Phase I study of the aurora A kinase inhibitor alisertib with induction chemotherapy in patients with acute myeloid leukemia.
Phase I study of the aurora A kinase inhibitor alisertib with induction chemotherapy in patients with acute myeloid leukemia.
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DOI：
10.3324/haematol.2016.158394
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发表时间：
2017-04
期刊：
影响因子：
10.1
通讯作者：
Chen YB
中科院分区：
文献类型：
--
作者：
Fathi AT;Wander SA;Blonquist TM;Brunner AM;Amrein PC;Supko J;Hermance NM;Manning AL;Sadrzadeh H;Ballen KK;Attar EC;Graubert TA;Hobbs G;Joseph C;Perry AM;Burke M;Silver R;Foster J;Bergeron M;Ramos AY;Som TT;Fishman KM;McGregor KL;Connolly C;Neuberg DS;Chen YB
极光激酶A的异常表达与包括急性髓性白血病在内的多种肿瘤的发生有关。Alisertib是一种Aurora A激酶抑制剂，在骨髓恶性肿瘤试验中已证明其作为单药治疗的疗效，与常规化疗联合使用时，该疗效似乎有所增强。在这项I期、剂量递增研究中，新诊断患者接受阿糖胞苷和依达鲁肽的常规诱导治疗，之后给予alisertib 7天。通过队列进行剂量递增。然后，患者可以接受最多4个周期的巩固治疗，合并alisertib，然后接受长达12个月的alisertib维持治疗。22例患者入组。在剂量水平2发生了一次剂量限制性毒性（长期血小板减少症），推荐的II期剂量确定为30 mg每日两次。常见的治疗相关毒性包括血细胞减少和粘膜炎。仅3例（14%）患者在周期中期出现持续性疾病，需要“5+2”再诱导。复合缓解率（完全缓解和完全缓解伴中性粒细胞不完全恢复）为86%（22例患者中有19例; 90%CI 68-96%）。在65岁以上和高危疾病（继发性急性白血病或细胞遗传学高危疾病）患者中，复合缓解率分别为88%和100%。中位随访时间为13.5个月。在接受推荐II期剂量治疗的患者中，12个月总生存期和无进展生存期分别为62%（90% CI 33-81%）和42%（90% CI 17-65%）。联合诱导化疗治疗急性髓性白血病时，阿利舍替耐受性良好，具有良好的疗效。（clinicaltrials.gov标识符：01779843）。
Aberrant expression of aurora kinase A is implicated in the genesis of various neoplasms, including acute myeloid leukemia. Alisertib, an aurora A kinase inhibitor, has demonstrated efficacy as monotherapy in trials of myeloid malignancy, and this efficacy appears enhanced in combination with conventional chemotherapies. In this phase I, dose-escalation study, newly diagnosed patients received conventional induction with cytarabine and idarubicin, after which alisertib was administered for 7 days. Dose escalation occurred via cohorts. Patients could then receive up to four cycles of consolidation, incorporating alisertib, and thereafter alisertib maintenance for up to 12 months. Twenty-two patients were enrolled. One dose limiting toxicity occurred at dose level 2 (prolonged thrombocytopenia), and the recommended phase 2 dose was established at 30mg twice daily. Common therapy-related toxicities included cytopenias and mucositis. Only three (14%) patients had persistent disease at mid-cycle, requiring “5+2” reinduction. The composite remission rate (complete remission and complete remission with incomplete neutrophil recovery) was 86% (nineteen of twenty-two patients; 90% CI 68–96%). Among those over age 65 and those with high-risk disease (secondary acute leukemia or cytogenetically high-risk disease), the composite remission rate was 88% and 100%, respectively. The median follow up was 13.5 months. Of those treated at the recommended phase 2 dose, the 12-month overall survival and progression-free survival were 62% (90% CI 33–81%) and 42% (90% CI 17–65%), respectively. Alisertib is well tolerated when combined with induction chemotherapy in acute myeloid leukemia, with a promising suggestion of efficacy. (clinicaltrials.gov Identifier:01779843).