University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.
Columbia University Medical Center, New York, New York.
Clin Cancer Res. 2021 Jan 1;27(1):60-69. doi: 10.1158/1078-0432.CCR-20-2649. Epub 2020 Sep 30.
Alvocidib is a cyclin-dependent kinase 9 inhibitor leading to downregulation of the antiapoptotic BCL-2 family member, MCL-1. Alvocidib has shown clinical activity in a timed sequential regimen with cytarabine and mitoxantrone in relapsed/refractory and newly diagnosed acute myeloid leukemia (AML) but has not been studied in combination with traditional 7+3 induction therapy.
A multiinstitutional phase I dose-escalation study of alvocidib on days 1-3 followed by 7+3 (cytarabine 100 mg/m/day i.v. infusion days 5-12 and daunorubicin 60 mg/m i.v. days 5-7) was performed in newly diagnosed AML ≤65 years. Core-binding factor AML was excluded.
There was no MTD on this study; the recommended phase II dose of alvocidib was 30 mg/m i.v. over 30 minutes followed by 60 mg/m i.v. infusion over 4 hours. There was one dose-limiting toxicity of cytokine release syndrome. The most common grade ≥3 nonhematologic toxicities were diarrhea (44%) and tumor lysis syndrome (34%). Overall, 69% (22/32) of patients achieved complete remission (CR). In an exploratory cohort, eight of nine (89%) patients in complete remission had no measurable residual disease, as determined by a centralized flow cytometric assay. Clinical activity was seen in patients with secondary AML, AML with myelodysplastic syndrome-related changes, and a genomic signature of secondary AML (50%, 50%, and 92% CR rates, respectively).
Alvocidib can be safely administered prior to 7+3 induction with encouraging clinical activity. These findings warrant further investigation of alvocidib combinations in newly diagnosed AML. This study was registered at clinicaltrials.gov identifier NCT03298984.
阿伐麦布是一种细胞周期蛋白依赖性激酶 9 抑制剂，可导致抗凋亡 BCL-2 家族成员 MCL-1 的下调。阿伐麦布在复发/难治性和新诊断的急性髓系白血病（AML）中与阿糖胞苷和米托蒽醌进行计时序贯治疗方案中显示出临床活性，但尚未与传统的 7+3 诱导治疗联合研究。
在新诊断的 AML≤65 岁的患者中进行了一项多中心 I 期剂量递增研究，阿伐麦布在第 1-3 天静脉滴注，随后进行 7+3（阿糖胞苷 100mg/m/天静脉输注第 5-12 天和柔红霉素 60mg/m 静脉输注第 5-7 天）。核心结合因子 AML 除外。
该研究未达到最大耐受剂量；阿伐麦布的推荐 II 期剂量为 30mg/m 静脉滴注 30 分钟，然后 60mg/m 静脉输注 4 小时。有一例细胞因子释放综合征的剂量限制毒性。最常见的≥3 级非血液学毒性是腹泻（44%）和肿瘤溶解综合征（34%）。总体而言，69%（22/32）的患者达到完全缓解（CR）。在一个探索性队列中，22 例完全缓解患者中有 8 例（89%）通过中央流式细胞仪检测确定无可测量残留疾病。在继发性 AML、伴骨髓增生异常相关改变的 AML 和继发性 AML 的基因组特征的患者中均观察到临床活性（分别为 50%、50%和 92%CR 率）。
阿伐麦布可在 7+3 诱导前安全给药，具有令人鼓舞的临床活性。这些发现证明了在新诊断的 AML 中进一步研究阿伐麦布联合用药的必要性。该研究在 clinicaltrials.gov 注册，标识符为 NCT03298984。
