Venetoclax With Ibrutinib or Acalabrutinib in Pts. With High-risk CLL

Primary Objective: 1\. To estimate the therapeutic efficacy of venetoclax consolidation in patients who have detectable CLL after receiving ibrutinib or acalabrutinib for at least 12 months and who have high risk CLL. High risk is defined as the presence of at least one of: del(17p); TP53 mutation; complex metaphase karyotype; patients who have developed mutations in BTK and/or PLCG2, will be eligible if they have no clinical or laboratory evidence of progressive disease. The primary endpoint will be the rate of MRD-negativity in the bone marrow, using an assay method with at least 0.01% sensitivity after 12 cycles of combination therapy. One cycle is 4 weeks of treatment. Secondary Objectives: 1. Determine CR/CRi rate after 6, 12 18 and 24 cycles of combination therapy, in patients who were not in CR/Cri at study initiation and estimate the time to best response with this combination. 2. Determine the cumulative rate of bone marrow minimal residual disease (MRD)-free complete responders by an assay method with at least 0.01% sensitivity and median time to MRD-negativity. 3. Determine the safety of combined ibrutinib and venetoclax. 4. Determine the progression-free and overall survival. OUTLINE: This is a dose-escalation study of venetoclax. Patients receive venetoclax orally (PO) once daily (QD) and ibrutinib PO QD and acalabrutinib PO BID. Treatment repeat every 4 weeks for up to 24 cycles in the absence of disease progression or unaccepted toxicity. After completion of study treatment, patients are followed up every 6-12 months.