Inclusion Criteria:

• Diagnosis of CLL/SLL meeting criteria established in International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 criteria

• Age ≥ 18 years

• Indications for treatment as defined by the iwCLL 2018 Guidelines

• Received prior treatment or not depending on cohort

  • Frontline cohort:

    • CLL/SLL who are treatment-naïve and have met criteria 1 through 3 above

  • Second line cohort:

    • Must have received time-limited venetoclax based therapy in the front line. This is defined as treatment with venetoclax and an-anti-CD20 antibody, venetoclax and a BTKi, or treatment with venetoclax and a BTKi, and an anti-CD20 monoclonal antibody that was given for a fixed-duration. Patients who discontinue ibrutinib, due to intolerance, in a BTKi and venetoclax +/- obinutuzumab combination are eligible provided they completed other drugs in the regimen and in the opinion of the treating investigator the intolerance will not limit treatment with zanubrutinib and venetoclax. Patients who discontinued BTKi other than ibrutinib or who discontinued venetoclax due to intolerance will be excluded
    • At least 2 years since completion of initial CLL treatment
    • Only 1 prior line of therapy. Treatment with rituximab or other anti-CD20 monoclonal antibody for idiopathic thrombocytopenic purpura (ITP) or autoimmune hemolytic anemia (AIHA) is not considered a prior line of CLL/SLL therapy

• Eastern Cooperative Oncology Group (ECOG) performance 0-2

• Absolute neutrophil count (ANC) > 1000/mm^3 (independent of growth factor support at screening, unless cytopenias are due to marrow involvement by CLL/SLL)

• Platelets > 30,000/mm^3 at screening (independent of growth factor support at screening, unless cytopenias are due to marrow involvement by CLL/SLL)

• Hemoglobin > 7 g/dL (independent of growth factor support at screening, unless cytopenias are due to marrow involvement by CLL/SLL)

• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 3 x the upper limit of normal (ULN) or ≤ 5 x ULN with documented liver involvement

• Bilirubin ≤ 1.5 x ULN or ≤ 3 x ULN with documented liver involvement and/or Gilbert's disease

• Creatinine clearance (CrCl) ≥ 50 according to modified Cockcroft-Gault equation

• Willing and able to complete study activities and treatment

• Willing and capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol

• Willingness of men and women of reproductive potential and their partners to observe conventional and highly effective or acceptable birth control methods for the duration of treatment and for 1 week following the last dose of zanubrutinib or 30 days following the last dose of venetoclax, whichever is longer

Exclusion Criteria:

• Second line arm only: Patients who progressed per iwCLL 2018 criteria on therapy or within two years of completing time-limited, venetoclax based treatment

• Frontline arm only: Patients with deletion 17p and/or TP53 mutation

• Active Richter's transformation

• Prior zanubrutinib exposure

• Known hypersensitivity to any of the excipients of zanubrutinib or venetoclax

• Need for treatment with warfarin or other vitamin K antagonist during study treatment

• History of stroke or intracranial hemorrhage within 6 months

• Known bleeding diathesis

• Inability to take pills or oral medications

• Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of either zanubrutinib or venetoclax

• Active second malignancy unless in remission and with life expectancy > 2 years. Adjuvant endocrine therapy for breast or prostate cancer that is expected to be cured is allowed. Non-melanoma skin cancers are permitted if adequately treated

• Psychiatric illness, or social situations that would limit compliance with study requirements

• Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia [AIHA], idiopathic thrombocytopenic purpura [ITP]) for which new therapy was introduced or existing therapy was escalated within the 4 weeks prior to study enrollment to maintain adequate blood counts

• Evidence of other clinically significant uncontrolled condition(s) including but not limited to, uncontrolled systemic bacterial, viral, fungal or parasitic infection (except for fungal nail infection), or other clinically significant active disease process which in the opinion of the investigator may pose a risk for patient participation. Screening for chronic conditions is not required

• Significant cardiovascular disease defined as:

  • Unstable angina or acute coronary syndrome within the past 2 months

  • History of myocardial infarction within 3 months

  • Documented left ventricular ejection fraction (LVEF) by any method of ≤ 40% within 12 months

  • ≥ grade 3 New York Heart Association (NYHA) functional classification system of heart failure

  • Uncontrolled or symptomatic arrhythmias

    • Note: Patients with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker

• Prolongation of the QT interval corrected for heart rate (QTcF) > 470 msec. QTcF is calculated using Fridericia's Formula (QTcF)

  • Correction of suspected drug induced QTcF prolongation can be attempted at the investigator's discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation
  • Correction for underlying bundle branch block (BBB) allowed

• Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection based on criteria below:

  • Hepatitis B virus (HBV): Patients with positive hepatitis B surface antibody (HBsAb) are not excluded. Patients with positive hepatitis B core antibody (anti-HBc) and negative HBsAg require hepatitis B polymerase chain reaction (PCR) evaluation before inclusion. Patients who are hepatitis B PCR positive at time of screening will be excluded. Those who have hepatitis B core antibody positive and a negative PCR will be included if they are agreeable to receive antiviral prophylaxis
  • Hepatitis C virus (HCV): If hepatitis C antibody is positive, patients will need to have a negative result for hepatitis C ribonucleic acid (RNA) before inclusion. Patients who are hepatitis C RNA positive at time of screening will be excluded. Patients previously treated for hepatitis C > 6 months previously with a negative RNA test are eligible
  • Patients who are receiving intravenous immunoglobulin (IVIG) who test positive for any hepatitis B or C serologies and have a negative PCR and who are deemed likely to have received antibodies passively through IVIG and not from prior infection will be included without viral prophylaxis

• Treatment with a strong cytochrome P450 (CYP)3A inhibitor or inducer and/or strong P-glycoprotein (P-gp) inhibitors within 3 days of starting and during study treatment

• Patients may not plan to consume grapefruit or grapefruit products, Seville oranges or products from Seville oranges, or star fruit

• Pregnancy, lactation, or plan to breastfeed during treatment with or within 2 weeks of the last dose of zanubrutinib or 1 month of the last dose of venetoclax

• Major surgery within 4 weeks prior to screening

• Vaccination with live vaccine within 28 days of screening

• Currently incarcerated

• Current central nervous system involvement by CLL/SLL