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FLT3 (Fms-related tyrosine kinase 3)
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
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2d
Design, Synthesis, and Biological Activities Evaluation of Type I FLT3 Inhibitors for the Treatment of Acute Myeloid Leukemia. (PubMed, Drug Dev Res)
In our cellular mechanistic studies, FW-1 also effectively induced apoptosis by arresting cell cycle progression in the G0/G1 phase. This study introduces FW-1 as a promising lead for type I FLT3 inhibitor, warranting further optimization.
Journal
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3 expression
3d
Discovery of IRAK1/4/pan-FLT3 Kinase Inhibitors as Treatments for Acute Myeloid Leukemia. (PubMed, ACS Med Chem Lett)
Optimization of this series has produced compound 31 which displays potent and selective inhibition of IRAK1, IRAK4, FLT3, and all mutant forms of FLT3, as well as good in vitro ADME and pharmacokinetic properties. In a mouse xenograft model of AML, 31 produces survival prolongation equal to that of Gilteritinib, the leading marketed FLT3 inhibitor currently used to treat AML.
Journal
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FLT3 (Fms-related tyrosine kinase 3) • IRAK1 (Interleukin 1 Receptor Associated Kinase 1) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
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FLT3 mutation
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Xospata (gilteritinib)
3d
Cooperative blockade of FLT3 and ALK synergistically suppresses growth of osteosarcoma. (PubMed, Oncogene)
The combinatorial use of an ALK inhibitor could reverse this process. Thus, our study demonstrates that the cooperative blockade of FLT3 and ALK synergistically suppresses osteosarcoma, providing a potential alternative for its treatment.
Journal
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FLT3 (Fms-related tyrosine kinase 3)
3d
A Combinatorial Functional Precision Medicine Platform for Rapid Therapeutic Response Prediction in AML. (PubMed, Cancer Med)
Overall, this study demonstrates the feasibility of applying QPOP as a functional combinatorial precision medicine platform to predict therapeutic sensitivities in AML and provides the basis for prospective clinical trials evaluating ex vivo-guided combination therapy.
Journal
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FLT3 (Fms-related tyrosine kinase 3) • FOXM1 (Forkhead Box M1)
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FLT3 mutation
4d
Computational and theoretical insights into the cytotoxic prospects of compounds isolated from Elaeodendron buchananii against Leukemia. (PubMed, Toxicol Rep)
Per-residue decomposition plots also revealed high energy contributions in the interactions' binding sites residues. These results indicate that the cytotoxic prospects of the isolated compounds against leukemia as indicated by its molecular interactions with FLT3 and MLV.
Journal
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FLT3 (Fms-related tyrosine kinase 3)
4d
Menin inhibitors for the treatment of acute myeloid leukemia: challenges and opportunities ahead. (PubMed, J Hematol Oncol)
More importantly, approval of the combination of the BCl-2 inhibitor, venetoclax, and hypomethylating agents or low dose cytarabine provided unprecedented breakthrough for the frontline treatment of older, unfit AML patients. Recent development of menin inhibitors targeting AML with KMT2A rearrangements or NPM1 mutations could represent a promising new horizon of treatment for patients within these subsets of AML. Our current review will focus on a summary and updates of recent developments of menin inhibitors in the treatment of AML, on the challenges ahead arising from drug resistance, as well as on the opportunities of novel combinations with menin inhibitors.
Review • Journal • IO biomarker
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FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A)
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NPM1 mutation • KMT2A rearrangement • MLL rearrangement
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Venclexta (venetoclax) • cytarabine
6d
TIPIC syndrome in a patient following sorafenib treatment for acute myeloid leukemia: a rare case report. (PubMed, Front Oncol)
Treatment involved a one-week course of oral steroid therapy with dexamethasone and non-steroidal anti-inflammatory drugs, which led to complete clinical recovery. TIPIC syndrome involves transient nonspecific perivascular inflammation of the carotid adventitia; however, the precise underlying cause remains unclear. In this study, we report a rare case and explore the potential pathophysiological mechanisms through a review of the existing literature.
