R-CHOP + R-HAD vs R-CHOP Followed by Maintenance Lenalidomide + Rituximab vs Rituximab for Older Patients With MCL

This study aims to evaluate whether the addition of lenalidomide to rituximab-maintenance improves progression free survival (PFS) compared to standard rituximab maintenance after induction treatment consisting of R-CHOP + R-HAD versus R-CHOP alone in older patients (≥ 60 year old) with mantle cell lymphoma. 643 patients will be randomized in induction phase and 433 in maintenance phase.

The treatments consist of two phases:

• induction treatment will be 3 cycles of R-CHOP21 + 3 cycles of R-HAD28(alternating) versus 8 cycles of R-CHOP21 alone
• maintenance treatment will be 13 cycles of rituximab every 8 weeks + 26 cycles of lenalidomide every 4 weeks vs 13 cycles of rituximab every 8 weeks.

Patients will be followed 2.5 years after the last patient randomized for maintenance for final analysis. All subjects who complete or discontinue the maintenance treatment for any reason will be followed for at least 3 years after his/her last study treatment administration in maintenance period for Second Primary Malignancies (SPM). A long term follow-up for progression/death will be done up to the end of period of SPM data collection.

Inclusion criteria

Signed informed consent form Biopsy-proven MCL according to WHO classification

≥ 60 years of age and ineligible for autologous transplant Ann Arbor stage II-IV Previously untreated ECOG PS ≤ 2

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.

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 counselled about pregnancy precautions and risks of foetal exposure.

Additional criteria for randomization in maintenance phase:

• CR, CRu or PR after induction treatment, determined as per Cheson 1999 criteria
• During the run-in period of 6 months starting from the date of the first randomization in the trial: in case of direct randomization into maintenance phase, patient must have been treated in first line by 6-8 cycles of R-CHOP.

Exclusion criteria

Female of childbearing potential

Any of the following laboratory abnormalities at diagnosis, if not related to lymphoma:

Absolute neutrophils count <1,000 /mm3 Platelet count < 75,000/mm3 AST/SGOT or ALT/SGPT >3.0 UNL Serum total bilirubin > 1.5 ULN (except if due to Gilbert's syndrome) Calculated creatinine clearance (Cockcroft-Gault formula or MDRD) < 30 mL / min Central Nervous System involvement by lymphoma Contraindication for medical DVT prophylaxis for patients at high risk for DVT

Prior history of malignancies other than MCL unless the subject has been free of the disease for ≥ 5 years. Exceptions include the following:

• Basal cell carcinoma 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). Any serious medical condition, laboratory abnormality or psychiatric illness that would prevent the patient to receive the study medication as planned.

Seropositivity for human immunodeficiency virus at study entry Seropositivity for hepatitis C virus at study entry,

Active viral infection with hepatitis B virus at study entry:

• HBsAg positive
• HBsAg negative, anti-HBs positive and anti-HBc positive

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.

Prior ≥ Grade 3 allergic hypersensitivity to thalidomide. Prior ≥ Grade 3 rash or any desquamating (blistering) rash while taking thalidomide.

Known anti-murine antibody (HAMA) reactivity or known hypersensitivity to murine antibodies.

Subjects with ≥ Grade 2 neuropathy. Prior use of lenalidomide Participation in another clinical trial within three weeks before randomization in this study

Additional criteria for randomization in maintenance phase:

• SD or PD after induction treatment determined as per Cheson 1999 criteria
• Patient treated by induction immuno-chemotherapy other than 6-8 cycle of R-CHOP21 or 2-3 cycles of R-CHOP21 / 2-3 cycles of R-HAD28 (alternating)
• Patients with serious underlying medical conditions, which could impair the ability to receive maintenance treatment
• Calculated creatinine clearance of < 30 mL / min
• ANC is < 1,000 cells/mm³
• Platelet count is < 50,000 cells/mm³