Efficacy of alternating immunochemotherapy consisting of RCHOP + R-HAD versus R-CHOP alone, followed by maintenance therapy consisting of additional lenalidomide with rituximab versus rituximab alone for older patients with mantle cell lymphoma

Randomization 1:
1. signed informed consent form
2. Biopsy-proven mantle cell lymphoma according to WHO classification,
including evidence of cyclin D1 overexpression or the translocation
t(11;14)(q13;q32),
3. >= 60 years of age and ineligible for autologous transplant
4. Ann Arbor stage II-IV
5. previously untreated (except for patients randomized directly for
maintenance treatment who will receive 8 RCHOP before registration in the trial)
6. ECOG performance status <= 2
7. Male subjects must:
- agree to use a condom during sexual contact with a woman of childbearing
potential, even if they have had a vasectomy, throughout lenalidomide therapy
- agree to not donate semen during lenalidomide therapy.
8. All subjects must:
- have an understanding that the lenalidomide could have a potential
teratogenic risk.
- agree to abstain from donating blood while taking lenalidomide therapy
- agree not to share study medication with another person.
- be counseled about pregnancy precautions and risks of foetal exposure.,
Randomization 2:
To be randomized for maintenance, the patient must satisfy all inclusion /
exclusion criteria for randomization 1 and the following criteria:
9. CR, CRu or PR after induction treatment, determined as per Cheson 1999
criteria by investigator
10. During the run-in period of 6 months starting from the date of the first
randomization, in the case of direct randomization into maintenance phase,
patient must have been treated in first line by 6-8 cycles of R-CHOP.

Randomization 1:
1. Female of child-bearing potential (without natural menopause for at least 24
consecutive months, a hysterectomy or bilateral oophorectomy)
2. Any of the following laboratory abnormalities, if not related to lymphoma:
- Absolute neutrophils count (ANC) <1,000 /mm^3 (1.0 x 10^9/L) if not result
of a BM infiltration.
- Platelet counts < 75,000/mm^3 (75 x 10^9/L) if not result of a BM
infiltration.
- Serum aspartate transaminase (AST/SGOT) or alanine transaminase(ALT/SGPT)
>3.0 x upper limit of normal (ULN).
- Serum total bilirubin > 1.5 UNL (except if due to Gilbert*s syndrome)
3. Calculated creatinine clearance (Cockcroft-Gault formula or MDRD) < 30 mL /
min
4. Central nervous system involvement by lymphoma
5. Contraindication for medicamentous DVT prophylaxis for patients at high risk
for DVT
6. Prior history of malignancies other than MCL unless the subject has been
free of the disease for >= 5 years (Exceptions: Basal or squamous cell carcinoma
of the skin, Carcinoma in situ of the cervix or of the breast, Incidental
histologic finding of prostate cancer (TNM stage of T1a or T1b).
7. Any serious medical condition, laboratory abnormality, or psychiatric
illness that would prevent the patient to receive the study medication as
planned.
8. Poor cardiac function (LVEF <50%) on echocardiography
9. Seropositivity for human immunodeficiency virus (HIV, mandatory test)
Seropositivity for hepatitis C virus (HCV, mandatory test), Active viral
infection with hepatitis B virus (HBV, mandatory test):
- HBsAg positive
- HBsAg negative, anti-HBs positive and anti-HBc positive
Patients with prior Hepatitis B must be given antiviral prophylaxis and HBV DNA
monitored. Note: Patients who are HBsAg negative, anti-HBs positive and/or
anti-HBc positive but viral DNA negative are eligible.
10. Uncontrolled illness including, but not limited to:
- Active infection requiring parenteral antibiotics
- Uncontrolled diabetes mellitus
- Chronic symptomatic congestive heart failure (Class NYHA III or IV).
- Unstable angina pectoris, angioplasty, stenting, or myocardial infarction
within 6 months
- Clinically significant cardiac arrhythmia that is symptomatic or requires
treatment, or asymptomatic sustained ventricular tachycardia.
11. Prior >= Grade 3 allergic hypersensitivity to thalidomide.
12. Prior >= Grade 3 rash or any desquamating (blistering) rash while taking
thalidomide.
13. Subjects with >= Grade 2 neuropathy.
14. Known anti-murine antibody (HAMA) reactivity or known hypersensitivity to
murine antibodies
15. Prior use of lenalidomide.
16. Participation in another clinical trial within three weeks before
randomization in this study., Randomization 2:
The presence of any exclusion criteria of randomization 1 or of the following
criteria will exclude a subject from enrollment in the maintenance phase:
17. SD or PD after induction treatment determined as per Cheson 1999 criteria
assessed by investigator.
18. Patients who had not received at least 6 cycles of R-CHOP21 or 2 cycles of
R-CHOP21 / 2 cycles of R-HAD28 (alternating)
19. Patients with serious underlying medical conditions, which could impair the
ability to receive maintenance treatment
20. Calculated creatinine clearance (Cockcroft-Gault formula or MDRD) of < 30
mL /min at screening for maintenance.
21. ANC < 1,000 cells/mm³ (1.0 X 10^9/L) at screening for maintenance;
22. Platelet count < 50,000 cells/mm³ (50 X 10^9/L) at screening for
maintenance.