文章：

MK-0457治疗BCR-ABL T315I突变型慢性髓性白血病和费城染色体阳性急性淋巴细胞白血病的2期研究

A phase 2 study of MK-0457 in patients with BCR-ABL T315I mutant chronic myelogenous leukemia and philadelphia chromosome-positive acute lymphoblastic leukemia

原文发布日期：2014-08-15

DOI: 10.1038/bcj.2014.60

类型: Original Article

开放获取: 是

英文摘要：

Aurora kinase overexpression has been observed in patients with hematologic malignancies. MK-0457, a pan-aurora kinase inhibitor that also inhibits the ABL T315I mutant, was evaluated to treat patients with chronic myelogenous leukemia (CML) or Philadelphia chromosome (Ph+) acute lymphoblastic leukemia (ALL) with the T315I mutation. Adults with Ph+ chronic phase (CP)-, accelerated phase (AP)- or blast phase (BP)-CML, or ALL and documented BCR-ABL T315I mutation were treated with a 5-day continuous infusion of MK-0457 administered every 14 days at 40 mg/m2/h, 32 mg/m2/h or 24 mg/m2/h. Fifty-two patients (CP, n=15; AP, n=14; BP, n=11; Ph+ ALL, n=12) were treated. Overall, 8% of patients achieved major cytogenetic response; 6% achieved unconfirmed complete or partial response; 39% had no response. Two patients (CP CML) achieved complete hematologic response. No patients with advanced CML or Ph+ ALL achieved major hematologic response. The most common adverse event (AE) was neutropenia (50%). The most common grade 3/4 AEs were neutropenia (46%) and febrile neutropenia (35%). MK-0457 demonstrated minimal efficacy and only at higher, intolerable doses; lower doses were tolerated and no unexpected toxicities were observed. These data will assist in the development of future aurora kinase inhibitors and in the selection of appropriate target patient populations.

摘要翻译： 

在血液系统恶性肿瘤患者中观察到极光激酶过度表达的现象。MK-0457是一种泛极光激酶抑制剂，同时能抑制ABL T315I突变体，本研究评估其用于治疗慢性髓系白血病（CML）或携带T315I突变的费城染色体阳性（Ph+）急性淋巴细胞白血病（ALL）的疗效。入组成年患者为Ph+慢性期（CP）、加速期（AP）或急变期（BP）CML，或经确诊携带BCR-ABL T315I突变的ALL患者，接受MK-0457连续5天持续静脉输注（每14天为一个周期），剂量分别为40 mg/m²/h、32 mg/m²/h或24 mg/m²/h。共52例患者接受治疗（CP组15例、AP组14例、BP组11例、Ph+ ALL组12例）。总体而言，8%的患者达到主要细胞遗传学缓解；6%获得未确认的完全或部分缓解；39%无治疗反应。两例CP期CML患者达到完全血液学缓解。晚期CML或Ph+ ALL患者均未实现主要血液学缓解。最常见的不良事件为中性粒细胞减少症（50%）。最常见的3/4级不良事件包括中性粒细胞减少症（46%）和发热性中性粒细胞减少症（35%）。MK-0457仅在高剂量（耐受性差）时显示有限疗效，低剂量虽可耐受但疗效不足，且未观察到非预期毒性。这些数据将为后续极光激酶抑制剂的研发及合适目标患者群体的选择提供参考。

原文链接：

A phase 2 study of MK-0457 in patients with BCR-ABL T315I mutant chronic myelogenous leukemia and philadelphia chromosome-positive acute lymphoblastic leukemia