A phase 1/2 study of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory acute myeloid leukemia
A phase 1/2 study of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory acute myeloid leukemia
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DOI：
10.1182/blood-2011-10-383406
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发表时间：
2012-04-26
期刊：
影响因子：
20.3
通讯作者：
DiPersio, John F.
中科院分区：
文献类型：
--
作者：
Uy, Geoffrey L.;Rettig, Michael P.;DiPersio, John F.
急性髓性白血病（AML）母细胞与白血病微环境的相互作用被认为是化疗耐药性和疾病复发的重要介导因素。我们假设小分子抑制剂普乐沙福对CXCR 4/CXCL 12轴的抑制作用会破坏白血病原始细胞与环境的相互作用，并增加AML原始细胞对化疗的敏感性。在这项I/II期研究中，52例复发性或难治性AML患者接受普乐沙福联合米托蒽醌、依托泊苷和阿糖胞苷治疗。在I期研究中，普乐沙福剂量递增至最大0.24 mg/kg/d，未出现任何剂量限制性毒性。在II期，46例患者接受普乐沙福0.24 mg/kg/d联合化疗治疗，总体完全缓解和完全缓解，血细胞计数不完全恢复率（CR + CRi）为46%。相关研究表明，白血病原始细胞进入外周循环的动员增加了2倍。添加普乐沙福后，未观察到症状性白细胞增多或计数恢复延迟的证据。我们的结论是，在细胞毒性化疗中加入普乐沙福治疗AML是可行的，相关研究显示CXCR 4/CXCL 12轴破坏的体内证据，缓解率令人鼓舞。本研究注册于www.clinical trials.gov，编号NCT 00512252。（血。2012;119（17）：3917-3924）
The interaction of acute myeloid leukemia (AML) blasts with the leukemic microenvironment is postulated to be an important mediator of resistance to chemotherapy and disease relapse. We hypothesized that inhibition of the CXCR4/CXCL12 axis by the small molecule inhibitor, plerixafor, would disrupt the interaction of leukemic blasts with the environment and increase the sensitivity of AML blasts to chemotherapy. In this phase 1/2 study, 52 patients with relapsed or refractory AML were treated with plerixafor in combination with mitoxantrone, etoposide, and cytarabine. In phase 1, plerixafor was escalated to a maximum of 0.24 mg/kg/d without any dose-limiting toxicities. In phase 2, 46 patients were treated with plerixafor 0.24 mg/kg/d in combination with chemotherapy with an overall complete remission and complete remission with incomplete blood count recovery rate (CR + CRi) of 46%. Correlative studies demonstrated a 2-fold mobilization in leukemic blasts into the peripheral circulation. No evidence of symptomatic hyperleukocytosis or delayed count recovery was observed with the addition of plerixafor. We conclude that the addition of plerixafor to cytotoxic chemotherapy is feasible in AML, and results in encouraging rates of remission with correlative studies demonstrating in vivo evidence of disruption of the CXCR4/CXCL12 axis. This study was registered at www.clinical trials.gov, no. NCT00512252. (Blood. 2012;119(17):3917-3924)