Please select the eligibility criteria that correspond to the clinical trial below.
Title: Fludarabine/Rituximab Combined With Escalating Doses of Lenalidomide Followed by Rituximab/Lenalidomide in Untreated Chronic Lymphocytic Leukemia (CLL) - a Dose-finding Study With Concomitant Evaluation of Safety and Efficacy.
Brief Summary: The aim of this study is to determine the maximal tolerated dose level of lenalidomide combined with fludarabine/rituximab in the therapy of patients with previously untreated CD20-positive chronic lymphocytic leukemia. Following a dose escalation phase lenalidomide will be given at the pre-determined maximum tolerated dose in combination with rituximab to further determine the efficacy and tolerability of this regimen.


Options:
A: Inclusion Criteria:

1. Must understand and voluntarily sign an informed consent form.
2. Age ≥ 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 CLL (IWCLL guidelines for the diagnosis and treatment of chronic lymphocytic leukemia1.
5. Must have been treated with one of the first line induction therapies: fludarabine/cyclophosphamide, fludarabine/rituximab, fludarabine/cyclophosphamide/rituximab, pentostatin/cyclophosphamide/rituximab or bendamustine/rituximab.
6. Must have achieved a response of at least PR ((IWCLL guidelines for the diagnosis and treatment of chronic lymphocytic leukemia )following completion (minimum 4 cycles) of first line induction therapy prior to randomization, and have either:

   * MRD levels in the peripheral blood at final restaging of ≥10-2 or
   * MRD levels in the peripheral blood at final restaging of ≥10-4 - \<10-2 combined with an unmutated IGHV-status or 17p-deletion or TP53 mutation.
7. Must have completed last cycle of at least 4 cycles of first-line induction no less than 8 weeks (56 days) and no greater than 20 weeks (140 days) prior to randomization.
8. Subjects who completed first-line induction treatment with less than 6 cycles but at least 4 cycles should document reason for early discontinuation.
9. Must have an Eastern Cooperative Oncology Group (ECOG see appendix 11.13) performance status score of ≤2.
10. Negative serological Hepatitis B test or negative PCR in case of positive serological test without evidence of an active infection, negative testing of Hepatitis C RNA, negative HIV test within 6 weeks prior to randomization.
11. 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 intercourse (which must be reviewed on a monthly basis) or agree to use, and be able to comply with, two reliable forms of effective contraception simultaneously to achieve a PEARL-Index \<1 without without interruption (Highly effective methods: Intrauterine device (IUD), Hormonal (birth control pills, injections, implants), Tubal ligation, Partner's vasectomy, Additional effective methods: Male condom, Diaphragm, Cervical Cap). 28 days prior to starting study drug, during the study therapy (including dose interruptions), and for 28 days after discontinuation of study therapy.
12. Male subjects must:

    * 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.
13. 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.
    * Be counseled about pregnancy precautions and risks of fetal exposure.
14. Willingness to inform the general practitioner

Exclusion Criteria:

1. A CIRS Score of more than 6 or a single score of 4 for an organ system limiting the ability to receive an intensive treatment
2. Active infections requiring systemic antibiotics.
3. Systemic infection CTC grade 3 or 4 that has not resolved \> 2 months prior to randomization in spite of adequate anti-infective therapy.
4. Autologous or allogeneic bone marrow transplant as first line therapy.
5. Pregnant or lactating females.
6. Systemic treatment for CLL in the interval between completing the last cycle of first-line induction therapy and randomization.
7. Participation in any clinical study or having taken any investigational therapy which would interfere with the study drug 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 (CNS) 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 histological finding of prostate cancer (TNM stage of T1a or T1b)
11. History of renal failure requiring dialysis.
12. Prior therapy with lenalidomide.
13. Any of the following laboratory abnormalities:

