Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.
Department of Hematology, Nephrology and Rheumatology, Akita University Hospital, Akita, Japan.
Cancer Sci. 2024 Apr;115(4):1250-1260. doi: 10.1111/cas.16054. Epub 2024 Feb 7.
Glasdegib is a potent, selective, oral inhibitor of the hedgehog signaling pathway. In this phase I study, previously untreated Japanese patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes were treated with glasdegib (100 mg once daily) combinations: low-dose cytarabine (20 mg twice daily; cohort 1, n = 6; expansion cohort, n = 15); daunorubicin and cytarabine (60 mg/m i.v.; cohort 2, n = 6); or azacitidine (100 mg/m i.v.; cohort 3, n = 6). Patients, except cohort 2, were ineligible for intensive chemotherapy. The primary end-point was dose-limiting toxicity in cohorts 1-3 and disease-modifying response in the expansion cohort. Disease-modifying response rate was tested with the null hypothesis of 6.8%, which was set based on the results from the phase II BRIGHT AML 1003 study (NCT01546038). No dose-limiting toxicities were observed in cohorts 1 or 3; one patient in cohort 2 experienced a dose-limiting toxicity of grade 3 erythroderma. The most common grade ≥3 treatment-related adverse events were neutropenia and thrombocytopenia (66.7% each) in cohort 1 and thrombocytopenia (60.0%) in the expansion cohort. In the expansion cohort, the disease-modifying response rate was 46.7% (90% confidence interval, 24.4-70.0; p < 0.0001), with all patients achieving either a complete response or complete response with incomplete blood count recovery. Median overall survival was 13.9 months. In this study, the primary disease-modifying response end-point with glasdegib plus low-dose cytarabine was met. The study confirms the safety and efficacy of glasdegib plus low-dose cytarabine in Japanese patients with AML ineligible for intensive chemotherapy.
吉西他滨是一种有效的、选择性的 Hedgehog 信号通路抑制剂。在这项 I 期研究中，未经治疗的日本急性髓细胞白血病（AML）或高危骨髓增生异常综合征患者接受了吉西他滨（100mg 每日一次）联合治疗：低剂量阿糖胞苷（20mg 每日两次；队列 1，n=6；扩展队列，n=15）；柔红霉素和阿糖胞苷（60mg/m 静脉注射；队列 2，n=6）；或阿扎胞苷（100mg/m 静脉注射；队列 3，n=6）。除队列 2 外，患者不适合强化化疗。主要终点是队列 1-3 的剂量限制毒性和扩展队列的疾病改良反应。疾病改良反应率采用 6.8%的无效假设进行检验，这是基于 BRIGHT AML 1003 期研究（NCT01546038）的结果设定的。在队列 1 和 3 中未观察到剂量限制毒性；队列 2 中有 1 名患者出现 3 级红皮病的剂量限制毒性。最常见的≥3 级治疗相关不良事件是中性粒细胞减少症和血小板减少症（各 66.7%），在扩展队列中是血小板减少症（60.0%）。在扩展队列中，疾病改良反应率为 46.7%（90%置信区间，24.4-70.0；p<0.0001），所有患者均达到完全缓解或不完全血细胞计数恢复的完全缓解。中位总生存期为 13.9 个月。在这项研究中，吉西他滨联合低剂量阿糖胞苷的主要疾病改良反应终点达到了。该研究证实了吉西他滨联合低剂量阿糖胞苷在不适合强化化疗的日本 AML 患者中的安全性和疗效。
