Hospital, Southern Medical University, Guangzhou, CHINA, Guangz- hou, China Bcr-Abl tyrosine kinase inhibitors (TKIs) have revolutionized CML treatment. However, these agents have limited activity against blast crisis (BC) CML, and are unable to eliminate leukemia stem cells. Interestingly, b-catenin, required for the maintenance of CML stem cells is constitutively activated in BC CML, which reputedly drives BC self-renewal capacity. We investigated the therapeutic potential of combined inhibition of b-catenin and Bcr-Abl tyrosine kinase in BC CML. First we deter- mined the expression of b-catenin, its down-stream target proteins, and Bcr-Abl signaling in cells from TKI-resistant BC CML patients using CyTOF mass cytometry. This novel technology can measure the expression of multiple proteins in phenotypically-defined cell pop- ulations at the single-cell level. SPADE analysis of the CyTOF data revealed that b-catenin was overexpressed in CD34+CD38+ CML progenitor cells, especially in CD34+CD38+CD123+ cells and highest in CD34+CD38+CD123+Timhi cells which also expressed the highest levels of b-catenin target proteins including CD44 and c-Myc, and Bcr-Abl signaling molecules such as p-STAT5. We then treated cells from TKI-resistant BC CML patients with C82 (a small-molecule Wnt/b-catenin signaling inhibitor), TKIs, or both. C82 induced apoptosis in bulk and CD34+CD38-/CD34+CD38+ CML stem/ progenitor cells, also in proliferating and quiescent CD34+ CML stem/ progenitor cells, which was synergistically enhanced with TKIs. The combination treatment had minimal toxicity against normal bone marrow CD34+ cells. Next, we treated NOD/SCID/IL2gnull mice xenografted with cells harboring T315I/E255V mutations from a BC CML patient with C82 pro-drug PRI-724, nilotinib, or both. Bone marrow cells were analyzed by CyTOF at the end of treatment. PRI-724 and the combination reduced leukemia burden, and the effect was most profound in the CD34+CD38+CD123+Timhi granulocyte- macrophage stem/progenitor cell compartment, which expressed the highest b-catenin and its target proteins. The results were confirmed by conventional flow cytometry. Importantly, PRI-724 (P < 0.05) and the combination (P < 0.01) significantly prolonged the mouse survival, as compared to control or nilotinib treated groups. Collectively, our study demonstrates that combined inhibition of b-catenin and Bcr-Abl synergistically targets BC and stem/progen- itor CML cells and overcomes TKI-resistance in vitro and in vivo suggesting the combination being a novel strategy for treating pa- tients with TKI-resistant BC CML. CML-148 A Nationwide Observational Study of Ponatinib in CML Patients Outside of Clinical Trials- The Israeli Experience Irina Amiati  , 1 Adi Shacham-Abulafia, 1,2 Roy Ratzon, 2 Pia Raanani, 1,2 David Lavie, 3 Yulia Volchek, 4 Ron Ram, 2,5 Ilana Hellmann, 6 Liat Shargian, 1 Anna Gourevietch, 7 Evgeni Chubar, 8 Uri Rozovski 1,2 1 Institute of Hematology, Davidoff Cancer Centre, Beilinson Hospital, Rabin Medical Centre, Petah-Tiqva, Israel; 2 Sackler School of Medicine, Tel Aviv University, Tel-Aviv, Israel; 3 Department of Hema- tology, Hadassah-Hebrew University Medical Centre, Jerusalem, Israel; 4 Hematology Division, Chaim Sheba Medical Centre, Tel- Hashomer, Israel; 5 Bone Marrow Transplantation Unit, Sourasky Medical Center, Tel-Aviv, Israel; 6 Department of Hematology, Meir Medical Center, Kfar Saba, Israel; 7 Hematology Institute, Soroka University Medical Centre, Beer-Sheva, Israel; 8 Hematology unit, HaEmek Medical Centre, Afula, Israel Background: The oral tyrosine kinase inhibitor (TKI) ponatinib is indicated for T315I positive CML patients and for patients who cannot be prescribed any other TKI. Currently, there is little real- life information regarding the use of ponatinib outside of clinical trials. Aims: To characterize patients and assess safety and efficacy of ponatinib outside of clinical trials. Methods and Results: Between 4/2011 and 7/2015 (51 months) 24 CML patients in 7 medical centers received ponatinib. The median age was 44 years (range: 23- 79) and most were in advanced phases when ponatinib was initiated (5 in accelerated phase and 10 in blast crisis). Prior to ponatinib, patients were treated for a median of 55 months (range: 1-215) with 1 to 3 different TKIs (median: 3). Mutations were detected in 11 patients (69%) and T315I mutation in 8 of those. Based on their medical history, 48% were at-risk for vascular complications either because of prior cerebrovascular event or myocardial infarction (18%) or because of vascular risk factors (30%). Patients: were followed for a median of 6 months at time of analysis and during this time 4 patients died and 14 were still receiving ponatinib. Patients discontinued the treatment either because of major cardiovascular events (N¼3), severe pancytopenia (N¼1), planned bone-marrow transplantation (N¼1) or because they were lost to follow-up (N¼1). 17 patients were available for response assessment at the time of analysis and the overall response rate was 77%. 5 of the 6 patients in chronic phase achieved either complete or major molecular response. 8 of 11 patients who were in accelerated phase or at blast crisis achieved either hematological (5/ 11) or molecular response (3/11). Physicians mentioned severe weakness, myalgia and reduced blood counts as major concerns. Conclusions: In the real-life settings, ponatinib is generally used as last resort. Only 1/3 of patients tolerated the recommended dose. Yet, response rate was relatively high, suggesting that a daily dose of 30mg might be appropriate. The response rate and overall contri- bution to quality of life in patients who already experienced failure of other TKIs support the use of ponatinib in this setting. CML-158 Treatment-Free Remission (TFR) Following Frontline or Second-Line Nilotinib in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP): ENESTfreedom and ENESTop François-Xavier Mahon, 1,2 Andreas Hochhaus, 3 Timothy Hughes, 4 Sikander Ailawadhi, 5 Jeffrey Lipton, 6 Johannes Wolff, 7 Giuseppe Saglio 8 Abstracts S64 - Clinical Lymphoma, Myeloma & Leukemia September 2016