Mutations in the gene are associated with poor prognosis in patients with AML, even after consolidation with allogeneic hematopoietic cell transplantation (alloHCT) in first remission. Treatment failure in -mutated AML is largely driven by excessive risk of relapse compared to other genetic subtypes, including in patients post-alloHCT. As a result, there is substantial interest in studying posttransplant maintenance therapy in -mutated AML as an approach to optimize disease control and improve long-term outcomes. Clinical trials utilizing posttransplant FLT3 inhibitors, such as sorafenib and midostaurin, have shown feasibility, safety, and encouraging posttransplant outcomes, and there are ongoing studies using newer-generation tyrosine-kinase inhibitors as posttransplant maintenance therapy. Here, we review the toxicities and efficacy of FLT3 inhibitors as posttransplant maintenance, recommendations on the use of FLT3 inhibitors by international consensus guidelines, and highlight key remaining questions.
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http://dx.doi.org/10.2147/BLCTT.S281252 | DOI Listing |
Life Sci
January 2025
Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. Electronic address:
The protein deacetylase HDAC6 has been controversially linked to cancer cell proliferation and viral propagation. We analyzed whether a pharmacological depletion of HDAC6 with a recent proteolysis-targeting chimera (PROTAC) kills tumor cells. We show that low micromolar doses of the cereblon-based PROTAC TH170, but not its inactive analog TH170E, induce proteasomal degradation of HDAC6.
View Article and Find Full Text PDFEur J Med Chem
December 2024
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD, 21201, USA; University of Maryland Marlene & Stewart Greenebaum Comprehensive Cancer Center, 22 S. Greene St., Baltimore, MD, 21201, USA. Electronic address:
Current treatments for acute myeloid leukemias (AMLs) cure fewer than 30 % of patients. This low efficacy is due, in part, to the inter-patient and intra-patient heterogeneity of AMLs; accordingly, all current AML treatment regimens involve drug combinations (polypharmacy). A recently-completed clinical trial in relapsed/refractory AML using a combination of two newer targeted antileukemics, the BCL-2 inhibitor venetoclax (VEN) plus the FLT3 inhibitor gilteritinib (GIL), yielded highly promising results for this two-drug polypharmacy combination.
View Article and Find Full Text PDFTransl Oncol
January 2025
The First Clinical Medical College of Lanzhou University, Lanzhou 730000, China; Department of Hematology, The First Hospital of Lanzhou University, Lanzhou 730000, China. Electronic address:
Gilteritinib treats acute myeloid leukemia (AML) with the FMS-like receptor tyrosine kinase-3 (FLT3) internal tandem duplication (ITD) mutation. Dysregulation of histone modification affects the genesis and progression of AML. Strategies targeting key histone regulators have not been applied to the treatment of AML.
View Article and Find Full Text PDFLeukemia
January 2025
The Clara D. Bloomfield Center for Leukemia Outcomes Research, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
The FLT3 gene frequently undergoes mutations in acute myeloid leukemia (AML), with internal tandem duplications (ITD) and tyrosine kinase domain (TKD) point mutations (PMs) being most common. Recently, PMs and deletions in the FLT3 juxtamembrane domain (JMD) have been identified, but their biological and clinical significance remains poorly understood. We analyzed 1660 patients with de novo AML and found FLT3-JMD mutations, mostly PMs, in 2% of the patients.
View Article and Find Full Text PDFTher Adv Drug Saf
January 2025
Department of Pharmacy, Daping Hospital, Army Medical University, No. 10 Changjiang Branch Road, Yuzhong District, Chongqing 400042, China.
Background: Gilteritinib and midostaurin are FLT3 inhibitors that have made significant progress in the treatment of acute myeloid leukemia. However, their real-world safety profile in a large sample population is incomplete.
Objectives: We aimed to provide a pharmacovigilance study of the adverse events (AEs) associated with gilteritinib and midostaurin through the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database.
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