地西他滨联合 CLAG 方案作为表观遗传学诱导剂改善复发或难治性儿童急性髓系白血病的疗效。
Decitabine as epigenetic priming with CLAG induce improved outcome of relapsed or refractory acute myeloid leukemia in children.
机构信息
Department of Hematology and Oncology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, No. 1400, West Beijing Road, Shanghai, 200040, China.
Department of Neonatology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, No. 355, Luding Road, Shanghai, 200062, China.
出版信息
Clin Epigenetics. 2024 May 9;16(1):63. doi: 10.1186/s13148-024-01677-z.
BACKGROUND
Decitabine (DAC), a DNA methyltransferase inhibitor, has shown efficacy combined with chemotherapy for relapsed or refractory (R/R) acute myeloid leukemia (AML) in adults, but less is known about its efficacy in children. Accordingly, we conducted a study which involved a priming regimen consisting of DAC with cladribine, cytarabine, and granulocyte-stimulating factor (DAC-CLAG) and compared the efficacy and safety of this regimen with CLAG alone.
METHODS
A total of 39 R/R AML children who received the CLAG or DAC-CLAG regimen in Shanghai Children's Hospital were retrospectively enrolled in this non-randomized study. These regimens were studied sequentially over time. Twenty-two patients received CLAG from 2015, while 17 patients were administered epigenetic priming with DAC before CLAG from 2020. Patients were subsequently bridged to stem cell transplantation (SCT) or consolidation chemotherapy. Complete remission (CR) and adverse effects were analyzed by Fisher's exact test, and survival was analyzed by the Kaplan-Meier method.
RESULTS
DAC-CLAG conferred a numerically higher CR compared to CLAG (70.59% vs 63.64%; P = 0.740). High CR rates occurred in patients with good cytogenetics (P = 0.029) and prior induction without cladribine (P = 0.099). The 1-year event-free survival (EFS) was 64.71% ± 11.59% and 63.31% ± 10.35% in the DAC-CLAG and CLAG group (P = 0.595), and 1-year overall survival (OS) was 81.45% ± 9.72% and 77.01% ± 9.04%, respectively (P = 0.265). The 1-year OS and EFS after SCT were higher in the DAC-CLAG than in the CLAG cohort (100% vs 92.31% ± 7.39%, P = 0.072; 92.31% ± 7.39% vs 85.71% ± 9.35%, P = 0.158). Univariate analysis revealed that a good prognosis included good cytogenetics (P = 0.002), non-complex karyotype (P = 0.056), CR on reinduction (P < 0.0001), and bridging to SCT (P = 0.0007). Use of a hypomethylating agent (P = 0.049) and bridging to SCT (P = 0.011) were independent prognostic factors. Grade 3/4 hematologic toxicity and infection were the main adverse events.
CONCLUSIONS
DAC prior to the CLAG regimen improved remission in pediatric R/R AML, and was feasible and well tolerated. CLAG ± DAC as a salvage therapy prior to SCT induced improved survival.
背景
地西他滨（DAC）是一种 DNA 甲基转移酶抑制剂，已显示出与化疗联合治疗成人复发/难治性（R/R）急性髓系白血病（AML）的疗效，但关于其在儿童中的疗效知之甚少。因此，我们进行了一项研究，该研究涉及一个由地西他滨、克拉屈滨、阿糖胞苷和粒细胞集落刺激因子组成的诱导方案（DAC-CLAG），并比较了该方案与单独使用 CLAG 的疗效和安全性。
方法
共纳入 39 例在上海儿童医学中心接受 CLAG 或 DAC-CLAG 方案治疗的 R/R AML 儿童进行回顾性研究。这些方案是按时间顺序进行的。22 例患者于 2015 年接受 CLAG，17 例患者于 2020 年接受 DAC 进行表观遗传学诱导后接受 CLAG。随后患者桥接至干细胞移植（SCT）或巩固化疗。通过 Fisher 确切检验分析完全缓解（CR）和不良反应，通过 Kaplan-Meier 法分析生存情况。
结果
DAC-CLAG 诱导的 CR 率高于 CLAG（70.59% vs 63.64%；P=0.740）。在细胞遗传学良好（P=0.029）和无克拉屈滨诱导（P=0.099）的患者中，高 CR 率发生。DAC-CLAG 和 CLAG 组的 1 年无事件生存率（EFS）分别为 64.71%±11.59%和 63.31%±10.35%（P=0.595），1 年总生存率（OS）分别为 81.45%±9.72%和 77.01%±9.04%（P=0.265）。SCT 后 DAC-CLAG 组的 1 年 OS 和 EFS 高于 CLAG 组（100% vs 92.31%±7.39%，P=0.072；92.31%±7.39% vs 85.71%±9.35%，P=0.158）。单因素分析显示，良好的预后包括良好的细胞遗传学（P=0.002）、非复杂核型（P=0.056）、再诱导时的 CR（P<0.0001）和桥接至 SCT（P=0.0007）。使用低甲基化剂（P=0.049）和桥接至 SCT（P=0.011）是独立的预后因素。3/4 级血液学毒性和感染是主要的不良事件。
结论
在 CLAG 方案之前使用 DAC 可改善儿科 R/R AML 的缓解率，且该方案可行且耐受性良好。CLAG±DAC 作为 SCT 前的挽救性治疗可诱导改善生存。
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