    * Calculated (method of Cockcroft-Gault) creatinine clearance of \<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)
14. Uncontrolled hyperthyroidism or hypothyroidism.
15. Venous thromboembolism within one year.
16. ≥ Grade-2 neuropathy.
17. Uncontrolled autoimmune hemolytic anemia or thrombocytopenia.
18. Disease transformation (active) (i.e. Richter's Syndrome, prolymphocytic leukemia).
19. Known allergy to allopurinol if the subject has bulky disease.
20. Prisoners, or subjects who are institutionalized by regulatory or court order or persons who are who are in dependence to the sponsor or an investigator.
B: Inclusion Criteria:

* B-CLL (CD23+, CD5+, CD19+, CD20+)
* Treatment indication according to NCI criteria
* Age \>= 18 yrs
* No previous treatment of CLL by chemo-, radio- or immunotherapy
* Life expectancy \> 6 months
* Written informed consent
* Women of non-childbearing potential or women of childbearing potential and men using effective contraception

Exclusion Criteria:

* Active bacterial, viral or fungal infection
* Positivity for HIV, Hepatitis B or C
* Reduce organ functions and bone marrow dysfunction not due to CLL
* Creatinine clearance below 30 ml/min
* Patients with medical conditions requiring long-term use of systemic corticosteroids during study treatment
* Patients with a history of severe cardiac disease
* Other known co-morbidity with the potential to dominate survival
* Transformation to aggressive B-cell malignancy
* Known hypersensitivity to humanised monoclonal antibodies or any of the study drugs
* Pregnant or breast-feeding women
* Any co-existing medical or psychological condition that would preclude participation in the study or compromise ability to give informed consent
C: 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.
D: DISEASE CHARACTERISTICS:

* Diagnosed B-cell chronic lymphocytic leukemia (CLL) defined by the National Cancer Institute (NCI) Working Group criteria
* Meets 1 of the following criteria:

  * Binet stage C disease
  * Binet stage B disease AND ≥ 1 of the following signs or symptoms\*:

    * B symptoms (night sweats, weight loss ≥ 10% within the previous 6 months, fevers \> 38°C or 100.4°F for ≥ 2 weeks without evidence of infection), or constitutional symptoms (fatigue)
    * Continuous progression (doubling of peripheral lymphocyte count within the past 6 months and absolute lymphocyte count \> 50 G/I)
    * Evidence of progressive marrow failure as manifested by the development/worsening of anemia and/or thrombocytopenia
    * Massive, progressive or painful splenomegaly or hypersplenism
    * Massive lymph nodes or lymph node clusters (\> 10 cm in longest diameter), danger of organ complications through large lymphoma (e.g., vascular compression or tracheal narrowing), or progressive lymphadenopathy
    * Occurrence of symptomatic hyperviscosity problems at leukocyte counts \> 200 G/I (symptomatic leukostasis) NOTE: \* Marked hypogammaglobulinemia or the development of a monoclonal protein in the absence of any of the above criteria for active disease is not sufficient for eligibility
* No Binet stage A disease
* No transformation to an aggressive B-cell malignancy (e.g., diffuse large cell lymphoma, Richter's syndrome, or prolymphocytic leukemia)

PATIENT CHARACTERISTICS:

* Eastern Cooperative Oncology Group (ECOG) performance status 0-1
* Cumulative Illness Rating Scale (CIRS) score \> 6
* Life expectancy \> 6 months
* Bilirubin ≤ 2 times upper limit of normal (ULN)
* Alkaline phosphatase and transaminases ≤ 2 times ULN
* Creatinine clearance ≥ 70 mL/min
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception during and for 2 months after study treatment
* No known hypersensitivity with anaphylactic reaction to humanized monoclonal antibodies or any of the study drugs
* No cerebral dysfunction that precludes chemotherapy
* No active bacterial, viral, or fungal infection
* No clinically significant autoimmune cytopenia or Coombs-positive hemolytic anemia
* No other active malignancy requiring concurrent treatment except basal cell carcinoma or tumors treated curatively by surgery
* No medical or psychological condition that would preclude study therapy
* No concurrent disease that requires prolonged (\> 1 month) therapy involving glucocorticoids

PRIOR CONCURRENT THERAPY:

* No previous treatment of CLL by chemotherapy, radiotherapy, or immunotherapy

Answer: B