clinical trials. Gathering real-world data to estimate prognosis of FLT3 mutations is crucial for accurate risk stratification, and this can be done more easily with EHR data.
    Clinical • Real-world evidence • Real-world
    |
    FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1)
    |
    FLT3-ITD mutation • FLT3 mutation • NPM1 mutation • FLT3 D835
    |
    sorafenib • Xospata (gilteritinib) • Rydapt (midostaurin) • Vanflyta (quizartinib)
    1year
    Persistence of FLT3-TKD in Blood Prior to Allogeneic Transplant Is Associated with Increased Relapse and Death in Adults with AML in First Remission (ASH 2023)
    Detectable persistence of FLT3-TKD variants in blood from AML patients in first remission prior to first alloHCT is rare, but at a VAF level of 0.1% was strongly associated with increased relapse and death after transplant compared to those testing negative. In contrast to FLT3-ITD NGS-MRD, no evidence was found to support lowering the NGS-MRD VAF threshold from 0.1% to 0.01% for FLT3-TKD. Alternative methodology may further improve NGS-MRD test performance.
    Clinical
    |
    FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1)
    |
    FLT3-ITD mutation • FLT3 D835 • FLT3 I836
    1year
    T-Cell Receptor-Engineered T Cells Targeting FLT3-D835 Mutation-Derived Neoantigens in Acute Myeloid Leukemia (ASH 2023)
    Taken together, we present novel neoantigens with promise as immunotherapy targets for AML and other hematologic malignancies with FLT3-D835 mutations. Future studies will evaluate the efficacy of Neo-D835H-specific TCR-engineered T-cell-based immunotherapy in vivo in patient-derived xenograft murine model and TCR-based therapeutic approaches targeting other FLT3-TKD mutations.
    IO biomarker
    |
    FLT3 (Fms-related tyrosine kinase 3) • CD8 (cluster of differentiation 8) • HLA-A (Major Histocompatibility Complex, Class I, A) • IFNG (Interferon, gamma) • TRB (T Cell Receptor Beta Locus)
    |
    FLT3 mutation • FLT3-TKD mutation • FLT3 D835Y • FLT3 D835 • HLA-A*02:01 • HLA-A*02 • FLT3 D835H
    1year
    BGS-2456 Is a Novel Potent Covalent Inhibitor of FLT3 That Highly Discriminates Against KIT and Is Not Toxic Toward Normal Hematopoiesis in Vitro (ASH 2023)
    While there are numerous examples of KIT TKIs that do not inhibit FLT3 (imatinib, avapritinib, dasatinib), to date, all clinically active FLT3 TKIs (quizartinib, gilteritinib, midostaurin, sorafenib) fail to spare KIT inhibition...Compared to FF-10101 and gilteritinib, BGS-2456 exhibited the least amount of hematologic toxicity, facilitating in vitro proliferation and differentiation of normal hematopoietic progenitor cells even at 100x EC50 concentration against Molm14 cells... This is the first description of a potent and exquisitely specific FLT3 inhibitor that spares KIT inhibition and displays no myelosuppression in vitro at >100x EC50 concentration. The potent inhibitory effects of BGS-2456 on both D835Y and F691L mutants support its promise as a best-in-class TKI for the treatment of FLT3-mutant AML. Efforts to molecularly dissect the basis of the high degree of selectivity of BGS-2456 are ongoing.
