A systematic review of second-generation FLT3 inhibitors for treatment of patients with relapsed/refractory acute myeloid leukemia

Leuk Res. 2024 Jun:141:107505. doi: 10.1016/j.leukres.2024.107505. Epub 2024 Apr 17.

Abstract

Background: Acute myeloid leukemia (AML) is a complex disease with diverse mutations, including prevalent mutations in the FMS-like receptor tyrosine kinase 3 (FLT3) gene that lead to poor prognosis. Recent advancements have introduced FLT3 inhibitors that have improved outcomes for FLT3-mutated AML patients, however, questions remain on their application in complex conditions such as relapsed/refractory (R/R) disease. Therefore, we aimed to evaluate the clinical effectiveness of second-generation FLT3 inhibitors in treating patients with R/R AML.

Methods: A systematic literature search of PubMed, MEDLINE, SCOPUS and Google Scholar databases was made to identify relevant studies up to January 30, 2024. This study was conducted following the guidelines of the PRISMA.

Results: The ADMIRAL trial revealed significantly improved overall survival and complete remission rates with gilteritinib compared to salvage chemotherapy, with manageable adverse effects. Ongoing research explores its potential in combination therapies, showing synergistic effects with venetoclax and promising outcomes in various clinical trials. The QuANTUM-R trial suggested longer overall survival with quizartinib compared to standard chemotherapy, although concerns were raised regarding trial design and cardiotoxicity. Ongoing research explores combination therapies involving quizartinib, such as doublet or triplet regimens with venetoclax, showing promising outcomes in FLT3-mutated AML patients.

Conclusion: These targeted therapies offer promise for managing this subgroup of AML patients, but further research is needed to optimize their use. This study underscores the importance of personalized treatment based on genetic mutations in AML, paving the way for more effective and tailored approaches to combat the disease.

Keywords: AML; FLT3; FLT3 Inhibitor; Relapse/Refractory.

Publication types

  • Systematic Review
  • Review

MeSH terms

  • Aniline Compounds / therapeutic use
  • Benzothiazoles
  • Drug Resistance, Neoplasm
  • Humans
  • Leukemia, Myeloid, Acute* / drug therapy
  • Leukemia, Myeloid, Acute* / genetics
  • Leukemia, Myeloid, Acute* / mortality
  • Mutation
  • Neoplasm Recurrence, Local / drug therapy
  • Neoplasm Recurrence, Local / pathology
  • Phenylurea Compounds / therapeutic use
  • Protein Kinase Inhibitors* / therapeutic use
  • Pyrazines / therapeutic use
  • fms-Like Tyrosine Kinase 3* / antagonists & inhibitors
  • fms-Like Tyrosine Kinase 3* / genetics

Substances

  • fms-Like Tyrosine Kinase 3
  • FLT3 protein, human
  • Protein Kinase Inhibitors
  • gilteritinib
  • quizartinib
  • Aniline Compounds
  • Phenylurea Compounds
  • Pyrazines
  • Benzothiazoles