Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized Phase III Study of Bendamustine Plus Rituximab Versus Ibrutinib Plus Rituximab Versus Ibrutinib Alone in Untreated Older Patients (&gt;/= 65 Years of Age) With Chronic Lymphocytic Leukemia (CLL)
Brief Summary: 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.


Options:
A: 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
B: Inclusion Criteria:

* Diagnosis of CLL according to the National Cancer Institute (NCI)/Internal Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria or small lymphocytic lymphoma (SLL) according to the World Health Organization (WHO) criteria; this includes previous documentation of:

  * Biopsy-proven small lymphocytic lymphoma or
  * Diagnosis of CLL according to the NCI/IWCLL criteria as evidenced by all of the following:

    * Peripheral blood lymphocyte count of greater than 5 x 10\^9/L
    * Immunophenotype consistent with CLL defined as:

      * The predominant population of lymphocytes share both B-cell antigens (cluster of differentiation \[CD\]19, CD20 \[typically dim expression\], or CD23) as well as CD5 in the absence of other pan-T-cell markers (CD3, CD2, etc)
      * Clonality as evidenced by kappa or lambda light chain restriction (typically dim immunoglobulin expression)
  * Negative FISH analysis for t(11;14)(immunoglobulin heavy locus \[IgH\]/cyclin D1 \[CCND1\]) on peripheral blood or tissue biopsy (e.g. marrow aspirate) or negative immunohistochemical stains for cyclin D1 staining on involved tissue biopsy (e.g. marrow aspirate or lymph node biopsy)
* No prior chemotherapy, Bruton's tyrosine kinase (BTK) inhibitor therapy, or monoclonal anti-body therapy for treatment of CLL or SLL
* Has met at least one of the following indications for treatment:

  * Evidence of progressive marrow failure as manifested by the development of worsening anemia (hemoglobin \[Hg\] \< 11 g/dl) and/or thrombocytopenia (platelets \< 100 x 10\^9/L)
  * Symptomatic or progressive lymphadenopathy, splenomegaly, or hepatomegaly
  * One or more of the following disease-related symptoms:

    * Weight loss \>= 10% within the previous 6 months
    * Grade 2 or 3 fatigue attributed to CLL
    * Fevers \> 100.5 Fahrenheit (F) for 2 weeks without evidence of infection
    * Clinically significant night sweats without evidence of infection
  * Progressive lymphocytosis (not due to the effects of corticosteroids) with an increase of \> 50% over a two-month period or an anticipated doubling time of less than six months
* ECOG performance status between 0-2
* Life expectancy of \>= 12 months
* Ability to tolerate FCR based therapy
* No deletion of 17p13 on cytogenetic analysis by FISH
* Glomerular filtration rate (GFR) \> 40 mL/minute as calculated by the Cockcroft-Gault formula (obtained =\< 14 days prior to registration)
* Total bilirubin =\< 2.5 x upper limit of normal (ULN) (obtained =\< 14 days prior to registration) unless due to Gilbert's disease; for those with a total bilirubin \> 2.5 x ULN, a direct bilirubin should be performed and must be \< 1.5 mg/dL for Gilbert's to be diagnosed

  * If value is higher due to hepatic involvement by CLL, patient is eligible
* Serum glutamic oxaloacetic transaminase (SGOT) (aspartate transaminase \[AST\])/serum glutamate-pyruvate transaminase (SGPT) (alanine transaminase \[ALT\]) =\< 3.0 x the institutional ULN (obtained =\< 14 days prior to registration)

  * If value is higher due to hepatic involvement by CLL, patient is eligible
* Prothrombin time (PT)/international normalized ratio (INR) \< 1.5 ULN and partial thromboplastin time (PTT) (activated partial thromboplastin time \[aPTT\]) \< 1.5 X ULN (obtained =\< 14 days prior to registration)

  * If value is higher due to hepatic involvement by CLL, patient is eligible
* No active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic treatment; patients who have a positive Coombs test but no evidence of hemolysis are NOT excluded from participation
* No current use of corticosteroids; EXCEPTION: low doses of steroids (\< 10 mg of prednisone or equivalent dose of other steroid) used for treatment of non-hematologic medical condition (e.g. chronic adrenal insufficiency) is permitted
* No previous use of corticosteroids for autoimmune complications that have developed since the initial diagnosis of CLL; prior use of corticosteroids for reasons other than treatment of autoimmune complications is allowed
* No other active primary malignancy (other than non-melanomatous skin cancer or carcinoma in situ of the cervix) requiring treatment or limiting expected survival to =\< 2 years; NOTE: if there is a history of prior malignancy, they must not be receiving other specific treatment (other than hormonal therapy for their cancer)
* Able to adhere to the study visit schedule and other protocol requirements
* No major surgery within the last 4 weeks (28 days) of first dose of study drug or minor surgery within 3 days of first dose of study drug
* No radiation therapy =\< 4 weeks prior to registration
* Patients with human immunodeficiency virus (HIV) infection may be eligible provided they meet the following criteria:

