Patterns of Resistance Differ in Patients with Acute Myeloid Leukemia Treated with Type I versus Type II FLT3 inhibitors.
Patterns of Resistance Differ in Patients with Acute Myeloid Leukemia Treated with Type I versus Type II FLT3 inhibitors.
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DOI：
10.1158/2643-3230.bcd-20-0143
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发表时间：
2021-03
影响因子：
11.2
通讯作者：
Daver N
中科院分区：
文献类型：
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作者：
Alotaibi AS;Yilmaz M;Kanagal-Shamanna R;Loghavi S;Kadia TM;DiNardo CD;Borthakur G;Konopleva M;Pierce SA;Wang SA;Tang G;Guerra V;Samra B;Pemmaraju N;Jabbour E;Short NJ;Issa GC;Ohanian M;Garcia-Manero G;Bhalla KN;Patel KP;Takahashi K;Andreeff M;Cortes JE;Kantarjian HM;Ravandi F;Daver N
尽管 FLT3 抑制剂 (FLT3i) 取得了有希望的结果，但反应持续时间仍然很短。我们研究了接受基于 FLT3i 的疗法治疗的 FLT3 突变 AML 患者的治疗前和复发骨髓样本（二级耐药队列），以及对基于 FLT3i 的疗法无反应的患者的治疗前骨髓样本（一级耐药队列）。复发时的靶向下一代测序发现了涉及靶向 FLT3、表观遗传修饰剂、RAS/MAPK 通路以及不太常见的 WT1 和 TP53 的新突变。 RAS/MAPK 和 FLT3-D835 突变分别在基于 FLT3i 的 I 型和 II 型治疗后最常见。与没有突发突变的患者相比，复发时出现突发突变的患者的总生存期较差。在治疗前 RAS 突变的患者中，治疗前队列水平的 RAS 变异等位基因频率在无反应者中较高，尤其是基于 I 型 FLT3i 的治疗，这表明在原发性耐药中也存在潜在作用。这些数据表明，I 型和 II 型 FLT3i 治疗的 FLT3 突变 AML 具有不同的耐药途径。
Despite promising results with FLT3 inhibitors (FLT3i), response durations remain short. We studied pretreatment and relapse bone marrow samples from patients with FLT3-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 FLT3, epigenetic modifiers, RAS/MAPK pathway, and less frequently WT1, and TP53. RAS/MAPK and FLT3-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 RAS mutated patients, pretreatment cohort level variant allelic frequencies for RAS 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 FLT3-mutated AML treated with type I versus II FLT3i.