    Preclinical
    |
    FLT3 (Fms-related tyrosine kinase 3) • ABL1 (ABL proto-oncogene 1) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • CSF1R (Colony stimulating factor 1 receptor)
    |
    FLT3-ITD mutation • FLT3 mutation • KIT mutation • FLT3 D835Y • FLT3 F691L • FLT3 D835 • PDGFRA mutation • FLT3 D835V • FLT3 F691L + FLT3 D835V • FLT3-ITD mutation + FLT3 D835Y + FLT3 F691L
    |
    dasatinib • sorafenib • imatinib • Xospata (gilteritinib) • Rydapt (midostaurin) • Vanflyta (quizartinib) • Ayvakit (avapritinib) • FF-10101 • BGS-2456
    1year
    Optimizing FLT3 Inhibitor Use in Adult Acute Myeloid Leukemia with FLT3 Mutations Using Proteomics (ASH 2023)
    Of 137 with FLT3 ITD or D835 mutations, 54 who were treated with FLT3I (Sorafenib=22, Quizartinib=11, Midostaurine=6, Gilteritinib=4 and Crenolanib=1) combined with other agents (Hypomethylating agents (HMA)=23, HMA+Venetoclax (VTX)=5, Idarrubicin+Cytarabine (AraC)+Purine Analogs (IA+Pur)=19, IA+Pur+VTX=2, AraC=3, Fludarabine+AraC (FA)=1, none=1) were selected for analyses. Protein profiling identified cohorts of FLT3 mutant patients that achieved the highest benefit from FLT3I addition, regardless of all other clinical or molecular characteristics. We identified targetable proteins that are elevated in adverse signatures, and hypothesized that these may be targets for modulation to improve FLT3I response. Moreover, a small set of 6 proteins accurately classifies patients and could be used clinically to triage patients for treatment recommendation.
    Clinical
    |
    TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • NPM1 (Nucleophosmin 1) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • DNMT3A (DNA methyltransferase 1) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • SLFN11 (Schlafen Family Member 11) • WT1 (WT1 Transcription Factor) • BCL2L11 (BCL2 Like 11) • CD34 (CD34 molecule) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • AKT2 (V-akt murine thymoma viral oncogene homolog 2) • DDB1 (Damage Specific DNA Binding Protein 1) • SIRT6 (Sirtuin 6) • SMARCA2 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2) • AIF1 (Allograft Inflammatory Factor 1) • BBC3 (BCL2 Binding Component 3) • RHEB (Ras Homolog, MTORC1 Binding) • SDHA (Succinate Dehydrogenase Complex Flavoprotein Subunit A)
    |
    TP53 mutation • FLT3-ITD mutation • IDH1 mutation • FLT3 mutation • NPM1 mutation • DNMT3A mutation • ASXL1 mutation • TET2 mutation • FLT3 D835 • CEBPA mutation
    |
    Venclexta (venetoclax) • sorafenib • cytarabine • Xospata (gilteritinib) • Rydapt (midostaurin) • Vanflyta (quizartinib) • crenolanib (ARO-002) • fludarabine IV
    1year
    A T cell receptor targeting a recurrent driver mutation in FLT3 mediates elimination of primary human acute myeloid leukemia in vivo. (PubMed, Nat Cancer)
    TCR cells rejected both CD34 and CD34 AML in mice engrafted with primary leukemia from patients, reaching minimal residual disease-negative levels, and eliminated primary CD34 AML leukemia-propagating cells in vivo. Thus, T cells targeting a single shared mutation can provide efficient immunotherapy toward selective elimination of clonally involved primary AML cells in vivo.
    Preclinical • Journal • IO biomarker
    |
    FLT3 (Fms-related tyrosine kinase 3) • CD34 (CD34 molecule)
    |
    FLT3 mutation • FLT3 D835Y • FLT3 D835
    1year
    Morphological, cytogenetic and molecular characterisation of FLT3 mutations in Pakistani patients with de novo acute myeloid leukaemia: A single centre experience. (PubMed, Malays J Pathol)
    The cytogenetic data of adult AML from Pakistan showed presence of favourable prognostic karyotype with comparable prevalence as reported in international data. Moreover, FLT3/ITD mutations are commonly found in our patients as determined by molecular analysis. Therefore, inclusion of this unfavourable prognostic marker should be routine in molecular diagnostic testing of AML.
