Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Tsukuba Research Laboratories, Eisai Company, Ltd, Tsukuba, Ibaraki, Japan.
Cancer. 2018 Jul 1;124(13):2758-2765. doi: 10.1002/cncr.31398. Epub 2018 Apr 16.
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.
The authors designed a phase 2 study of indisulam in combination with idarubicin and cytarabine in patients who had relapsed/refractory acute myeloid leukemia AML and high-risk myelodysplastic syndrome. In stage 1, patients received intravenous indisulam at 400 mg/m on days 1 and 8 of a 28-day cycle. If they had no response, then patients received same dose schedule of indisulam followed by intravenous idarubicin 8 mg/m daily for 3 days and cytarabine 1.0 g/m over 24 hours daily on days 9 through 12 (for those aged < 60 years) or days 9 through 11 (for those aged > 60 years) of a 28-day cycle. Primary endpoints included the overall response rate, and secondary objectives included overall survival.
Forty patients were enrolled. Of the 37 evaluable patients, 31 received indisulam with chemotherapy. Of these, 11 (35%) responded for a median duration of 5.3 months. The estimated 1-year overall survival rate was 51% for responders compared with 8 % for nonresponders (P < .001). The most common grade ≥3 nonhematologic toxicities were electrolyte abnormalities (50%) and febrile neutropenia (28%).
The combination of indisulam with idarubicin and cytarabine yielded a 35% response rate in heavily pretreated patients with AML. With emerging data identifying the expression of DCAF15 (DDB1 and CUL4-associated factor 15) 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 who have splicing factor mutations. Cancer 2018;124:2758-65. © 2018 American Cancer Society. Cancer 2018;124:2758-2765. © 2018 American Cancer Society.
因伐单抗通过下调多种细胞周期检查点分子来发挥抗癌作用，从而阻断视网膜母细胞瘤蛋白的磷酸化，并诱导 p53 和 p21。因伐单抗与核苷类似物和拓扑异构酶抑制剂具有协同作用。
作者设计了一项 2 期研究，评估因伐单抗联合伊达比星和阿糖胞苷治疗复发/难治性急性髓系白血病（AML）和高危骨髓增生异常综合征患者的疗效。在第 1 阶段，患者在 28 天周期的第 1 天和第 8 天接受静脉注射因伐单抗，剂量为 400mg/m2。如果患者无反应，则接受相同剂量的因伐单抗，随后在第 9 天至第 12 天（60 岁以下患者）或第 9 天至第 11 天（60 岁以上患者）接受静脉注射伊达比星 8mg/m2，每日 1 次，持续 3 天，并在第 9 天至第 12 天（60 岁以下患者）或第 9 天至第 11 天（60 岁以上患者）接受阿糖胞苷 1.0g/m2，持续 24 小时，每天 1 次，为一个 28 天周期。主要终点包括总缓解率，次要终点包括总生存。
共纳入 40 例患者。在 37 例可评估患者中，31 例接受了因伐单抗联合化疗。其中，11 例（35%）有反应，中位缓解持续时间为 5.3 个月。与无反应者 8%的 1 年总生存率相比，反应者的 1 年总生存率为 51%（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（28%）。
在 AML 患者中，因伐单抗联合伊达比星和阿糖胞苷的联合治疗反应率为 35%。鉴于表达 DCAF15（DDB1 和 CUL4 相关因子 15）作为活性的潜在生物标志物的新数据，因伐单抗联合伊达比星和阿糖胞苷的联合治疗应该在基于生物标志物的试验中或在具有剪接因子突变的患者中进行研究。癌症 2018；124：2758-65。©2018 美国癌症协会。癌症 2018；124：2758-2765。©2018 美国癌症协会。
