Testing the Addition of a New Anti-cancer Drug, Venetoclax, to the Usual Treatment (Ibrutinib and Obinutuzumab) in Untreated, Older Patients With Chronic Lymphocytic Leukemia

Inclusion Criteria:

• PRE-REGISTRATION ELIGIBILITY CRITERIA (STEP 0)

• Patients must have been diagnosed with chronic lymphocytic leukemia (CLL) (> 5000B-cells per uL of peripheral blood at any point during the course of their disease)or small lymphocytic lymphoma (SLL) with < 5000 B-cells per uL of blood but withdisease-associated lymphadenopathy

• This blood submission is mandatory prior to registration/randomization to performfluorescence in situ hybridization (FISH) centrally that will be used forstratification. It should be obtained as soon after pre-registration as possible

• REGISTRATION ELIGIBILITY CRITERIA (STEP 1)

• Patients must be diagnosed with CLL or SLL in accordance with 2018 InternationalWorkshop on Chronic Lymphocytic Leukemia (IWCLL) criteria that includes all of thefollowing:

• >= 5 x10^9 B lymphocytes (5000/uL) in the peripheral blood measured by flowcytometry at any point in the course of the disease or less peripheral bloodinvolvement but disease-associated lymphadenopathy

• On local morphologic review, the leukemic cells must be small maturelymphocytes, and prolymphocytes must not exceed 55% of the blood lymphocytes

• Neoplastic cells on immunophenotype (performed locally) must reveal a clonalB-cell population, which express the B cell surface markers of CD19 and CD20,as well as the T-cell antigen CD5. Patients with bright surface immunoglobulinexpression or lack of CD23 expression in >10% of cells must lack t(11;14)translocation by interphase cytogenetics

• Patients must be intermediate or high-risk Rai stage CLL or SLL

• Intermediate risk (formerly stage I/II) is defined by lymphadenopathy and/orhepatomegaly or splenomegaly without anemia or thrombocytopenia

• High risk (formerly stage III/IV) is defined by splenomegaly and/or anemia (hemoglobin < 11g/dL) not attributable to autoimmune hemolytic anemia and/orthrombocytopenia (platelets [plt] < 100 x10^9/L) not attributable to autoimmunethrombocytopenia

• Patients must meet criteria for treatment as defined by 2018 IWCLL guidelines whichincludes at least one of the following criteria:

• Evidence of marrow failure as manifested by the development or worsening ofanemia or thrombocytopenia (not attributable to autoimmune hemolytic anemia orthrombocytopenia)

• Massive (>= 6 cm below the costal margin), progressive or symptomaticsplenomegaly

• Massive nodes (>= 10 cm) or progressive or symptomatic lymphadenopathy

• Progressive lymphocytosis with a lymphocyte doubling time < 6 months or anincrease of >= 50% over a 2 month period

• Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standardtherapy

• Symptomatic or functional extranodal involvement (e.g. skin, kidney, lung,spine)

• Constitutional symptoms, which include any of the following:

• Unintentional weight loss of 10% or more within 6 months

• Significant fatigue

• Fevers > 100.5 degrees Fahrenheit (F) for 2 weeks or more without evidenceof infection

• Night sweats >= 1 month without evidence of infection

• Treatment with rituximab and/or high dose corticosteroids for autoimmunecomplications of CLL/SLL must be complete at least 4 weeks prior to enrollment.Palliative steroids must be at a dose not higher than 20 mg/day of prednisone orequivalent corticosteroid at the time of registration

• Age >= 65 years

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

• Absolute neutrophil count (ANC) >= 1,000/mm^3 except if due to bone marrowinvolvement

• Platelet count (untransfused) >= 30,000/mm^3 except if due to bone marrowinvolvement

• Calculated (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

• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limitof normal (ULN) except if due to liver involvement

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

• Please note: Intravenous immunoglobulin therapy (IVIG) can cause a false positivehepatitis B serology. If patients receiving routine IVIG have core antibody orsurface antigen positivity without evidence of active viremia (negative hepatitis Bdeoxyribonucleic acid [DNA]) they may still participate in the study, must havehepatitis serologies and hepatitis B DNA monitored periodically by the treatingphysician

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

• Human immunodeficiency virus (HIV)-infected patients on effective antiretroviraltherapy with undetectable viral load within 6 months are eligible for this trial

• Central fluorescent in situ hybridization (FISH) blood results are mandatory priorto registration/randomization for it will be used for stratification

• Patients must be able to swallow capsules and not have the following conditions:disease significantly affecting gastrointestinal absorption, resection of thestomach or small bowel, partial or complete bowel obstruction

• Patients must be able to receive either a xanthine oxidase inhibitor or rasburicasefor prophylaxis/treatment of tumor lysis syndrome (TLS)

• RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2)

• Completion of treatment through cycle 14 day 28, and remain on ibrutinib therapy

• Receipt of central BM MRD results

• Response assessment completed with CR determination

Exclusion Criteria:

• Patients must not have had prior therapy for CLL/SLL (except palliative steroids ortreatment of autoimmune complications of CLL with rituximab or steroids)

• Patients must not have any history of Richter's transformation or prolymphocyticleukemia (prolymphocytes in blood > 55%)

• 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

• Patients who have had a myocardial infarction, intracranial bleed, or stroke withinthe past 6 months are not eligible

• 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 allowed onthis study. Patients on strong CYP3A inhibitors must discontinue the drug for 14days prior to registration on the study

• Chronic concomitant treatment with strong CYP3A4/5 inducers is not allowed. Patientsmust discontinue the drug 14 days prior to registration on the study

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

• Patients must not have uncontrolled active systemic infection requiring intravenousantibiotics

• Patients must not have a known allergy to mannitol

• Patients must not have prior significant hypersensitivity to rituximab (notincluding infusion reactions)

• Patients may not have had major surgery within 10 days prior to registration, orminor surgery within 7 days prior to registration. Examples of minor surgery includedental surgery, insertion of a venous access device, skin biopsy, or aspiration fora joint. The decision about whether a surgery is major or minor can be made at thediscretion of the treating physician