PURPOSE Treatment failure from drug resistance is the primary reason for relapse in acute lymphoblastic leukemia (ALL). Improving outcomes by targeting mechanisms of drug resistance is a potential solution. PATIENTS AND METHODS We report results investigating the epigenetic modulators decitabine and vorinostat with vincristine, dexamethasone, mitoxantrone, and PEG-asparaginase for pediatric patients with relapsed or refractory B-cell ALL (B-ALL). Twenty-three patients, median age 12 years (range, 1-21) were treated in this trial. RESULTS The most common grade 3-4 toxicities included hypokalemia (65%), anemia (78%), febrile neutropenia (57%), hypophosphatemia (43%), leukopenia (61%), hyperbilirubinemia (39%), thrombocytopenia (87%), neutropenia (91%), and hypocalcemia (39%). Three subjects experienced dose-limiting toxicities, which included cholestasis, steatosis, and hyperbilirubinemia (n = 1); seizure, somnolence, and delirium (n = 1); and pneumonitis, hypoxia, and hyperbilirubinemia (n = 1). Infectious complications were common with 17 of 23 (74%) subjects experiencing grade ≥3 infections including invasive fungal infections in 35% (8/23). Nine subjects (39%) achieved a complete response (CR + CR without platelet recovery + CR without neutrophil recovery) and five had stable disease (22%). Nine (39%) subjects were not evaluable for response, primarily due to treatment-related toxicities. Correlative pharmacodynamics demonstrated potent in vivo modulation of epigenetic marks, and modulation of biologic pathways associated with functional antileukemic effects. CONCLUSIONS Despite encouraging response rates and pharmacodynamics, the combination of decitabine and vorinostat on this intensive chemotherapy backbone was determined not feasible in B-ALL due to the high incidence of significant infectious toxicities. This study is registered at http://www.clinicaltrials.gov as NCT01483690.

中文翻译：

---

地西他滨和伏立诺他联合化疗治疗小儿复发性急性淋巴细胞白血病：TACL初步研究。

目的耐药性导致的治疗失败是急性淋巴细胞白血病（ALL）复发的主要原因。通过靶向耐药机制改善结果是一种潜在的解决方案。病人和方法我们报告的结果调查了长春新碱，地塞米松，米托蒽醌和PEG-天冬酰胺酶与地西他滨和伏立诺他的表观遗传调节剂对复发或难治性B细胞ALL（B-ALL）的儿科患者的研究结果。该试验治疗了23位中位年龄为12岁（范围1-21）的患者。结果最常见的3-4级毒性包括低血钾（65％），贫血（78％），发热性中性粒细胞减少症（57％），低磷血症（43％），白细胞减少症（61％），高胆红素血症（39％），血小板减少症（87） ％），中性粒细胞减少症（91％）和低钙血症（39％）。三名受试者出现了剂量限制性毒性，其中包括胆汁淤积，脂肪变性和高胆红素血症（n = 1）；癫痫发作，嗜睡和del妄（n = 1）；以及肺炎，缺氧和高胆红素血症（n = 1）。感染并发症常见于23名患者中的17名（74％），其≥3级感染，包括35％的侵袭性真菌感染（8/23）。9名受试者（39％）达到了完全缓解（CR + CR，无血小板恢复+ CR，无中性粒细胞恢复），五名患者病情稳定（22％）。九名（39％）受试者的反应性无法评估，这主要是由于与治疗相关的毒性。相关药效学证明了体内对表观遗传标记的有效调节，以及与功能性抗白血病作用相关的生物学途径的调节。结论尽管反应率和药效学令人鼓舞，由于强感染性毒物的高发生率，在这种强化化学疗法骨架上联合使用地西他滨和伏立诺他是不可行的。该研究在http://www.clinicaltrials.gov上注册为NCT01483690。