Journal
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3 mutation
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sorafenib • dexamethasone
6d
Approaching a therapeutic inflection point for FLT3-mutated AML. (PubMed, Blood)
Finally, recent data also suggest FLT3 inhibitors could transform outcomes in patients unsuitable for intensive therapy. If confirmed, this has important implications for fit patients and could revolutionize the treatment paradigm.
Journal
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3 mutation
7d
Quizartinib: a potent and selective FLT3 inhibitor for the treatment of patients with FLT3-ITD-positive AML. (PubMed, J Hematol Oncol)
Finally, we highlight some of the ongoing studies that test quizartinib in patients with FLT3-ITD-positive AML, patients with FLT3-ITD-negative AML, in both the first-line and R/R settings, in patients fit or unfit for intensive chemotherapy, including studies for quizartinib-based combination with other compounds such as decitabine and venetoclax. Future research should aim to further optimize the clinical value of quizartinib and explore its use in additional clinical settings, which could be achieved by testing quizartinib with other drugs, better characterization of the mechanisms of resistance, identification of the role of quizartinib as a maintenance therapy after allo-HCT, and investigating quizartinib in patients with FLT3-ITD-negative AML.
Review • Journal
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FLT3 (Fms-related tyrosine kinase 3)
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Venclexta (venetoclax) • Vanflyta (quizartinib) • decitabine
7d
Molecular measurable residual disease monitoring and transplant indications in NPM1 mutated acute myeloid leukemia. (PubMed, Bone Marrow Transplant)
In this review, we evaluate the prognostic role of MRD monitoring in NPM1 mutated AML and its use as a predictive biomarker to refine risk stratification and inform decision making regarding treatment. We explore the impact of pre-HCT MRD positivity on post-HCT outcomes in this AML subset, and how HCT-related factors such as conditioning intensity may influence this risk.
Review • Journal
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FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1)
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FLT3-ITD mutation • NPM1 mutation
7d
Human Dendritic Cell Differentiation in Hematopoietic Stem Cell-Transplanted NOG hFLT3L Tg/mFlt3 KO Humanized Mice. (PubMed, Immunol Lett)
Furthermore, major subsets of human DC populations, cDC1, cDC2, and pDC, and skin Langerhans cells were significantly differentiated in FL Tg/KO mice. Therefore, these humanized mouse models are potentially valuable in the investigation of DC-mediated human adaptive immune responses in vivo.
Preclinical • Journal
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FLT3 (Fms-related tyrosine kinase 3) • CD34 (CD34 molecule) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • ITGAM (Integrin, alpha M) • CDK1 (Cyclin-dependent kinase 1)
7d
TFAP2C/FLT3 Axis Reduces Ferroptosis in Breast Cancer Cells by Inhibiting Mitochondrial Autophagy. (PubMed, Int J Biochem Cell Biol)
The TFAP2C/FLT3 axis reduced ferroptosis in BC cells by inhibiting mitochondrial autophagy. These research findings elucidated the mechanism by which FLT3 regulated ferroptosis in BC and provided potential targets for BC treatment.
Journal
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FLT3 (Fms-related tyrosine kinase 3) • TFAP2A (Transcription Factor AP-2 Alpha) • TFAP2C (Transcription Factor AP-2 Gamma)
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FLT3 expression
8d
Exploring the role of mitophagy-related genes in breast cancer: subtype classification and prognosis prediction. (PubMed, Int J Med Sci)
This nomogram was validated and showed good predictive performance, with area under the curve (AUC) values for 1-year, 3-year, and 5-year OS of 0.895, 0.765, and 0.728, respectively. Our findings underscore the profound impact of prognostic genes on the immune response and prognostic outcomes in BC, indicating that they can provide new avenues for personalized BC treatment and potentially improve clinical outcomes.
