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BIOMARKER:

FLT3 N676K

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:
5ms
Unraveling Clonal Evolution and Mechanisms of Treatment Resistance in Murine KMT2A-Rearranged Leukemia with Subclonal FLT3 N676K (ASH 2023)
Upon engraftment, recipients were subjected to different treatments, including chemotherapy (cytarabine for 5 days+doxorubicin for 3 days), the FLT3 inhibitor AC220, chemotherapy followed by AC220, or AC220+Trametinib, a MEK inhibitor. Taken together, the treatment given affected survival and impacted evolution of the FLT3 N676K-leukemia cells. The general absence of acquired mutations in most mice suggests that target-independent mechanisms may underline acquired resistance in most mice, and we propose the Six1/Wnt/ß-catenin axis as a potential vulnerability upon AC220-resistance.
Preclinical
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FLT3 (Fms-related tyrosine kinase 3) • KMT2A (Lysine Methyltransferase 2A) • ITGAM (Integrin, alpha M) • MLLT3 (MLLT3 Super Elongation Complex Subunit) • SIX1 (SIX Homeobox 1)
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MLL rearrangement • FLT3 N676K • KMT2A expression
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Mekinist (trametinib) • cytarabine • doxorubicin hydrochloride • Vanflyta (quizartinib)
5ms
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
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3-ITD mutation • FLT3 mutation • FLT3 D835 • FLT3 N676K • FLT3 wild-type • FLT3 D835E
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Xospata (gilteritinib) • Rydapt (midostaurin) • Vanflyta (quizartinib) • PHI-101 • tuspetinib (HM43239)
11ms
TREATMENT IS SHAPING CLONAL EVOLUTION AND RESISTANCE PATTERNS IN MURINE KMT2A-REARRANGED LEUKEMIA WITH SUBCLONAL FLT3N676K (EHA 2023)
Upon engraftment, treatment was started with either chemotherapy (cytarabine for 5 days+doxorubicin for 3 days), the FLT3 inhibitor AC220, chemotherapy followed by AC220, or AC220+Trametinib, a MEK inhibitor. The specific treatment given affected survival and impacted the evolution of genetically distinct cells. The general lack of acquired mutations upon targeted treatment suggests that target-independent mechanisms that result in alternate activation of survival/proliferation explains acquired resistance in a majority of mice. flt3 inhibitor, AML, KMT2A
Preclinical
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FLT3 (Fms-related tyrosine kinase 3) • KMT2A (Lysine Methyltransferase 2A) • MLLT3 (MLLT3 Super Elongation Complex Subunit) • SIX1 (SIX Homeobox 1)
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MLL rearrangement • FLT3 N676K • KMT2A expression
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Mekinist (trametinib) • cytarabine • doxorubicin hydrochloride • Vanflyta (quizartinib)
over1year
Clinical and Molecular Response Assessment of AML Harboring Non-Canonical FLT3 p.N676K Driver Mutations to FLT3 Inhibitor Therapies (ASH 2022)
Treatment of acute myeloid leukemia (AML) has been enhanced by the development and regulatory approval of a series of novel agents, including midostaurin and gilteritinib (FLT3 inhibitors), venetoclax (BCL2 inhibitor), ivosidenib (IDH1 inhibitor), and enasidenib (IDH2 inhibitor)...Follow-up studies in Ba/F3 cells demonstrated that the FLT3 N676K mutation is sensitive to midostaurin and quizartinib, but that co-occurrence of FLT3 N676K and ITD mutations confers resistance to both targeted agents...Three patients were treated with FLT3 inhibitors added to upfront standard induction therapy (midostaurin, n=2; sorafenib, n=1)...The presence of concurrent canonical FLT3 mutations was associated with loss of treatment response. Longer-term follow will help evaluate the durability of FLT3 inhibitor maintenance strategies in both transplant and non-transplant clinical settings.
Clinical • IO biomarker
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FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1)
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FLT3-ITD mutation • FLT3 mutation • FLT3 N676K
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Venclexta (venetoclax) • sorafenib • Xospata (gilteritinib) • Rydapt (midostaurin) • Vanflyta (quizartinib) • Tibsovo (ivosidenib) • Idhifa (enasidenib)
over1year
Clinical and Molecular Features of FTL3 non Canonical and Activation Loop Mutations (ASH 2022)
In this limited group, no OS differences between AML patients treated with PTK inhibitors (13 cases receiving midostaurin, 3 gilteritinib and 1 sorafenib) and non-treated patients were observed in either FLT3AL or FLT3NC. In addition, although differences were noted in less advanced diseases, once patients progressed to AML no specific features, clinical parameters or prognosis differed between cases with FLT3 point mutations/deletions within the activation loop, which appeared to be similar to patients with other types of point mutations outside this region. We also report on the use of PTKs in FLT3NC, whose therapeutic response in association with such FLT3 molecular patterns should warrant further studies.
