Small Donald
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University, Baltimore, MD 21231, USA.
Semin Hematol. 2008 Jul;45(3 Suppl 2):S17-21. doi: 10.1053/j.seminhematol.2008.07.007.
FLT3 is a receptor tyrosine kinase with important roles in hematopoietic stem/progenitor cell survival and proliferation. It is frequently overexpressed in acute leukemias and is frequently mutated in acute myeloid leukemia (AML). FLT3 internal tandem duplication (ITD) mutations in AML portend poor prognosis in both adult and pediatric patients. A number of small molecule tyrosine kinase inhibitors (TKIs) with activity against FLT3 have been discovered. Many of these are still in preclinical development, but several have entered clinical phase I and II trials as monotherapy in patients with relapsed AML. These trials have resulted in frequent but short-lived responses of peripheral blasts and less frequent responses of bone marrow blasts. This led to clinical testing of FLT3 TKIs in combination with conventional chemotherapy. Several combination trials are ongoing or planned in both relapsed and newly diagnosed FLT3-mutant AML patients. Anti-FLT3 antibodies may also prove to be an excellent way of targeting FLT3 in AML and acute lymphocytic leukemia (ALL) by inhibiting signaling and through antibody-dependent cell-mediated cytotoxicity.
FLT3是一种受体酪氨酸激酶，在造血干细胞/祖细胞的存活和增殖中发挥重要作用。它在急性白血病中经常过度表达，在急性髓系白血病（AML）中经常发生突变。AML中的FLT3内部串联重复（ITD）突变预示着成人和儿童患者的预后不良。已经发现了许多对FLT3有活性的小分子酪氨酸激酶抑制剂（TKI）。其中许多仍处于临床前开发阶段，但有几种已进入临床I期和II期试验，作为复发AML患者的单一疗法。这些试验导致外周血原始细胞频繁但短暂的反应，骨髓原始细胞的反应较少。这导致了FLT3 TKI与传统化疗联合的临床试验。在复发和新诊断的FLT3突变AML患者中，正在进行或计划进行多项联合试验。抗FLT3抗体也可能被证明是通过抑制信号传导和抗体依赖性细胞介导的细胞毒性在AML和急性淋巴细胞白血病（ALL）中靶向FLT3的一种极佳方法。