Journal • Tumor mutational burden
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TMB (Tumor Mutational Burden) • FLT3 (Fms-related tyrosine kinase 3) • CHI3L1 (Chitinase 3-like 1) • CLIC6 (Chloride Intracellular Channel 6) • PRKAA2 (Protein Kinase AMP-Activated Catalytic Subunit Alpha 2)
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TMB-L
8d
The Immunomodulatory Effect of Different FLT3 Inhibitors on Dendritic Cells. (PubMed, Cancers (Basel))
Our results suggest different immunosuppressive effects of these three FLT3i and may, therefore, provide an additional rationale for optimal maintenance therapy after alloHSCT of FLT3-positive AML patients to prevent infectious complications and GvHD mediated by DCs.
Journal • Immunomodulating
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FLT3 (Fms-related tyrosine kinase 3) • IL6 (Interleukin 6) • TNFA (Tumor Necrosis Factor-Alpha) • CD86 (CD86 Molecule)
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FLT3 mutation • FLT3 positive
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Xospata (gilteritinib) • Rydapt (midostaurin) • Vanflyta (quizartinib)
8d
Acute myeloid leukemia in the next-generation sequencing era : Real-world data from an Austrian tertiary cancer care center. (PubMed, Wien Klin Wochenschr)
Our study validates data from CCIT and supports their relevance for treatment decisions in a real-world setting. Moreover, they demonstrate the feasibility and benefits of NGS within a routine clinical setting.
Journal • Real-world evidence • Next-generation sequencing • Real-world
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FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • TET2 (Tet Methylcytosine Dioxygenase 2)
8d
Homoharringtonine Added to Venetoclax and Azacitidine Improves Outcome and Mitigates Genetic Impact in Relapsed/Refractory AML: A Multi-center Cohort Study. (PubMed, Clin Cancer Res)
Our findings suggest the addition of HHT to VA might enhance response and mitigate the negative impact of certain genetic patterns in RR-AML while being well tolerated.
Journal
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KRAS (KRAS proto-oncogene GTPase) • FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • TET2 (Tet Methylcytosine Dioxygenase 2)
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KRAS mutation • FLT3-ITD mutation • FLT3 mutation • DNMT3A mutation • TET2 mutation
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Venclexta (venetoclax) • azacitidine • Synribo (omacetaxine mepesuccinate)
8d
In vivo models of subclonal oncogenesis and dependency in hematopoietic malignancy. (PubMed, Cancer Cell)
We next use a generalizable, reversible approach to demonstrate that mutation reversion results in rapid leukemic regression with distinct differentiation patterns depending upon co-occurring mutations. These studies provide a path to experimentally model sequential mutagenesis, investigate mechanisms of transformation and probe oncogenic dependency in disease evolution.
Preclinical • Journal
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FLT3 (Fms-related tyrosine kinase 3) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1)
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FLT3 mutation • NPM1 mutation • DNMT3A mutation
9d
OXPHOS mediators in acute myeloid leukemia patients: Prognostic biomarkers and therapeutic targets for personalized medicine. (PubMed, World J Surg Oncol)
This study identifies NDUFA6 and SDHA as novel companion prognostic biomarkers which might present a rational strategy for personalized therapy of AML patients.
Journal
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FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • NPM1 (Nucleophosmin 1) • SRSF2 (Serine and arginine rich splicing factor 2) • GPX4 (Glutathione Peroxidase 4) • CYB5A (Cytochrome B5 Type A) • CPT1A (Carnitine Palmitoyltransferase 1A) • SDHA (Succinate Dehydrogenase Complex Flavoprotein Subunit A)
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FLT3-ITD mutation • IDH1 mutation • NPM1 mutation • SRSF2 mutation • NPM1 expression • NPM1 mutation + SRSF2 mutation
9d
Evaluation of drug-drug interactions of a novel potent FLT3 inhibitor SKLB1028 in healthy subjects. (PubMed, Clin Transl Sci)
Based on the preclinical characterization of SKLB1028 metabolism, three drug-drug interaction clinical studies were performed to investigate the effects of itraconazole, rifampin (CYP3A4 inhibitor and inducer, respectively), and gemfibrozil (CYP2C8 inhibitor) on the metabolism of SKLB1028. Co-administration with rifampin reduced the AUC of SKLB1028 by ~30%, while the Cmax did not change significantly. All treatments were well tolerated in all three studies.
