Midostaurin shapes macroclonal and microclonal evolution of FLT3-mutated acute myeloid leukemia

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• Frontline treatment for FLT3-mutated acute myeloid leukemia (AML) with midostaurin (MIDO) and intensive chemotherapy (ICT) yields incomplete remission and high relapse rates.
• Understanding molecular mechanisms of refractory/relapsed (R/R) disease in FLT3-mutated AML is crucial for improving outcomes.

Purpose of the Study:

• To investigate the molecular mechanisms driving refractory/relapsed (R/R) disease in patients with Fms-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML).
• To analyze the evolution of FLT3 clones and comutations in patients treated with midostaurin (MIDO) plus intensive chemotherapy (ICT) versus ICT alone.

Main Methods:

• Retrospective, multicenter study of 150 patients with R/R FLT3-mutated AML.
• Targeted high-throughput sequencing of paired diagnosis-relapsed/refractory samples to analyze FLT3 clones and comutations.
• Utilized a dedicated algorithm for detecting FLT3-internal tandem duplication (ITD) microclones (AR < 0.05) and macroclones (AR ≥ 0.05).

Main Results:

• FLT3-ITD persistence at R/R disease was lower in patients treated with ICT + MIDO (68%) compared to ICT alone (87.5%).
• In patients receiving ICT + MIDO, multiple FLT3-ITD clones at diagnosis were associated with higher FLT3-ITD persistence (88%) at R/R disease.
• A significant proportion of FLT3-ITD microclones at diagnosis evolved into macroclones by relapse (43%).

Conclusions:

• Midostaurin treatment is associated with reduced FLT3-ITD clone persistence in relapsed/refractory AML.
• The presence of multiple FLT3-ITD clones at diagnosis is a key parameter influencing treatment resistance and relapse.
• These findings highlight critical factors affecting the fitness and persistence of FLT3-ITD clones in AML.