Phase 1 study of arsenic trioxide, high-dose cytarabine, and idarubicin to down-regulate constitutive signal transducer and activator of transcription 3 activity in patients aged <60 years with acute myeloid leukemia.
Phase 1 study of arsenic trioxide, high-dose cytarabine, and idarubicin to down-regulate constitutive signal transducer and activator of transcription 3 activity in patients aged <60 years with acute myeloid leukemia.
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DOI：
10.1002/cncr.26097
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发表时间：
2011-11-01
期刊：
影响因子：
6.2
通讯作者：
Baumann H
中科院分区：
文献类型：
--
作者：
Wetzler M;Andrews C;Ford LA;Tighe S;Barcos M;Sait SN;Block AW;Nowak NJ;Baer MR;Wang ES;Baumann H
在大约50%的急性髓细胞白血病（AML）患者的原始细胞中检测到信号转导和转录激活因子3（STAT 3）的组成性激活，并发现与不良结局相关。用三氧化二砷（ATO）体外处理AML原始细胞在6小时内下调STAT 3活性，并在48小时内降低活力。进行了一项I期临床试验，以评估ATO与高剂量阿糖胞苷（Hidac）和伊达比林（Ida）联合治疗<60岁AML患者的体内生物学有效剂量（BED）和/或最大耐受剂量（MTD）。将数据与历史上117例接受Hidac/Ida治疗的AML患者进行比较。共61例患者入组11个不同剂量水平（0.01 - 0.65 mg/kg理想体重）。MTD为0.5 mg/kg。与历史对照相比，ATO/Hidac/Ida患者虽然具有相似的治疗前特征，但总生存期更好（p=0.039）。ATO预激可能改善了用Hidac/Ida治疗的<60岁AML患者的结果。提示ATO可增强化疗效果。这种新的组合的进一步研究是必要的。
Constitutive activation of signal transducer and activator of transcription-3 (STAT3) was detected in blasts from approximately 50% of acute myeloid leukemia (AML) patients and was found to correlate with adverse outcome. In vitro treatment of AML blasts with arsenic trioxide (ATO) down-regulates STAT3 activity within six hours associated with a reduced viability within 48 hours. A phase I clinical trial to evaluate the biologically effective dose (BED) and/or the maximally tolerated dose (MTD) of ATO in vivo in conjunction with high-dose cytarabine (Hidac) and idarubicin (Ida) in AML patients <60 years old was conducted. Data were compared with historical 117 AML patients treated with Hidac/Ida. A total of 61 patients were enrolled onto 11 different dose levels (0.01 to 0.65 mg/kg ideal body weight). The MTD was 0.5 mg/kg. In comparison to historical controls, ATO/Hidac/Ida patients, while having similar pretreatment characteristics, had better overall survival (p=0.039). ATO priming may have improved the outcome of <60 year old AML patients treated with Hidac/Ida. These data suggest that ATO might enhance the effect of chemotherapy. Further studies of this novel combination are warranted.
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