Journal
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3-ITD mutation
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itraconazole • rifampicin • ruserontinib (SKLB-1028)
9d
Safety and Efficacy Study of CI-135 CAR-T Cells in Subjects with Relapsed or Refractory Acute Myeloid Leukemia (clinicaltrials.gov)
P1, N=0, Withdrawn, Beijing Boren Hospital | Trial completion date: Dec 2025 --> Dec 2023 | Recruiting --> Withdrawn | Trial primary completion date: Dec 2024 --> Dec 2023
Trial completion date • Trial withdrawal • Trial primary completion date • CAR T-Cell Therapy
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3 mutation • FLT3 expression
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cyclophosphamide • CI-135 CAR-T
10d
Development and Performance of SNAQ-SEQ Spike-in Standards in AML NGS Diagnostic and MRD Testing (AMP 2024)
We have demonstrated that the addition of SNAQ-SEQ IS spike-in standards produced expected VAF in response to dilution, and for AML samples, provided a direct per sample 0.3% VAF sensitivity QC. The IS variants replace the need for an external positive reference run control sample, enabling an additional patient sample to be run to increase testing throughput, flow cell utilization, and reduced testing cost. Second, the ability to compare the known versus measured IS VAF conveys the reporting accuracy of the test on a per-sample basis.
Next-generation sequencing
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FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1)
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Oncomine™ Myeloid MRD Assays
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
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FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • JAK2 (Janus kinase 2)
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FLT3-ITD mutation • NPM1 mutation • FLT3 D835Y • FLT3 D835 • IDH2 R172K • KIT D816V • IDH1 R132C • JAK2 V617F • IDH1 R132 • IDH2 R172
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SureSeq™ Myeloid MRD Panel
10d
DNA and RNA NGS for Myeloid Neoplasms Using Oncomine Myeloid Assay GX v2 on GeneXus: An Assessment of Clinical Utility (AMP 2024)
This DNA- and RNA-based 80-gene panel has proven to be a powerful tool for genomic profiling of myeloid neoplasms. The results were provided to hematopathologists/oncologists in timely fashion with the critical information for diagnosis confirmation, and disease classification, as well as assessment of patient response to treatment.
Clinical • Next-generation sequencing
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KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • JAK2 (Janus kinase 2) • 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) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • SRSF2 (Serine and arginine rich splicing factor 2) • BCOR (BCL6 Corepressor) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • STAG2 (Stromal Antigen 2) • DDX41 (DEAD-Box Helicase 41) • CALR (Calreticulin) • ZRSR2 (Zinc Finger CCCH-Type, RNA Binding Motif And Serine/Arginine Rich 2)
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FLT3-ITD mutation • NPM1 mutation • U2AF1 mutation • CEBPA mutation • JAK2 V617F
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Oncomine Myeloid Assay GX
10d
Rapid and Accurate Detection of Myeloid Malignancy Mutations Using the Oncomine Myeloid Assay Gx V2 on the GeneXus System (AMP 2024)
With the applied filters and cutoffs established during the validation, the Oncomine Myeloid V.2 assay performed on the GeneXus System provides a rapid, accurate, and reliable method for detecting actionable mutations in myeloid malignancies. Its high performance, coupled with a short turnaround time and compatibility with low input material, supports its utility in clinical practice for guiding personalized treatment decisions.