  * CD4-positive cell count \>= lower limit of institutional normal
  * HIV viral load \< 10,000 copies HIV ribonucleic acid (RNA)/mL (if not on anti-HIV therapy) OR \< 50 copies HIV RNA/mL (if on anti-HIV therapy)
  * No evidence of hepatitis B or C infection
  * No evidence of resistant strains of HIV
  * No history of acquired immune deficiency syndrome (AIDS)-defining condition
* Patients must not have any of the following conditions:

  * Congestive heart failure or New York Heart Association Functional Classification III or IV congestive heart failure
  * History of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to registration
  * Recent infections requiring systemic treatment; need to have completed anti-biotic therapy \> 14 days before the first dose of study drug
  * Cerebral vascular accident or intracranial bleed within the last 6 months
  * Infection with known chronic, active hepatitis C
  * Serologic status reflecting active hepatitis B or C infection; patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment (PCR positive patients will be excluded)
* Patients are not eligible if they require treatment with a strong cytochrome P450 (CYP) family 3, subfamily A (3A) inhibitor
* Patients may not be on any other investigational agents
* Patients may not have received warfarin or another vitamin K antagonist in the preceding 30 days
* Women must not be pregnant or breast-feeding since this study involves an investigational agent whose genotoxic, mutagenic, and teratogenic effects on the developing fetus and newborn are unknown; female patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to registration to rule out pregnancy; female patients who are of non-reproductive potential are those who are post-menopausal by history (i.e. no menses for \>= 1 year); OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy)
* Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse for 90 days after the last dose of study drug
* Patient must be able to swallow capsules and not have the following conditions:

  * Disease significantly affecting gastrointestinal function
  * Resection of the stomach or small bowel
  * Symptomatic inflammatory bowel disease
  * Ulcerative colitis
  * Partial or complete bowel obstruction
* Patient must not be on any other systemic immunosuppressant therapy other than corticosteroids within 28 days of the first dose of study drug
* Patient must not be vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug
* Patient must not have any known bleeding disorders (e.g., von Willebrand's disease) or hemophilia
* Patient must not have currently active, clinically significant hepatic impairment (\>= moderate hepatic impairment according to the NCI/Child Pugh)
C: Key Inclusion Criteria:

* Unsuitable for chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR)
* Confirmed diagnosis of CD20-positive CLL or SLL, requiring treatment
* Measurable disease by imaging
* Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
* Life expectancy ≥ 6 months
* Adequate bone marrow function
* Adequate renal and hepatic function

Key Exclusion Criteria:

* Previous systemic treatment for CLL/SLL
* Requires ongoing need for corticosteroid treatment
* Known prolymphocytic leukemia or history of or suspected Richter's transformation.
* Clinically significant cardiovascular disease
* Prior malignancy within the past 3 years, except for curatively treated basal or squamous cell skin cancer, non-muscle-invasive bladder cancer, carcinoma in situ of the cervix of breast, or localized Gleason score 6 prostate cancer
* History of severe bleeding disorder
* History of stroke or intracranial hemorrhage within 6 months before the first dose of study drug
* Severe or debilitating pulmonary disease
* Inability to swallow capsules or disease affecting gastrointestinal function
* Active infection requiring systemic treatment
* Known central nervous system involvement by leukemia or lymphoma
* Underlying medical condition that will render the administration of study drug hazardous or obscure interpretation of toxicity or AEs
* Known infection with human immunodeficiency virus (HIV) or active hepatitis B or C infection
* Major surgery ≤ 4 weeks prior to start of study treatment
* Pregnant or nursing females
* Vaccination with live vaccine within 35 days prior to the first dose of study drug.
* Ongoing alcohol or drug addiction
* Known hypersensitivity to zanubrutinib, bendamustine, rituximab, or venetoclax (as applicable) or any other ingredients of the study drugs
* Requires ongoing treatment with strong cytochrome P450 (CYP3A) inhibitor or inducer
* Concurrent participation in another therapeutic clinical study

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
D: Inclusion Criteria:

* Adult participants who are: (a) greater than or equal to (\>=) 65 years old or, (b) 18 to 64 years old and have at least 1 of the following:

  1. Cumulative Illness Rating Scale (CIRS) score \> 6
  2. Creatinine clearance (CrCl) estimated less than (\<) 70 milliliter per minute (mL/min) using Cockcroft-Gault equation
* Diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) that meets International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria
* Measurable nodal disease (by computed tomography \[CT\]), defined as at least one lymph node \> 1.5 centimeter (cm) in longest diameter
* Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Grade less than or equal to (\<=) 2
* Active CLL/SLL requiring treatment per the iwCLL criteria

Exclusion Criteria:

* Prior anti-leukemic therapy for CLL or SLL
* Presence of deletion of the short arm of chromosome 17 (del17p) or known TP53 mutation detected at a threshold of \>10 percent (%) variable allele frequency (VAF)
* Major surgery within 4 weeks of first dose of study treatment
* Known bleeding disorders (example, von Willebrand's disease or hemophilia)
* Central nervous system (CNS) involvement or suspected Richter's syndrome

Answer: A