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

This is a single center, open-label, phase II study of venetoclax (ABT-199) added to ibrutinib or acalabrutinib in patients with high-risk CLL who have received at least 12 months of ibrutinib or acalabrutinib monotherapy. The study will 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.

Inclusion Criteria: 1. Patients must have a diagnosis of CLL/CLL and have high-risk cytogenetic features or molecular features, defined as: del(17p), mutated TP53, complex metaphase karyotype (defined as 3 unrelated chromosomal abnormalities, present in at least 2 metaphases on conventional, stimulated cytogenetic analysis) \*\*\* Note: some patients treated with ibrutinib or acalabrutinib may no longer have detectable FISH, karyotypic or molecular abnormalities after 12 months of therapy. These patients will be eligible if they fulfill the above criteria on a bone marrow biopsy or peripheral blood specimen taken either prior to starting ibrutinib or acalabrutinib, provided they did not receive treatment for their CLL between the date of the lab test and starting ibrutinib or acalabrutinib or at some time during their ibrutinib therapy and analyzed at a CLIA-accredited laboratory. 2. Patients must have received at least 12 months of ibrutinib or acalabrutinib therapy and have measurable CLL by at least one of the following: * Absolute monoclonal lymphocyte count \> 4000/L; OR * Measurable lymph nodes with at least one node \>1.5 cm in diameter on CT; OR * Bone marrow with \>/= 30% lymphocytes on aspirate differential OR * Detectable CLL cells using a standardized flow cytometry assay for minimal residual disease 3. Age 18 years or older. 4. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2. 5. Patients must have adequate renal and hepatic function: * Serum bilirubin ≤1.5 x upper limit of normal (ULN) or ≤3 x ULN for patients with Gilbert's disease. * Serum creatinine clearance of 50ml/min (calculated or measured). * ALT and AST ≤3.0 x ULN, unless clearly due to disease involvement. 6. Adequate bone marrow function: * Platelet count of greater than 50,000/µl, with no platelet transfusion in prior 2 weeks. * ANC ≥1000/µl in the absence of growth factor support unless due to compromised bone marrow production from CLL, indicated by 80% CLL in marrow. * Hemoglobin ≥8mg/dL. 7. INR \20mg prednisone daily or equivalent, within 7 days of starting venetoclax. 11. Received other investigational therapeutic agent for CLL/SLL within 21 days of starting venetoclax. 12. Concurrent use of warfarin. 13. Received strong CYP3A inhibitors or strong CYP3A inducers within 7 days of starting venetoclax. 14. Consuming grapefruit, grapefruit products, Seville oranges, or star fruit within 7 days of starting venetoclax. 15. Prior treatment with venetoclax or other Bcl-2 inhibitor. 16. Malabsorption syndrome or other condition that precludes enteral route of administration