Rational combinations of targeted agents in AML

Despite modest improvements in survival over the last several decades the treatment of AML continues to present a formidable challenge Most patients are elderly and these individuals as well as those with secondary therapy-related or relapsed/refractory AML are particularly difficult to treat owing to both aggressive disease biology and the high toxicity of current chemotherapeutic regimens It has become increasingly apparent in recent years that coordinated interruption of cooperative survival signaling pathways in malignant cells is necessary for ptimal therapeutic results The modest efficacy of monotherapy with both cytotoxic and targeted agents in AML testifies to this As the complex biology of AML continues to be elucidated many “synthetic lethal” strategies involving rational combinations of targeted agents have been developed Unfortunately relatively few of these have been tested clinically although there is growing interest in this area In this article the preclinical and where available clinical data on some of the most promising rational combinations of targeted agents in AML are summarized While new molecules should continue to be combined with conventional genotoxic drugs of proven efficacy there is perhaps a need torethink traditional philosophies of clinical trial evelopment and regulatory approval with a focus on mechanism-based synergistic strategies