This is a dose-escalation to determine the MTD and/or RPII for combinations of ibrutinib (PCI-32765) plus lenalidomide/rituximab in patients with relapsed/refractory mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a relatively rare subtype (3% to 6% (Zhou, 2008) of mature B cell non-Hodgkin lymphomas (NHL), with a median age at diagnosis in mid to late 60's, a male predominance (3/1) and typically advanced stage presentation though only about 1/3 of patients are truly symptomatic at baseline (Armitage, 1998). Although significant controversies remain in the management of MCL, all would agree that the challenges associated with MCL, particularly the poor results with standard chemotherapy and frequent chemoresistance have pushed the community to be more innovative and active in clinical research. Hence the median OS has clearly improved over the last 3 decades (from 2-3y to >5y) (Goy, 2011a), thanks to deeper responses obtained with intensive regimens in younger patients (an early CR translates into clearly better outcome) and also better salvage therapies with now MCL being the only lymphoma with 4 new biologicals approved (3 in the US and 1 in EU).

Inclusion Criteria:

• Age greater than or equal to 18 years.
• Histologically or cytologically confirmed diagnosis of MCL.
• Relapsed or refractory MCL patients who have received at least one prior therapy are eligible. Patients who have previously received high-dose chemotherapy with peripheral stem cell support are eligible.
• Presence of at least one lymph node evaluable or mass measurable for response.
• Eastern Cooperative Oncology Group Performance Status greater than 2.
• Platelets > 75,000/μL and absolute neutrophils count (ANC) > 1,000/μL within 14 days of study registration (unless the treating physician deems the neutropenia is related to bone marrow involvement, then an ANC of > 750/mm 3 is allowed)
• Normal renal function defined as serum creatinine less than 2.
• Recovery from any previous treatment therapy.
• Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test
• All study participants must be registered into the mandatory Revlimid REMS® program, and be willing and able to comply with the requirements of the REMS® program.
• Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS® program.
• Ability to understand, and willingness to sign, a written informed consent document.
• Able to take aspirin (81 or 325 mg) daily as prophylactic anti-coagulation (patients intolerant to ASA may use low molecular weight heparin).
• Normal organ and bone marrow function parameter:

Laboratory tests Required value WBC >3000/μL* Absolute neutrophils count >1,000/μL* Platelets >75,000/μL Total bilirubin < 1.5Within normal institutional limits AST (SGOT) and ALT (SGPT) <3 x institutional upper limit of normal Creatinine or creatinine clearance <1.5 within normal institutional limits >60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal (calculated by Cockcroft-Gault formula)

Exclusion Criteria:

• Concomitant use of warfarin or other Vit K antagonists
• Central nervous system (CNS) involvement by lymphoma at time of enrollment.
• Other medical conditions that would potentially interfere with patient participation in this trial.
• A second malignancy, other than basal cell carcinoma of the skin or in situ carcinoma of the cervix (unless for other tumor type patient was treated with curative intent at least 2 years previously.)
• Known human immunodeficiency virus (HIV-1) infection or chronic hepatitis B, or C (Hep B serology positive without active infection will be eligible)
• Active, clinically serious infection > CTCAE grade 2. Patients may be eligible upon resolution of the infection.
• Major surgery or significant traumatic injury within 28 days of the first dose of study drug.
• Use of any other standard chemotherapy, radiation therapy, or experimental drug therapy for the treatment of MCL within 21 days of starting treatment or 5 half life times (whatever is shorter)
• Patients with grade 3/4 cardiac problems, as defined by the New York Heart Association (NYHA) criteria:
• History of uncontrolled or symptomatic angina
• History of uncontrolled arrhythmias
• Myocardial infarction < 6 months from study entry
• Uncontrolled or symptomatic congestive heart failure
• Ejection fraction below the institutional normal limit
• Any other cardiac condition that, in the opinion of the treatment physician, would make this protocol unreasonably hazardous for the patient
• Patients unwilling or unable to comply with the protocol.