FLT3 mutation

P1, N=36, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Feb 2026 --> Feb 2027 | Trial primary completion date: Feb 2026 --> Feb 2027

To evaluate the impact of this trafficking difference, we synthesised an anti-FLT3 mAb-MMAE, linked via a Val-Cit-PAB linker at the Fc N-glycan, which exhibited lower cytotoxicity in MV4-11 than THP-1 cells, indicating that the impaired lysosomal trafficking of FLT3-ITD limits drug release and reduces ADC potency. These findings highlight that effective lysosomal targeting is essential for ADC activity and suggest that optimising linker design or restoring lysosome trafficking may enhance FLT3-targeted ADC in AML.

We analyzed 523 adults with FLT3-ITD AML in first complete remission who underwent allo-HCT between 2011 and 2023 in 13 German transplant centers participating in the national DRST registry; 22% received FLT3i maintenance (sorafenib 49%, midostaurin 37%, gilteritinib 5%, unknown 9%). Sorafenib maintenance (n=50) demonstrated superior efficacy with 5-year OS of 85% versus 62% (HR 2.979, p=0.0045) and RFS of 84% versus 55% (HR 2.771, p=0.0043) compared to no maintenance. These real-world findings, while limited by the retrospective design and potential selection bias, align with randomized trial data and support the use of FLT3i maintenance as part of post-transplant care for FLT3-ITD AML.

P1/2, N=70, Active, not recruiting, Astellas Pharma Global Development, Inc. | Recruiting --> Active, not recruiting

While differentiation therapy revolutionized acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), its extension into non-APL AML has been limited until recent targeted agents...IDH1/2 inhibitors (ivosidenib, enasidenib, olutasidenib) yield overall response rates (ORRs) of 30-94% in AML with DS in 10-19%. Menin inhibitors (revumenib, ziftomenib, enzomenib, bleximenib) achieve ORRs of 33-88% in KMT2A-rearranged or NPM1-mutated AML, with DS in 10-25% and QT prolongation as key toxicities. FLT3 inhibitors (gilteritinib, quizartinib) improve survival in FLT3-mutated AML with DS in 1-5%...Improved recognition of DS and rational combination approaches will be essential to maximize the therapeutic benefit. Future research should address mechanisms of resistance and biomarkers to achieve cures beyond APL.

Targeted therapies have improved outcomes in molecularly defined subsets of AML, with menin, IDH and FLT3 inhibitors representing major advances. However, TP53-mutated AML continues to carry a dismal prognosis, underscoring the need for more effective therapeutic strategies. Continued biomarker-driven research, novel drug combinations, and mechanistic insights will be essential to further refine AML treatment and improve long-term survival across disease subsets.

Dual targeting of FLT3/SYK (TAK-659) and the proteasome (Ixazomib) showed strong synergy across genetically defined AML subsets, irrespective of FLT3 mutant status. These findings define a therapeutically targetable axis linking FLT3/SYK/β-catenin signaling to stress adaptation, provide a mechanistic basis for combinatorial targeting in high-risk AML. Trial registration: NCT04079738, Date of registration 03 September 2019.

Current inhibitors show efficacy, yet resistance and toxicity remain challenges. Emerging approaches, including selective inhibitors, proteolysis-targeting chimeras, and protein degraders, offer enhanced potency, sustained suppression, and combinatorial potential, representing a precision-based advancement in AML treatment.

AML-MR and MDS/AML form a biological continuum with shared molecular and clinical features, supporting the ICC classification update. Our integrated model may improve prognostic stratification and guide clinical decision-making for these high-risk patients.

P1, N=35, Active, not recruiting, Biomea Fusion Inc. | Trial completion date: Jan 2026 --> Apr 2026 | Trial primary completion date: Jan 2026 --> Apr 2026

FLT3 inhibitors - midostaurin (first-generation), gilteritinib and quizartinib (second-generation) - have been developed to block FLT3 activation. The only exception was an higher risk of ALT increased with gilteritinib (RR = 2.40, 95% CI: 1.16-4.95). Future studies should stratify safety outcomes by demographic and clinical characteristics and incorporate long-term follow-up for a more comprehensive safety assessment in clinical practice.