FLT3-TKD mutation

All fit patients with FLT3m-AML must receive intensive chemotherapy plus a FLT3i (midostaurin or quizartinib) and be evaluated for allo-HSCT. For unfit patients, the current standard of HMA + venetoclax is considered suboptimal, making the search for alternative strategies imperative...In the R/R setting, retesting the FLT3 status is mandatory, and gilteritinib is the standard treatment, serving as a bridge-to-transplant and for post-HSCT maintenance. The integration of FLT3i has shifted FLT3m-AML into a more favorable intermediate prognostic category, enhancing the role of curative strategies like allo-HSCT. This consensus paper provides a structured evidence-based comprehensive guide, translating complex data into clear actionable clinical recommendations that minimize practice variability and ultimately optimize management for this high-risk population.

P3, N=300, Not yet recruiting, Institute of Hematology & Blood Diseases Hospital, China

P2, N=19, Active, not recruiting, Centre Antoine Lacassagne | Recruiting --> Active, not recruiting | N=50 --> 19 | Trial completion date: Mar 2027 --> Jul 2028 | Trial primary completion date: Mar 2027 --> Jul 2028

P2, N=153, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2025 --> Dec 2027 | Trial primary completion date: Dec 2025 --> Dec 2027

The complexity of AML was influenced by various cytogenetic and molecular abnormalities, which contributed to patients' heterogeneous presentation and survival outcomes. In addition to the previous data, IDH1, IDH2, and DNMT3A mutations might have affected survival outcomes in AML patients in our retrospective cohort. However, further studies with larger sample sizes are needed to validate these observations.

Triplet combinations of an HMA, venetoclax and a FLT3 inhibitor result in durable remission and encouraging long-term OS in older adults with newly diagnosed FLT3-mutated AML. However, better strategies to prevent FLT3 wild type relapses and to overcome RAS pathway-mediated resistance are still needed.

P1, N=22, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial primary completion date: Jan 2025 --> Feb 2027 | Trial completion date: May 2026 --> Mar 2027

We described the distribution of FLT3 mutations; further work is needed to understand prevalence estimate heterogeneity.

FLT3-TKDmut AML commonly harbors NPM1 co-mutation, which has key prognostic implications. Lack of NPM1 co-mutation portends a poor prognosis, and allogenic stem cell transplantation should be strongly considered for patients in first remission.

FASN inhibition resulted in reduced levels of phospho-Akt (pAkt) and phospho-S6 kinase (pS6) and decreased expression of Hedgehog-Gli1, confirming non-canonical regulation of Gli by FLT3-ITD signaling. Combining TVB-3166 with the Gli inhibitor GANT61 significantly reduced the survival of MOLM13 and MV411 cells.

P1, N=22, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial primary completion date: May 2025 --> Jan 2025

The molecular dynamics study of 4ACP and 22b was conducted to explain the significant changes in activity resulting from subtle structural alterations. Altogether, these findings establish 22b as a potent mutant FLT3 inhibitor, warranting further investigation and optimization to target resistant AML.