Treatment with FLT3 inhibitor in patients with FLT3-mutated acute myeloid leukemia is associated with development of secondary FLT3-tyrosine kinase domain mutations.
Treatment with FLT3 inhibitor in patients with FLT3-mutated acute myeloid leukemia is associated with development of secondary FLT3-tyrosine kinase domain mutations.
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DOI：
10.1002/cncr.28705
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发表时间：
2014-07-15
期刊：
影响因子：
6.2
通讯作者：
Cortes, Jorge E.
中科院分区：
文献类型：
--
作者：
Alvarado, Yesid;Kantarjian, Hagop M.;Luthra, Rajyalakshmi;Ravandi, Farhad;Borthakur, Gautam;Garcia-Manero, Guillermo;Konopleva, Marina;Estrov, Zeev;Andreeff, Michael;Cortes, Jorge E.
在大约30%的AML患者中发现了Flt3-内部串联复制(ITD)突变。Flt3抑制剂在患有Flt3-ITD的AML患者中表现出临床活性，但反应通常是短暂的。我们回顾了69例Flt3突变的AML患者，用不同的Flt3抑制剂治疗，以分析新突变的出现。基线时，87%的患者有ITD突变，7%的患者有D835/I836突变，6%的患者有ITD和D835/I836联合突变。32%的患者有反应，均为Flt3-ITD；D835/I836或ITD+D835/I836患者均无反应。在停止使用Flt3抑制剂时的突变评估显示，68%的患者没有变化，10%的患者变得无法检测，22%的患者从单一的ITD进展到ITD+D835/I836的联合突变。进展期Flt3突变不变的患者中位生存期为5个月，而未检测到突变和ITD-D835/I836联合突变患者的中位生存期分别为7个月。这一数据证实了在体外观察到，在单一的Flt3-ITD突变的AML患者使用Flt3抑制剂后，可能会出现继发性TKD突变，这一现象与耐药性和预后不良有关。
FLT3-internal tandem duplication (ITD) mutations are found in approximately 30% of AML patients. FLT3 inhibitors have shown clinical activity in AML with FLT3-ITD but responses are usually short lived. We reviewed 69 FLT3 mutated AML patients, treated with different FLT3 inhibitors to analyze emergence of new mutations. At baseline 87% of patients had an ITD mutation, 7% had a D835/I836 mutation and 6% had combined ITD and D835/I836 mutations. Responses occurred in 32% of patients, all with FLT3-ITD; none of the patients with D835/I836 or ITD+D835/I836 responded. Mutational assessment at the time FLT3 inhibitor discontinuation showed that 68% of patients were unchanged, 10% had become undetectable, and 22% of patients progressed from a single ITD to have combined ITD+D835/I836 mutations. In those patients with unchanged FLT3 mutation at progression the median survival was 5 months, while in those with undetectable and with combined ITD-D835/I836 mutations the median survival was 7 months respectively. This data confirm in vitro observations that a secondary TKD mutation may arise after the use of FLT3 inhibitors in patients with single FLT3-ITD mutated AML, a phenomenon that is associated with resistance and a poor prognosis.
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影响因子：
20.3
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