This is a prospective multicenter phase II pilot trial designed with the purpose of dose finding to evaluate the efficacy and safety of treatment with Lenalidomide plus R-CHOP21 (LR-CHOP21) for elderly patients with untreated Diffuse Large B Cell Lymphoma (DLBCL).

Inclusion Criteria:

1. Understand and voluntarily sign an informed consent form

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

3. Histologic subtypes as follows:

   • CD20 positive Diffuse large B-Cell lymphoma
   • CD20 positive Follicular grade IIIb

4. Age 60-80

5. Untreated patients. In patients with bulky mass or systemic symptoms or compressive disease or rapidly progressive adenopathies a pre-study treatment is allowed with steroids and/or a single dose of Vincristine 1.4 mg/mq (max 2) in the seven days prior the start of the study treatment

6. Measurable and/or evaluable disease

7. Ann Arbor stage II, III, IV

8. International Prognostic Index at low-intermediate, intermediate-high, high risk (2/3/4-5)

9. Adequate haematological counts: ANC > 1.5 x 109/L and platelet count > 75 x 109/L unless due to bone marrow involvement

10. Conjugated bilirubin up to 2 x UNL

11. Alkaline phosphatase and transaminases up to 2 x UNL

12. Creatinine clearance > 50 ml/min

13. HIV negativity

14. HCV negativity

15. HBV negativity or patients with HBVcAb +, HbsAg -, HBs Ab+/- with HBV-DNA negative

16. Cardiac ejection fraction (MUGA scan or echocardiography) > 45%

17. Non peripheral neuropathy or CNS disease. Non testicular Lymphoma

18. Life expectancy > 6 months

19. Performance status < 2 according to ECOG scale

20. Comprehensive geriatric assessment (CGA) as outlined in Appendix 15 showing absence of any impairment in activity of daily living (ADL), of any condition defining a geriatric syndrome, and of any grade 4 comorbidity or of more than three grade 3 comorbidities according to CIRS-G scale

21. Disease 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

22. Females of childbearing potential (FCBP) must agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the following time periods related to this study: for at least 28 days before starting study drug;while participating in the study; for at least 28 days after discontinuation from the study

    • The two methods of reliable contraception must include one highly effective method (i.e., intrauterine device (IUD), hormonal [birth control pills, injections, or implants], tubal ligation, partner's vasectomy) and one additional effective (barrier) method (i.e., latex condom, diaphragm, cervical cap)
    • FCBP must be referred to a qualified provider of contraceptive methods if needed

Exclusion Criteria:

1. Lymphoblastic Lymphoma
2. Burkitt Lymphoma
3. Non Hodgkin lymphoma CD 20 negative
4. Mantle Cell Lymphoma
5. Follicular Non Hodgkin Lymphoma grade I-II-IIIa
6. Primitive mediastinal diffuse large B cell lymphoma with only mediastinal involvement
7. International Prognostic Index at low risk (1)
8. Has known or suspected hypersensitivity or intolerance to Rituximab
9. History of evolutive malignancy within the last 3 years other than squamous cell and basal cell carcinoma of the skin or carcinoma in situ of the cervix or breast
10. Extensive radiation therapy, systemic chemotherapy, or other antineoplastic therapy before enrollment within 3 years before the start of treatment
11. Exposure to Rituximab prior to study entry
12. Have received an experimental drug or used an experimental medical device within 4 weeks before the planned start of treatment. Concurrent participation in non-treatment studies is allowed, if it will not interfere with participation in this study
13. CNS disease (meningeal and/or brain involvement by lymphoma) or Testicular involvement
14. DVT in the last year
15. History of clinically relevant liver or renal insufficiency; significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, rheumatologic, hematologic, psychiatric, or metabolic disturbances
16. Uncontrolled diabetes (if receiving antidiabetic agents, subjects must be on a stable dose for at least 3 months before first dose of study drug
17. Uncontrolled or severe cardiovascular disease including myocardial infarction within 6 months of enrollment, New York Heart Association (NYHA) Class III or IV heart failure (Attachment 5, NYHA Classification of Cardiac Disease), uncontrolled angina, clinically significant pericardial disease, or cardiac amyloidosis
18. Creatinine clearance < 50 ml/min
19. Presence of major neurological disorders
20. HIV positivity
21. HBV positivity with the exception of patients with HBVcAb +, HbsAg -, HBs Ab+/- with HBV-DNA negative
22. HCV positivity
23. Active opportunistic infection
24. Comprehensive geriatric assessment (CGA) as outlined in Appendix 15 showing presence of any impairment in activity of daily living (ADL), of any condition defining a geriatric syndrome, and of any grade 4 comorbidity or of more than three grade 3 comorbidities according to CIRS-G scale
25. Any other co-existing medical or psychological condition that would preclude participation in the study or compromise ability to give informed consent