If stem cell transplant is not feasible, M.D. Anderson patients with relapsed AML typically receiveinvestigational agents as first 'salvage therapy,' particularly if their initial remission has lasted less than oneyear. Although new agents are available, we do not know how a patient's AML will respond. In this programproject, we will study therapies for which a 'target' has been proposed, enabling us to examine relationshipsbetween 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 biologicmarkers to assign patients to specific therapies. A confounding difficulty with Specific Aim 1 is the rarity ofCR in relapsed AML. This rarity has motivated new definitions of response (e.g. CR p), which are lessdemanding than the criteria for CR. Preliminary data in untreated patients suggest that, while CR is essentialfor cure, patients who achieve CR p live longer than patients who achieve neither CR nor CR p afteraccounting for the time needed to achieve these responses. These data, and the low rate of CR p in thepatients to be studied here, have prompted a plan to continue initial therapy in patients as long as they haveneither clinical complications nor a rising peripheral blast count. This approach will allow us to compare theeffect of various prospectively-defined responses on survival (Specific Aim 2). Two of the agents we willinvestigate (GX15-070MS, an inhibitor of the BH3 binding domain of Bcl-2 family members, and the kinaseinhibitior 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 inhibitorof CXCR4 and thus of the blast cell-marrow stroma interaction), while themselves also non-cytotoxic, will becombined with idarubicin + ara-C (IA); these combinations will thus be called 'cytotoxic.' We will comparesurvival in: (a) patients given one of the two cytotoxic combinations only after an unsuccessful trial of one ofthe two non- cytotoxic agents, (b) patients in whom the alternate approachwas used and (c) patients givenIA alone in previous studies. This approach will allow us to test the hypothesis that it appropriate to givesome 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 survivalremains unknown. Demonstration that, in at least one case, the obvious appeal of this strategy is not offsetby a decrease in survival time would presumably be reassuring to patients.
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