Maintenance therapy with decitabine for acute myeloid leukemia in first remission

描述（由申请人提供）：通过对细胞生长和分化至关重要的基因的启动子甲基化进行的转录沉默在髓性白血病发生中起关键作用。许多基因在急性髓细胞白血病（AML）中经常甲基化，包括p15、雌激素受体（ER）和降钙素等。[1-治疗AML和其他骨髓疾病的有前景的药物是DNA甲基转移酶抑制剂（DNMT）抑制剂地西他滨，5-氮杂-2 '-脱氧胞苷。[5-10]地西他滨在低剂量（和重复周期）给药时对AML和骨髓增生异常综合征（MDS）具有显著的活性，这有利于脱甲基活性，而不是细胞毒性。我们已经发表了地西他滨在AML中的I期研究结果[11]，该研究基于表观遗传学沉默基因的再表达确定了地西他滨的最佳日剂量为20 mg/m2/天。在第1周期治疗早期检测到的ER再表达与随后达到缓解（CR/CRi）相关。2008年6月，我们完成了地西他滨单药治疗年龄>60岁、未经治疗且不适合强化治疗的AML患者的II期研究的入组（N=33）。诱导期给予地西他滨20 mg/m2/d，10 d/周期，缓解后治疗5 d/周期。迄今为止，本研究中根据IWG标准[12]的CR率为42%（14/33）; CR+CRi率为58%（19/33）。该方法相对于标准细胞毒性治疗具有降低的毒性，并且缓解似乎持久（迄今为止2-13个月）。即使是年老体弱的AML患者也能很好地耐受维持治疗方案。基于这些有前景的临床和药效学结果，并在癌症和白血病组B（CALGB）的支持下，我们将这种活性药物纳入新诊断AML的年轻患者（年龄<60岁）的综合一线治疗计划。我们设计了一项为期一年的地西他滨维持治疗研究，用于在完成既定诱导和强化方案后仍处于首次缓解状态的AML患者（CALGB 10503）。研究的具体目标如下：1）确定给予<60岁的新诊断的患有糖尿病的患者一年维持地西他滨的一年无病生存（DFS）、可行性和毒性，在既定诱导和强化方案后达到并维持首次缓解的未经治疗的AML（与先前在CALGB中用相同方案治疗的患者的基准历史对照相比）和2）确定预后价值（分别在诊断和缓解时）检测AML的甲基化特异性标志物，如总体DNA甲基化和靶基因特异性异常启动子高甲基化，以及地西他滨维持治疗对这些和其他微小残留病（MRD）标志物调节的影响。公共卫生相关性：我们建议增加低剂量，门诊地西他滨治疗的年轻患者谁仍然在缓解后，密集化疗的急性髓细胞白血病。人们希望地西他滨能清除化疗结束后可能残留的白血病残留物（称为微小残留病），从而有助于预防AML复发。该项目成功的重要因素是开发新的检测方法来预测AML的结果，以及检测缓解患者微小残留疾病的新方法。我们希望更准确地预测治疗反应并评估复发风险。

DESCRIPTION (provided by applicant): Transcriptional silencing via promoter methylation of genes critically important for cell growth and differentiation plays a key role in myeloid leukemogenesis. Many genes are frequently methylated in acute myeloid leukemia (AML) including p15, estrogen receptor (ER), and calcitonin, among others.[1- 4] A promising drug in the treatment of AML and other myeloid disorders is the DNA methyltransferase inhibitor (DNMT) inhibitor decitabine, 5-aza-2'-deoxycytidine.[5-10] Decitabine has significant activity in AML and myelodysplastic syndrome (MDS) when given at low doses (and repetitive cycles) which favor demethylating activity, rather than cytotoxicity. We have published results of a phase I study of decitabine in AML[11] which determined an optimal daily dose of decitabine at 20mg/m2/day based on re-expression of epigenetically silenced genes. Re-expression of ER, detected early in cycle 1 of therapy, correlated with subsequent achievement of response (CR/CRi). In June 2008, we completed enrollment (N=33) of a phase II study of single agent decitabine in previously untreated AML patients age >60 years who were not candidates for intensive therapy. Decitabine was given at 20mg/m2/day for 10 days/cycle during induction and for 5 days/cycle during post-remission therapy. To date, the CR rate by IWG criteria[12] on this study is 42% (14/33); the CR+CRi rate is 58% (19/33). The approach has reduced toxicity relative to standard cytotoxic therapy and remissions appear durable (2-13 months to date). The maintenance schedule is well tolerated even by older and infirm AML patients. On the basis of these promising clinical and pharmacodynamic results, and with the support of the Cancer and Leukemia Group B (CALGB), we have moved this active agent into a comprehensive first line treatment plan for younger patients (age <60) with newly diagnosed AML. We designed a study of maintenance therapy with decitabine for one year, for AML patients who remain in first remission after completing an established induction and intensification regimen (CALGB 10503). The specific aims of the study are the following: 1) To determine 1 year disease free survival (DFS), feasibility, and toxicities of one year of maintenance decitabine given to patients <60 years with newly diagnosed, untreated AML who achieve and maintain first remission following an established induction and intensification regimen (compared to a benchmark historical control of patients treated with the same regimens in the CALGB previously) and 2) To determine the prognostic value (at diagnosis and remission, respectively) of methylation-specific markers of AML such as global DNA methylation and target gene- specific aberrant promoter hypermethylation, and the impact of decitabine maintenance therapy on modulation of these and other markers of minimal residual disease (MRD). PUBLIC HEALTH RELEVANCE: We propose adding low dose, outpatient decitabine treatment for younger patients who remain in remission after intensive chemotherapy for AML. It is hoped that decitabine will wipe out the remnants of leukemia that may be leftover after completion of chemotherapy (called minimal residual disease) and thus help to prevent relapse of AML. Important to the success of the project are the development of new tests to predict outcomes in AML and new methods to detect minimal residual disease in patients who are in remission. We hope to more accurately predict response to treatment and assess risk of relapse.