A Study of Lenalidomide Maintenance for High-risk Patients With CLL Following First-line Therapy

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 andtreatment 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 orbendamustine/rituximab.
6. Must have achieved a response of at least PR ((IWCLL guidelines for the diagnosis andtreatment of chronic lymphocytic leukemia )following completion (minimum 4 cycles) offirst 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 combinedwith 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 lessthan 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 atleast 4 cycles should document reason for early discontinuation.
9. Must have an Eastern Cooperative Oncology Group (ECOG see appendix 11.13) performancestatus score of ≤2.
10. Negative serological Hepatitis B test or negative PCR in case of positive serologicaltest 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 studytherapy. She must agree to ongoing pregnancy testing during the course of thestudy, and after end of study therapy. This applies even if the subject practicescomplete and continued sexual abstinence.
• Either commit to continued abstinence from heterosexual intercourse (which mustbe reviewed on a monthly basis) or agree to use, and be able to comply with, tworeliable 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 studytherapy.

12. Male subjects must:

• Agree to use a condom during sexual contact with a FCBP, even if they have had avasectomy, throughout study drug therapy, during any dose interruption and aftercessation of study therapy.
• Agree to not donate semen during study drug therapy and for a period after end ofstudy drug therapy.

13. All subjects must:

• Have an understanding that the study drug could have a potential teratogenicrisk.
• Agree to abstain from donating blood while taking study drug therapy andfollowing 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 theability 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 torandomization 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 offirst-line induction therapy and randomization.
7. Participation in any clinical study or having taken any investigational therapy whichwould interfere with the study drug for a disease other than CLL within 28 days priorto initiating maintenance therapy.
8. Known presence of alcohol and/or drug abuse.
9. Central nervous system (CNS) involvement as documented by spinal fluid cytology orimaging. Subjects who have signs or symptoms suggestive of leukemic meningitis or ahistory of leukemic meningitis must have a lumbar puncture procedure performed withintwo weeks prior to randomization.
10. Prior history of malignancies, other than CLL, unless the subject has been free of thedisease 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 orpersons who are who are in dependence to the sponsor or an investigator.