FLT3 (Fms-related tyrosine kinase 3)
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Oncomine Myeloid Assay GX
13d
Venetoclax combined with medium-dose cytarabine as consolidation therapy after standard induction chemotherapy in patients with Fit AML: a multicenter, prospective, observational clinical study (ChiCTR2400090947)
P4, N=180, Not yet recruiting, Qilu Hospital of Shandong University; Qilu Hospital of Shandong University
New P4 trial
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3 mutation
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Venclexta (venetoclax) • cytarabine
16d
Characteristics and Outcome of FLT3-ITD-Positive Acute Myeloid Leukemia. (PubMed, Clin Lab)
Allo-HSCT immediately following complete remission could improve outcomes for young adults diagnosed with FLT3-ITD-positive AML. However, we found no statistical difference in the overall response rate (ORR) and clinical outcome between sorafenib combined with chemotherapy and chemotherapy alone.
Retrospective data • Journal
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FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1)
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FLT3-ITD mutation • NPM1 mutation
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sorafenib
16d
Safety and Efficacy of Quizartinib in Children and Young Adults With Acute Myeloid Leukemia (AML), a Cancer of the Blood (clinicaltrials.gov)
P1/2, N=65, Active, not recruiting, Daiichi Sankyo | Recruiting --> Active, not recruiting
Enrollment closed • Combination therapy
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3-ITD mutation
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cytarabine • etoposide IV • Vanflyta (quizartinib) • fludarabine IV
16d
Tretinoin and Arsenic Trioxide in Treating Patients With Untreated Acute Promyelocytic Leukemia (clinicaltrials.gov)
P3, N=158, Active, not recruiting, Children's Oncology Group | Trial completion date: Sep 2024 --> Sep 2025
Trial completion date
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FLT3 (Fms-related tyrosine kinase 3) • RARA (Retinoic Acid Receptor Alpha) • PML (Promyelocytic Leukemia)
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FLT3 mutation • FLT3 wild-type
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cytarabine • idarubicin hydrochloride • mitoxantrone • Vesanoid (tretinoin) • arsenic trioxide • Hemady (dexamethasone tablets) • Starasid (cytarabine ocfosfate)
16d
Measurable residual mutated IDH1 before allogeneic transplant for acute myeloid leukemia. (PubMed, Bone Marrow Transplant)
For patients with IDH1 mutated AML co-mutated with NPM1 and/or FLT3-ITD, only detection of persistent mutated NPM1 and/or FLT3-ITD was associated with significantly higher rates of relapse (p = 0.01). These data, from the largest study to date, do not support the detection of IDH1 mutation in CR1 blood prior to alloHCT as evidence of AML MRD for increased post-transplant relapse risk.
Journal
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FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • NPM1 (Nucleophosmin 1)
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FLT3-ITD mutation • IDH1 mutation • FLT3 mutation • NPM1 mutation
17d
A phase 1/2 study of gilteritinib in combination with chemotherapy in newly diagnosed patients with AML in Asia. (PubMed, Int J Hematol)
In this interim analysis, gilteritinib 120 mg/day in combination with chemotherapy was well tolerated, with similar CRc rates to previous studies.
P1/2 data • Journal • Combination therapy
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3 mutation
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cytarabine • Xospata (gilteritinib) • idarubicin hydrochloride
17d
Development and Validation of a Biopsy-Free Scoring System for Screening Myelodysplastic Syndrome (MDS) and Associated Diseases in Cytopenic Patients (ASH 2024)
For patients with a probability score < 45%, a bone marrow study may not be needed, with a recommended follow-up every 6–12 months. This comprehensive analysis provides a useful and non-invasive predictive model that enhances diagnostic accuracy which potentially reduces unnecessary procedures.
