Related Experiment Video
Updated: Nov 4, 2025
Comet Assay to Quantify DNA Damage in FLT3 Mutant-expressing 32D Cells after Exposure to Type I and Type II FLT3 Inhibitors
Published on: October 17, 2025
FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm
Naval Daver1, Sangeetha Venugopal2, Farhad Ravandi2
1Department of Leukemia, The University of Texas - MD Anderson Cancer Center, Houston, TX, USA. ndaver@mdanderson.org.
Abstract:
Approximately 30% of patients with newly diagnosed acute myeloid leukemia (AML) harbor mutations in the fms-like tyrosine kinase 3 (FLT3) gene. While the adverse prognostic impact of FLT3-ITDmut in AML has been clearly proven, the prognostic significance of FLT3-TKDmut remains speculative. Current guidelines recommend rapid molecular testing for FLT3mut at diagnosis and earlier incorporation of targeted agents to achieve deeper remissions and early consideration for allogeneic stem cell transplant (ASCT). Mounting evidence suggests that FLT3mut can emerge at any timepoint in the disease spectrum emphasizing the need for repetitive mutational testing not only at diagnosis but also at each relapse. The approval of multi-kinase FLT3 inhibitor (FLT3i) midostaurin with induction therapy for newly diagnosed FLT3mut AML, and a more specific, potent FLT3i, gilteritinib as monotherapy for relapsed/refractory (R/R) FLT3mut AML have improved outcomes in patients with FLT3mut AML. Nevertheless, the short duration of remission with single-agent FLT3i's in R/R FLT3mut AML in the absence of ASCT, limited options in patients refractory to gilteritinib therapy, and diverse primary and secondary mechanisms of resistance to different FLT3i's remain ongoing challenges that compel the development and rapid implementation of multi-agent combinatorial or sequential therapies for FLT3mut AML.
Insights
Approximately 30% of acute myeloid leukemia (AML) patients have FLT3 gene mutations. New FLT3 inhibitors improve outcomes, but resistance necessitates combination therapies for better AML treatment.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- About 30% of newly diagnosed acute myeloid leukemia (AML) patients harbor fms-like tyrosine kinase 3 (FLT3) gene mutations.
- While FLT3-ITD mutations clearly indicate a poor prognosis in AML, the prognostic value of FLT3-TKD mutations is still uncertain.
- Current guidelines advocate for prompt FLT3 mutation testing at diagnosis to guide treatment decisions and consider allogeneic stem cell transplant (ASCT).
Purpose of the Study:
- To review the current landscape of FLT3 mutations in AML, including their prognostic impact and the evolving role of targeted therapies.
- To highlight the challenges posed by resistance mechanisms and limited treatment options in relapsed/refractory FLT3-mutated AML.
- To emphasize the need for developing and implementing novel combination or sequential therapies for FLT3-mutated AML.
Main Methods:
- Literature review of studies on FLT3 mutations in AML.
- Analysis of current treatment guidelines and clinical trial data for FLT3 inhibitors.
- Discussion of resistance mechanisms and future therapeutic strategies.
Main Results:
- FLT3 mutations are common in AML and impact prognosis, with FLT3-ITD being particularly adverse.
- FLT3 inhibitors like midostaurin and gilteritinib have improved outcomes in newly diagnosed and relapsed/refractory FLT3-mutated AML, respectively.
- Resistance to single-agent FLT3 inhibitors and limited options for refractory disease remain significant challenges.
Conclusions:
- FLT3 mutation testing is crucial at diagnosis and relapse for guiding AML treatment.
- While FLT3 inhibitors have advanced AML therapy, achieving durable remissions, especially in relapsed/refractory settings without ASCT, remains difficult.
- Multi-agent combinatorial or sequential therapies are essential for overcoming resistance and improving outcomes in FLT3-mutated AML.