Clinical • Tumor Mutational Burden
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TMB (Tumor Mutational Burden) • FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1)
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FLT3-ITD mutation • FLT3 mutation • FLT3 N676K
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sorafenib • Xospata (gilteritinib) • Rydapt (midostaurin)
over1year
A Potent Small Molecule Inhibitor of FLT3, PHI-101 Overcomes Resistance in Acute Myeloid Leukemia: Efficacy and PK/PD Profile in Phase 1 First in Human Study (ASH 2022)
Seventy percent of enrolled patients had more than 3 prior anti-leukemic treatment attempts, and four patients had relapsed or refractory disease after treatment with other FLT3 inhibitors including gilteritinib, quizartinib, or HM43239. A dose-escalating phase 1a clinical data of PHI-101, which reflects up to cohort 4 of the study, indicates that PHI-101 generated potent FLT3 inhibition leading to encouraging anti-leukemic responses in R/R AML patients, including in those with prior FLT3 TKI therapeutic failure. PHI-101 showed good tolerance and favorable safety profile and reduced leukemic blasts significantly with 28-day dosing. PHI-101 sustained its activity to clear FLT3-ITD and/or FLT3-TKD mutations including D835Y or N676K identified in AML patients.
Clinical • P1 data • PK/PD data
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3-ITD mutation • FLT3 mutation • FLT3-TKD mutation • FLT3 D835Y • FLT3 D835 • FLT3 N676K
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Xospata (gilteritinib) • Vanflyta (quizartinib) • PHI-101 • tuspetinib (HM43239)
over1year
Next-Generation Sequencing Identifies Frequent FLT3 N676K Mutations in Myeloid Neoplasms (AMP 2022)
This is the first study to comprehensively evaluate FLT3 N676K variants in MN patients. Similar to the canonical TKD variants, N676K mutations were frequent in patients with de novo and secondary AML. Compared to ITD, N676K and D835 mutant AML conferred significantly better OS after bone marrow transplant.
Next-generation sequencing • Tumor Mutational Burden
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TMB (Tumor Mutational Burden) • FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1)
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FLT3-ITD mutation • FLT3 mutation • NPM1 mutation • FLT3 D835 • FLT3 N676K
2years
Successful treatment with gilteritinib for relapsed acute myeloid leukemia with FLT3-N676K mutation (PubMed, Rinsho Ketsueki)
She did not achieve CR by salvage chemotherapy with cytarabine-aclarubicin-G-CSF regimen. Finally, the patient died of the uncontrolled primary disease. This is a case in which comprehensive gene mutation analysis was useful in determining a treatment strategy.
Journal
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FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog)
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NRAS mutation • FLT3 N676K
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cytarabine • Xospata (gilteritinib) • aclarubicin
over2years
Treatment Shapes Clonal Evolution and Resistance Patterns in Murine KMT2A-Rearranged Leukemia with Subclonal FLT3N676K (ASH 2021)
Upon engraftment, treatment was started with either chemotherapy (cytarabine for 5 days + doxorubicin for 3 days), the FLT3 inhibitor AC220, chemotherapy followed by AC220, or AC220+Trametinib, a MEK inhibitor. Taken together, these results show that the specific treatment given not only affected survival of the FLT3 N676K mutated KMT2A-MLLT3 leukemia, but also impacted how the genetically distinct cells evolved. The general lack of acquired mutations upon targeted treatment suggests that target-independent mechanisms that result in alternate activation of survival/proliferation explains acquired resistance in a majority of mice and provides novel insights into treatment resistance.