Clinical • Biopsy
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KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • JAK2 (Janus kinase 2) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • SRSF2 (Serine and arginine rich splicing factor 2) • BCOR (BCL6 Corepressor) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • STAG2 (Stromal Antigen 2) • SETBP1 (SET Binding Protein 1) • ZRSR2 (Zinc Finger CCCH-Type, RNA Binding Motif And Serine/Arginine Rich 2)
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TP53 mutation • KRAS mutation • NRAS mutation • IDH2 mutation • NPM1 mutation • ASXL1 mutation • TET2 mutation • SF3B1 mutation • SRSF2 mutation • U2AF1 mutation • STAG2 mutation
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Oncomine Myeloid Research Assay
17d
Measurable Residual Mutated NPM1 before Allogeneic Transplant for Acute Myeloid Leukemia (ASH 2024)
NPM1 MRD positive patients receiving nonmyeloablative conditioning or reduced-intensity conditioning (RIC) without melphalan (mel) had increased risk of relapse or death compared to patients receiving myeloablative conditioning or RIC with mel, regardless of FLT3-ITD co-mutational status (3yrs: relapse 87% vs 55%, P=0.006; OS 15% vs 42%, P=0.013). In patients with NPM1 mutated AML from the Pre-MEASURE study, we show that detection of residual NPM1 variants in pre-transplant blood during CR1 using a highly sensitive DNA-based assay is associated in a dose-dependent manner with a significantly increased risk of relapse and death after allo-HCT, which can be mitigated in part by conditioning regimen. In patients co-mutated for both FLT3-ITD and NPM1 at diagnosis, NPM1 should be prioritized as a target for NGS-MRD if only one test is available.
FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1)
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FLT3-ITD mutation • FLT3 mutation • NPM1 mutation
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FLT3 ITD MRD Assay • NPM1 Mutation Assay
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melphalan
17d
Prognostic Role of NGS-Based MRD Assessment in FLT3-TKD Mutated Patients with Acute Myeloid Leukemia (ASH 2024)
Only two patients in the MRD negative group received the FLT3 inhibitor midostaurin combined with chemotherapy...NGS-MRD was not prognostic in this cohort of FLT3-TKD mutated AML patients. Shared first authors: Isabell Arnhardt, Christian M Vonk Shared senior authorship: Michael Heuser, Peter J.M. Valk
Clinical • Next-generation sequencing
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FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2)
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FLT3-ITD mutation • NPM1 mutation • DNMT3A mutation • ASXL1 mutation • TET2 mutation • SF3B1 mutation • FLT3-TKD mutation
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TruSight Myeloid Sequencing Panel
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Rydapt (midostaurin)
17d
Prognostic Significance of Low Copy Number FLT3 and NPM1 mrd As Detected By Ultra-Sensitive Next Generation Sequencing (ASH 2024)
To our knowledge, our study is the first to assess the clinical impact of MRD detected below the clinically-validated limit of detection by ultra-sensitive NGS. Findings from our retrospective study were consistent with previously published data suggesting the presence of “high level” MRD (i.e. above the current clinically-validated limit of detection) is associated with increased risk of AML relapse in both NPM1 and FLT3-ITD mutated AML.
Next-generation sequencing
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FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1)
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FLT3-ITD mutation • NPM1 mutation • FLT3‐ITD + NPM1 mutation
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FLT3 ITD MRD Assay • NPM1 Mutation Assay
17d
Longitudinal Sequencing to Investigate Clonal Evolution in Myeloid Neoplasms (ASH 2024)
We analyzed 851 patients with MN at Karmanos Cancer Institute; 444 with serial samples. Among these patients, 174 (39%) had primary AML (pAML), 144 (32%) had secondary AML (sAML), 58 (13%) had MDS, 18 (4%) had MDS/MPN and 50 (11%) had MPN. Median age for primary AML was 56 ys (19-82), secondary AML was 64 ys (31-86) and MDS was 66 ys (23-90).
TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • SRSF2 (Serine and arginine rich splicing factor 2) • STAG2 (Stromal Antigen 2)
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TP53 mutation • DNMT3A mutation • STAG2 mutation
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TruSight Myeloid Sequencing Panel
17d
T/NK Cell-Associated Transcriptomic Profile Informs Response to FLT3 Inhibitors in Acute Myeloid Leukemia (ASH 2024)
We then profiled a wet-lab cohort of 37 FLT3-mut AML patients treated either with Midostaurin plus chemotherapy (M) or Gilteritinib (G) at Bologna Hematology Institute by using the PanCancer IO 360 Panel (NanoString Technologies, San Diego, CA). This study provides evidence that FLT3 mutational status is associated with a unique T-cell activation profile and AML maturation state, and that T/NK cell-associated genes correlate with response to FLT3i. Our RNA metric of FLT3 mutational status could be utilized to refine patient stratification in future clinical trials. S.R.
