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FLT3 inhibitors in the treatment of acute myeloid leukemia: current status and future perspectives.
- Source :
-
Minerva medica [Minerva Med] 2020 Oct; Vol. 111 (5), pp. 427-442. Date of Electronic Publication: 2020 Sep 21. - Publication Year :
- 2020
-
Abstract
- Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene arise in 25-30% of all acute myeloid leukemia (AML) patients. These mutations lead to constitutive activation of the protein product and are divided in two broad types: internal tandem duplication (ITD) of the juxtamembrane domain (25% of cases) and point mutations in the tyrosine kinase domain (TKD). Patients with FLT3 ITD mutations have a high relapse risk and inferior cure rates, whereas the role of FLT3 TKD mutations still remains to be clarified. Additionally, growing research indicates that FLT3 status evolves through a disease continuum (clonal evolution), where AML cases can acquire FLT3 mutations at relapse - not present in the moment of diagnosis. Several FLT3 inhibitors have been tested in patients with FLT3-mutated AML. These drugs exhibit different kinase inhibitory profiles, pharmacokinetics and adverse events. First-generation multi-kinase inhibitors (sorafenib, midostaurin, lestaurtinib) are characterized by a broad-spectrum of drug targets, whereas second-generation inhibitors (quizartinib, crenolanib, gilteritinib) show more potent and specific FLT3 inhibition, and are thereby accompanied by less toxic effects. Notwithstanding, all FLT3 inhibitors face primary and acquired mechanisms of resistance, and therefore the combinations with other drugs (standard chemotherapy, hypomethylating agents, checkpoint inhibitors) and its application in different clinical settings (upfront therapy, maintenance, relapsed or refractory disease) are under study in a myriad of clinical trials. This review focuses on the role of FLT3 mutations in AML, pharmacological features of FLT3 inhibitors, known mechanisms of drug resistance and accumulated evidence for the use of FLT3 inhibitors in different clinical settings.
- Subjects :
- Aniline Compounds pharmacology
Benzimidazoles pharmacology
Benzothiazoles pharmacology
Carbazoles pharmacology
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Forecasting
Furans
Hematopoietic Stem Cell Transplantation
Humans
Imidazoles pharmacology
Leukemia, Myeloid, Acute genetics
Leukemia, Myeloid, Acute therapy
Maintenance Chemotherapy methods
Mutation
Phenylurea Compounds pharmacology
Piperidines pharmacology
Point Mutation
Pyrazines pharmacology
Pyridazines pharmacology
Recurrence
Staurosporine analogs & derivatives
Staurosporine pharmacology
Antineoplastic Agents pharmacology
Leukemia, Myeloid, Acute drug therapy
Protein Kinase Inhibitors pharmacology
Sorafenib pharmacology
fms-Like Tyrosine Kinase 3 antagonists & inhibitors
fms-Like Tyrosine Kinase 3 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1827-1669
- Volume :
- 111
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Minerva medica
- Publication Type :
- Academic Journal
- Accession number :
- 32955823
- Full Text :
- https://doi.org/10.23736/S0026-4806.20.06989-X