Evaluating Therapeutic Strategies in MDS

在60岁未经治疗的高危MDS患者中使用高强度AML类化疗(HI)(国际 预后评分系统中2级或更高级别)尚未提高相对于支持性护理的存活率， 导致35%的治疗相关死亡率(TRM)和60%的治疗“抵抗率”。新高 [例如，氯法拉滨+阿糖胞苷]可能会减少耐药性，从而提高老年患者的存活率。另一种方法 强调在这类患者中使用低强度的“靶向”治疗(LI)。作为单一代理人，LIS可能会产生更低的 短期TRM比率高于HI，但到目前为止，CR率也较低。这一点值得注意，因为至少 对于HI，只有获得CR的患者才能获得潜在的长期生存优势。因此，目前还不清楚 未经治疗的患有高危MDS的老年患者应在失败时首先接受HI治疗，然后接受LI(两者：疗程策略HI， LI)，或者，或者，只有在LI不及格后才获得HI(两个课程策略LI，HI)。我们的第一个具体目标是比较 这些策略适用于此类患者。我们将采用我们最近发布的统计设计泰国不仅允许 各处理的比较(H1=氯法拉滨+Ara-C，L11=PKC412，LI2=R115777，LI3=地西他滨)， 用于初始治疗或抢救治疗，但也允许选择最佳策略，L11、LI2或LI3，然后是 HI故障，或故障时的HI，然后是L11、LI 2或LI 3。选择基于响应和 死亡允许在这些结果之间进行“权衡”，这样一来，几个潜在的应答率 另一方面，手和死亡被认为是平等的。为了帮助评估MDS中的LIS，NCI工作组已经 最近公布的反应标准。其中包括几类“轻微反应”(MR，小于CR)。使用 嗨，我们已经证明了CR延长生存的程度比先生要大得多；因此，第二个特异点 该项目的目的是评估LL诱导的MR对于生存和“生活质量”的重要性。的“结果” 任何治疗都是不同患者的结果的平均值，其中一些人的治疗可能是有帮助的，也可能是有害的。 而不是一个假想的“普通”病人。我们以前试图识别这样的子组时，使用了统计学方法 评估治疗和临床预后因素之间相互作用的模型，例如细胞遗传学。相比之下，LIS 这里使用的是针对在实验室中可以量化的目标。因此，我们的第三个具体目标是识别患者 通过检验临床结果和治疗前状态之间的相关性来对特定LI作出反应的亚组 目标或李氏调节目标的能力。这将与项目2-4和核心A-C合作完成。

Use of high intensity, AML-type chemotherapy (HI) in patients age > 60 with untreated high-risk MDS (International Prognostic Scoring System categories intermediate-2 or high) has yet to improve survival relative to supportive care, consequent to both a 35% rate of treatment -related mortality (TRM) and a 60% rate of "resistance" to therapy. New HI {e.g. clofarabine + ara-C) may decrease resistance, thereby increasing survival in older patients. Another approach emphasizes use of lower intensity, "targeted", therapies (LI) in such patients. As single agents, LIs likely produce lower short-term TRM rates than HI, but, to date, have also produced lower CR rates. This is noteworthy because, at least with HI, only patients who achieve CR achieve a potential long-term survival advantage. Thus, it is unclear whether untreated older patients with high-risk MDS should receive HI first followed at failure by LI (the two:course strategy HI, LI), or, alternatively, receive HI only after failing LI (the two-course strategy LI, HI). Our first specific aim is to compare these strategies in such patients. We will employ our recently published statistical design thai not only permits comparison of the individual treatments (Hl= clofarabine + ara-C, L11 = PKC412, LI 2= R115777, LI 3= decitabine), used either as initial or as salvage therapy, but also allows selection of the best strategy, L11, LI 2, or LI 3, followed at failure by HI, or HI followed at failure by L11, LI 2, or LI 3. Selection is based on probabilities of both response and death allowing for "trade-offs" between these outcomes such that that several potential rates of response, on the one hand, and death, on the other, are considered equal. To aid in evaluation of LIs in MDS, an NCI Working Group has recently published criteria for response. These include several categories of "minor response"(MR, less than CR). With HI, we have demonstrated that CR prolongs survival to a much greater extent than MR. Therefore; the second specific aim of the Project is to evaluate the significance of Ll-induced MR, for both survival and "quality of life". The "results" of any therapy are an average of results from different patients, some of whom the therapy may have helped or harmed more than a hypothetical" average" patient. Our previous attempts at identifying such subgroups have used statistical models to assess interactions between treatment and clinical prognostic factors, e.g. cytogenetics. In contrast, the LIs used here are directed at targets that are quantifiable in the laboratory. Thus our third specific aim is to identify patient subgroups responsive to a particular LI by testing for correlations between clinical outcome and the pre-treatment status of the target or the Li's ability to modulate the target. This will be done in collaboration with Projects 2-4 and Cores A-C.