Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
US Oncology Research, Woodlands, Texas.
Am J Hematol. 2018 Oct;93(10):1199-1206. doi: 10.1002/ajh.25216. Epub 2018 Sep 3.
CC-486 (oral azacitidine) is an epigenetic modifier in clinical development for treatment of hematological cancers. This study of extended CC-486 dosing included patients with myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML). After a pharmacokinetic assessment period, 31 patients (MDS n = 18, CMML n = 4, and AML n = 9) entered a clinical phase in which they received CC-486 300 mg once-daily for 21 days of repeated 28-day cycles. Median age was 71 years (range: 53-93); 42% of patients were aged ≥75 years. A total of 5 patients with AML (63%) had prior MDS. Median number of CC-486 treatment cycles was 4 (range: 1-32). The most common treatment-emergent adverse events (TEAEs) were gastrointestinal (84% of patients) and hematologic (81%). Most common grade 3-4 TEAEs were neutropenia (n = 13, 42%) and anemia (n = 9, 29%). Ten patients experienced grade 4 neutropenia. Infrequently, CC-486 dose was interrupted or reduced due to gastrointestinal (n = 5, 16%) or hematologic (n = 6, 19%) TEAEs. Overall response rate (complete remission [CR], CR with incomplete hematological recovery [CRi], partial remission [PR], marrow CR) in the MDS/CMML subgroups was 32% and in the AML subgroup (CR/CRi/PR) was 22%. Red blood cell transfusion independence rates in the MDS/CMML and AML subgroups were 33% and 25%, respectively, and 2 MDS/CMML patients attained hematologic improvement as a best response on-study. No baseline gene mutation was predictive of response/nonresponse. CC-486 allows flexible dosing and schedules to improve tolerability or response. Neutropenia in early treatment cycles deserves scrutiny and may warrant initiation of prophylactic antibiotics. KEY POINTS: The safety profile of oral CC-486 was comparable to that of injectable azacitidine; most adverse events were hematological and gastrointestinal. Extended (21-day/cycle) CC-486 dosing induced responses in patients with hematological malignancies, many of whom had prior DNMTi failure.
CC-486（口服阿扎胞苷）是一种在临床开发中用于治疗血液系统恶性肿瘤的表观遗传修饰剂。这项 CC-486 扩展剂量研究纳入了骨髓增生异常综合征（MDSs）、慢性粒单核细胞白血病（CMML）或急性髓系白血病（AML）患者。在药代动力学评估期后，31 名患者（MDS 患者 18 例，CMML 患者 4 例，AML 患者 9 例）进入临床阶段，接受 CC-486 300mg 每日一次，28 天周期的 21 天重复周期。中位年龄为 71 岁（范围：53-93 岁）；42%的患者年龄≥75 岁。共有 5 例 AML 患者（63%）既往有 MDS。中位 CC-486 治疗周期数为 4（范围：1-32）。最常见的治疗相关不良事件（TEAEs）是胃肠道（84%的患者）和血液学（81%）。最常见的 3-4 级 TEAEs 是中性粒细胞减少症（n=13，42%）和贫血（n=9，29%）。10 名患者发生 4 级中性粒细胞减少症。由于胃肠道（n=5，16%）或血液学（n=6，19%）TEAEs，CC-486 剂量偶尔会中断或减少。MDS/CMML 亚组的总缓解率（完全缓解[CR]、CR 伴不完全血液学恢复[CRi]、部分缓解[PR]、骨髓 CR）为 32%，AML 亚组（CR/CRi/PR）为 22%。MDS/CMML 和 AML 亚组的红细胞输血独立性率分别为 33%和 25%，2 例 MDS/CMML 患者在研究期间获得了最佳反应的血液学改善。无基线基因突变可预测反应/无反应。CC-486 允许灵活的剂量和方案以提高耐受性或反应。早期治疗周期中的中性粒细胞减少症值得仔细研究，可能需要开始预防性抗生素治疗。关键点：口服 CC-486 的安全性与注射用阿扎胞苷相当；大多数不良事件为血液学和胃肠道。延长（21 天/周期）CC-486 剂量可诱导血液系统恶性肿瘤患者产生缓解，其中许多患者先前曾使用过 DNMTi 治疗失败。
