A phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study of the
efficacy and safety of lenalidomide (Revlimid®) as maintenance therapy for high-risk patients with
chronic lymphocytic leukemia following first-line therapy

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/rituximab, or bendamustine/rituximab or
fludarabine/rituximab or fludarabine/cyclophosphamide,(in case of
hypersensitivity reactions to Rituximab).
6. Must have achieved a response of at least PR (IWCLL guidelines for the
diagnosis and treatment of chronic lymphocytic leukemia [Hallek, 2008])
following completion (minimum 4 cycles) of first-line induction therapy prior
to randomization (documentation of response status must be available).
and have either:
a. MRD levels in the peripheral blood at final restaging of >=10^2 or
b. MRD levels in the peripheral blood >=10^4 - <10^2 combined with at
least one of the following factors:
• an unmutated IGHV-status
• 17p-deletion or
• TP53 mutation1
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
but at least 4 cycles should document reason for early discontinuation
9. Must have an Eastern Cooperative Oncology Group (ECOG)
performance status score of <=2.
10. Negative serological Hepatitis B test, negative testing of Hepatitis C
RNA, negative HIV test within 6 weeks prior to randomization.
11. Females of childbearing potential (FCBP)*
• 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.
must:
• 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
interruption (Highly effective methods: Intrauterine device (IUD),
Hormonal (birth control pills, injections, implants), Tubal ligation,
Partner*s vasectomy, Additional effective methods: Male condom,
*
Definition: This protocol defines a female of childbearing potential as a sexually mature woman who: 1) has not undergone a hysterectomy or
bilateral oophorectomy or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing
potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
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CLLM1 Protocol of the DCLLSG version 2.1of 4th June 2012 University of Cologne
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 practicioner

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 therapy for CLL
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 folowing:
- 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 Cockroft-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 glutamicoxaloacetic 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