PURPOSE DNA-hypomethylating agents are studied in combination with other epigenetic drugs, such as histone deacetylase inhibitors or differentiation inducers (eg, retinoids), in myeloid neoplasias. A randomized, phase II trial with a 2 × 2 factorial design was conducted to investigate the effects of the histone deacetylase inhibitor valproate and all-trans retinoic acid (ATRA) in treatment-naive elderly patients with acute myeloid leukemia (AML). PATIENTS AND METHODS Two hundred patients (median age, 76 years; range, 61-92 years) ineligible for induction chemotherapy received decitabine (20 mg/m2 intravenously, days 1 to 5) alone (n = 47) or in combination with valproate (n = 57), ATRA (n = 46), or valproate + ATRA (n = 50). The primary endpoint was objective response, defined as complete and partial remission, tested at a one-sided significance level of α = .10. Key secondary endpoints were overall survival, event-free survival, and progression-free survival and safety. RESULTS The addition of ATRA resulted in a higher remission rate (21.9% with ATRA v 13.5% without ATRA; odds ratio, 1.80; 95% CI, 0.86 to 3.79; one-sided P = .06). For valproate, no effect was observed (17.8% with valproate v 17.2% without valproate; odds ratio, 1.06; 95% CI, 0.51 to 2.21; one-sided P = .44). Median overall survival was 8.2 months with ATRA v 5.1 months without ATRA (hazard ratio, 0.65; 95% CI, 0.48 to 0.89; two-sided P = .006). Improved survival was observed across risk groups, including patients with adverse cytogenetics, and was associated with longer response duration. With valproate, no survival difference was observed. Toxicities were predominantly hematologic, without relevant differences between the 4 arms. CONCLUSION The addition of ATRA to decitabine resulted in a higher remission rate and a clinically meaningful survival extension in these patients with difficult-to-treat disease, without added toxicity.

中文翻译：

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丙戊酸和视黄酸联合地西他滨治疗老年非健康急性髓系白血病患者：多中心、随机、2 × 2、II 期试验的结果

目的 将 DNA 低甲基化剂与其他表观遗传药物（如组蛋白去乙酰化酶抑制剂或分化诱导剂（如类视黄醇））联合用于骨髓瘤形成的研究。一项采用 2 × 2 析因设计的随机 II 期试验旨在研究组蛋白去乙酰化酶抑制剂丙戊酸和全反式维甲酸 (ATRA) 对未经治疗的老年急性髓性白血病 (AML) 患者的影响。患者和方法 200 名不适合诱导化疗的患者（中位年龄，76 岁；范围，61-92 岁）接受了地西他滨（20 mg/m2 静脉注射，第 1 天至第 5 天）单独治疗（n = 47）或与丙戊酸盐联合治疗（ n = 57)、ATRA (n = 46) 或丙戊酸盐 + ATRA (n = 50)。主要终点是客观反应，定义为完全和部分缓解，在 α = .10 的单边显着性水平上进行检验。关键的次要终点是总生存期、无事件生存期和无进展生存期和安全性。结果 添加 ATRA 导致更高的缓解率（使用 ATRA 时为 21.9%，未使用 ATRA 时为 13.5%；优势比，1.80；95% CI，0.86 至 3.79；单侧 P = .06）。对于丙戊酸盐，未观察到任何影响（丙戊酸盐为 17.8%，无丙戊酸盐为 17.2%；优势比，1.06；95% CI，0.51 至 2.21；单侧 P = .44）。使用 ATRA 的中位总生存期为 8.2 个月，不使用 ATRA 为 5.1 个月（风险比，0.65；95% CI，0.48 至 0.89；双侧 P = .006）。在包括具有不良细胞遗传学的患者在内的风险组中观察到生存率提高，并且与更长的反应持续时间相关。使用丙戊酸盐，未观察到存活差异。毒性主要是血液毒性，4 臂之间没有相关差异。结论 在地西他滨中加入 ATRA 可提高这些难治性疾病患者的缓解率和具有临床意义的生存期延长，且不会增加毒性。