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Venetoclax, a BCL2 inhibitor, has a promising single-agent activity in mantle cell lymphoma (MCL), acute lymphoblastic leukemia (ALL), and large B-cell lymphomas (LBCL), but remissions were generally short, which calls for rational drug combinations. Using a panel of 21 lymphoma and leukemia cell lines and 28 primary samples we demonstrated strong synergy between venetoclax and A1155463, a BCL-XL inhibitor. Immunoprecipitation experiments, and studies on clones with knockout of expression, or transgenic expression of BCL-XL confirmed its key role in mediating inherent and acquired venetoclax resistance. Of note, the venetoclax and A1155463 combination was synthetically lethal even in the cell lines with lack of expression of the pro-apoptotic BCL2L11/BIM, and in the derived clones with genetic knockout of BCL2L11/BIM. This is clinically important because BCL2L11/BIM deletion, downregulation, or sequestration results in venetoclax resistance. Immunoprecipitation experiments further suggested that the pro-apoptotic effector BAX belongs to principal mediators of the venetoclax and A1155463 mode of action in the BIM-deficient cells. Lastly, the efficacy of the new pro-apoptotic combination was confirmed in vivo on a panel of 9 PDX models including MCL (n = 3), B-ALL (n = 2), T-ALL (n = 1), and DLBCL (n = 3). Because continuous inhibition of BCL-XL causes thrombocytopenia, we proposed and tested an interrupted 4 days ON / 3 days OFF treatment regimen, which retained the desired anti-tumor synergy with manageable platelet toxicity. The proposed VEN and A1155463 combination represents an innovative chemotherapy-free regimen with significant preclinical activity across diverse BCL2-positive hematologic malignancies irrespective of the BCL1L11/BIM status.