Background: Outcomes in adult Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph⁺ALL) remain poor with a 5 year overall survival of less than 40%. Addition of the targeted BCR-ABL inhibitors (TKI) to standard cytotoxic therapy has greatly improved upfront treatment, yet relapse remains common with a median survival of just 4.5 months. Therefore identification of targeted agents that could enhance the activity of TKIs is urgently needed. ABT 199 is a BCL-2 inhibitor which has shown pre-clinical activity against a variety of B cell malignancies. Here we evaluate the combination of ABT199 across a panel of TKIs to explore potential mechanisms of synergy in hopes to better define the optimal combination for future clinical studies. Methods: Drug efficacy in vitro was determined using the Ph⁺ALL cell line SupB15. Cells were incubated with varying concentrations of dasatinib, imatinib, nilotinib or ponatinib in combination with ABT199 for 72 hours. Cell viability was assessed using a colorimetric MTS assay, and cell apoptosis was assessed with annexin V staining. Combination effects were calculated using Calculsyn software. Standard immunoblots were used to assess inhibition of downstream pathways. Results: The combination index (CI) values for each of the TKIs with ABT199 ranged between 0.13 – 1.4 for Imatinib, 0.4 – 1.05 for Nilotinib, 0.06 – 0.33 for Ponatinib, and 0.07 – 0.64 for Dasatinib, where CI < 1 predicted synergy. As a single agent, ABT199 induced the highest degree of apoptosis, enhanced preferentially by dasatinib and ponatinib. Evaluation of key phosphorylated kinases showed that all four TKIs effectively inhibited the downstream ABL1 target pCRKL. In addition, both dasatinib and ponatinib inhibited pLYN while dasatinib also inhibited pBTK. Conclusions: Combination of BCL-2 and BCR-ABL targeting in Ph⁺ALL is synergistic in vitro. The enhanced synergy seen with dasatinib and ponatinib may be due to the ability of these agents to target additional pathways active in leukemic cells. The addition of ABT-199 as part of TKI therapy for adult Ph⁺ALL warrants further clinical investigation, particularly in patients with relapsed or refractory disease.