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
INSERM UMR1277, Centre National de la Recherche Scientifique UMR9020-CANTHER, Lille University Hospital, Université de Lille, Lille, France.
Hematology Laboratory, Centre Hospitalier Universitaire de Lille, Lille, France.
Blood Adv. 2025 Jan 28;9(2):365-374. doi: 10.1182/bloodadvances.2024014672.
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 <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.
尽管使用米哚妥林（MIDO）联合强化化疗（ICT）作为Fms样酪氨酸激酶3（FLT3）突变的急性髓系白血病（AML）的一线治疗方法，但完全缓解率接近60%至70%，且超过40%的病例会复发。在此，我们研究了FLT3突变的AML患者难治/复发（R/R）疾病的分子机制。我们进行了一项回顾性多中心研究，纳入了150例R/R AML患者，这些患者在诊断时通过标准方法评估存在FLT3内部串联重复（ITD）（n = 130）和/或FLT3酪氨酸激酶结构域突变（n = 26）。根据米哚妥林的诊断日期和标签，患者接受ICT + MIDO治疗（n = 54）或仅接受ICT治疗（n = 96）。通过靶向高通量测序分析配对的诊断-R/R样本中FLT3克隆和共突变的演变。使用专门的FLT3-ITD检测算法，在两个时间点均检测到189个FLT3-ITD微克隆（等位基因比例[AR]<0.05）和225个宏克隆（AR≥0.05）。在R/R疾病阶段，接受ICT + MIDO治疗的患者中FLT3-ITD持续存在的比例低于未接受米哚妥林治疗的患者（68%对87.5%；P = 0.011）。在接受ICT + MIDO治疗的患者中，检测到多个FLT3-ITD克隆与R/R疾病时更高的FLT3-ITD持续存在率相关（多个克隆：88%对单个克隆：57%；P = 0.049）。如果诊断时检测到的FLT3-ITD微克隆在复发时仅有24%保留，43%则变成了宏克隆。总之，这些结果确定了影响FLT3-ITD克隆适应性的参数。
