A phase 2 trial of the FLT3 inhibitor lestaurtinib (CEP701) as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy
A phase 2 trial of the FLT3 inhibitor lestaurtinib (CEP701) as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy
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DOI：
10.1182/blood-2006-04-015560
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发表时间：
2006-11-15
期刊：
影响因子：
20.3
通讯作者：
Small, Donald
中科院分区：
文献类型：
--
作者：
Knapper, Steven;Burnett, Alan K.;Small, Donald
FMS样酪氨酸激酶3(Flt3)的激活突变存在于约三分之一的急性髓系白血病(AML)患者中，并与不良预后相关。Flt3在原始细胞的存活和增殖中所起的重要作用，以及在大多数AML患者中的过度表达，使Flt3成为一个有吸引力的治疗靶点。我们进行了Flt3选择性酪氨酸激酶抑制剂来妥替尼(CEP701)的2期试验，用于未经治疗的AML患者的单一治疗，这些患者被认为不适合强化化疗，无论Flt3突变状态如何。Lestaurtinib口服8周，最初剂量为60毫克，每天两次，后来增加到每天两次80毫克，总体耐受性良好。临床活动，表现为一过性骨髓和外周血母细胞减少或更长时间的输血独立，在5例突变的Flt3患者中有3例(60%)，在22例可评估的野生型Flt3患者中有5例(23%)。实验室数据表明，当持续的Flt3抑制药物水平与体外成纤维细胞对来妥替尼的细胞毒敏感性相结合时，就会出现临床反应。在Flt3突变和野生型患者中，进一步评估该化合物与细胞毒性化疗或其他靶向药物的结合是有必要的。
Activating mutations of FMS-like tyrosine kinase 3 (FLT3) are present in approximately one third of patients with acute myeloid leukemia (AML) and are associated with adverse prognosis. The important role played by FLT3 in the survival and proliferation of blasts, and its overexpression in most patients with AML, make FLT3 an attractive therapeutic target. We undertook a phase 2 trial of the FLT3-selective tyrosine kinase inhibitor lestaurtinib (CEP701) used as monotherapy in untreated older patients with AML not considered fit for intensive chemotherapy, irrespective of FLT3 mutation status. Lestaurtinib was administered orally for 8 weeks, initially at a dose of 60 mg twice daily, escalating to 80 mg twice daily, and was generally well tolerated. Clinical activity, manifest as transient reductions in bone marrow and peripheral-blood blasts or longer periods of transfusion independence, was seen in 3 (60%) of 5 patients with mutated FLT3 and 5 (23%) of 22 evaluable wild-type FLT3 patients. Laboratory data demonstrated that clinical responses occurred where the presence of sustained FLT3-inhibitory drug levels were combined with in vitro cytotoxic sensitivity of blasts to lestaurtinib. Further evaluation of this compound, in combination with cytotoxic chemotherapy or other targeted agents, is warranted in both FLT3 mutant and wild-type patients.