Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia
Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia
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DOI：
10.1182/blood-2003-11-3775
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发表时间：
2004-05-15
期刊：
影响因子：
20.3
通讯作者：
Small, D
中科院分区：
文献类型：
--
作者：
Smith, BD;Levis, M;Small, D
FMS样酪氨酸激酶3（FLT 3）的激活突变存在于约30%的新发急性髓性白血病（AML）患者中，并与标准化疗治疗的治愈率较低相关。通过抑制FLT 3的酪氨酸激酶活性靶向突变对携带FLT 3突变的细胞系和原代AML细胞具有细胞毒性。成功的FLT 3抑制还可以改善FLT 3激活的白血病小鼠模型的存活率。CEP-701是一种口服的新型受体酪氨酸激酶抑制剂，可选择性抑制FLT 3自磷酸化。我们进行了一项1/2期试验，以确定CEP-701单药作为难治性、复发性或低风险AML表达FLT 3激活突变患者的挽救治疗的体内血液学效应。14名重度预治疗的AML患者用CEP-701治疗，初始剂量为60 mg，每日两次口服。CEP-701相关毒性极低。5例患者具有生物活性和可测量的临床反应的临床证据，包括骨髓和外周血原始细胞的显著减少。实验室数据证实，临床应答与CEP-701的持续FLT 3抑制相关。我们的研究结果表明，FLT 3抑制与携带FLT 3激活突变的AML患者的临床活性相关，并表明CEP-701有望成为该疾病的新型分子靶向治疗。(C)2004年，美国血液学会。
Activating mutations of FMS-like tyrosine kinase 3 (FLT3) are present in approximately 30% of patients with de novo acute myeloid leukemia (AML) and are associated with lower cure rates from standard chemotherapy-based treatment. Targeting the mutation by inhibiting the tyrosine kinase activity of FLT3 is cytotoxic to cell lines and primary AML cells harboring FLT3 mutations. Successful FLT3 inhibition can also improve survival in mouse models of FLT3-activated leukemia. CEP-701 is an orally available, novel, receptor tyrosine kinase inhibitor that selectively inhibits FLT3 autophosphorylation. We undertook a phase 1/2 trial to determine the in vivo hematologic effects of single-agent CEP-701 as salvage treatment for patients with refractory, relapsed, or poor-risk AML expressing FLT3-activating mutations. Fourteen heavily pretreated AML patients were treated with CEP-701 at an initial dose of 60 mg orally twice daily. CEP-701-related toxicities were minimal. Five patients had clinical evidence of biologic activity and measurable clinical response, including significant reductions in bone marrow and peripheral blood blasts. Laboratory data confirmed that clinical responses correlated with sustained FLT3 inhibition to CEP-701. Our results show that FLT3 inhibition is associated with clinical activity in AML patients harboring FLT3-activating mutations and indicate that CEP-701 holds promise as a novel, molecularly targeted therapy for this disease. (C) 2004 by The American Society of Hematology.