By using a synergism-focused, comprehensive drug combination screening approach in co-cultured patient and patient-derived xenograft ALL, we provide evidence for the potential therapeutic benefit of the combination of the MDM2 inhibitor idasanutlin and the BCL-xL/BCL-2 inhibitor navitoclax across a range of ALL subtypes, including high-risk and relapsed disease. This evidence concerns the gene BCL2L1 and acute lymphoblastic leukemia.