Venetoclax, Dasatinib, Prednisone, Rituximab and Blinatumomab for the Treatment of Newly Diagnosed or Relapsed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia or Mixed Phenotype Acute Leukemia

PRIMARY OBJECTIVES: I. Determine amaximum tolerated dose (MTD) and a subsequently recommended phase II dose (RP2D) of venetoclax in combination with dasatinib. II. Evaluate the safety of venetoclax in combination with dasatinib by assessing the frequency, type, and severity of adverse events. SECONDARY OBJECTIVES: I. Assess preliminary response to treatment based on minimal residual disease (MRD) negativity after venetoclax plus dasatinib induction and venetoclax, dasatinib, and blinatumomab consolidation. II. Estimate progression-free and overall survival. EXPLORATORY OBJECTIVES: I. Evaluate the distribution of BCR-ABL fusion sub-types. II. Assess changes in BCL-family dependence. III. Presence of co-occurring leukemia-specific mutations. IV. Assess ex vivo sensitivity to venetoclax and dasatinib using inhibitor plates and colorimetric cell viability (MTS) assay. V. Evaluate differences between two methods of detecting MRD for B ALL/mixed phenotype acute leukemia (MPAL): Real-time quantitative polymerase chain reaction (RQ PCR) analysis of BCR-ABL and next generation (NextGen) sequencing. VI. Assess response after consolidation with blinatumomab, venetoclax, and dasatinib. OUTLINE: This is dose-escalation study of venetoclax. INDUCTION PHASE CYCLE 1: Patients receive prednisone orally (PO) once daily (QD) on days -6 to 21 and rapid taper from days 22-28, dasatinib PO QD days 1-28, venetoclax PO QD days 3-28 or days 3-21, rituximab (for CD20+ patients) intravenously (IV) on days 8 and 15, and methotrexate intrathecally (IT) once during week 1 and once during week 3 as prophylaxis or once a week (QW) as therapy in the absence of disease progression or unacceptable toxicity. INDUCTION PHASE CYCLES 2-3: Patients receive dasatinib PO QD days 1-28, venetoclax PO QD on days 1-28 or 1-21, rituximab (for CD20+ patients) IV on days 1 and 15, and methotrexate IT on days 1 and 15. Treatment repeat every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients with clinical benefit may continue to receive treatment for up to 12 months per the discretion of the physician. CONSOLIDATION CYCLES 4-7 (ALL PATIENTS ONLY): Patients receive blinatumomab IV on days 1-28. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients continue to receive dasatinib PO QD and venetoclax PO QD as taken in cycles 1-3 and, if clinically indicated, methotrexate IT on day 1. Cycles repeat every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow biopsy and aspiration, lumbar puncture, and blood sample collection throughout the study MAINTENANCE THERAPY CYCLES 8+: Patients receive dasatinib PO QD and venetoclax PO QD as in consolidation cycles and, if clinically indicated, methotrexate IT on day 1 of cycles 8 and 9. Cycles repeat every 28 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 4 weeks and then every 12 weeks for up to 1 year. Additionally, patients undergo bone marrow biopsy and aspiration, lumbar puncture, and blood sample collection throughout the study. After completion of study treatment, patients are followed up at 4 weeks and then for up to 1 year.