    Journal
    |
    FLT3 (Fms-related tyrosine kinase 3)
    |
    FLT3-ITD mutation • FLT3 mutation • FLT3 D835 • Chr t(15;17)
    1year
    CPX-351 Versus Immediate Stem Cell Transplantation for the Treatment of High-Grade Myeloid Cancers With Measurable Residual Disease (clinicaltrials.gov)
    P2, N=1, Terminated, Fred Hutchinson Cancer Center | Active, not recruiting --> Terminated; Terminated due to low accrual
    Trial termination
    |
    KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • PTEN (Phosphatase and tensin homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • HRAS (Harvey rat sarcoma viral oncogene homolog) • DNMT3A (DNA methyltransferase 1) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • RB1 (RB Transcriptional Corepressor 1) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • JAK2 (Janus kinase 2) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • KMT2A (Lysine Methyltransferase 2A) • TET2 (Tet Methylcytosine Dioxygenase 2) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • SRSF2 (Serine and arginine rich splicing factor 2) • WT1 (WT1 Transcription Factor) • CSF3R (Colony Stimulating Factor 3 Receptor) • STAT3 (Signal Transducer And Activator Of Transcription 3) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • STAG2 (Stromal Antigen 2) • GATA2 (GATA Binding Protein 2) • PHF6 (PHD Finger Protein 6) • ZRSR2 (Zinc Finger CCCH-Type, RNA Binding Motif And Serine/Arginine Rich 2)
    |
    DNMT3A mutation • ASXL1 mutation • TET2 mutation • FLT3 D835 • U2AF1 mutation • KRAS exon 2 mutation • FLT3 D835H • IDH1 R132
    |
    Vyxeos (cytarabine/daunorubicin liposomal formulation)
    1year
    OGILAR: Study Investigating the Efficacy and Safety of the Addition of Oral-azacitidine to Salvage Treatment by Gilteritinib in Subjects ≥18 Years of Age With Relapsed/Refractory FLT3-mutated Acute Myeloid Leukemia (clinicaltrials.gov)
    P2, N=33, Not yet recruiting, French Innovative Leukemia Organisation
    New P2 trial
    |
    FLT3 (Fms-related tyrosine kinase 3)
    |
    FLT3 mutation • FLT3 D835 • FLT3 I836
    |
    Xospata (gilteritinib) • Onureg (azacitidine oral)
    1year
    ADMIRAL: A Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation (clinicaltrials.gov)
    P3, N=371, Active, not recruiting, Astellas Pharma Global Development, Inc. | Trial completion date: Jul 2023 --> Jul 2024
    Trial completion date
    |
    FLT3 (Fms-related tyrosine kinase 3)
    |
    FLT3-ITD mutation • FLT3 mutation • FLT3 D835 • FLT3 I836
    |
    cytarabine • Xospata (gilteritinib) • azacitidine • etoposide IV • idarubicin hydrochloride • mitoxantrone • fludarabine IV
    1year
    Inhibition of FLT3-ITD Kinase in Acute Myeloid Leukemia by New Imidazo[1,2-b]pyridazine Derivatives Identified by Scaffold Hopping. (PubMed, J Med Chem)
    In vitro experiments confirmed suppression of FLT3 downstream signaling pathways. Finally, the treatment of MV4-11 xenograft-bearing mice with 34f at doses of 5 and 10 mg/kg markedly blocked tumor growth without any adverse effects.
