Phase I study of 5-aza-2?-deoxycitidine in acute lymphocytic leukemia

描述（由申请人提供）：复发或难治性急性淋巴细胞白血病（ALL）患者的预后非常差，并且在过去的十年中没有改变。我们小组广泛研究了异常DNA甲基化在ALL患者中的作用。我们已经证明，多个启动子相关的CpG岛的异常DNA甲基化是ALL中非常常见的现象，并且特定分子途径的异常表观遗传沉默，特别是细胞周期控制途径，预示着ALL患者的预后非常差。这些甲基化改变在复发时是稳定的，并且可以在复发高风险患者的初始缓解时检测到。我们实验室的数据还表明，淋巴细胞对低甲基化剂5-aza-2'-脱氧胞苷的体外敏感性与髓系白血病细胞相似。此外，在我们的机构进行的几项低剂量5-aza-2'-脱氧胞苷的I期研究数据表明，低剂量方案对晚期急性白血病患者是安全且有效的。基于这些信息，我们提出低剂量5-aza-2'-脱氧胞苷在复发/难治性ALL患者中单独使用或与hypervad化疗联合使用是安全有效的，并且这种治疗与整体和基因特异性甲基化和基因表达模式的变化有关。为了验证这一假设，我们提出以下具体目标：#1)在复发/难治性ALL患者中进行低剂量5-aza-2'-脱氧胞苷的I期研究。根据先前的数据，我们设计了一个方案，包括每天5-aza-2'-脱氧胞苷，每隔一周服用5天。如果患者对5-aza-2′-脱氧胞苷没有反应或进展，研究的下一阶段将包括5-aza-2′-脱氧胞苷与hypervad基础化疗的联合。#2)分析在上述治疗期间整体和基因特异性异常DNA甲基化和基因表达模式的顺序变化。这项研究的意义是多方面的和重要的。这包括：1)为晚期ALL患者开发一种新的治疗方案的潜力；2) ALL表观遗传治疗过程中甲基化/表达变化动态分析；3)对于未经治疗的ALL患者纳入5-aza-2'-脱氧胞苷的前期治疗至关重要的信息。复发或难治性急性淋巴细胞白血病是儿童中最常见的癌症，目前尚无积极的治疗方法。在这个提案中，我们计划为这些患者开发一种新的低剂量化疗药物，地西他滨。早期的结果表明，这是积极和安全的。

DESCRIPTION (provided by applicant): The prognosis of patients with relapsed or refractory acute lymphocytic leukemia (ALL) is extremely poor and it has not changed over the last decade. Our group has extensively studied the role of aberrant DNA methylation in patients with ALL. We have demonstrated that aberrant DNA methylation of multiple promoter associated CpG islands is a very frequent phenomenon in ALL, and that aberrant epigenetic silencing of specific molecular pathways, in particular a cell cycle control pathway, predicts for very poor prognosis in patients with ALL. These methylation alterations are stable at the time of relapse and can be detected at the time of initial remission in patients at high-risk for relapse. Data from our laboratory also indicates that the in vitro sensitivity of lymphoid cells to the hypomethylating agent 5-aza-2'-deoxycytidine is similar to that observed in myeloid leukemic cells. Furthermore, data from several phase I studies conducted at our institution of low dose 5-aza-2'-deoxycytidine have indicated that a low dose schedule is safe and active in patients with advanced acute leukemias. Based on this information, we propose the hypothesis that a low dose schedule of 5-aza-2'-deoxycytidine will be safe and active in patients with relapsed/refractory ALL used either as a single agent or in combination with hyperCVAD chemotherapy, and that this therapy is associated with changes in global and gene specific methylation and gene expression patterns. To test this hypothesis, we propose the following Specific Aims: #1) To conduct a phase I study of low dose 5-aza-2'-deoxycytidine in patients with relapsed/refractory ALL. Based on prior data, we have designed a schedule that consists in the administration of 5-aza-2'- deoxycitidine daily for 5 days every other week. If patients do not respond or progress to 5-aza-2'-deoxycytidine, a subsequent phase of the study will consist in the combination of 5-aza-2'-deoxycytidine with hyperCVAD based chemotherapy. #2) To analyze changes in global and gene specific aberrant DNA methylation and gene expression patterns sequentially during the above therapy. The implications of this study are multiple and of importance. This include: 1) the potential development of a new therapeutic alternative for patients with advanced ALL; 2) the analysis of the dynamics of methylation/expression changes during epigenetic therapy in ALL; and 3) crucial information for the incorporation of 5-aza-2'-deoxycytidine up-front therapy for patients with untreated ALL. There is no active treatment for relapsed or refractory acute lymphocytic leukemia, the most common cancer in children. In this proposal, we plan to develop a new form of low-dose chemotherapy, decitabine, for these patients. Early results indicate that this is active and safe.