Phase 1/2 study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemia
Phase 1/2 study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemia
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DOI：
10.1182/blood-2006-03-009142
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发表时间：
2006-11-15
期刊：
影响因子：
20.3
通讯作者：
Issa, Jean-Pierre
中科院分区：
文献类型：
--
作者：
Garcia-Manero, Guillermo;Kantarjian, Hagop M.;Issa, Jean-Pierre
我们对晚期白血病患者（包括未经治疗的老年患者）进行了 5-aza-2'-脱氧胞苷（地西他滨）和组蛋白脱乙酰酶抑制剂丙戊酸 (VPA) 联合治疗的 1/2 期研究。一组 54 名患者接受固定剂量的地西他滨（15 mg/m(2)，每天静脉注射，持续 10 天），同时口服递增剂量的 VPA，持续 10 天。发现每日 50 毫克/公斤剂量的 VPA 是安全的。 12 例 (22%) 患者获得客观缓解，其中 10 例 (19%) 患者完全缓解 (CR)，2 例 (3%) 患者血小板不完全恢复 (CRp)。在 10 名患有急性髓性白血病或骨髓增生异常综合征的老年患者中，5 名（50%）有缓解（4CR，1CRp）。 1 名 (2%) 患者观察到诱导死亡。 8 名反应者中有 6 人记录了主要细胞遗传学反应。缓解持续时间为 7.2 个月（范围：1.3-12.6+ 个月）。应答者的总生存期为 15.3 个月（范围为 4.6-20.2+ 个月）。诱导短暂的 DNA 低甲基化和整体组蛋白 H3 和 H4 乙酰化，并与 p15 重新激活相关。治疗前 p15 甲基化水平较低的患者的缓解率显着较高。总之，这种表观遗传疗法组合治疗白血病是安全且有效的，并且与异常表观遗传标记的短暂逆转相关。该试验在 www.clinicaltrials.gov 上注册为#NCT00075010。
We conducted a phase 1/2 study of the combination of 5-aza-2'-deoxycytidine (decitabine) and the histone deacetylase inhibitor valproic acid (VPA) in patients with advanced leukemia, including older untreated patients. A group of 54 patients were treated with a fixed dose of decitabine (15 mg/m(2) by IV daily for 10 days) administered concomitantly with escalating doses of VPA orally for 10 days. A 50 mg/kg daily dose of VPA was found to be safe. Twelve (22%) patients had objective response, including 10 (19%) complete remissions (CRs), and 2 (3%) CRs with incomplete platelet recovery (CRp). Among 10 elderly patients with acute myelogenous leukemia or myelodysplastic syndrome, 5 (50%) had a response (4CRs, 1CRp's). Induction mortality was observed in 1 (2%) patient. Major cytogenetic response was documented in 6 of 8 responders. Remission duration was 7.2 months (range, 1.3-12.6+ months). Overall survival was 15.3 months (range, 4.6-20.2+ months) in responders. Transient DNA hypomethylation and global histone H3 and H4 acetylation were induced, and were associated with p15 reactivation. Patients with lower pretreatment levels of p15 methylation had a significantly higher response rate. In summary, this combination of epigenetic therapy in leukemia was safe and active, and was associated with transient reversal of aberrant epigenetic marks. This trial was registered at www.clinicaltrials.gov as #NCT00075010.