Safe Accelerated Venetoclax Escalation in CLL

Inclusion Criteria: * Must have a confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic lymphoma per IW-CLL 201814 requiring therapy based on at least one of the following criteria as listed below: * Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin \<11.0 g/L) and/or thrombocytopenia (platelets \<100 x 109/L) * Massive (≥6 cm below the left costal margin), progressive, or symptomatic splenomegaly * Massive nodes (at least 10 cm longest diameter), progressive, or symptomatic * lymphadenopathy * Progressive lymphocytosis with an increase of more than 50% over a 2-month period or LDT of \<6 months. Lymphocyte doubling time may be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months. * Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy * Documented constitutional symptoms, defined as 1 or more of the following disease related symptoms or signs: unintentional weight loss \>10% within 6 months prior to screening, significant fatigue (inability to work or perform usual activities), fevers \>100.5° F or 38.0° C for 2 or more weeks prior to screening without evidence of infection, night sweats for more than 1 month prior to screening without evidence of infection * Both previously untreated and relapsed or refractory patients will be eligible, including those who will be receiving venetoclax as monotherapy or in combination with anti-CD20 monoclonal antibody therapy * Age greater or equal to 18 years * ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A) * Patients must meet the following hematologic criteria at screening, unless they have significant bone marrow involvement of CLL confirmed on biopsy: * Absolute neutrophil count ≥1000 cells/mm3. Growth factor is allowed in order to achieve this * Platelet count ≥25,000 cells/mm3 (25 x 109/L) independent of transfusion within 7 days of screening * Adequate hepatic function defined as: * Serum aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x upper limit of normal (ULN), bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin) * Adequate renal function as defined as: * Serum creatinine ≤1.5 times the ULN or creatinine clearance ≥ 50 mL/min using a 24-hour urine collection * Women of child-bearing potential and men must agree to use adequate contraception (hormonal, barrier method or abstinence) prior to study entry and for the duration of study participation * Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: * Treatment with venetoclax within the past 6 months * Transformation of CLL to aggressive NHL (Richter's transformation or pro-lymphocytic leukemia) * Patients receiving cancer therapy (i.e., chemotherapy, radiation therapy, immunotherapy, biologic therapy, surgery within 2 weeks of Cycle 1/Day 1 with the following exceptions: * CD20 antibody therapy (i.e. rituximab or obinutuzumab) if it is being used as part of the venetoclax regimen (see inclusion criteria 3.1.2) * For patients on targeted therapies, a washout of least five half lives is required * Patients who experience clinical deterioration may start therapy after a shorter washout period with prior approval by the PI * Corticosteroid therapy (prednisone or equivalent \<=20 mg daily) is allowed * Confirmed central nervous system involvement * Allogeneic hematologic stem cell transplant within 6 months of starting study treatment or active graft vs. host disease (GVHD) requiring treatment or prophylaxis * Active malignancy requiring therapy that would interact with venetoclax as per the discretion of the treating investigator * Any active systemic infection requiring IV antibiotics or other uncontrolled, active infections * Known history of human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV) * Major surgery within 4 weeks of first dose of study drug * Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months of initial dosing on study * Use of Coumadin for anticoagulation (other anticoagulants permitted) * Lactating or pregnant * Concurrent administration of medications or foods that are strong inhibitors or inducers of CYP3A . The concomitant use of drugs or foods that are strong or moderate inhibitors or inducers of CYP3A are not allowed beginning 1 week prior to the first dose of venetoclax. * Patients with ongoing use of prophylactic antibiotics are eligible as long as there is no evidence of active infection and the antibiotic is not included on the list of prohibited medications * Unable to swallow capsules or malabsorption syndrome, active disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction resulting in malabsorption or chronic diarrhea * Active abuse of alcohol