Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized Phase III Study of Ibrutinib (PCI-32765)-Based Therapy vs Standard Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in Untreated Younger Patients With Chronic Lymphocytic Leukemia (CLL)
Brief Summary: This phase III trial studies ibrutinib and rituximab to see how well they work compared to fludarabine phosphate, cyclophosphamide, and rituximab in treating patients with untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as fludarabine phosphate and cyclophosphamide, 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. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. It is not yet known whether fludarabine phosphate, cyclophosphamide, and rituximab may work better than ibrutinib and rituximab in treating patients with untreated chronic lymphocytic leukemia or small lymphocytic lymphoma.


Options:
A: Inclusion Criteria:

* Histologically confirmed chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)
* No prior cytotoxic chemotherapy for their disease; prior therapy with single-agent rituximab is permitted
* Understand and voluntarily sign an informed consent document
* In cases of SLL, subjects must have at least one bidimensionally measurable lesion at least \>= 1.5 cm measured in one dimension
* Eastern Cooperative Oncology Group (ECOG) performance status of =\< 2 at study entry
* Absolute neutrophil count \>= 1500/uL
* Platelet count \>= 100,000/uL
* Subjects with neutrophils \< 1500/uL or platelets \< 100,000/uL with splenomegaly or extensive bone marrow involvement as the etiology for their cytopenias are eligible
* Subjects must have adequate renal function with a creatinine clearance of \>= 40 mL/min as determined by the Cockcroft-Gault calculation
* Total bilirubin =\< 2 x upper limit laboratory normal (ULN); subjects with non-clinically significant elevations of bilirubin due to Gilbert's disease are not required to meet these criteria
* Serum transaminases aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 5 x ULN
* Serum alkaline phosphatase =\< 5 x ULN
* Disease-free of prior malignancies for \>= 2 years with the exception of basal or squamous cell skin carcinoma, carcinoma "in situ" of the breast or cervix, or localized prostate cancer (treated definitively with hormone therapy, radiotherapy, or surgery)
* Life expectancy of at least 3 months
* All study participants must be willing to be registered into the mandatory Revlimid REMS program after completion of induction chemoimmunotherapy and prior to maintenance therapy, and be willing and able to comply with the requirements of the Revlimid REMS program
* Subjects must not have a known history of hypersensitivity to mannitol
* Prior therapy with rituximab is permitted, even in the setting of rituximab-refractory disease
* Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS program
* Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (subjects intolerant to aspirin may use warfarin or low molecular weight heparin) if clinically indicated
* Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days and again within 24 hours prior to prescribing lenalidomide for cycle 1 (prescriptions must be filled within 7 days as required by the Revlimid REMS® program) and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide; FCBP must also agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy

Exclusion Criteria:

* Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent document or complying with the protocol treatment
* Pregnant or breast-feeding females; lactating females must agree not to breast-feed while taking lenalidomide
* Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study
* Subjects are not eligible if there is a prior history or current evidence of central nervous system or leptomeningeal involvement
* Known hypersensitivity to thalidomide
* Concurrent use of other anti-cancer agents or treatments
* Known to be positive for human immunodeficiency virus (HIV) or infectious hepatitis (type B or C)
* Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical or breast cancer, or other cancer from which the subject has been disease free for at least 2 years
* Severe or life-threatening anaphylaxis or hypersensitivity reaction when previously exposed to rituximab or other monoclonal antibody therapy
* Chronic hepatitis B or hepatitis C infection
* New York Heart Association class 3-4 heart failure
* More than one grade 2 or higher transaminase elevation
B: Inclusion Criteria:

* documented chronic lymphocytic leukemia (CLL) requiring treatment according to International Working Group on CLL (iwCLL) criteria
* adequate renal function: a creatinine clearance ≥30ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured with 24 hr. urine collection
* adequate hematologic function: platelets ≥ 25.000/µl, neutrophils ≥ 1.000/µl and hemoglobin ≥8.0 g/dL, unless directly attributable to the patient´s CLL (e.g. bone marrow infiltration)
* adequate liver function: total bilirubin ≤2x, aspartate aminotransferase (AST) / alanin aminotransferase (ALT) ≤2.5x the institutional upper Limit of normal (ULN) value, unless directly attributable to the patient's CLL or to Gilbert's Syndrome
* negative serological testing for hepatitis B, negative testing for hepatitis-C RNA and negative HIV test within 6 weeks prior to registration
* age ≥ 18 years
* Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 2, ECOG 3 is only permitted if related to CLL
* life expectancy ≥ 6 months
* ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements

Exclusion Criteria:

* transformation of CLL (i.e. Richter's transformation, prolymphocytic leukemia)
* known central nervous system (CNS) involvement
* confirmed progressive multifocal leukoencephalopathy (PML)
* malignancies other than CLL currently requiring systemic therapies
* uncontrolled infection requiring systemic treatment
* any comorbidity or organ system impairment rated with a cumulative illness rating scale (CIRS) score of 4, excluding the eyes/ears/nose/throat/larynx organ system or any other life-threatening illness, medical condition or organ system dysfunction that - in the investigator´s opinion - could compromise the patients safety or interfere with the absorption or metabolism of the study drugs (e.g, inability to swallow tablets or impaired resorption in the gastrointestinal tract)
* requirement of therapy with strong cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitors/inducers or anticoagulant with warfarin, phenprocoumon (marcumar) or other vitamin K-antagonists
* use of investigational agents within 28 days prior to registration
* known hypersensitivity to GA101 (obinutuzumab), ABT-199 (venetoclax, GDC-0199) or any of the excipients
* pregnant women and nursing mothers
* fertile men or women of childbearing potential unless surgically sterile or ≥ 2 years after the onset of menopause, or willing to use two methods of reliable contraception including one highly effective (Pearl Index \<1) and one additional effective (barrier) method during study treatment and for 18 months after end of study treatment
* vaccination with a live vaccine ≤28 days prior to registration
* legal incapacity
* prisoners or subjects who are institutionalized by regulatory or court order
* persons who are in dependence to the sponsor or an investigator

