Efficacy and safety of first-line therapy with chlorambucil, rituximab and lenalidomide (Revlimid®) (CR2) in elderly patients and young frail patients with advanced Chronic Lymphocytic Leukemia (CLL): A phase II trial.

1. Diagnosis of CLL without prior treatment;

2. Patients with symptomatic (according to IWCLL guidelines) stage A or stage B or stage C;

3. Age ≥ 65 years at the time of signing the informed consent form, or age < 65 years and CIRS ≥ 7;

4. Able to adhere to the study visit schedule and other protocol requirements;

5. WHO performance status of ≥ 2;

6. Laboratory test results within these ranges: absolute neutrophil count ≥ 1.0 x 10^9/l, platelet count ≥ 30 x 10^9/l, creatinine clearance ≤ 60 ml/min, total bilirubin ≤ 25 umol/L, AST & ALT ≤ 2 x ULN;

7. Females of childbearing potential must have a negative serum or urine pregnancy test within 10 - 14 days prior to and again within 24 hours of starting lenalidomide;

8. Patients who are willing and capable to use adequate contraception during the therapy (all men, all pre-menopausal women). Patients must be able to adhere to the requirements of the Lenalidomide Pregnancy Prevention Risk Management Plan;

9. Written informed consent.

1. Patients that are unable or unwilling to adhere to the requirements of the Lenalidomide Pregnancy Prevention Risk Management Plan;

2. Intolerance of exogenous protein administration;

3. Hepatitis B Ag positive, Hepatitis C positive and/or HIV positive patients;

4. Patients with uncontrolled Autoimmune Hemolytic Anemia (AIHA) or autoimmune thrombocytopenia (ITP);

5. Active fungal, bacterial, and/or viral infection;

6. Pregnant or breast-feeding females (lactating females must agree not to breast feed while taking lenalidomide);

7. Use of any other experimental drug or therapy within 28 days of baseline;

8. Known hypersensitivity and/or serious adverse reactions to lenalidomide or similar drugs;

9. Any prior use of lenalidomide;

10. Concurrent use of other anti-cancer agents or treatments;

11. Uncontrolled hyperthyroidism or hypothyroidism;

12. Patients with history of idiopathic deep venous thrombus and/or pulmonary embolism within last three years;

13. Neuropathy ≥ grade 2;

14. History of active malignancy during the past 5 years with the exception of basal carcinoma of the skin; squamous cell carcinoma of the skin, carcinoma in situ of the cervix, carcinoma in situ of the breast, prostate cancer (TNM stage of T1a or T1b);

15. Current inclusion in other clinical trials;

16. Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.