    Journal
    |
    FLT3 (Fms-related tyrosine kinase 3)
    |
    FLT3-ITD mutation • FLT3 mutation • FLT3 D835Y • FLT3 D835 • FLT3 expression • FLT3-ITD expression
    over1year
    NCI-2019-04959: Azacitidine, Venetoclax, and Gilteritinib in Treating Patients With Recurrent/Refractory FLT3-Mutated Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia, or High-Risk Myelodysplastic Syndrome/Myeloproliferative Neoplasm (clinicaltrials.gov)
    P1/2, N=42, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Sep 2024 --> Sep 2025 | Trial primary completion date: Sep 2023 --> Sep 2025
    Trial completion date • Trial primary completion date
    |
    FLT3 (Fms-related tyrosine kinase 3)
    |
    FLT3-ITD mutation • FLT3 mutation • FLT3 D835
    |
    Venclexta (venetoclax) • Xospata (gilteritinib)
    over1year
    COMMODORE: A Study of ASP2215 Versus Salvage Chemotherapy In Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FLT3 Mutation (clinicaltrials.gov)
    P3, N=276, Active, not recruiting, Astellas Pharma Inc | Trial completion date: Nov 2025 --> Mar 2026 | Trial primary completion date: Nov 2025 --> Feb 2024
    Trial completion date • Trial primary completion date
    |
    FLT3 (Fms-related tyrosine kinase 3)
    |
    FLT3-ITD mutation • FLT3 mutation • FLT3 D835 • FLT3 I836
    |
    cytarabine • Xospata (gilteritinib) • etoposide IV • mitoxantrone • fludarabine IV
    over1year
    How acute myeloid leukemia (AML) escapes from FMS-related tyrosine kinase 3 (FLT3) inhibitors? Still an overrated complication? (PubMed, Cancer Drug Resist)
    A class of drugs, tyrosine-kinase inhibitors (TKI), targeting mutated FLT3, is already available with 1 and 2 generation molecules, but only midostaurin and gilteritinib are currently approved...Indeed, FLT3 inhibitors have significantly contributed to reducing the negative impact of FLT3 mutations on the prognosis of AML patients who are no longer considered at high risk by the European LeukemiaNet (ELN) 2022. Finally, several ongoing efforts to overcome resistance to FLT3-inhibitors will be presented: new generation FLT3 inhibitors in monotherapy or combined with standard chemotherapy, hypomethylating drugs, or IDH1/2 inhibitors, Bcl2 inhibitors; novel anti-human FLT3 monoclonal antibodies (e.g., FLT3/CD3 bispecific antibodies); FLT3-CAR T-cells; CDK4/6 kinase inhibitor (e.g., palbociclib).
    Review • Journal • IO biomarker
    |
    FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    FLT3-ITD mutation • FLT3 mutation • FLT3 D835 • FLT3 I836
    |
    Ibrance (palbociclib) • sorafenib • Xospata (gilteritinib) • Rydapt (midostaurin) • Vanflyta (quizartinib) • crenolanib (ARO-002)
    over1year
    LACEWING: A Study of ASP2215 (Gilteritinib) by Itself, ASP2215 Combined With Azacitidine or Azacitidine by Itself to Treat Adult Patients Who Have Recently Been Diagnosed With Acute Myeloid Leukemia With a FLT3 Gene Mutation and Who Cannot Receive Standard Chemotherapy (clinicaltrials.gov)
    P3, N=183, Active, not recruiting, Astellas Pharma Global Development, Inc. | Trial completion date: Dec 2023 --> Jun 2024
    Trial completion date
    |
    FLT3 (Fms-related tyrosine kinase 3)
    |
    FLT3 mutation • FLT3 D835 • FLT3 I836
    |
    Xospata (gilteritinib) • azacitidine
    over1year
    Novel spiroindoline quinazolinedione derivatives as anticancer agents and potential FLT3 kinase inhibitors. (PubMed, Bioorg Med Chem)
    Finally, the docking and simulation studies revealed the important interactions of compound 5f with wild type and mutant FLT3. The results of this study showed that some novel spiroindoline quinazolinedione compounds could be potential candidates for further development as novel targeted anticancer agents.