Preclinical
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FLT3 (Fms-related tyrosine kinase 3) • KMT2A (Lysine Methyltransferase 2A) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • MLLT3 (MLLT3 Super Elongation Complex Subunit)
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FLT3 D835Y • MLL rearrangement • FLT3 D835 • FLT3 N676K • KMT2A mutation • MLL mutation • KMT2A expression
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Mekinist (trametinib) • cytarabine • doxorubicin hydrochloride • Vanflyta (quizartinib)
over2years
Clinical Significance of FLT3 Mutations in a Comprehensive NGS Multicenter Study of AML: HM-Screen-Japan 01 (ASH 2021)
This is the first report to analyze R/R and ND unfit AML cases in a Japanese cohort using F1H NGS, revealing a higher incidence of FLT3 -ITD/TKD mutations than previously reported. Therefore, F1H mutational analyses for R/R and ND unfit AML patients harboring FLT3 -ITD/TKD mutations may reveal novel therapeutic targets that are sensitive to FLT3i. Samples from these patients showed non-canonical gain-of-function mutations, such as N676K, S451F, V592D, and F691L, which could guide the selection of optimal anti-FLT3 therapies.
Clinical • Next-generation sequencing
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KRAS (KRAS proto-oncogene GTPase) • 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) • RUNX1 (RUNX Family Transcription Factor 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • WT1 (WT1 Transcription Factor)
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KRAS mutation • FLT3 mutation • NPM1 mutation • DNMT3A mutation • RUNX1 mutation • FLT3 F691L • FLT3 N676K
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FoundationOne® Heme CDx
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Xospata (gilteritinib) • Vanflyta (quizartinib)
almost3years
[VIRTUAL] TREATMENT IS SHAPING CLONAL EVOLUTION AND RESISTANCE PATTERNS IN MURINE KMT2A-REARRANGED LEUKEMIA WITH SUBCLONAL FLT3N676K (EHA 2021)
Upon engraftment, treatment was started with either chemotherapy (cytarabine for 5 days (d)+doxorubicin for 3 d), the FLT3 inhibitor AC220, chemotherapy followed by AC220, or AC220+Trametinib, a MEK inhibitor. Conclusion The specific treatment given affected survival and impacted the evolution of genetically distinct cells. The general lack of acquired mutations upon targeted treatment suggests that target-independent mechanisms that result in alternate activation of survival/proliferation explains acquired resistance in a majority of mice.
Preclinical
|
FLT3 (Fms-related tyrosine kinase 3) • KMT2A (Lysine Methyltransferase 2A) • MLLT3 (MLLT3 Super Elongation Complex Subunit)
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FLT3 D835Y • MLL rearrangement • FLT3 D835 • FLT3 N676K
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Mekinist (trametinib) • cytarabine • doxorubicin hydrochloride • Vanflyta (quizartinib)
over3years
[VIRTUAL] Genomic Analysis of FLT3 Mutations in a Comprehensive NGS Multicenter Study of AML: HM-Screen-Japan 01 (ASH 2020)
"Upon treatment failure during gilteritinib or quizartinib monotherapy, we can switch to another FLT3 inhibitor treatment in Japan. Moreover, improved biomarker analysis methods for detecting additional FLT3 alternations, like FLT3 N676K, could guide patient selection for the most suitable anti-FLT3 therapies. Furthermore, serial comprehensive genome profiling analysis at the time of AML progression, especially after tyrosine kinase inhibitor treatment, will provide valuable information for clinical decision-making."
Clinical
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FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • RUNX1 (RUNX Family Transcription Factor 1)
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FLT3-ITD mutation • FLT3 mutation • FLT3-TKD mutation • FLT3 N676K
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FoundationOne® Heme CDx
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Xospata (gilteritinib) • Vanflyta (quizartinib)
over3years
[VIRTUAL] Patterns of Secondary Resistance Differ in Patients (pts) with Acute Myeloid Leukemia (AML) Treated with Type I Versus Type II FLT3-Inhibitors (FLT3i’s) (ASH 2020)
Among 67 pts, 31% received type I (gilteritinib 12 pts, midostaurin 7 pts or crenolanib 2 pts), and 69% type II FLT3i-based therapies (sorafenib 39 pts, quizartinib 7 pts). Understanding these differences and selecting type I or type II inhibitors with the optimal combination partner to target specific scenarios, may improve response durations. FLT3 mutations may no longer be detectable at relapse post FLT3i-based therapies highlighting the importance of repeated FLT3 testing at relapse.
Clinical
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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) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • CBL (Cbl proto-oncogene)
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TP53 mutation • KRAS mutation • FLT3 mutation • FLT3 F691L • CBL mutation • FLT3 D835 • FLT3 N676K
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sorafenib • Xospata (gilteritinib) • Rydapt (midostaurin) • Vanflyta (quizartinib) • crenolanib (ARO-002)