Clinical Trials in AML

如果干细胞移植不可行，复发AML的M.D.Anderson患者通常会接受研究药物作为第一个“挽救疗法”，特别是如果他们的初始缓解持续不到一年的话。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。在这个计划项目中，我们将研究已经提出“目标”的疗法，使我们能够检查临床反应和假定目标(特定目标1)状态之间的关系。患者将被随机分配， 我们将评估他们的反应是对目标的预测，并研究使用生物标记物将患者分配到特定的治疗方法。一个与特定目标1混淆的困难是复发AML中CR的罕见。这种罕见性促使了对反应的新定义(例如，CRp)，这些定义比CR的标准要求更低。未经治疗的患者的初步数据表明，尽管CR对于治愈是必不可少的，但获得CRP的患者比既没有达到CRP也没有达到CRP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，以及将在这里研究的患者的低CRp率，促使了一项计划，只要患者没有临床并发症或外周血原始细胞计数上升，就会继续对他们进行初步治疗。这一方法将使我们能够比较各种预期定义的反应对存活率的影响(具体目标2)。我们将研究的两种药物(BH3结合域抑制剂GX15-070MS和BAY43-9006)将在不化疗的情况下给予，我们将称之为“非细胞毒性”疗法。另外两种药物[XIAP反义寡核苷酸AEG35156和AMD3100，一种CXCR4的抑制剂，从而抑制了原始细胞与骨髓基质的相互作用]，虽然本身也没有细胞毒性，但将与伊达比星+阿糖胞苷(IA)结合，因此这些组合将被称为“细胞毒性”。我们将比较以下患者的生存率：(A)仅在两种非细胞毒性药物中的一种试验失败后才给予两种细胞毒性组合之一的患者，(B)在先前研究中使用替代方法的患者和(C)单独使用IA的患者。这种方法将使我们能够检验这样的假设，即给予一些复发的AML患者非细胞毒治疗作为复发的初始治疗是合适的(具体目标3)。 虽然这种做法在复发和未治疗的AML中越来越普遍，但它对生存的影响仍不清楚。证明，至少在一个案例中，这种策略的明显吸引力不会被生存时间的减少所抵消，这可能会让患者放心。

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.