SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes
SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes
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DOI：
10.1182/blood-2002-10-3023
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发表时间：
2003-08-01
期刊：
影响因子：
20.3
通讯作者：
Karp, JE
中科院分区：
文献类型：
--
作者：
Giles, FJ;Stopeck, AT;Karp, JE
骨髓血管生成和血管内皮生长因子（VEGF）水平升高是急性髓细胞白血病（AML）或骨髓增生异常综合征（MDS）患者的不良预后特征。VEGF是一种可溶性循环血管生成分子，通过受体酪氨酸激酶（RTK）刺激信号传导，包括VEGF受体2（VEGFR-2）。AML原始细胞可表达VEGFR-2、c-kit和FLT 3。SU 5416是VEGFR-2、c-kit以及野生型和突变型FLT 3的小分子RTK抑制剂（RTKI）。在难治性AML或MDS患者中进行了一项SU 5416的多中心II期研究。55例患者（33例AML：10例[30%]原发性难治性，23例[70%]复发; 22例MDS：15例[68%]复发）接受145 mg/m2 SU 5416每周两次静脉给药，中位时间为9周（范围：1-55周）。3级或4级药物相关毒性包括头痛（14%）、输注相关反应（11%）、呼吸困难（14%）、疲乏（7%）、血栓形成发作（7%）、骨痛（5%）和胃肠道紊乱（4%）。有11例患者（20%）未完成4周治疗（10例疾病进展，1例不良事件）; 3例患者（5%）获得部分缓解; 1例患者（2%）获得血液学改善。单药SU 5416对难治性AML/MDS具有生物学活性和适度的临床活性。AML患者的总体中位生存期为12周（范围，4-41周），MDS患者未达到。大多数观察到的毒性可归因于药物制剂（聚氧乙烯35蓖麻油或SU 5416制剂的高渗透压）。其他RTKI和/或其他抗血管生成方法的研究，以及相关研究，以检查生物学效应，可能需要在AML/MDS患者中进行。
Increased bone marrow angiogenesis and vascular endothelial growth factor (VEGF) levels are adverse prognostic features in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDSs). VEGF is a soluble circulating angiogenic molecule that stimulates signaling via receptor tyrosine kinases (RTKs), including VEGF receptor 2 (VEGFR-2). AML blasts may express VEGFR-2, c-kit, and FLT3. SU5416 is a small molecule RTK inhibitor (RTKI) of VEGFR-2, c-kit, and both wild-type and mutant FLT3. A multicenter phase 2 study of SU5416 was conducted in patients with refractory AML or MDS. For a median of 9 weeks (range, 1-55 weeks), 55 patients (33 AML: 10 [30%] primary refractory, 23 [70%] relapsed; 22 MDS: 15 [68%] relapsed) received 145 mg/m(2) SU5416 twice weekly intravenously. Grade 3 or 4 drug-related toxicities included headaches (14%), infusion-related reactions (11%), dyspnea (14%), fatigue (7%), thrombotic episodes (7%), bone pain (5%), and gastrointestinal disturbance (4%). There were 11 patients (20%) who did not complete 4 weeks of therapy (10 progressive disease, 1 adverse event); 3 patients (5%) who achieved partial responses; and 1 (2%) who achieved hematologic improvement. Single agent SU5416 had biologic and modest clinical activity in refractory AML/MDS. Overall median survival was 12 weeks in AML patients (range, 4-41 weeks) and not reached in MDS patients. Most observed toxicities were attributable to drug formulation (polyoxyl 35 castor oil or hyperosmolarity of the SU5416 preparation). Studies of other RTKI and/or other antiangiogenic approaches, with correlative studies to examine biologic effects, may be warranted in patients with AML/MDS.