Ueda Yasunori, Ogura Michinori, Miyakoshi Shigesaburo, Suzuki Takahiro, Heike Yuji, Tagashira Shuzo, Tsuchiya Satoru, Ohyashiki Kazuma, Miyazaki Yasushi
Department of Hematology/Oncology, Kurashiki Central Hospital, Kurashiki, Japan.
Department of Hematology and Oncology, Nagoya Daini Red Cross Hospital, Nagoya, Japan.
Cancer Sci. 2017 Dec;108(12):2445-2453. doi: 10.1111/cas.13409. Epub 2017 Oct 25.
WT4869 is a synthetic peptide vaccine derived from the Wilms' tumor gene 1 (WT1) protein. This phase 1/2 open-label study evaluated the safety and efficacy of WT4869, and biomarkers for response, in patients with myelodysplastic syndrome. WT4869 (5-1200 μg/dose) was administered intradermally every 2 weeks, according to a 3 + 3 dose-escalation method in higher-risk (International Prognostic Scoring System score ≥1.5) or lower-risk (score <1.5) red blood cell transfusion-dependent patients with myelodysplastic syndrome. Twenty-six patients were enrolled and treated (median age, 75 years; range, 32 to 89). The most common adverse event was injection site reaction (61.5%). Main grade 3 or 4 adverse events were neutropenia (30.8%), febrile neutropenia, pneumonia, elevated blood creatine phosphokinase levels and hypoalbuminemia (all 7.7%). Dose-limiting toxicities occurred in 1 patient in the 50 μg/dose cohort (pyrexia, muscle hemorrhage and hypoalbuminemia) and 1 patient in the 400 μg/dose cohort (pneumonitis); however, the maximum tolerated dose could not be determined from this trial. The overall response rate was 18.2%, the disease control rate was 59.1% and median overall survival was 64.71 weeks (95% confidence interval: 50.29, 142.86) as assessed by the Kaplan-Meier method. Subgroup analysis of azacitidine-refractory patients with higher-risk myelodysplastic syndrome (11 patients) showed median overall survival of 55.71 weeks (approximately 13 months). WT1-specific cytotoxic T lymphocyte induction was observed in 11 of 25 evaluable patients. WT4869 was well tolerated in patients with myelodysplastic syndrome and preliminary data suggest that WT4869 is efficacious. This trial was registered at www.clinicaltrials.jp as JapicCTI-101374.
WT4869是一种源自肾母细胞瘤基因1（WT1）蛋白的合成肽疫苗。这项1/2期开放标签研究评估了WT4869在骨髓增生异常综合征患者中的安全性和疗效以及反应生物标志物。WT4869（5 - 1200μg/剂量）按照3 + 3剂量递增方法，每2周皮内注射一次，用于治疗高风险（国际预后评分系统评分≥1.5）或低风险（评分<1.5）且依赖红细胞输血的骨髓增生异常综合征患者。共纳入26例患者并进行治疗（中位年龄75岁；范围32至89岁）。最常见的不良事件是注射部位反应（61.5%）。主要的3级或4级不良事件是中性粒细胞减少（30.8%）、发热性中性粒细胞减少、肺炎、血肌酸磷酸激酶水平升高和低白蛋白血症（均为7.7%）。剂量限制性毒性发生在50μg/剂量队列中的1例患者（发热、肌肉出血和低白蛋白血症）和400μg/剂量队列中的1例患者（肺炎）；然而，无法从该试验中确定最大耐受剂量。通过Kaplan - Meier方法评估，总缓解率为18.2%，疾病控制率为59.1%，中位总生存期为64.71周（95%置信区间：50.29，142.86）。对11例高风险骨髓增生异常综合征且对阿扎胞苷难治的患者进行亚组分析，中位总生存期为55.71周（约13个月）。在25例可评估患者中的11例观察到WT1特异性细胞毒性T淋巴细胞诱导。WT4869在骨髓增生异常综合征患者中耐受性良好，初步数据表明WT4869有效。该试验在www.clinicaltrials.jp注册，注册号为JapicCTI - 101374。
