Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study of the Efficacy and Safety of Lenalidomide (Revlimid®) as Maintenance Therapy for Patients With B-Cell Chronic Lymphocytic Leukemia Following Second-Line Therapy (The Continuum Trial)
Brief Summary: The purpose of this study is to determine if lenalidomide (Revlimid®) is safe and effective as a maintenance therapy at improving further the quality of the response you achieved with your last therapy and at prolonging the duration of your response. This study will compare the effects (good and bad) of lenalidomide with the dummy drug.


Options:
A: Inclusion Criteria:

1. 1.Patients must have a diagnosis of high-risk CLL/SLL and be previously treated with up to 3 lines of prior therapy. High-risk CLL and high-risk SLL is defined by the presence of a 17p deletion or 11q deletion or TP53 mutation. Any CLL and SLL patient who has a short remission duration of less than 3 years after prior first-line chemo-immunotherapy, such as the FCR regimen, also fulfills criteria of high-risk CLL/SLL, regardless of the presence or absence of cytogenetic abnormalities.
2. 2.CLL and SLL patients with 17p deletion or TP53 mutation will not be required to have received any prior therapy, given the poor outcome of CLL/SLL patients to standard frontline chemo-immunotherapy, such patients will be eligible if they are untreated or if they have received up to 3 lines of prior therapy.
3. Patients must have an indication for treatment by 2008 IWCLL Criteria.
4. Patients age \> 18 years at the time of signing informed consent. Understand and voluntarily sign an informed consent. Be able to comply with study procedures and follow-up examinations.
5. Eastern Cooperative Oncology Group (ECOG)/World Health Organization (WHO) performance status of 0-1.
6. Patients of childbearing potential must be willing to practice highly effective birth control (e.g., condoms, implants, injectables, combined oral contraceptives, some intrauterine devices \[IUDs\], sexual abstinence, or sterilized partner) during the study and for 30 days after the last dose of study drug. Women of childbearing potential include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal. Post menopause is defined as follows: Amenorrhea \>/= 12 consecutive months without another cause and a documented serum follicle stimulating hormone (FSH) level \>35 mIU/mL; a male of childbearing potential is any male that has not been surgically sterilized.
7. Adequate renal and hepatic function as indicated by all of the following: Total bilirubin \</=1.5 x institutional Upper Limit of Normal (ULN) except for patients with bilirubin elevation due to Gilbert's disease who will be allowed to participate; an Alanine (ALT) \</=2.5 x ULN; and an estimated creatinine clearance (CrCl) of \> 30 mL/min, as calculated by the Cockcroft-Gault equation unless disease related.
8. Free of prior malignancies for 3 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast.
9. A Urine Pregnancy Test (within 7 days of Day 1) is required for women with childbearing potential

Exclusion Criteria:

1. Pregnant or breast-feeding females.
2. Treatment including chemotherapy, chemo-immunotherapy , monoclonal antibody therapy, radiotherapy, high-dose corticosteroid therapy (more than 60 mg prednisone or equivalent daily), or immunotherapy within 21 days prior to enrollment or concurrent with this trial.
3. Investigational agent received within 30 days prior to the first dose of study drug or have previously taken PCI-32765. If received any investigational agent prior to this time point, drug-related toxicities must have recovered to Grade 1 or less prior to first dose of study drug.
4. Systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).
5. Patients with uncontrolled Autoimmune Hemolytic Anemia (AIHA) or autoimmune thrombocytopenia (ITP).
6. Patients with severe hematopoietic insufficiency, as defined by an absolute neutrophil count of less than 500/micro-L and/or a platelet count of less than 30,000/micro-L at time of screening for this protocol.
7. Any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney, liver or other organ system that may place the patient at undue risk to undergo therapy with PCI-32765 and rituximab.
8. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification.
9. Significant screening ECG abnormalities including left bundle branch block, 2nd degree AV block type II, 3rd degree block, bradycardia, and QTc \> 470 msec.
10. Any serious medical condition, laboratory abnormality, or psychiatric illness that places the subject at unacceptable risk if he/she were to participate in the study.
11. History of stroke or cerebral hemorrhage within 6 months.
12. Evidence of bleeding diathesis or coagulopathy.
13. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1, anticipation of need for major surgical procedure during the course of the study.
14. Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to Day 1. Bone marrow aspiration and/or biopsy are allowed.
15. Serious, non-healing wound, ulcer, or bone fracture.
16. Treatment with Coumadin. Patients who recently received Coumadin must be off Coumadin for at least 7 days prior to start of the study.
17. Any chemotherapy (e.g., bendamustine, cyclophosphamide, pentostatin, or fludarabine), immunotherapy (e.g., alemtuzumab, or ofatumumab), bone marrow transplant, experimental therapy, or radiotherapy is prohibited during therapy on this study.
18. Use of medications known to prolong QTc interval or that may be associated with Torsades de Pointes (refer to Appendix F) are prohibited within 7 days of starting study drug and during study-drug treatment.
19. Requires treatment with strong CYP3A4/5 and/or CYP2D6 inhibitors.
B: Key Inclusion Criteria:

* Previously treated recurrent CLL
* Measurable lymphadenopathy
* Requires therapy for CLL
* Has experienced CLL progression \< 36 months since the completion of the last prior therapy

Key Exclusion Criteria:

* Recent history of a major non-CLL malignancy
* Evidence of an ongoing infection
* CLL refractory to bendamustine
* Concurrent participation in another therapeutic clinical trial

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

* Specific Diagnosis of B-Cell CLL
* An absolute lymphocytosis of \> 5,000/μL
* Morphologically, the lymphocytes must appear mature with \< 55% prolymphocytes
* Bone marrow examination must include at least a unilateral aspirate and biopsy; the aspirate smear must show \> 30% of all nucleated cells to be lymphoid or the bone marrow core biopsy must show lymphoid infiltrates compatible with marrow involvement by CLL; the overall cellularity must be normocellular or hypercellular
* Local institution lymphocyte phenotype must reveal a predominant B-cell monoclonal population sharing a B-cell marker (CD19, CD20, CD23) with the CD5 antigen, in the absence of other pan-T-cell markers; additionally, the B-cells must be monoclonal with regard to expression of either κ or λ and have surface immunoglobulin expression of low density; patients with bright surface immunoglobulin levels must have CD23 co-expression
* Patients must be in the intermediate- or high-risk categories of the modified three-stage Rai staging system (i.e., stages I, II, III, or IV)
* Patients in the intermediate-risk group must have evidence of active disease as demonstrated by at least one of the following criteria:

  * Massive or progressive splenomegaly, hepatomegaly and/or lymphadenopathy;
  * Presence of weight loss \> 10% over the preceding 6 month period;
  * Grade 2 or 3 fatigue;
  * Fevers \> 100.5°F or night sweats for greater than 2 weeks without evidence of infection;
  * Progressive lymphocytosis with an increase of \> 50% over a 2 month period or an anticipated doubling time of less than 6 months
* No prior therapy for CLL including corticosteroids for autoimmune complications that have developed since the initial diagnosis of CLL
* No medical condition requiring chronic use of oral corticosteroids
* Performance Status 0 - 2
* Due to alterations in host immunity, patients with HIV may not be enrolled
* Due to the unknown teratogenic potential of alemtuzumab, pregnant or nursing women may not be enrolled; women and men of reproductive potential should agree to use an effective means of birth control
* Creatinine =\< 1.5 x upper limit of institutional normal value
* Coomb's Testing NEGATIVE

Answer: C