Kayser Sabine, Levis Mark J
Department of Internal Medicine III, University Hospital of Ulm , Germany.
Leuk Lymphoma. 2014 Feb;55(2):243-55. doi: 10.3109/10428194.2013.800198. Epub 2013 Jun 5.
Internal tandem duplications of the FMS-like tyrosine kinase 3 (FLT3) gene are one of the most frequent gene mutations in acute myeloid leukemia (AML) and are associated with poor clinical outcome. The remission rate is high with intensive chemotherapy, but most patients eventually relapse. During the last decade, FLT3 mutations have emerged as an attractive target for a molecularly specific treatment strategy. Targeting FLT3 receptor tyrosine kinases in AML has shown encouraging results in the treatment of FLT3 mutated AML, but in most patients responses are incomplete and not sustained. Newer, more specific compounds seem to have a higher potency and selectivity against FLT3. During therapy with FLT3 tyrosine kinase inhibitors (TKIs) the induction of acquired resistance has emerged as a clinical problem. Therefore, optimization of the targeted therapy and potential treatment options to overcome resistance is currently the focus of clinical research. In this review we discuss the use and limitations of TKIs as a therapeutic strategy for the treatment of FLT3 mutated AML, including mechanisms of resistance to TKIs as well as possible novel strategies to improve FLT3 inhibitor therapy.
FMS样酪氨酸激酶3（FLT3）基因的内部串联重复是急性髓系白血病（AML）中最常见的基因突变之一，与不良临床预后相关。强化化疗的缓解率较高，但大多数患者最终会复发。在过去十年中，FLT3突变已成为分子特异性治疗策略的一个有吸引力的靶点。在FLT3突变的AML治疗中，靶向FLT3受体酪氨酸激酶已显示出令人鼓舞的结果，但在大多数患者中，反应并不完全且不能持续。更新的、更具特异性的化合物似乎对FLT3具有更高的效力和选择性。在使用FLT3酪氨酸激酶抑制剂（TKIs）治疗期间，获得性耐药的诱导已成为一个临床问题。因此，优化靶向治疗以及克服耐药性的潜在治疗选择目前是临床研究的重点。在本综述中，我们讨论了TKIs作为治疗FLT3突变AML的治疗策略的应用和局限性，包括对TKIs的耐药机制以及改善FLT3抑制剂治疗的可能新策略。
