Background: Ph+ AML and CML MBP have poor outcomes. VEN synergizes with BCR-ABL TKIs in vitro and may eradicate Ph+ leukemic stem cells. However, the clinical activity of VEN+TKI regimens is unknown. Methods: We conducted a retrospective study on patients (pts) with Ph+ AML and CML MBP who received regimens with VEN+TKI at our institution. Results: We identified 6 pts with relapsed/refractory (R/R) Ph+ AML and 7 with CML MBP (2 transformed from chronic phase, 5 R/R). 10 pts (77%) were refractory to prior therapy and 3 (23%) had relapsed disease. Pt characteristics are shown in the Table. 5 AML pts (83%) had complex cytogenetics. Pts with CML MBP had received a median of 2 prior TKIs (range 1-3). 7 pts received decitabine-based combinations and 6 pts received intensive chemotherapy in combination with VEN+TKI. TKIs included ponatinib (n=7), dasatinib (n=4), bosutinib (n=1) and nilotinib (n=1). Among 12 evaluable pts, the overall response rate (CR + CRi + MLFS) was 50% (Table). In addition, 1 pt with AML developed aplastic marrow, underwent stem cell transplantation, and is still alive. Pts with CR/CRi vs. those without CR/CRi had higher median number of Ph+ metaphases (100% vs. 32%, p<0.01) and higher baseline BCR-ABL1 PCR (100% vs. 0.5% p=0.01). The only AML pt who achieved CR/CRi had 100% Ph+ metaphases. After a median follow-up of 10.9 months (mo), 5 pts are alive (1 AML, 4 CML MBP). The median overall survival for pts with AML and CML MBP were 2 mo and not reached, respectively. The median relapse-free survival was 8.2 mo. Conclusions: VEN+TKI combinations show encouraging activity in pre-treated, advanced Ph+ leukemias, particularly CML MBP. Clonal burden of Ph+ cells correlated with response. Prospective trials are needed to evaluate VEN+TKI combinations in Ph+ leukemias. Pt characteristics and outcomes (n/N [%] / median [range]).