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

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• Patients must not have had prior therapy for CLL/SLL (except palliative steroids or treatment of autoimmune complications of CLL with rituximab or steroids)
• Patients must not be receiving active systemic anticoagulation with heparin or warfarin. Patients on warfarin must discontinue the drug for at least 10 days prior to registration on the study
• Chronic concomitant treatment with strong inhibitors of CYP3A4/5 is not allowed on this study. Patients on strong CYP3A inhibitors must discontinue the drug for 14 days prior to registration on the study
• Chronic concomitant treatment with strong CYP3A4/5 inducers is not allowed. Patients must discontinue the drug 14 days prior to registration on the study
• Patients must not require more than 20 mg prednisone or equivalent corticosteroid daily
• Patients must not have prior significant hypersensitivity to rituximab (not including infusion reactions)
• Patients may not have had major surgery within 10 days prior to registration, or minor surgery within 7 days prior to registration. Examples of minor surgery include dental surgery, insertion of a venous access device, skin biopsy, or aspiration for a joint. The decision about whether a surgery is major or minor can be made at the discretion of the treating physician

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• Patients must not have any history of Richter's transformation or prolymphocytic leukemia (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 within the past 6 months are not eligible
• Patients must not have uncontrolled active systemic infection requiring intravenous antibiotics
• Patients must not have a known allergy to mannitol

• PRE-REGISTRATION ELIGIBILITY CRITERIA (STEP 0)
• Patients must have been diagnosed with chronic lymphocytic leukemia (CLL) (> 5000 B-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 with disease-associated lymphadenopathy
• This blood submission is mandatory prior to registration/randomization to perform fluorescence in situ hybridization (FISH) centrally that will be used for stratification. 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 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria that includes all of the following:
  • >= 5 x10\^9 B lymphocytes (5000/uL) in the peripheral blood measured by flow cytometry at any point in the course of the disease or less peripheral blood involvement but disease-associated lymphadenopathy
  • On local morphologic review, the leukemic cells must be small mature lymphocytes, and prolymphocytes must not exceed 55% of the blood lymphocytes
  • Neoplastic cells on immunophenotype (performed locally) must reveal a clonal B-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 immunoglobulin expression 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/or hepatomegaly 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/or thrombocytopenia (platelets [plt] < 100 x10\^9/L) not attributable to autoimmune thrombocytopenia
• Patients must meet criteria for treatment as defined by 2018 IWCLL guidelines which includes at least one of the following criteria:
  • Evidence of marrow failure as manifested by the development or worsening of anemia or thrombocytopenia (not attributable to autoimmune hemolytic anemia or thrombocytopenia)
  • Massive (>= 6 cm below the costal margin), progressive or symptomatic splenomegaly
  • Massive nodes (>= 10 cm) or progressive or symptomatic lymphadenopathy
  • Progressive lymphocytosis with a lymphocyte doubling time < 6 months or an increase of >= 50% over a 2 month period
  • Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy
  • 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 evidence of infection
  • Night sweats >= 1 month without evidence of infection
• Treatment with rituximab and/or high dose corticosteroids for autoimmune complications 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 or equivalent 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 marrow involvement
• Platelet count (untransfused) >= 30,000/mm\^3 except if due to bone marrow involvement
• 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 limit of normal (ULN) except if due to liver involvement
• If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy if indicated
• Please note: Intravenous immunoglobulin therapy (IVIG) can cause a false positive hepatitis B serology. If patients receiving routine IVIG have core antibody or surface antigen positivity without evidence of active viremia (negative hepatitis B deoxyribonucleic acid [DNA]) they may still participate in the study, must have hepatitis serologies and hepatitis B DNA monitored periodically by the treating physician
• If history of hepatitis C virus (HCV) infection, must be treated with undetectable HCV viral load
• Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral therapy with undetectable viral load within 6 months are eligible for this trial
• Central fluorescent in situ hybridization (FISH) blood results are mandatory prior to 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 the stomach or small bowel, partial or complete bowel obstruction
• Patients must be able to receive either a xanthine oxidase inhibitor or rasburicase for 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