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) (> 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

Exclusion Criteria:

   - 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 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 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 uncontrolled active systemic infection requiring intravenous
   antibiotics

   - Patients must not have a known allergy to mannitol

   - 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