An alvocidib-containing regimen is highly effective in AML patients through a mechanism dependent on MCL1 expression and function.

7062 Background: Through multiple Phase I/II studies, alvocidib (flavopiridol) has proven to be highly effective in both frontline and relapsed/refractory AML when sequentially administered before ara-C and mitoxantrone (FLAM). In frontline patients, FLAM resulted in a complete remission (CR) rate of 70% versus 46% CR with ara-C and daunorubicin (7+3). Among patients with secondary (s)AML, FLAM produced 60% CR versus 35% CR with 7+3. The clinical activity of alvocidib in AML strongly correlates with inhibition of cyclin-dependent kinase-9 (CDK9) and disruption of super enhancer mediated transcription. The myeloid leukemia cell 1 (MCL1) gene is critically regulated by CDK9 activity under SE-mediated transcriptional control. Methods: Studies with AML cell lines were conducted to model the sequential treatment of the FLAM regimen. MCL1 expression and apoptosis were monitored in these nonclinical experiments. To further substantiate this mechanism clinically, mitochondrial profiling was conducted on 63 archiv...