Combined venetoclax and alvocidib in acute myeloid leukemia

// James Bogenberger 1, * , Clifford Whatcott 2, * , Nanna Hansen 1 , Devora Delman 1 , Chang-Xin Shi 1 , Wontak Kim 2 , Hillary Haws 2 , Katherine Soh 2 , Ye Sol Lee 2 , Peter Peterson 2 , Adam Siddiqui-Jain 2 , Steven Weitman 2 , Keith Stewart 1 , David Bearss 2 , Ruben Mesa 1 , Steven Warner 2 and Raoul Tibes 1, 3 1 Mayo Clinic, Scottsdale, AZ, USA 2 Tolero Pharmaceuticals, Lehi, UT, USA 3 NYU School of Medicine, New York, NY, USA * These authors contributed equally to this work Correspondence to: Raoul Tibes, email: raoul.tibes@nyumc.org James Bogenberger, email: bogenberger.james@mayo.edu Keywords: acute myeloid leukemia (AML); alvocidib/flavopiridol; venetoclax/ABT-199; BCL-2 Received: July 22, 2017      Accepted: October 10, 2017      Published: November 03, 2017 ABSTRACT More effective treatment options for elderly acute myeloid leukemia (AML) patients are needed as only 25–50% of patients respond to standard-of-care therapies, response duration is typically short, and disease progression is inevitable even with some novel therapies and ongoing clinical trials. Anti-apoptotic BCL-2 family inhibitors, such as venetoclax, are promising therapies for AML. Nonetheless, resistance is emerging. We demonstrate that venetoclax combined with cyclin-dependent kinase (CDK) inhibitor alvocidib is potently synergistic in venetoclax-sensitive and -resistant AML models in vitro , ex vivo and in vivo . Alvocidib decreased MCL-1, and/or increased pro-apoptotic proteins such as BIM or NOXA, often synergistically with venetoclax. Over-expression of BCL-XL diminished synergy, while knock-down of BIM almost entirely abrogated synergy, demonstrating that the synergistic interaction between alvocidib and venetoclax is primarily dependent on intrinsic apoptosis. CDK9 inhibition predominantly mediated venetoclax sensitization, while CDK4/6 inhibition with palbociclib did not potentiate venetoclax activity. Combined, venetoclax and alvocidib modulate the balance of BCL-2 family proteins through complementary, yet variable mechanisms favoring apoptosis, highlighting this combination as a promising therapy for AML or high-risk MDS with the capacity to overcome intrinsic apoptosis mechanisms of resistance. These results support clinical testing of combined venetoclax and alvocidib for the treatment of AML and advanced MDS.