A Randomized Phase II Study Of Bruton Tyrosine Kinase Inhibitor With Or Without Venetoclax In Veterans With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

Inclusion Criteria:

• CLL or SLL diagnosis

• Patients must have been diagnosed with CLL (> 5000 B-cells per uL of peripheralblood at any point during the course of their disease) or small lymphocytic lymphoma (SLL) with <5000 B-cells per µL of blood but with disease-associated lymphadenopathyby 2018 IWCLL criteria.

• Prior treatment

• Patients must be currently receiving CLL/SLL directed therapy with a BTKi (i.e.,ibrutinib, acalabrutinib, zanubrutinib) for at least six months.

• The dose of BTKi must be stable for at least the past three months.

• Age 18 years

• ECOG performance status 0-2

• Detectable or measurable CLL/SLL in blood or imaging during the screening period.

Detectable CLL/SLL in the blood is defined either by elevation in absolute lymphocyte count or by diagnostic flow cytometry from blood demonstrating presence of CLL cells.

• Low TLS risk, defined as having all lymph nodes less than 5 cm in diameter (radiographically) and absolute lymphocyte count less than 25 x 109/L in blood,within 30 days of enrollment.

• Required initial laboratory values

• Absolute Neutrophil Count (ANC) 1,000/mm3 except if due to bone marrow involvement

• Platelet Count (untransfused) 30,000/mm3 except if due to bone marrow involvement

• Calc. Creatinine Clearance 40 mL/min (by Cockcroft-Gault)

• Bilirubin 1.5 x upper limit of normal (ULN) except if due to liver involvement,hemolysis, or Gilbert's disease

• AST / ALT 2.5 x upper limit of normal (ULN) except if due to liver involvement

• Other

• Patients must be able to swallow oral medications and not have the followingconditions: disease significantly affecting gastrointestinal absorption, resectionof the stomach or small bowel, partial or complete bowel obstruction.

• Patients must be able to receive either a xanthine oxidase inhibitor or rasburicase

Exclusion Criteria:

• Prior treatment

• Patients must not have progression of CLL/SLL on BTKi therapy prior to initiation ofthe study therapy.

• Patients must not have received the combination of BTKi + venetoclax previously.

• Comorbid conditions or other active diseases

• Patients must not have any history of Richter's transformation or prolymphocyticleukemia.

• If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must beundetectable and be on suppressive therapy, if indicated.

• Please note: IVIG can cause a false positive hepatitis B serology. If patientsreceiving routine IVIG have core antibody or surface antigen positivity withoutevidence of active viremia (negative hepatitis B DNA) they may still participate inthe study, must have hepatitis serologies and hepatitis B DNA monitored periodicallyby the treating physician.

• If history of hepatitis C virus (HCV) infection, must be treated with undetectableHCV viral load.

• Patients with Class III or Class IV heart failure by New York Heart Association,those with unstable angina, and those with uncontrolled arrhythmia are not eligible.

• Human immunodeficiency virus (HIV)-infected patients on effective antiretroviraltherapy are eligible for this trial.

• Concomitant medications

• Patients must not be receiving active systemic anticoagulation with heparin orwarfarin. Patients on warfarin must discontinue the drug for at least 10 days priorto registration on the study.

• Chronic concomitant treatment with strong inhibitors of CYP3A4/5 is not recommendedon this study. Patients on strong CYP3A inhibitors must discontinue the drug for 14days prior to registration on the study or discuss with the study principalinvestigator.

• Chronic concomitant treatment with strong CYP3A4/5 inducers is not recommended.Patients must discontinue the drug 14 days prior to registration on the study ordiscuss with the study principal investigator.

• Patients must not require more than 20 mg prednisone or equivalent corticosteroiddaily.

• Patients must not have uncontrolled active systemic infection requiring intravenousantibiotics