FLT3 N676K

Human KMT2A-r AML cells could be pharmacologically sensitized to NKG2D-CAR T cells by treatment with the histone deacetylase inhibitor LBH589 (panobinostat) which caused upregulation of NKG2D-ligand levels...Finally, the results were validated and extended to acute leukemia in infancy. Combined, activating mutations induced mutation-specific changes in the epigenetic landscape, leading to changes in transcriptional programs orchestrated by specific transcription factor networks.

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.

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.

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

Not available.

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.

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.

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.

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.

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.

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.

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.

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.

"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."

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.