FLT3 mutation

XY0206 exhibited a favorable safety profile and demonstrated potent antileukemic activity, particularly in FLT3mut+ R/R AML patients, supporting its further clinical development. Trial Registration: CTR20201214 (CDE); ClinicalTrials.gov ID: NCT04471064.

Functionally, MV4-11QR cells showed broad cross-resistance to clinically relevant agents, including midostaurin, venetoclax, and cytarabine. Importantly, pharmacological targeting of mutant p53 with eprenetapopt or MAPK signaling with trametinib restored sensitivity to quizartinib, inducing synergistic or additive cytotoxic effects and increased apoptosis. Together, these findings define a multilayered resistance program involving genetic, signaling, and metabolic adaptations and support rational combination strategies to overcome FLT3 inhibitor resistance in AML.

First-generation inhibitors, such as midostaurin, provided the foundation for targeted therapy, while recently developed agents such as gilteritinib and quizartinib have shown more selectivity and demonstrated superior clinical efficiency and improved tolerability. This review discusses the significance of FLT-3 mutations, the evolution of targeted therapies, current treatment guidelines, and ongoing challenges such as resistance and high relapse rates. We also discuss the emerging combinations of therapies and novel agents currently in clinical trials that aim to overcome resistance and improve long-term outcomes for patients with FLT-3-mutated AML.

In the subgroup analysis, post-HSCT gilteritinib showed an RFS benefit in cord blood transplantation (CBT; 79.4% vs. 26.1%, p < 0.001), but not in bone marrow or peripheral blood stem cell transplantation. This Japanese real-world study supports the tolerability and effectiveness of post-HSCT gilteritinib in R/R FLT3-mutated AML.

This case highlights potential ocular neurotoxicity associated with Gilteritinib, a targeted therapy not previously linked to corneal nerve dysfunction. Increased clinical awareness is recommended for ophthalmologists and hematologists managing patients with FLT3-mutated AML who are receiving targeted therapies.

Although the OS from diagnosis improved significantly in the FLT3i era, relapse after allo-HSCT remained a substantial challenge. Further studies are needed to optimize FLT3i maintenance therapy strategies.

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In vivo, FLC-8 inhibited MV4-11 xenograft growth (TGI: 136-178% at 10-50 mg/kg) without overt toxicity. These findings identify Cys807 as a covalent binding hotspot in FLT3 and establish FLC-8 as a promising scaffold for next-generation FLT3 inhibitor development.

Moreover, F-17 showed potent selectivity and inhibition activity for FLT3-mutated cells both in vitro and in vivo. Collectively, the work provided a new insight for FLT3 inhibitor development.

Mechanistically, KD rewired anabolism toward fatty acid oxidation and glycine-utilizing pathways, modulated the expression of FLT3 signaling pathways and lipid biosynthesis, and promoted tumor cell differentiation. In conclusion, this study shows that KD reduces FLT3i resistance, offering a promising therapeutic solution.

P1, N=18, Recruiting, Memorial Sloan Kettering Cancer Center | N=36 --> 18