Targeting FLT3 Mutations in AML (Acute Myeloid Leukemia)

Dear Colleagues,

Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene occur in about 30% of all acute myeloid leukemia (AML) patients. These mutations include internal tandem duplication (ITD) of the juxtamembrane domain (more frequent) and point mutations in the tyrosine kinase domain (TKD), both leading to constitutive activation of the protein kinase. Whilst FLT3-ITD mutations confer undoubtedly poor prognosis with higher risk of relapse and lower survival rate, the role of FLT3-TKD mutations still remains unclear.

FLT3 mutations are gatekeeper mutations in AML and, as demonstrated in different murine models, play a key role as co-operative mutation in AML development. This makes FLT3 mutation a valid target for therapy.

Several FLT3 inhibitors have been developed and are in clinical use in patients with FLT3-mutated AML, with midostaurine, FDA-approved as first-line treatment in association with chemotherapy, and gilteritinib, FDA-approved as single agent in relapsed/refractory AML with FLT3 mutations. These drugs exhibit different kinase inhibitory profiles, pharmacokinetics and toxicity. A variety of clinical studies are exploring the safety and efficacy of different FLT3-inhibitors in either novel combinations or sequential therapies.

Growing evidence indicates that FLT3 mutation status may change during the disease course as a manifestation of clonal evolution of the disease, with AML either acquiring or losing the mutation. Therefore, testing and re-testing for FLT3 mutations become essential at diagnosis and relapse for the establishment of the most proper therapeutic strategy.

With this Special Issue, we kindly invite our colleagues to submit their latest research findings, reviews or perspectives covering either biological or clinical aspects of FLT3 mutations in AML. The topics may include new knowledge on pathways involved in leukemogenesis, as well as description of in vitro and in vivo FLT3-mutated AML models. Clinical significance of FLT3 mutations in AML and related debated issues are invited to be addressed. Additionally, papers either describing the established therapeutic role or discussing the open questions on the clinical use of FLT3 inhibitors are welcome. We believe this Special Issue may offer insights onto relevant biological and clinical issues on FLT3 mutations in AML and targeted therapy, while providing new perspectives on patients management and future therapeutic approaches. 

We look forward to your contributions and will be happy to discuss your suggestions.

Prof. Dr. Maria Paola Martelli
Guest Editor

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