St. Jude Children's Research Hospital, Memphis, Tennessee.
College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.
Cancer. 2020 Nov 1;126(21):4800-4805. doi: 10.1002/cncr.33156. Epub 2020 Aug 18.
Novel therapies are urgently needed for pediatric patients with relapsed acute myeloid leukemia (AML).
To determine whether the histone deacetylase inhibitor panobinostat could be safely given in combination with intensive chemotherapy, a phase 1 trial was performed in which 17 pediatric patients with relapsed or refractory AML received panobinostat (10, 15, or 20 mg/m ) before and in combination with fludarabine and cytarabine.
All dose levels were tolerated, with no dose-limiting toxicities observed at any dose level. Pharmacokinetic studies demonstrated that exposure to panobinostat was proportional to the dose given, with no associations between pharmacokinetic parameters and age, weight, or body surface area. Among the 9 patients who had sufficient (>2%) circulating blasts on which histone acetylation studies could be performed, 7 demonstrated at least 1.5-fold increases in acetylation. Although no patients had a decrease in circulating blasts after single-agent panobinostat, 8 of the 17 patients (47%), including 5 of the 6 patients treated at dose level 3, achieved complete remission. Among the 8 complete responders, 6 (75%) attained negative minimal residual disease status.
Panobinostat can be safely administered with chemotherapy and results in increased blast histone acetylation. This suggests that it should be further studied in AML.
对于复发的急性髓系白血病（AML）患儿，急需新的治疗方法。
为了确定组蛋白去乙酰化酶抑制剂帕比司他与强化化疗联合应用是否安全，进行了一项 1 期临床试验，17 例复发或难治性 AML 患儿接受帕比司他（10、15 或 20mg/m ）治疗，在接受氟达拉滨和阿糖胞苷治疗前和治疗期间联合应用帕比司他。
所有剂量水平均耐受，未观察到任何剂量水平的剂量限制毒性。药代动力学研究表明，帕比司他的暴露量与所给剂量成正比，与年龄、体重或体表面积之间无相关性。在 9 例有足够（>2%）循环白血病细胞可供进行组蛋白乙酰化研究的患者中，有 7 例显示乙酰化至少增加 1.5 倍。尽管在单独使用帕比司他后没有患者的循环白血病细胞减少，但 17 例患者中有 8 例（47%），包括 3 级治疗的 6 例患者中的 5 例，达到完全缓解。在 8 例完全缓解者中，有 6 例（75%）达到阴性微小残留病状态。
帕比司他可与化疗安全联合应用，并导致白血病细胞的组蛋白乙酰化增加。这表明它应在 AML 中进一步研究。
