Article
作者: Preudhomme, Claude ; Tondeur, Sylvie ; Tavernier, Emmanuelle ; Peterlin, Pierre ; Lebon, Delphine ; Duployez, Nicolas ; Haddaoui, Lamya ; Flandrin-Gresta, Pascale ; Carre, Martin ; Bidet, Audrey ; Geffroy, Sandrine ; Berthon, Céline ; Salson, Mikaël ; Dombret, Hervé ; Hunault, Mathilde ; Fenwarth, Laurène ; Pigneux, Arnaud ; Delabesse, Eric ; Joudinaud, Romane ; Dumas, Pierre-Yves ; Bertoli, Sarah ; Itzykson, Raphael ; Boudry, Augustin ; Bouzy, Simon ; Récher, Christian
AbstractDespite 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 <0.05) and 225 macroclones (AR ≥ 0.05) were detected at both time points. At R/R disease, the rate of FLT3-ITD persistence was lower in patients treated with ICT + MIDO than in patients not receiving MIDO (68% vs 87.5%; P = .011). In patients receiving ICT + MIDO, detection of multiple FLT3-ITD clones was associated with a higher FLT3-ITD persistence rate at R/R disease (multiple clones: 88% vs single clones: 57%; P = .049). If only 24% of FLT3-ITD microclones detected at diagnosis were retained at relapse, 43% became macroclones. Together, these results identify parameters influencing the fitness of FLT3-ITD clones.