    Journal
    |
    FLT3 (Fms-related tyrosine kinase 3)
    |
    FLT3 mutation • FLT3 D835Y • FLT3 D835 • FLT3 wild-type
    over1year
    UNIFY: A Global Study of the Efficacy and Safety of Midostaurin + Chemotherapy in Newly Diagnosed Patients With FLT3 Mutation Negative (FLT3-MN) Acute Myeloid Leukemia (AML) (clinicaltrials.gov)
    P3, N=511, Completed, Novartis Pharmaceuticals | Terminated --> Completed
    Trial completion
    |
    FLT3 (Fms-related tyrosine kinase 3) • PML (Promyelocytic Leukemia)
    |
    FLT3 D835 • FLT3 I836
    |
    cytarabine • Rydapt (midostaurin) • daunorubicin • idarubicin hydrochloride
    over1year
    LACEWING: A Study of ASP2215 (Gilteritinib) by Itself, ASP2215 Combined With Azacitidine or Azacitidine by Itself to Treat Adult Patients Who Have Recently Been Diagnosed With Acute Myeloid Leukemia With a FLT3 Gene Mutation and Who Cannot Receive Standard Chemotherapy (clinicaltrials.gov)
    P3, N=183, Active, not recruiting, Astellas Pharma Global Development, Inc. | Trial primary completion date: Dec 2023 --> Mar 2023
    Trial primary completion date
    |
    FLT3 (Fms-related tyrosine kinase 3)
    |
    FLT3 mutation • FLT3 D835 • FLT3 I836
    |
    Xospata (gilteritinib) • azacitidine
    over1year
    Rational design of 4-((6-phenoxypyrimidin-4-yl)amino)-N-(4-(piperazin-1-yl)phenyl)-1H-pyrazole-3-carboxamide (LT-540-717) as orally bioavailable FLT3 inhibitor. (PubMed, Eur J Med Chem)
    Herein, we describe the discovery of compound LT-540-717 (32), a potent FLT3 inhibitor (IC: 0.62 nM), starting from FN-1501...Furthermore, 32 showed an acceptable bioavailability (F = 33.3% in rat and 72.7% in beagles), a suitable half-life time (T = 3.5 h in rat and T = 11.1 h in beagles), and a satisfactory metabolic stability. In summary, these results show the therapeutic potential of 32 to become a new anti-AML drug, especially for AML harboring dual FLT3 (ITD, TKD) mutations.
    Journal
    |
    FLT3 (Fms-related tyrosine kinase 3)
    |
    FLT3-ITD mutation • FLT3 mutation • FLT3 D835Y • FLT3 F691L • FLT3 D835 • FLT3 D835V
    |
    FN-1501
    over1year
    A Study of Gilteritinib, Venetoclax and Azacitidine as a Combined Treatment for People Newly Diagnosed With Acute Myeloid Leukemia (clinicaltrials.gov)
    P1/2, N=70, Recruiting, Astellas Pharma Global Development, Inc. | Trial completion date: Apr 2028 --> Jul 2028 | Trial primary completion date: Apr 2028 --> Jul 2028
    Trial completion date • Trial primary completion date
    |
    FLT3 (Fms-related tyrosine kinase 3)
    |
    FLT3 mutation • FLT3 D835 • FLT3 I836
    |
    Venclexta (venetoclax) • Xospata (gilteritinib) • azacitidine
    over1year
    Design, synthesis and pharmacological characterization of aminopyrimidine derivatives as BTK/FLT3 dual-target inhibitors against acute myeloid leukemia. (PubMed, Bioorg Chem)
    A novel class of aminopyrimidine-based Bruton's tyrosine kinase (BTK) and FMS-like tyrosine kinase 3 (FLT3) dual-target inhibitors based on the BTK inhibitor spebrutinib was designed for the treatment of acute myeloid leukemia...Finally, intraperitoneal administration of 14m at 20 mg/kg significantly repressed the growth of MV-4-11 cells with a TGI value of 95.68% with no apparent toxicity. These BTK/FLT3 dual-target inhibitors represent promising leads for further structural optimization and antitumor mechanism studies.
    Journal
    |
    FLT3 (Fms-related tyrosine kinase 3)
    |
    FLT3 D835Y • FLT3 D835
    |
    spebrutinib (CC-292)
    over1year
    LACEWING: A Study of ASP2215 (Gilteritinib) by Itself, ASP2215 Combined With Azacitidine or Azacitidine by Itself to Treat Adult Patients Who Have Recently Been Diagnosed With Acute Myeloid Leukemia With a FLT3 Gene Mutation and Who Cannot Receive Standard Chemotherapy (clinicaltrials.gov)
    P3, N=183, Active, not recruiting, Astellas Pharma Global Development, Inc. | Trial primary completion date: Jan 2023 --> Dec 2023
    Trial primary completion date
    |
    FLT3 (Fms-related tyrosine kinase 3)
    |
    FLT3 mutation • FLT3 D835 • FLT3 I836
    |
    Xospata (gilteritinib) • azacitidine