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    BIOMARKER:

    FLT3 D835H

    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
    6ms
    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
    8ms
    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)
    over1year
    CPX-351 Versus Immediate Stem Cell Transplantation for the Treatment of High-Grade Myeloid Cancers With Measurable Residual Disease (clinicaltrials.gov)
    P2, N=1, Active, not recruiting, Fred Hutchinson Cancer Center | Recruiting --> Active, not recruiting | N=130 --> 1 | Trial completion date: Jan 2028 --> Aug 2023 | Trial primary completion date: Jan 2026 --> Aug 2023
    Enrollment closed • Enrollment change • Trial completion date • Trial primary completion date
    |
    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)
    over1year
    A Novel Inhibitor of FLT3 and Its Drug-Resistant Mutants with Superior Activity to Gilteritinib in Molm-13 Preclinical Acute Myeloid Leukemia Xenograft Model (ASH 2022)
    Several FLT3 inhibitors have been developed such as the first generation multikinase inhibitor Midostaurin which is approved for newly diagnosed FLT3 mutant AML in combination with induction chemotherapy...Herein we describe 2082-0047, a novel tyrosine kinase inhibitor with sub-nanomolar potency against FLT3 mutant AML, including TKD mutations...Our non-GLP in vivo safety studies confirmed a broad therapeutic window of 2082-0047. Ongoing Investigational New Drug (IND) enabling studies will include comparing the effect of 2082-0047 to gilteritinib in an immunocompetent syngeneic AML murine model harboring both a Flt3-ITD and F691 TKD gatekeeper mutation.
    Preclinical
    |
    FLT3 (Fms-related tyrosine kinase 3)
    |
    FLT3-ITD mutation • FLT3 mutation • FLT3-TKD mutation • FLT3 D835Y • FLT3 F691L • FLT3 D835 • FLT3 D835V • FLT3 D835H
    |
    Xospata (gilteritinib) • Rydapt (midostaurin)
    almost2years
    MYELOID KINOME INHIBITOR HM43239 OVERCOMES ACQUIRED RESISTANCE IN ACUTE MYELOID LEUKEMIA MODELS (EHA 2022)
    HM43239 inhibited FcγR-induced SYK and JAK/STAT5 activation in KG-1a (FLT3-WT) cells that upregulate RAS signaling which is a mechanism of acquired resistance to gilteritinib. Its ability to also inhibit SYK and, by reducing the activity of these upstream kinases, to also impair the activity of EKR1/2 and JAK/STAT5 that participate in rescue pathways, makes this a particularly interesting molecule with the potential of offsetting the development of resistance that is common with other FLT3 inhibitors. A Phase 1/2 trial of HM43239 in patients with AML is open and accruing patients (NCT03850574).
    Preclinical
    |
    FLT3 (Fms-related tyrosine kinase 3) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • JAK2 (Janus kinase 2) • JAK1 (Janus Kinase 1) • SYK (Spleen tyrosine kinase)
    |
    FLT3-ITD mutation • FLT3 mutation • FLT3 D835Y • FLT3 F691L • FLT3 D835 • FLT3 D835V • FLT3 D835H • FLT3 overexpression • FLT3 wild-type • FLT3-ITD mutation + FLT3 F691L
    |
    Xospata (gilteritinib) • tuspetinib (HM43239)
    3years
    CPX-351 Versus Immediate Stem Cell Transplantation for the Treatment of High-Grade Myeloid Cancers With Measurable Residual Disease (clinicaltrials.gov)
    P2, N=130, Recruiting, Fred Hutchinson Cancer Research Center | Not yet recruiting --> Recruiting
    Clinical • Enrollment open
    |
    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)
    |
    DNMT3A mutation • ASXL1 mutation • TET2 mutation • FLT3 D835 • U2AF1 mutation • KRAS exon 2 mutation • FLT3 D835H
    |
    Vyxeos (cytarabine/daunorubicin liposomal formulation)
    over3years
    [VIRTUAL] Clinical Benefit and Tolerability of Crenolanib in Children with Relapsed Acute Myeloid Leukemia Harboring Treatment Resistant FLT3 ITD and Variant FLT3 TKD Mutations Treated on Compassionate Access (ASH 2020)
    Sorafenib has limited activity against tyrosine kinase domain mutations...Treatment: Crenolanib was given with curative intent to three patients, one in combination with Vyxeos (liposomal cytarabine/daunorubicin), one with high-dose cytarabine, and one as maintenance therapy after her second HSCT... This series of five children with multiply relapsed FLT3-mutant AML shows that treatment with full doses of crenolanib can be safely combined with salvage chemotherapy. Rapid remissions could be obtained even in patients with co-occurring KMT2A, 3q, and p53 mutations. Crenolanib, which is novel type-I pan FLT3 inhibitor, was able to inhibit variant FLT3 mutations (D835H, D835E and D848P).
    Clinical
    |
    TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • NOTCH1 (Notch 1)
    |
    TP53 mutation • FLT3-ITD mutation • FLT3 mutation • NOTCH1 mutation • FLT3-TKD mutation • MLL rearrangement • FLT3 D835 • FLT3 D835H • FLT3 D835E • MLL fusion
    |
    sorafenib • cytarabine • crenolanib (ARO-002) • daunorubicin • Vyxeos (cytarabine/daunorubicin liposomal formulation)
    over3years
    CPX-351 Versus Immediate Stem Cell Transplantation for the Treatment of High-Grade Myeloid Cancers With Measurable Residual Disease (clinicaltrials.gov)
    P2, N=130, Not yet recruiting, Fred Hutchinson Cancer Research Center | Trial completion date: Dec 2029 --> Jan 2028
    Clinical • Trial completion date
    |
    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)
    |
    DNMT3A mutation • ASXL1 mutation • TET2 mutation • FLT3 D835 • U2AF1 mutation • KRAS exon 2 mutation • FLT3 D835H
    |
    Vyxeos (cytarabine/daunorubicin liposomal formulation)
    over3years
    CPX-351 Versus Immediate Stem Cell Transplantation for the Treatment of High-Grade Myeloid Cancers With Measurable Residual Disease (clinicaltrials.gov)
    P2, N=130, Not yet recruiting, Fred Hutchinson Cancer Research Center
    Clinical • New P2 trial
    |
    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)
    |
    DNMT3A mutation • ASXL1 mutation • TET2 mutation • FLT3 D835 • U2AF1 mutation • KRAS exon 2 mutation • FLT3 D835H
    |
    Vyxeos (cytarabine/daunorubicin liposomal formulation)