This phase III trial compares adding a new anti-cancer drug (venetoclax) to the usual treatment (ibrutinib plus obinutuzumab) in older patients with chronic lymphocytic leukemia who have not received previous treatment. The addition of venetoclax to the usual treatment might prevent chronic lymphocytic leukemia from returning. This trial also will investigate whether patients who receive ibrutinib plus obinutuzumab plus venetoclax and have no detectable chronic lymphocytic leukemia after 1 year of treatment, can stop taking ibrutinib. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotherapy with obinutuzumab may induce changes in body's immune system and may interfere with the ability of cancer cells to grow and spread. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving ibrutinib and obinutuzumab with venetoclax may work better at treating chronic lymphocytic leukemia compared to ibrutinib and obinutuzumab.

PRIMARY OBJECTIVE:

I. To compare the progression-free survival (PFS) between control treatment and experimental treatment strategies: ibrutinib/obinutuzumab (IO) with ibrutinib maintenance (IM) versus ibrutinib/venetoclax/obinutuzumab (IVO) regardless of IM or observation.

SECONDARY OBJECTIVES:

I. To compare bone marrow (BM) minimal residual disease (MRD)- complete response (CR) rates, MRD- rates, and depth of response at cycle 15 day 1 between patients treated with IO versus IVO.

II. To compare overall survival (OS) between the control and experimental treatment strategies: IO with IM versus IVO regardless of IM or observation.

III. To compare the 5-year PFS and overall survival (OS) for the control and experimental treatment strategies: IO with IM versus IVO regardless of IM or observation.

IV. To describe the toxicity profile for each of the treatment strategies and by each treatment course.

CORRELATIVES SCIENCE OBJECTIVES:

I. To compare MRD status between blood and bone marrow at the end of induction treatment/cycle 15 day 1 to determine whether blood MRD can be used as a surrogate to bone marrow MRD with these treatment regimens.

II. To compare peripheral blood MRD status by standard central flow cytometry to next generation sequencing (NGS) using ClonoSeq technique to determine the agreement in MRD negativity of the two techniques.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28. Patients also receive obinutuzumab intravenously (IV) on days 1, 2, 8, and 15 of cycle 1, and on day 1 of cycles 2-6. Treatment repeats every 28 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity. Beginning cycle 15, patients receive ibrutinib PO QD every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive ibrutinib PO QD on days 1-28. Patients also receive obinutuzumab IV on days 1, 2, 8, and 15 of cycle 1, and on day 1 of cycles 2-6. Beginning cycle 3, patients also receive venetoclax PO QD on days 1-28. Treatment repeats every 28 days for 14 cycles in the absence of disease progression or unacceptable toxicity. All patients will then receive a 15th cycle of ibrutinib. Beginning cycle 16, patients who do not achieve a BM MRD negative CR, receive ibrutinib PO QD every 28 days in the absence of disease progression or unacceptable toxicity. Patients who achieve a BM MRD negative CR undergo observation every 3 cycles for 6 years, then every 6 cycles thereafter.

After completion of study treatment, patients are followed every 6 months until 10 years from registration.

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

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