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

•FLT3-ITD persists after ICT with and without MIDO in 68% and 87.5% of patients, respectively.•The number of initial FLT3-ITD microclones and macroclones affects the FLT3-ITD persistence rate after MIDO. [Display omitted] Despite the use of midostaurin (MIDO) with intensive chemotherapy (ICT) as fro...

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Published in:Blood advances 2025-01, Vol.9 (2), p.365-374
Main Authors: Joudinaud, Romane, Boudry, Augustin, Fenwarth, Laurène, Geffroy, Sandrine, Salson, Mikaël, Dombret, Hervé, Berthon, Céline, Pigneux, Arnaud, Lebon, Delphine, Peterlin, Pierre, Bouzy, Simon, Flandrin-Gresta, Pascale, Tavernier, Emmanuelle, Carre, Martin, Tondeur, Sylvie, Haddaoui, Lamya, Itzykson, Raphael, Bertoli, Sarah, Bidet, Audrey, Delabesse, Eric, Hunault, Mathilde, Récher, Christian, Preudhomme, Claude, Duployez, Nicolas, Dumas, Pierre-Yves
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Female
fms-Like Tyrosine Kinase 3 - genetics
Hematology
Human health and pathology
Humans
Leukemia, Myeloid, Acute - drug therapy
Leukemia, Myeloid, Acute - genetics
Life Sciences
Male
Middle Aged
Mutation
Retrospective Studies
Staurosporine - analogs & derivatives
Staurosporine - therapeutic use
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Summary:•FLT3-ITD persists after ICT with and without MIDO in 68% and 87.5% of patients, respectively.•The number of initial FLT3-ITD microclones and macroclones affects the FLT3-ITD persistence rate after MIDO. [Display omitted] Despite the use of midostaurin (MIDO) with intensive chemotherapy (ICT) as frontline treatment for Fms-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML), complete remission rates are close to 60% to 70%, and relapses occur in >40% of cases. Here, we studied the molecular mechanisms underlying refractory/relapsed (R/R) disease in patients with FLT3-mutated AML. We conducted a retrospective and multicenter study involving 150 patients with R/R AML harboring FLT3–internal tandem duplication (ITD) (n = 130) and/or FLT3–tyrosine kinase domain mutation (n = 26) at diagnosis assessed by standard methods. Patients were treated with ICT + MIDO (n = 54) or ICT alone (n = 96) according to the diagnosis date and label of MIDO. The evolution of FLT3 clones and comutations was analyzed in paired diagnosis–R/R samples by targeted high-throughput sequencing. Using a dedicated algorithm for FLT3-ITD detection, 189 FLT3-ITD microclones (allelic ratio [AR] of
ISSN:2473-9529
2473-9537
2473-9537
DOI:10.1182/bloodadvances.2024014672