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Minerva Medica 2020 October;111(5):427-42

DOI: 10.23736/S0026-4806.20.06989-X


lingua: Inglese

FLT3 inhibitors in the treatment of acute myeloid leukemia: current status and future perspectives

Adrián MOSQUERA ORGUEIRA 1, 2, 3 , Laura BAO PÉREZ 1, 2, Alicia MOSQUERA TORRE 1, 2, Andrés PELETEIRO RAÍNDO 1, 2, 3, Miguel CID LÓPEZ 1, 2, 3, José Á. DÍAZ ARIAS 1, 2, Roi FERREIRO FERRO 1, Beatriz ANTELO RODRÍGUEZ 1, 2, 3, Marta S. GONZÁLEZ PÉREZ 1, 2, Manuel ALBORS FERREIRO 1, 2, Natalia ALONSO VENCE 1, 2, Manuel M. PÉREZ ENCINAS 1, 2, 3, José L. BELLO LÓPEZ 1, 2, 3, Giovanni MARTINELLI 4, Claudio CERCHIONE 4

1 Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain; 2 Division of Hematology, Complexo Hospitalario Universitario de Santiago de Compostela (CHUS - SERGAS), Santiago de Compostela, Spain; 3 University of Santiago de Compostela, Santiago de Compostela, Spain; 4 Unit of Hematology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Forlì-Cesena, Italy

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.

KEY WORDS: Antagonists and inhibitors; Leukemia, myeloid, acute; Midostaurin; Gilteritinib

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