Molica, M.; Perrone, S.; Rossi, M. Gilteritinib: The Story of a Proceeding Success into Hard-to-Treat FLT3-Mutated AML Patients. J. Clin. Med.2023, 12, 3647.
Molica, M.; Perrone, S.; Rossi, M. Gilteritinib: The Story of a Proceeding Success into Hard-to-Treat FLT3-Mutated AML Patients. J. Clin. Med. 2023, 12, 3647.
Molica, M.; Perrone, S.; Rossi, M. Gilteritinib: The Story of a Proceeding Success into Hard-to-Treat FLT3-Mutated AML Patients. J. Clin. Med.2023, 12, 3647.
Molica, M.; Perrone, S.; Rossi, M. Gilteritinib: The Story of a Proceeding Success into Hard-to-Treat FLT3-Mutated AML Patients. J. Clin. Med. 2023, 12, 3647.
Abstract
The traditionally dismal outcome of acute myeloid leukemia (AML) patients carrying the FMS-related tyrosine kinase 3 (FLT3) mutations has been mitigated by the recent introduction into the clinics of tyrosine kinase inhibitors (TKI) such as midostaurin and gilteritinib. The present work summarizes the clinical data that led to the use of gilteritinib in clinical practice. Gilteritinib is a 2nd generation TKI with deeper single-agent activity than 1st generation drugs against both FLT3-ITD and TKD mutations, in human studies. Moreover, the phase I/II dose-escalation, dose-expansion Chrysalis trial showed an acceptable safety profile of gilteritinib (diarrhea, elevated aspartate aminotransferase, febrile neutropenia, anemia, thrombocytopenia, sepsis, and pneumonia) and a 49% overall response rate (ORR) in 191 FLT3-mutated relapsed/refractory (R/R) AML patients. In 2019, the pivotal ADMIRAL trial showed that the median overall survival was significantly longer in patients treated with gilteritinib than among those receiving chemotherapy (9.3 vs 5.6 months, respectively) and the ORR to gilteritinib was 67.6%, outperforming the 25.8% for chemotherapy arm and leading to the license for its clinical use by the US Food and Drug Administration. Since then, several real-world experiences confirmed the positive results in the R/R AML setting. Finally, gilterinib based combinations currently under investigation with several compounds (venetoclax, azacitidine, conventional chemotherapy, etc.) and some practical tips (maintenance after allogeneic transplantation, interaction with antifungal drugs, extramedullary disease, and onset of resistance) will be analyzed in detail in the review.
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