Venetoclax, Ponatinib, and Dexamethasone in Participants With Philadelphia Chromosome or BCR-ABL Positive Relapsed or Refractory Acute Lymphoblastic Leukemia or Chronic Myelogenous Leukemia

PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of venetoclax, ponatinib, and dexamethasone in patients with relapsed/refractory Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL) or lymphoid blastic phase (BP)-chronic myelogenous leukemia (CML). (Phase I) II. To determine the efficacy of the regimen, as defined by the rate of complete remission (CR) or CR with incomplete count recovery (CRi). (Phase II) SECONDARY OBJECTIVES: I. To determine efficacy outcomes, including rate of minimal residual disease negativity by polymerase chain reaction (PCR) for BCR-ABL1 transcripts, median relapse-free survival (RFS), and median overall survival (OS). II. To determine the proportion of patients proceeding to allogeneic stem cell transplant (ASCT). III. To preliminarily determine the safety of the combination regimen. EXPLORATORY OBJECTIVES: I. To evaluate the effect of single-agent ponatinib on apoptotic proteins and Bcl-2 dependency. II. To correlate apoptotic protein expression and Bcl-2 dependency on response and resistance to the combination regimen. III. To assess impact of baseline genomics on outcomes with the combination regimen. OUTLINE: This is a phase I, dose-escalation study of venetoclax followed by a phase II study. INDUCTION (COURSE 1): Participants who have not received ponatinib within 2 weeks of the anticipated start date receive ponatinib orally (PO) daily on days 1-35, venetoclax PO daily on days 8-35, and dexamethasone PO or intravenously (IV) over 15 minutes on days 8-11. Participants who have received ponatinib within 2 weeks of the anticipated start date receive ponatinib PO and venetoclax PO daily on days 1-28 and dexamethasone PO or IV over 15 minutes on days 1-4. Participants with CD20 expression receive rituximab IV over 2-6 hours on days 14 and 21 at the discretion of the treating physician after the maximum dose of venetoclax has been reached. CONSOLIDATION (COURSES 2-4): Participants receive ponatinib PO and venetoclax PO daily on days 1-28 and dexamethasone PO or IV over 15 minutes on days 1-4. Participants with CD20 expression receive rituximab IV over 2-6 hours for up to 2 doses each course at the discretion of the treating physician after the maximum dose of venetoclax has been reached. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE (COURSES 5+): Participants receive ponatinib PO and venetoclax PO daily on days 1-28 and dexamethasone PO or IV over 15 minutes on days 1-4. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Participants achieving remission undergo ASCT at the discretion of the treating physician. After completion of study treatment, participants are followed up at 30 days.