Clinical response and pharmacokinetics from a phase 1 study of an active dosing schedule of flavopiridol in relapsed chronic lymphocytic leukemia
Clinical response and pharmacokinetics from a phase 1 study of an active dosing schedule of flavopiridol in relapsed chronic lymphocytic leukemia
复制标题
DOI：
10.1182/blood-2008-07-168583
复制
发表时间：
2009-03-19
期刊：
影响因子：
20.3
通讯作者：
Dalton, James T.
中科院分区：
文献类型：
--
作者：
Phelps, Mitch A.;Lin, Thomas S.;Dalton, James T.
我们先前报道了一项在慢性淋巴细胞性白血病（CLL）患者中进行的1期试验的中期结果，其中flavopiridol静脉内给药为30分钟推注，然后输注4小时。我们现在报告完整的药代动力学（PK）数据，PK与临床结局的相关性，以及最终缓解和无进展生存期（PFS）。52例复发性CLL患者中有21例（40%）达到部分缓解（PR），中位PFS为12个月。应答者包括43例氟达拉滨难治性患者中的17例（40%）、18例del（17 p13）患者中的7例（39%）和19例del（11 q22）患者中的14例（74%）。6例缓解者在复发时接受了重复治疗，5例再次缓解，第二个中位PFS为10个月。使用非房室分析和非线性混合效应模型估计PK参数并评价协变量。CL、V1、Q和V2的两室群体参数估计值分别为31.4 L/h、65.8 L、8.49 L/h和157 L。Flavopiridol血浆浓度-时间曲线下面积（AUC）与临床反应和细胞因子释放综合征相关，而葡糖苷酸代谢物AUC与肿瘤溶解综合征相关。这些复合结果证实了这种药代动力学衍生的方案在复发性遗传高风险CLL中的高活性。此外，PK描述了反应和毒性的一些但非全部变异性。（血。2009;113：2637-2645）
We previously reported interim results of a phase 1 trial in patients with chronic lymphocytic leukemia (CLL) whereby flavopiridol was administered intravenously as a 30-minute bolus followed by 4-hour infusion. We now report full pharmacokinetic (PK) data, correlations of PK with clinical outcomes, and final response and progression-free survival (PFS). Twenty-one (40%) of 52 patients with relapsed CLL achieved a partial response (PR) with a median PFS of 12 months. Responders included 17 (40%) of 43 fludarabine refractory patients, 7 (39%) of 18 patients with del(17p13), and 14 (74%) of 19 patients with del(11q22). Six responders received repeat therapy at relapse, and 5 responded again with a second median PFS of 10 months. Noncompartmental analysis and nonlinear mixed effects modeling was used to estimate PK parameters and evaluate covariates. Two-compartment population parameter estimates were 31.4 L/h, 65.8 L, 8.49 L/h, and 157 L for CL, V1, Q, and V2, respectively. Flavopiridol area under the plasma concentration-time curve (AUC) correlated with clinical response and cytokine release syndrome, and glucuronide metabolite AUC correlated with tumor lysis syndrome. These composite results confirm high activity of this pharmacokinetically derived schedule in relapsed, genetically high-risk CLL. Furthermore, PK describes some, but not all, variability in response and toxicity. (Blood. 2009;113:2637-2645)