Maddocks Kami, Wei Lai, Rozewski Darlene, Jiang Yao, Zhao Yuan, Adusumilli Mikhil, Pierceall William E, Doykin Camille, Cardone Michael H, Jones Jeffrey A, Flynn Joseph, Andritsos Leslie A, Grever Michael R, Byrd John C, Johnson Amy J, Phelps Mitch A, Blum Kristie A
Division of Hematology, Department of Internal Medicine, The Ohio State University, Comprehensive Cancer Center, The Ohio State University, College of Pharmacy, The Ohio State University, Ohio.
Am J Hematol. 2015 Apr;90(4):327-33. doi: 10.1002/ajh.23946. Epub 2015 Feb 25.
Flavopiridol and lenalidomide have activity in refractory CLL without immunosuppression or opportunistic infections seen with other therapies. We hypothesized that flavopiridol treatment could adequately de-bulk disease prior to lenalidomide therapy, decreasing the incidence of tumor flare with higher doses of lenalidomide. In this Phase I study, the maximum tolerated dose was not reached with treatment consisting of flavopiridol 30 mg m(-2) intravenous bolus (IVB) + 30 mg m(-2) continuous intravenous infusion (CIVI) cycle (C) 1 day (D) 1 and 30 mg m(-2) IVB + 50 mg m(-2) CIVI C1 D8,15 and C2-8 D3,10,17 with lenalidomide 15 mg orally daily C2-8 D1-21. There was no unexpected toxicity seen, including no increased tumor lysis, tumor flare (even at higher doses of lenalidomide) or opportunistic infection. Significant clinical activity was demonstrated, with a 51% response rate in this group of heavily pretreated patients. Biomarker testing confirmed association of mitochondrial priming of the BH3 only peptide Puma with response.
氟维司群和来那度胺对难治性慢性淋巴细胞白血病（CLL）具有活性，且不会出现其他疗法所导致的免疫抑制或机会性感染。我们推测，在来那度胺治疗前，氟维司群治疗可充分减少肿瘤负荷，降低使用更高剂量来那度胺时肿瘤 flare 的发生率。在这项 I 期研究中，对于由氟维司群 30 mg m(-2)静脉推注（IVB）+ 30 mg m(-2)持续静脉输注（CIVI）第 1 周期（C）第 1 天（D）1 和 30 mg m(-2)IVB + 50 mg m(-2)CIVI C1 D8、15 以及 C2 - 8 D3、10、17 联合来那度胺 15 mg 每日口服 C2 - 8 D1 - 21 组成的治疗方案，未达到最大耐受剂量。未观察到意外毒性，包括未出现肿瘤溶解增加、肿瘤 flare（即使在更高剂量来那度胺时）或机会性感染。在这组经过大量预处理的患者中显示出显著的临床活性，缓解率为 51%。生物标志物检测证实仅含 BH3 结构域的肽 Puma 的线粒体启动与反应相关。
