Maintenance therapy with decitabine for acute myeloid leukemia in first remission

描述(由申请人提供)：通过启动子甲基化对细胞生长和分化至关重要的基因转录沉默在髓系白血病的发生中起着关键作用。许多基因在急性髓系白血病(AML)中经常发生甲基化，包括p15、雌激素受体(ER)和降钙素等。[1-4]治疗AML和其他髓系疾病的一个有前景的药物是DNA甲基转移酶(DNMT)抑制剂地西他滨，5-氮-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)有显著的活性，有利于去甲基化活性，而不是细胞毒性。我们已经公布了急性髓细胞白血病中地西他滨的I期研究结果[11]，该研究基于表观遗传沉默基因的重新表达，确定了20 mg/m2/天的最佳地西他滨每日剂量。在治疗第1周期早期检测到的ER的重新表达与随后的应答(CR/CRI)相关。2008年6月，我们完成了单药地西他滨II期研究的登记(N=33)，研究对象为年龄60岁、未接受强化治疗的未经治疗的AML患者。地西他滨20 mg/m2/d，诱导期10天/周期，缓解期5天/周期。到目前为止，根据IWG标准[12]本研究的CR率为42%(14/33)；CR+CRI率为58%(19/33)。与标准的细胞毒治疗相比，该方法的毒性降低，缓解似乎持久(到目前为止2-13个月)。即使是年长和虚弱的急性髓细胞白血病患者也能很好地耐受维护计划。在这些有希望的临床和药效学结果的基础上，在癌症和白血病B组(CALGB)的支持下，我们将这种活性物质纳入了新诊断的年轻AML患者(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，用于完成既定的诱导和强化方案后仍处于首次缓解状态的急性髓细胞白血病患者(CALGB 10503)。本研究的具体目的如下：1)确定患者服用地西他滨一年的无病生存期(DFS)、可行性和毒性；本研究的目的是：1)研究新诊断、未经治疗的急性髓细胞白血病患者60年来的进展情况，这些患者经过既定的诱导和强化治疗方案后获得并维持首次缓解(相比之下，CALGB中采用相同方案治疗的患者的基准历史对照)；2)确定AML特定甲基化标志物的预后价值(分别在诊断和缓解时)，例如全局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标志物(MRD)调节的影响。公共卫生相关性：我们建议对急性髓细胞白血病强化化疗后仍处于缓解状态的年轻患者增加低剂量的门诊地西他滨治疗。人们希望地西他滨能清除化疗完成后可能残留的白血病残留物(称为微小残留病)，从而有助于防止AML复发。对该项目的成功至关重要的是开发新的测试来预测急性髓细胞白血病的结果，以及新的方法来检测缓解期患者的微小残留病。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.