Growing evidence indicates that aberrant DNA hypermethylation is associated with leukemogenesis, chemotherapy resistance, and relapse. DNA methyltransferase inhibitors such as azacitidine and decitabine have been shown to reverse drug resistance and prime leukemia cells to cytotoxic agents in vitro. Here we report the first pediatric phase 1 study using azacitidine in sequence with chemotherapy in patients with relapsed/refractory leukemia. Fourteen patients were enrolled, twelve with acute myeloid leukemia (AML) and two with acute lymphoblastic leukemia (ALL). All patients received azacitidine 75mg/m2/day subcutaneously for 5 days, followed by fludarabine 30mg/m2/day and cytarabine 2gm/m2/day intravenously for 5 days. The median number of prior regimens was 2 (range 1-5). Toxicities were typical of intensive chemotherapy. Febrile neutropenia and infection were the most common non-hematologic toxicities. No patients experienced dose-limiting toxicity. Seven of twelve AML patients achieved complete response after the first cycle. Illumina HumanMethylation450 BeadChip arrays identified a single region at gene body of farnesyldiphosphate farnesyl-transferase 1 gene (FDFT1) that showed methylome-wide significant differential methylation between patients who achieved response and those who did not (p = 0.002). The prognostic significance of this region was further analyzed in a separate data set from a phase II study of decitabine with combination chemotherapy in children with de novo AML. Our study indicates azacitidine plus fludarabine and cytarabine is well tolerated and active in children with relapsed leukemia and warrants further testing. The prognostic significance of the methylation biomarker merits further evaluation. This study was registered at http://www.clinicaltrials.gov (NCT01861002).

中文翻译：

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阿扎胞苷联合化疗治疗儿童白血病的 1 期研究：来自 TACL 联盟的报告

越来越多的证据表明异常的 DNA 高甲基化与白血病发生、化疗耐药和复发有关。DNA 甲基转移酶抑制剂如阿扎胞苷和地西他滨已被证明可在体外逆转耐药性并使白血病细胞对细胞毒剂产生诱导作用。在这里，我们报告了在复发/难治性白血病患者中使用阿扎胞苷与化疗顺序进行的第一项儿科 1 期研究。入组了 14 名患者，其中 12 名患有急性髓性白血病 (AML)，2 名患有急性淋巴细胞白血病 (ALL)。所有患者均接受阿扎胞苷 75mg/m2/天皮下注射 5 天，随后氟达拉滨 30mg/m2/天和阿糖胞苷 2g/m2/天静脉注射 5 天。先前方案的中位数为 2（范围 1-5）。毒性是强化化疗的典型。发热性中性粒细胞减少和感染是最常见的非血液学毒性。没有患者出现剂量限制性毒性。12 名 AML 患者中有 7 名在第一个周期后达到完全缓解。Illumina HumanMethylation450 BeadChip 阵列在法尼基二磷酸法尼基转移酶 1 基因 (FDFT1) 的基因体上鉴定出一个区域，该区域显示出获得反应的患者和未获得反应的患者之间的全甲基化显着差异甲基化 (p = 0.002)。该区域的预后意义在一个单独的数据集中进行了进一步分析，该数据集来自地西他滨联合化疗治疗儿童新发 AML 的 II 期研究。我们的研究表明阿扎胞苷加氟达拉滨和阿糖胞苷对复发性白血病儿童具有良好的耐受性和活性，值得进一步测试。甲基化生物标志物的预后意义值得进一步评估。该研究在 http://www.clinicaltrials.gov (NCT01861002) 注册。