This randomized phase III trial studies rituximab with bendamustine hydrochloride or ibrutinib to see how well they work compared to ibrutinib alone in treating older patients with previously untreated chronic lymphocytic leukemia. Rituximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Chemotherapy drugs, such as bendamustine hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known whether rituximab with bendamustine hydrochloride may work better than rituximab and ibrutinib or ibrutinib alone in treating chronic lymphocytic leukemia.

PRIMARY OBJECTIVE:

I. To determine whether progression free survival (PFS) is superior after therapy with bendamustine hydrochloride (bendamustine) in combination with rituximab, ibrutinib alone, or ibrutinib in combination with rituximab in patients age 65 or older with previously untreated chronic lymphocytic leukemia (CLL).

SECONDARY OBJECTIVES:

I. To determine 2-year PFS in each of the three treatment arms. II. To determine which treatment arm produces superior overall survival (OS). III. To determine the complete response (CR) rate, complete and nodular partial response (CR/nPR) rate, and overall response (PR+nPR+CR) rate (ORR) among the three treatment arms and compare these arms.

IV. To determine the impact of minimal residual disease (MRD)-negative disease at time of CR documentation and at 2 years on PFS and OS in each of the treatment arms.

V. To determine duration of response after each of the three treatments and compare these treatment arms.

VI. To determine toxicity and tolerability of the three treatment regimens. VII. To determine response and PFS of patients initially on the bendamustine in combination with rituximab arm who cross over to ibrutinib.

OTHER PRE-SPECIFIED OBJECTIVES:

I. To determine whether baseline cytogenetic markers, Zap-70 methylation, IgVH mutational status, or select deoxyribonucleic acid (DNA) mutations predict outcomes or time to response in these three arms.

II. To determine whether local fluorescence in situ hybridization (FISH) results for del(11q22.3) and del(17p13.1) are consistent with central analysis.

III. To determine whether baseline micro ribonucleic acid (RNA) and gene expression markers are correlated with clinical outcomes of interest (e.g. progression-free and alive at 2 years versus not), as well as to explore changes in microRNA expression from baseline to post-treatment time points, with a focus on those with persistent lymphocytosis and relapse.

IV. To determine whether eradication of MRD predicts longer duration of response with standard therapy and ibrutinib-based regimens.

V. To describe the baseline functional status, comorbid medical conditions, and number of medications of older CLL patients who meet criteria for therapy.

VI. To determine how functional status changes with therapy using baseline to 3-month evaluation and end-of-study/2-year evaluation; to determine whether this change is different among the treatment groups.

VII. To determine whether geriatric assessment variables known to be associated with chemotherapy toxicity in other disease groups can also predict therapy-associated toxicity in the CLL population.

VIII. To assess whether the FCGR3A polymorphism (rs396991) is correlated with depth of response (MRD status) to ibrutinib plus rituximab after 6 cycles, with secondary endpoints CR rate, rapidity of response, and progression-free survival (PFS).

IX. To assess whether C1QA polymorphism (rs172378) is correlated with MRD status, CR rate, rapidity of response, and PFS.

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM I: Patients receive rituximab intravenously (IV) on day 1 (day 0 course 1) and bendamustine hydrochloride IV over 30 minutes on days 1-2. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover to Arm II.

ARM II: Patients receive ibrutinib orally (PO) daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM III: Patients receive ibrutinib as in Arm II. Patients receive rituximab IV on days 1, 8, 15, and 22 of course 2 and on day 1 of courses 3-6. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Additionally, patients undergo bone marrow aspiration and biopsy, blood sample collection, and computed tomography (CT) throughout the study.

After completion of study treatment, patients are followed up every 6 months for up to 10 years.

Inclusion Criteria:

• PRE-REGISTRATION (STEP 0)

• All patients are REQUIRED to be pre-registered to A041202 in order to submit peripheral blood to the Alliance Hematologic Malignancy Biorepository (HEME) for central Zap-70 methylation. This specimen submission is mandatory prior to registration as results will be used for stratification

• REGISTRATION (STEP 1)

• Patients must be diagnosed with CLL in accordance with International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria that includes all of the following:

  • >= 5 x 10^9 B lymphocytes (5000/uL) in the peripheral blood
  • On morphologic review, the leukemic cells must be small mature lymphocytes, and prolymphocytes must not exceed 55% of the blood lymphocytes
  • CLL 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

  • Intermediate risk (formerly Rai stage I/II) is defined by lymphocytosis plus enlarged lymph nodes at any site, with or without hepatomegaly or splenomegaly
  • High risk (formerly Rai stage III/IV) is defined by lymphocytosis with or without enlarged nodes and spleen plus disease-related anemia (hemoglobin < 11 g/dL) or thrombocytopenia (platelet count < 100 x 10^9/L) that is not attributable to autoimmune hemolytic anemia or thrombocytopenia

• Patients must meet criteria for treatment as defined by IWCLL 2008 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

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

  • Constitutional symptoms, which include any of the following:

    • Unintentional weight loss of 10% or more within 6 months
    • Significant fatigue
    • Fevers > 100.5 degrees F for 2 weeks or more without evidence of infection
    • Night sweats > 1 month without evidence of infection

• Prior treatment

  • Patients must not have had prior therapy for CLL (except palliative steroids or treatment of autoimmune complications of CLL with rituximab or steroids)
  • Treatment with rituximab and/or high dose corticosteroids for autoimmune complications of CLL 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

• Patients with active hepatitis B defined by hepatitis B surface antigen positivity or core antibody positivity in the presence of hepatitis B DNA are not eligible for this study; patients with a positive hepatitis B core antibody but with negative hepatitis B DNA may participate, but must have hepatitis serologies and hepatitis B DNA monitored periodically by the treating physician

  • Intravenous immunoglobulin (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 DNA) they may still participate in the study, but should have hepatitis serologies and hepatitis B DNA monitored periodically by the treating physician

• Patients must not be receiving active systemic anticoagulation with heparin or warfarin; patients must be off warfarin therapy for at least 30 days prior to enrollment

• 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 with known human immunodeficiency virus (HIV) are eligible if their CD4 count is >= 350 cells/mm^3 and if they are not taking prohibited CYP-interacting medications

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

• 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 continued requirement for therapy with a strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitor or inducer

• 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 of enrollment, or minor surgery within 7 days of enrollment; examples of minor surgery include dental surgery, insertion of a venous access device, skin biopsy, or aspiration of a joint; the decision about whether a surgery is major or minor can be made at the discretion of the treating physician

• Absolute neutrophil count (ANC) >= 1,000/uL unless due to bone marrow involvement

• Aspartate aminotransferase (AST) or alanine aminotransferase (AST) =< 2.5 x upper limits of normal except if due to disease infiltration of the liver

• Bilirubin =< 1.5 x upper limits of normal (unless due to liver involvement, hemolysis, or Gilbert's disease)

• Creatinine clearance >= 40 mL/min

  • To be calculated by modified Cockcroft-Gault formula

• Platelet count (untransfused) >= 30,000/uL