Patterns of molecular response to and relapse after combination of sorafenib, idarubicin, and cytarabine in patients with FLT3 mutant acute myeloid leukemia.
Patterns of molecular response to and relapse after combination of sorafenib, idarubicin, and cytarabine in patients with FLT3 mutant acute myeloid leukemia.
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DOI：
10.1016/j.clml.2011.06.007
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发表时间：
2011-08
期刊：
影响因子：
--
通讯作者：
Ravandi F
中科院分区：
文献类型：
--
作者：
Al-Kali A;Cortes J;Faderl S;Jones D;Abril C;Pierce S;Brandt M;Kantarjian H;Ravandi F
FMS样酪氨酸激酶3(Flt3)是一种参与造血祖细胞发育的III型受体酪氨酸激酶。据报道，大约三分之一的急性髓系白血病(AML)患者存在Flt3基因突变，而Flt3的抑制剂是临床上感兴趣的药物。索拉非尼是一种口服活性的多激酶抑制剂，具有很强的抗Flt3和Raf/ERK/MEK激酶途径的活性。我们研究了18例用索拉非尼、伊达比星和阿糖胞苷联合治疗的突变Flt3患者的分子反应和复发模式。中位随访时间为9个月。16例患者获得完全缓解(CR)，另外2例患者达到CR但缺乏血小板恢复，总有效率为100%。10例患者的Flt3突变克隆被根除，6例患者显示残留的Flt3突变细胞，2例患者显示持续的Flt3突变细胞。然而，在形态CR时消除Flt3突变人群并不能预测复发。中位随访9个月(1~16个月)，复发10例(55%)，中位CR时间8.8个月(1~9.5个月)。通过DNA测序，在被测试的7名患者中，在复发时没有证据表明获得性Flt3点突变，这表明存在其他机制的索拉非尼耐药。索拉非尼联合化疗在获得CR方面是有效的，但复发仍有发生。
FMS-like tyrosine kinase 3 (FLT3) is a class III receptor tyrosine kinase involved in hematopoietic progenitor cell development. Mutations of FLT3 have been reported in about a third of patients with acute myeloid leukemia (AML), and inhibitors of FLT3 are of clinical interest. Sorafenib is an orally active multikinase inhibitor with potent activity against FLT3 and the Raf/ERK/MEK kinase pathway. We studied the patterns of molecular response and relapse in 18 patients with mutated FLT3 treated with the combination of sorafenib, idarubicin, and cytarabine. The median follow-up was 9 months. Sixteen patients achieved complete remission (CR), and the other 2 patients achieved CR but lacked platelet recovery for an overall response rate of 100%. Ten patients had their FLT3-mutated clone eradicated, with 6 patients who showed some residual FLT3-mutated cells, and 2 patients who showed persistent FLT3-mutated cells. The elimination of FLT3-mutated population at the time of morphologic CR, however, was not predictive of relapse. After a median follow-up of 9 months (range, 1–16 months), 10 (55%) patients had relapsed, with a median CR duration of 8.8 months (range, 1–9.5 months). By DNA sequencing, there was no evidence of an acquired FLT3 point mutation at the time of relapse in 7 patients tested, which suggested the presence of other mechanisms of sorafenib resistance. Sorafenib, combined with chemotherapy, is effective in attaining CR, but relapses still occur.
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