Inclusion/Exclusion criteria for extended follow-up and re-treatment

* Patients must have participated in the CLL2-BAG trial and must have benefitted from study treatment
* Only patients with a confirmed progression of CLL who are in need of treatment according to iwCLL 2008 criteria are eligible for retreatment with venetoclax and obinutuzumab
* Patients who received any subsequent treatment for CLL outside the study are ineligible
C: 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)
D: Inclusion Criteria:

1. Must understand and voluntarily sign an informed consent form.
2. Must be greater than or equal to 18 years at the time of signing the informed consent form.
3. Must be able to adhere to the study visit schedule and other protocol requirements.
4. Must have a documented diagnosis of B-cell CLL (IWCLL guidelines for the diagnosis and treatment of chronic lymphocytic leukemia \[Hallek, 2008\]).
5. Must have been treated with one of the following in first and/or second line:

   * a purine analog-containing regimen
   * a bendamustine-containing regimen
   * an anti-CD20 antibody-containing regimen
   * a chlorambucil-containing regimen
   * an alemtuzumab-containing regimen (for those subjects with a 17p deletion)
6. Must have achieved a minimum response of partial response (PR, nPR, CRi, CR, and MRD-negative CR) (IWCLL guidelines for the diagnosis and treatment of chronic lymphocytic leukemia \[Hallek, 2008\]) following completion of second-line induction therapy prior to randomization (documentation of response status must be available). Second-line induction therapy must be documented to have been of sufficient duration.
7. Must have completed last cycle of second-line induction no less than 8 weeks (56 days) and no greater than 20 weeks (140 days) prior to randomization.
8. Must have an ECOG performance status score of less than or equal to 2.
9. Females of childbearing potential (FCBP)† must:

   * Have two negative medically supervised pregnancy tests prior to starting of study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy. This applies even if the subject practices complete and continued sexual abstinence.
   * Either commit to continued abstinence from heterosexual contact (which must be reviewed on a monthly basis) or agree to use, and be able to comply with, effective contraception without interruption, 28 days prior to starting study drug, during the study therapy (including dose interruptions), and for 28 days after discontinuation of study therapy.
10. Male subjects must:

    * Commit to continued abstinence from heterosexual contact or agree to use a condom during sexual contact with a FCBP, even if they have had a vasectomy, throughout study drug therapy, during any dose interruption and after cessation of study therapy.
    * Agree to not donate semen during study drug therapy and for a period after end of study drug therapy.
11. All subjects must:

    * Have an understanding that the study drug could have a potential teratogenic risk.
    * Agree to abstain from donating blood while taking study drug therapy and following discontinuation of study drug therapy. • Agree not to share study medication with another person.
    * All subjects must be counseled about pregnancy precautions and risks of fetal exposure.

Exclusion Criteria:

1. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
2. Active infections requiring systemic antibiotics.
3. Systemic infection that has not resolved \> 2 months prior to initiating lenalidomide treatment in spite of adequate anti-infective therapy
4. Autologous or allogeneic bone marrow transplant as second-line therapy.
5. Pregnant or lactating females.
6. Systemic treatment for B-cell CLL in the interval between completing the last cycle of second-line induction therapy and randomization.
7. Participation in any clinical study or having taken any investigational therapy for a disease other than CLL within 28 days prior to initiating maintenance therapy.
8. Known presence of alcohol and/or drug abuse.
9. Central nervous system involvement as documented by spinal fluid cytology or imaging. Subjects who have signs or symptoms suggestive of leukemic meningitis or a history of leukemic meningitis must have a lumbar puncture procedure performed within two weeks prior to randomization.
10. Prior history of malignancies, other than CLL, unless the subject has been free of the disease for ≥5 years. Exceptions include the following:

    * Basal cell carcinoma of the skin
    * Squamous cell carcinoma of the skin
    * Carcinoma in situ of the cervix
    * Carcinoma in situ of the breast
    * Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b)
11. History of renal failure requiring dialysis.
12. Known Human Immunodeficiency Virus (HIV), active Hepatitis B Virus (HBV), and/or active Hepatitis C Virus (HCV) infection.
13. Prior therapy with lenalidomide.
14. Evidence of TLS per the Cairo-Bishop definition of laboratory TLS (subjects may be enrolled upon correction of electrolyte abnormalities).
15. Any of the following laboratory abnormalities:

    * Calculated (method of Cockroft-Gault) creatinine clearance \<60 mL/min.
    * Absolute neutrophil count (ANC) \<1,000/μL (1.0 X 109/L)
    * Platelet count \<50,000/μL (50 X 109/L)
    * Serum aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) or alanine transaminase (ALT)/serum glutamate pyruvate transaminase (SGPT) \> 3.0 x upper limit of normal (ULN)
    * Serum total bilirubin \>2.0 mg/dL (with the exception of Gilbert's Syndrome)
16. Grade 4 rash due to prior thalidomide treatment
17. Uncontrolled hyperthyroidism or hypothyroidism
18. Venous thromboembolism within one year
19. Greater than or equal to Grade-2 neuropathy
20. Uncontrolled autoimmune hemolytic anemia or thrombocytopenia
21. Disease transformation (active) (ie, Richter's Syndrome, prolymphocytic leukemia)
22. Known allergy to allopurinol for subjects assessed with PR following their second-line induction therapy.
23. Prisoners.
24. More than 2 prior lines of CLL therapy.

Answer: C