The Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
The Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Blood Cancer Discov. 2021 Mar;2(2):125-134. doi: 10.1158/2643-3230.BCD-20-0143. Epub 2020 Dec 6.
Despite promising results with FLT3 inhibitors (FLT3i), response durations remain short. We studied pretreatment and relapse bone marrow samples from patients with -mutated AML treated with FLT3i-based therapies (secondary resistance cohort), and pretreatment bone marrow samples from patients with no response to FLT3i-based therapies (primary resistance cohort). Targeted next generation sequencing at relapse identified emergent mutations involving on-target , epigenetic modifiers, pathway, and less frequently , and . and D835 mutations emerged most commonly following type I and type II FLT3i-based therapies, respectively. Patients with emergent mutations at relapse had inferior overall survival compared with those without emergent mutations. Among pretreatment mutated patients, pretreatment cohort level variant allelic frequencies for were higher in non-responders, particularly with type I FLT3i-based therapies, suggesting a potential role in primary resistance as well. These data demonstrate distinct pathways of resistance in -mutated AML treated with type I versus II FLT3i.
尽管 FLT3 抑制剂（FLT3i）有很有前景的结果，但反应持续时间仍然很短。我们研究了接受基于 FLT3i 的治疗（继发耐药队列）的突变 AML 患者的预处理和复发骨髓样本，以及对基于 FLT3i 的治疗无反应的患者（原发耐药队列）的预处理骨髓样本。复发时的靶向下一代测序确定了涉及靶标、表观遗传修饰剂、途径的新出现突变，并且较少出现和。和 D835 突变分别在 I 型和 II 型基于 FLT3i 的治疗后最常见。与没有新出现突变的患者相比，在复发时出现新出现突变的患者的总生存情况较差。在预处理突变的患者中，非应答者的预处理队列水平的变体等位基因频率更高，尤其是在接受 I 型基于 FLT3i 的治疗的患者中，这表明其在原发耐药中也有潜在作用。这些数据表明，在接受 I 型和 II 型 FLT3i 治疗的突变 AML 中存在不同的耐药途径。
