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

5-aza-2?-脱氧胞苷治疗急性淋巴细胞白血病的I期研究

• 批准号: 7331323
• 负责人: GUILLERMO GARCIA-MANERO
• 金额: $ 29.26万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-12 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7331323
• 关键词: Aberrant DNA Methylation; Acute Lymphocytic Leukemia; Acute leukemia; Adult; Cell Cycle Regulation; Cell Line; Child; Childhood; Clinical; Commit; Coupled; CpG Islands; DNA; DNA Methylation; Daily; Data; Decitabine; Deoxycytidine; Development; Disease; Disease remission; Dose; Effectiveness of Interventions; Epigenetic Process; Gene Expression; Genes; Goals; In Vitro; Institution; Laboratories; Leukemic Cell; Lymphoid; Lymphoid Cell; Malignant Neoplasms; Marrow; Methylation; Modality; Molecular; Myelogenous; Myeloid Cells; Numbers; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Population; Population Study; Refractory; Relapse; Risk; Role; Safety; Schedule; Staging; Testing; Time; Toxic effect; Week; base; chemotherapy; day; design; in vivo; innovation; leukemia; novel therapeutics; outcome forecast; promoter

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.

描述（由申请人提供）：复发性或难治性急性淋巴细胞白血病（ALL）患者的预后极差，并且在过去十年中没有改变。我们的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（特别是细胞周期控制途径）的异常表观遗传沉默预示着 ALL 患者的预后非常差。这些甲基化改变在复发时是稳定的，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，体外淋巴细胞对低甲基化剂 5-aza-2'-脱氧胞苷的敏感性与在骨髓白血病细胞中观察到的相似。此外，我们机构进行的几项低剂量 5-aza-2'-脱氧胞苷 I 期研究的数据表明，低剂量方案对于晚期急性白血病患者是安全且有效的。基于这些信息，我们提出这样的假设：5-aza-2'-脱氧胞苷的低剂量方案对于复发/难治性 ALL 患者作为单一药物或与 hyperCVAD 化疗联合使用将是安全且有效的，并且该疗法与整体和基因特异性甲基化和基因表达模式的变化有关。为了检验这一假设，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，我们设计了一个时间表，其中包括每隔一周每天施用 5-aza-2'-脱氧胞苷，持续 5 天。如果患者对 5-aza-2'-脱氧胞苷没有反应或进展，研究的后续阶段将包括 5-aza-2'-脱氧胞苷与基于 hyperCVAD 的化疗的组合。 #2) 在上述治疗过程中依次分析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重且重要的。这包括：1）为晚期 ALL 患者开发新的治疗替代方案的潜力； 2) ALL表观遗传治疗过程中甲基化/表达变化的动态分析； 3) 对于未经治疗的 ALL 患者纳入 5-aza-2'-脱氧胞苷前期治疗的重要信息。对于复发性或难治性急性淋巴细胞白血病（儿童最常见的癌症），目前尚无积极的治疗方法。在这项提案中，我们计划为这些患者开发一种新形式的低剂量化疗药物地西他滨。早期结果表明这是积极且安全的。