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

描述(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，在过去十年中没有改变。我们小组广泛研究了DNA甲基化异常在急性淋巴细胞白血病患者中的作用。我们已经证明，多个启动子相关的CpG岛的DNA甲基化异常在ALL中是一种非常常见的现象，而特定分子通路，特别是细胞周期控制通路的表观遗传学异常沉默，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，在复发高危患者的初始缓解时可以检测到。我们实验室的数据还表明，淋巴细胞对去甲基化药物5-氮-2‘-脱氧胞苷的体外敏感性与髓系白血病细胞相似。此外，在我们研究所进行的几个I期研究的数据表明，低剂量5-氮杂-2‘-脱氧胞苷对晚期急性白血病患者是安全和有效的。基于这一信息，我们提出一个假设，即小剂量5-氮-2‘-脱氧胞苷方案对复发/难治性ALL患者将是安全和有效的，无论是作为单一药物使用，还是与高CVAD化疗联合使用，并且这种治疗与全局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，我们提出了以下具体目标：#1)开展小剂量5-氮杂-2‘-脱氧胞苷在复发/难治性ALL患者中的I期研究。根据先前的数据，我们设计了一个时间表，包括每隔一周每天服用5-氮杂-2‘-脱氧胞苷5天。如果患者对5-氮-2‘-脱氧胞苷没有反应或进展，下一阶段的研究将包括将5-氮-2’-脱氧胞苷与基于高CVAD的化疗相结合。2)分析上述治疗过程中整体和基因特异性异常DNA甲基化和基因表达模式的变化。这项研究的意义是多方面的，具有重要意义。这包括：1)为晚期ALL患者开发一种新的治疗替代方案的可能性；2)对ALL患者在表观遗传治疗过程中甲基化/表达变化的动态分析；以及3)将5-氮-2‘-脱氧胞苷预先用于未经治疗的ALL患者的关键信息。复发或难治性急性淋巴细胞白血病是儿童最常见的癌症，目前还没有积极的治疗方法。在这项提案中，我们计划为这些患者开发一种新的低剂量化疗方式，地西他滨。早期结果表明，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.