Rücker Frank G, Bullinger Lars, Cocciardi Sibylle, Skambraks Sabrina, Luck Tamara J, Weber Daniela, Krzykalla Julia, Pozek Ema, Schneider Isabelle, Corbacioglu Andrea, Gaidzik Verena I, Meid Annika, Aicher Sophia, Stegelmann Frank, Schrade Anika, Theis Frauke, Fiedler Walter, Salih Helmut R, Wulf Gerald, Salwender Hans, Schroeder Thomas, Götze Katharina S, Kühn Michael W M, Lübbert Michael, Schlenk Richard F, Benner Axel, Thol Felicitas, Heuser Michael, Ganser Arnold, Döhner Hartmut, Döhner Konstanze
Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
Department of Hematology, Oncology and Cancer Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
Blood Adv. 2024 Dec 10;8(23):6067-6080. doi: 10.1182/bloodadvances.2024013758.
Measurable residual disease (MRD) monitoring in acute myeloid leukemia (AML) with an FLT3 internal tandem duplication (FLT3-ITDpos) has been hampered by the broad heterogeneity of ITD mutations. Using our recently developed FLT3-ITD paired-end next-generation sequencing (NGS)-based MRD assay (limit of detection 10-4 to 10-5), we evaluated the prognostic impact of MRD at different time points in 157 patients with FLT3-ITDpos AML who were enrolled in the German-Austrian Acute Myeloid Leukemia Study Group 16-10 trial and who were treated with a combination of intensive chemotherapy and midostaurin, followed by midostaurin maintenance. MRD negativity (MRDneg) after 2 cycles of chemotherapy (Cy2), which was observed in 111 of 142 (78%) patients, was predictive of superior 4-year rates of cumulative incidence of relapse (CIR) (4y-CIR; 26% vs 46%; P = .001) and overall survival (OS) (4y-OS; 70% vs 44%; P = .012). This survival advantage was also seen among patients who underwent allogeneic hematopoietic-cell transplantation during first complete remission (4y-CIR, 14% vs 39%; P = .001; 4y-OS, 71% vs 49%; P = .029). Multivariate models for CIR and OS after Cy2 revealed FLT3-ITD MRDneg as the only consistent favorable variable for CIR (hazard ratio [HR], 0.29; P = .006) and OS (HR, 0.39; P = .018). During follow-up, conversion from MRDneg to MRD positivity (MRDpos) was a strong, independent factor for inferior CIR (HR, 16.64; P < .001) and OS (HR, 4.05; P < .001). NGS-based FLT3-ITD MRD monitoring identifies patients at high risk for relapse and death following treatment with intensive chemotherapy and midostaurin. Using NGS-based technology.
急性髓系白血病（AML）伴FLT3内部串联重复（FLT3-ITD阳性）患者的可测量残留病（MRD）监测一直受到ITD突变广泛异质性的阻碍。我们使用最近开发的基于FLT3-ITD双末端新一代测序（NGS）的MRD检测方法（检测限为10-4至10-5），评估了157例FLT3-ITD阳性AML患者在不同时间点MRD的预后影响，这些患者参加了德国-奥地利急性髓系白血病研究组16-10试验，并接受了强化化疗与米哚妥林联合治疗，随后进行米哚妥林维持治疗。在142例患者中的111例（78%）中观察到化疗2个周期（Cy2）后MRD阴性（MRDneg），这预测了4年累积复发率（CIR）（4年CIR；26%对46%；P = 0.001）和总生存期（OS）（4年OS；70%对44%；P = 0.012）更优。在首次完全缓解期接受异基因造血细胞移植的患者中也观察到了这种生存优势（4年CIR，14%对39%；P = 0.001；4年OS，71%对49%；P = 0.029）。Cy2后CIR和OS的多变量模型显示，FLT3-ITD MRDneg是CIR（风险比[HR]，0.29；P = 0.006）和OS（HR，0.39；P = 0.018）唯一一致的有利变量。在随访期间，从MRDneg转变为MRD阳性（MRDpos）是CIR较差（HR，16.64；P < 0.001）和OS较差（HR，4.05；P < 0.001）的一个强烈、独立因素。基于NGS的FLT3-ITD MRD监测可识别出接受强化化疗和米哚妥林治疗后复发和死亡风险高的患者。使用基于NGS的技术。
