Zhang Lei-Si, Wang Jun, Xu Ming-Zhu, Wu Tian-Mei, Huang Si-Man, Cao Han-Yu, Sun Ai-Ning, Liu Song-Bai, Xue Sheng-Li
National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China.
Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, People's Republic of China.
Onco Targets Ther. 2022 Feb 18;15:159-164. doi: 10.2147/OTT.S336715. eCollection 2022.
The presence of FLT3-ITD mutation is associated with relapse and poor survival in AML patients. Venetoclax combined with hypomethylating agents (VEN+HMA) was approved for the frontline treatment of elderly or unfit AML patients, which leads to noteworthy impacts on AML management. The combination therapy is associated with encouraging efficacy in FLT3-mutated AML among both newly diagnosed unfit and relapsed/refractory patients. However, we found that two AML patients with FLT3-ITD mutation did not respond to venetoclax plus azacitidine (VEN+AZA). Given that the combined efficacy of venetoclax and the FLT3 inhibitor has been proved in pre-clinical models of FLT3+ AML, it is a scientific rationale to investigate venetoclax combined with the FLT3 inhibitor in AML patients with FLT3-ITD mutation. This is the first report of assessing the safety and response of gilteritinib (the first and only targeted second-generation FLT3 tyrosine kinase inhibitor approved by the US FDA) and venetoclax-based therapy in two AML patients with FLT3-ITD mutation unresponsive to VEN+AZA, which may bring new hope to FLT3 mutated patients who are unresponsive to VEN+HMA.
FLT3-ITD突变的存在与AML患者的复发和不良生存相关。维奈克拉联合低甲基化药物（VEN+HMA）被批准用于老年或不适合接受强化疗的AML患者的一线治疗，这对AML的治疗产生了显著影响。在新诊断的不适合接受强化疗和复发/难治性患者中，联合治疗在FLT3突变的AML中显示出令人鼓舞的疗效。然而，我们发现两名携带FLT3-ITD突变的AML患者对维奈克拉加阿扎胞苷（VEN+AZA）无反应。鉴于在FLT3+ AML的临床前模型中已证实维奈克拉与FLT3抑制剂联合使用的疗效，在携带FLT3-ITD突变的AML患者中研究维奈克拉与FLT3抑制剂联合使用具有科学依据。这是首篇评估吉瑞替尼（美国食品药品监督管理局批准的首个也是唯一的靶向第二代FLT3酪氨酸激酶抑制剂）和基于维奈克拉的治疗方案对两名对VEN+AZA无反应的携带FLT3-ITD突变的AML患者的安全性和反应的报告，这可能为对VEN+HMA无反应的FLT3突变患者带来新希望。
