Gilteritinib: The Story of a Proceeding Success into Hard-to-Treat <i>FLT3</i>-Mutated AML Patients
The traditionally dismal outcome of acute myeloid leukemia (AML) patients carrying the FMS-related tyrosine kinase 3 (<i>FLT3</i>) mutations has been mitigated by the recent introduction of tyrosine kinase inhibitors (TKI) into clinics, such as midostaurin and gilteritinib. The present w...
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| Format: | Article |
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MDPI AG
2023-05-01
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| Series: | Journal of Clinical Medicine |
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| Online Access: | https://www.mdpi.com/2077-0383/12/11/3647 |
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| author | Matteo Molica Salvatore Perrone Marco Rossi |
| author_facet | Matteo Molica Salvatore Perrone Marco Rossi |
| author_sort | Matteo Molica |
| collection | DOAJ |
| description | The traditionally dismal outcome of acute myeloid leukemia (AML) patients carrying the FMS-related tyrosine kinase 3 (<i>FLT3</i>) mutations has been mitigated by the recent introduction of tyrosine kinase inhibitors (TKI) into clinics, 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 second-generation TKI with deeper single-agent activity than first-generation drugs against both <i>FLT3–ITD</i> 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 <i>FLT3</i>-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 have confirmed the positive results in the R/R AML setting. Finally, gilteritinib-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 this review. |
| first_indexed | 2024-03-11T03:04:20Z |
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| issn | 2077-0383 |
| language | English |
| last_indexed | 2024-03-11T03:04:20Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Journal of Clinical Medicine |
| spelling | doaj.art-0f9087685e5a40bb82c2397bda296be52023-11-18T08:04:30ZengMDPI AGJournal of Clinical Medicine2077-03832023-05-011211364710.3390/jcm12113647Gilteritinib: The Story of a Proceeding Success into Hard-to-Treat <i>FLT3</i>-Mutated AML PatientsMatteo Molica0Salvatore Perrone1Marco Rossi2Department of Hematology-Oncology, Azienda Ospedaliera Pugliese-Ciaccio, 88100 Catanzaro, ItalyDepartment of Hematology, Polo Universitario Pontino, S.M. Goretti Hospital, 04100 Latina, ItalyDepartment of Hematology-Oncology, Azienda Ospedaliera Pugliese-Ciaccio, 88100 Catanzaro, ItalyThe traditionally dismal outcome of acute myeloid leukemia (AML) patients carrying the FMS-related tyrosine kinase 3 (<i>FLT3</i>) mutations has been mitigated by the recent introduction of tyrosine kinase inhibitors (TKI) into clinics, 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 second-generation TKI with deeper single-agent activity than first-generation drugs against both <i>FLT3–ITD</i> 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 <i>FLT3</i>-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 have confirmed the positive results in the R/R AML setting. Finally, gilteritinib-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 this review.https://www.mdpi.com/2077-0383/12/11/3647<i>FLT3</i> mutationsresistant/relapsed acute myeloid leukemiatyrosine kinase inhibitorsgilteritinib |
| spellingShingle | Matteo Molica Salvatore Perrone Marco Rossi Gilteritinib: The Story of a Proceeding Success into Hard-to-Treat <i>FLT3</i>-Mutated AML Patients Journal of Clinical Medicine <i>FLT3</i> mutations resistant/relapsed acute myeloid leukemia tyrosine kinase inhibitors gilteritinib |
| title | Gilteritinib: The Story of a Proceeding Success into Hard-to-Treat <i>FLT3</i>-Mutated AML Patients |
| title_full | Gilteritinib: The Story of a Proceeding Success into Hard-to-Treat <i>FLT3</i>-Mutated AML Patients |
| title_fullStr | Gilteritinib: The Story of a Proceeding Success into Hard-to-Treat <i>FLT3</i>-Mutated AML Patients |
| title_full_unstemmed | Gilteritinib: The Story of a Proceeding Success into Hard-to-Treat <i>FLT3</i>-Mutated AML Patients |
| title_short | Gilteritinib: The Story of a Proceeding Success into Hard-to-Treat <i>FLT3</i>-Mutated AML Patients |
| title_sort | gilteritinib the story of a proceeding success into hard to treat i flt3 i mutated aml patients |
| topic | <i>FLT3</i> mutations resistant/relapsed acute myeloid leukemia tyrosine kinase inhibitors gilteritinib |
| url | https://www.mdpi.com/2077-0383/12/11/3647 |
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