Clinical Trials in AML

如果干细胞移植不可行，M.D.Anderson复发的AML患者通常会接受 将研究药物作为第一种“挽救疗法”，特别是如果他们最初的缓解持续时间不到一次 年。虽然有新的药物可用，但我们不知道患者的急性髓细胞白血病会有什么反应。在这个节目中 项目中，我们将研究已经提出的治疗方法，使我们能够检查它们之间的关系 临床反应和假定目标的状态(特定目标1)之间的关系。患者将被随机分配， 我们将评估他们的反应对目标的预测性，并研究生物学的使用 标记将患者分配到特定的治疗方案。具体目标1的一个令人困惑的困难是 复发AML的CR。这种罕见的情况促使对反应的新定义(例如，CRp)，这些定义较少 对CR的标准要求更高。未经治疗的患者的初步数据表明，虽然CR是必不可少的 在治愈方面，达到CR p的患者比既没有达到CR p也没有达到CR p的患者存活时间更长。 考虑到实现这些反应所需的时间。这些数据，以及CRp在 在这里进行研究的患者，已经促使计划继续对患者进行初步治疗，只要他们已经 既没有临床并发症，也没有外周血细胞计数的上升。此方法将允许我们比较 各种前瞻性反应对生存的影响(特定目标2)。我们将派出两名特工 研究(GX15-070MS)，一种BH3结合结构域的抑制物，Bc l-2家族成员，以及 抑制剂BAY43-9006)将在不进行化疗的情况下给予；我们称其为“非细胞毒性” 治疗。另外两种药物[XIAP反义寡核苷酸AEG35156和抑制剂AMD3100 CXCR4和因此原始细胞-骨髓基质相互作用)，虽然它们本身也不具有细胞毒性，但将是 与伊达比星+阿糖胞苷(IA)联合使用；这些组合因此被称为“细胞毒性”。我们会比较一下 存活率：(A)仅在其中一种试验失败后才给予两种细胞毒性组合中的一种的患者 两种非细胞毒性药物，(B)使用替代方法的患者和(C)给予 在以前的研究中，仅有IA。这种方法将允许我们测试这样的假设，即它适合于 部分复发AML患者以非细胞毒治疗作为初治复发(特定目标3)。 虽然这种做法在复发和未经治疗的AML中越来越普遍，但它对生存的影响 仍然不为人知。证明，至少在一种情况下，这一战略的明显吸引力不会被抵消 通过减少存活时间，可能会让患者放心。

If stem cell transplant is not feasible, M.D. Anderson patients with relapsed AML typically receive investigational agents as first "salvage therapy," particularly if their initial remission has lasted less than one year. Although new agents are available, we do not know how a patient's AML will respond. In this program project, we will study therapies for which a "target" has been proposed, enabling us to examine relationships between clinical response and the status of the putative target (Specific Aim 1). Patients will be randomized, and we will assess their responses as being predictive of the target as well as study the use of biologic markers to assign patients to specific therapies. A confounding difficulty with Specific Aim 1 is the rarity of CR in relapsed AML. This rarity has motivated new definitions of response (e.g. CR p), which are less demanding than the criteria for CR. Preliminary data in untreated patients suggest that, while CR is essential for cure, patients who achieve CR p live longer than patients who achieve neither CR nor CR p after accounting for the time needed to achieve these responses. These data, and the low rate of CR p in the patients to be studied here, have prompted a plan to continue initial therapy in patients as long as they have neither clinical complications nor a rising peripheral blast count. This approach will allow us to compare the effect of various prospectively-defined responses on survival (Specific Aim 2). Two of the agents we will investigate (GX15-070MS, an inhibitor of the BH3 binding domain of Bcl-2 family members, and the kinase inhibitior BAY43-9006) will be given without chemotherapy; we will refer to these as "non-cytotoxic" therapies. The other two agents [the XIAP antisense oligonucleotide AEG35156 and AMD3100, an inhibitor of CXCR4 and thus of the blast cell-marrow stroma interaction), while themselves also non-cytotoxic, will be combined with idarubicin + ara-C (IA); these combinations will thus be called "cytotoxic." We will compare survival in: (a) patients given one of the two cytotoxic combinations only after an unsuccessful trial of one of the two non- cytotoxic agents, (b) patients in whom the alternate approachwas used and (c) patients given IA alone in previous studies. This approach will allow us to test the hypothesis that it appropriate to give some patients with relapsed AML non-cytotoxic therapy as initial treatment for relapse (Specific Aim 3). While such practice is increasingly widespread both in relapsed and untreated AML, its effect on survival remains unknown. Demonstration that, in at least one case, the obvious appeal of this strategy is not offset by a decrease in survival time would presumably be reassuring to patients.