Department of Hematology/Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California, USA.
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Cancer. 2024 Mar 1;130(5):727-739. doi: 10.1002/cncr.35077. Epub 2023 Oct 28.
This study evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of 8-chloro-adenosine (8-Cl-Ado) in patients with relapsed/refractory acute myeloid leukemia (AML).
8-Cl-Ado was administered daily for 5 days; the starting dose was 100 mg/m , the highest dose tested was 800 mg/m . The end points were toxicity, disease response, and PK/PD measurements.
The predominant nonhematologic toxicity was cardiac with grade ≥3 toxicity. Plasma PK in all patients suggested heterogeneity among patients, yet, some dose-dependency for the accumulation of 8-Cl-Ado. Two 8-Cl-Ado metabolites accumulated at similar levels to 8-Cl-Ado. Cellular PK in eight patients indicated accumulation of 8-Cl-ATP, which was associated with AML blast cytoreduction in peripheral blood. The authors determined the RP2D of 8-Cl-Ado to be 400 mg/m .
Given the cardiac adverse events observed, patients require monitoring for arrhythmias and QT interval during infusion. Although peripheral blood cytoreduction was observed, responses were transient, suggesting combination strategies will be required.
本研究评估了 8-氯-腺嘌呤（8-Cl-Ado）在复发/难治性急性髓系白血病（AML）患者中的安全性、药代动力学（PK）和药效动力学（PD）。
8-Cl-Ado 每日给药 5 天；起始剂量为 100mg/m ，最高测试剂量为 800mg/m 。终点为毒性、疾病反应和 PK/PD 测量。
主要的非血液学毒性是心脏毒性，≥3 级毒性。所有患者的血浆 PK 表明患者之间存在异质性，但 8-Cl-Ado 的积累存在一定的剂量依赖性。两种 8-Cl-Ado 代谢物的积累水平与 8-Cl-Ado 相似。8 名患者的细胞 PK 表明 8-Cl-ATP 的积累与外周血中 AML 原始细胞的细胞减少有关。作者确定 8-Cl-Ado 的 RP2D 为 400mg/m 。
鉴于观察到的心脏不良事件，在输注过程中患者需要监测心律失常和 QT 间期。尽管观察到外周血细胞减少，但反应是短暂的，这表明需要联合治疗策略。