FLT3 (Fms-related tyrosine kinase 3) • CD8 (cluster of differentiation 8) • CD4 (CD4 Molecule) • GLI2 (GLI Family Zinc Finger 2)
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FLT3 mutation
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nCounter® PanCancer IO 360™ Panel
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Xospata (gilteritinib) • Rydapt (midostaurin)
17d
KMT2A (MLL1) Rearrangements in Hematolymphoid Malignancies: A Genomic Landscape Study (ASH 2024)
Rearrangements in the KMT2A gene in AML are common and may emerge as a new target of therapy for AML patients. This genomic landscape study reveals significant differences in import GA associated with AML in KMT2Ara and KMT2Anra cases.
Tumor mutational burden
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KRAS (KRAS proto-oncogene GTPase) • TMB (Tumor Mutational Burden) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • ASXL1 (ASXL Transcriptional Regulator 1) • KMT2A (Lysine Methyltransferase 2A) • TET2 (Tet Methylcytosine Dioxygenase 2) • WT1 (WT1 Transcription Factor)
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KRAS G12C • KMT2A rearrangement • KRAS G12 • MLL rearrangement • MLL rearrangement • MLL mutation
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FoundationOne® Heme CDx
17d
Rare Types of NPM1 Mutations Share a Similar Molecular Background to the Common NPM1 Variant and Have No Impact on Survival in Adults with Acute Myeloid Leukemia (ASH 2024)
The rare NPM1 mutation subtypes share a similar pattern of co-mutations with the common NPM1 type A, are similarly affected by the FLT3 status and by the presence of a TM-phenotype and feature similar OS. Publicly available datasets can be exploited to collect information on rare entities which would be otherwise poorly characterized.
Clinical
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FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • TET2 (Tet Methylcytosine Dioxygenase 2)
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NPM1 mutation • DNMT3A mutation • FLT3 wild-type
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MSK-IMPACT Heme
18d
New P1/2 trial
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FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1)
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Venclexta (venetoclax) • cytarabine • azacitidine • Vanflyta (quizartinib)
18d
Roles of DNMT3B and PARP1 Genes Expression in Cytogenetically Normal Acute Myeloid Leukemia. (PubMed, Clin Med Insights Oncol)
Our findings highlight the importance of considering DNMT3B and PARP1 expression levels as potential prognostic biomarkers for progression and aggressiveness of CN-AML patients in AML. Assessing their expression levels could be an indicator to guide treatment decisions and potentially improve patient outcomes.
Journal • PARP Biomarker
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FLT3 (Fms-related tyrosine kinase 3) • PARP1 (Poly(ADP-Ribose) Polymerase 1) • DNMT3B (DNA Methyltransferase 3 Beta)
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DNMT3B overexpression
18d
Pre-emptive therapeutic decisions based on measurable residual disease status in acute myeloid leukemia: ready for prime time? (PubMed, Leukemia)
Therefore, preemptive interventions on the natural history of MRD positivity are an active area of research beyond its initial prognostic function. Targeting MRD in AML with innovative treatment strategies can improve patient outcomes.
Review • Journal
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FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1)
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NPM1 mutation
19d
PRDM16 Induces Methylation of FLT3 to Promote FLT3-ITD Signaling and Leukemia Progression. (PubMed, Cancer Res)
Altogether, these results suggest that PRDM16 boosts oncogenic FLT3 signaling in leukemic cells by prompting FLT3-ITD methylation. Therefore, PRDM16 may serve as a therapeutic target for AML.
Journal
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FLT3 (Fms-related tyrosine kinase 3) • PRDM16 (PR/SET Domain 16)
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FLT3-ITD mutation • FLT3 wild-type • FLT3 expression • FLT3-ITD expression
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