Final results of a phase 2, open-label study of indisulam, idarubicin, and cytarabine in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome.
Final results of a phase 2, open-label study of indisulam, idarubicin, and cytarabine in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome.
复制标题
DOI：
10.1002/cncr.31398
复制
发表时间：
2018-07-01
期刊：
影响因子：
6.2
通讯作者：
Borthakur G
中科院分区：
文献类型：
--
作者：
Assi R;Kantarjian HM;Kadia TM;Pemmaraju N;Jabbour E;Jain N;Daver N;Estrov Z;Uehara T;Owa T;Cortes JE;Borthakur G
Indisulam通过下调各种细胞周期检查点分子，从而阻断视网膜母细胞瘤蛋白的磷酸化并诱导p53和p21而具有抗癌特性。茚磺草胺表现出与核苷类似物和拓扑异构酶抑制剂的协同作用。我们设计了一项II期研究，研究indisulam联合idarlavine和阿糖胞苷治疗复发性/难治性AML和高危骨髓增生异常综合征。在第1阶段，患者在28天周期的第1天和第8天静脉内接受400 mg/m2的茚磺仑治疗。如果没有反应，患者接受相同剂量方案的indisulam，然后在第9-12天（年龄<60岁）或第9-11天（年龄> 60岁）接受idarlavin 8 mg/m2 IV每日x3和阿糖胞苷1.0 g/m2每日24小时。主要终点包括总缓解率，次要目标包括总生存期。入组了40例患者。在37例可评价患者中，31例接受了茚磺仑联合化疗。其中，11例（35%）缓解的中位持续时间为5.3个月。估计的1年总生存率为51%，而无反应者为8%（p<0.001）。最常见的≥3级非血液学毒性为电解质异常（50%）和发热性中性粒细胞减少症（28%）。茚磺草胺与依达拉奉和阿糖胞苷的组合在重度预治疗的AML患者中产生35%的响应率。随着DCAF 15表达的新数据，作为活性的潜在生物标志物，应在生物标志物驱动的试验中或在剪接因子突变的患者中研究indisulam与伊达洛酮和阿糖胞苷的组合。Indisulam是一种细胞周期检查点抑制剂，在重度预治疗的AML患者中表现出35%的缓解率。这种组合值得在具有剪接因子突变的AML患者中进行评估，因为indisulam的活性依赖于DCAF 15和RBM 39。
Indisulam possesses anticancer properties through down-regulation of various cell cycle checkpoint molecules, thereby blocking the phosphorylation of retinoblastoma protein and inducing p53 and p21. Indisulam exhibits synergy with nucleoside analogs and topoisomerase inhibitors. We designed a phase 2, study of indisulam in combination with idarubicin and cytarabine in relapsed/refractory AML and high-risk myelodysplastic syndrome. In stage 1, patients were treated with indisulam at 400 mg/m2 intravenously on days 1 and 8 in a 28-day cycle. If no response, patients received same dose-schedule of indisulam followed by idarubicin 8 mg/m2 IV daily x3 and cytarabine 1.0 g/m2 over 24 hours daily on days 9–12 (age <60 years) or days 9–11 (age>60 years) in a 28-day cycle. Primary endpoints included overall response rate and secondary objectives included overall survival. Forty patients were enrolled. Of the 37 evaluable patients, 31 received indisulam with chemotherapy. Of them, 11 (35%) responded for a median duration of 5.3 months. The estimated 1-year overall survival was 51% for responders compared to 8 % for non-responders (p<0.001). The most common grade ≥3 non-hematological toxicities were electrolyte abnormalities (50%) and febrile neutropenia (28%). The combination of indisulam with idarubicin and cytarabine yielded a 35% response rate in heavily pre-treated AML patients. With emerging data identifying expression of DCAF15, as a potential biomarker for activity, the combination of indisulam with idarubicin and cytarabine should be studied in a biomarker-driven trial or in patients with splicing factors mutations. Indisulam, is a cell cycle checkpoint inhibitor which exhibits 35% response rate in heavily pre-treated AML patients. This combination deserves evaluation in AML patients with splicing factors mutations following the dependence of indisulam’s antineoplastic activity on DCAF15 and RBM39.
登录
查看更多内容
影响因子：
11.4
作者：
通讯作者：
--
影响因子：
45.3
作者：
Breems, DA;Van Putten, WLJ;Löwenberg, B
通讯作者：
Löwenberg, B
影响因子：
56.9
作者：
Han, Ting;Goralski, Maria;Nijhawan, Deepak
通讯作者：
Nijhawan, Deepak
影响因子：
8.4
作者：
Ozawa, Y;Sugi, NH;Yoshimatsu, K
通讯作者：
Yoshimatsu, K
影响因子：
8.8
作者：
Siegel-Lakhai, W. S.;Zandvliet, A. S.;Huitema, A. D. R.;Tibben, M. M.;Milano, G.;Girre, V.;Dieras, V.;King, A.;Richmond, E.;Wanders, J.;Beijnen, J. H.;Schellens, J. H. M.
通讯作者：
Schellens, J. H. M.