Inclusion Criteria:
* Histologically confirmed diagnosis of mantle cell lymphoma
* Age ≥ 18 years
* No prior systemic therapy for lymphoma
* Measurable disease defined by a tumor mass ≥ 1.5 cm in one dimension and measurable in two dimensions; measurable spleen disease is allowed
* Treatment should be indicated according to the treating physician
* ECOG performance status ≤ 2
* Required initial laboratory parameters:
* Absolute neutrophil count (ANC) ≥ 1000 cells/mm3
* Platelet count ≥ 75,000 cells/mm3
* Calculated creatinine clearance ≥ 30 ml/min by Cockcroft-Gault formula
* Total bilirubin ≤ 2.0 x ULN
* AST/SGOT and ALT/SGPT ≤ 3.0 x ULN
* Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use low molecular weight heparin).
* All subjects must be registered into the mandatory Revlimid REMS® program, and be willing and able to comply with the requirements of Revlimid REMS®.
* Patients of reproductive potential agree to use birth control throughout their participation in this study, and for 28 days following study termination.
* Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS® program. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days). FCBP must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before and continue for at least 28 days after the last dose of lenalidomide (or 2 days after the last dose of acalabrutinib, whichever is longer). FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual activity with a FCBP through one week post last dose even if they have had a successful vasectomy. Men must also agree to refrain from sperm donation during the same timeframe. See Appendix: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods.
* Understand and voluntarily sign an ICF prior to any study related assessments and procedures are conducted.
* Able to adhere to the study visit schedule and other protocol requirements.
Exclusion Criteria:
* Patients with blastoid histology
* Patients with known or suspected CNS involvement
* Viral infection with HIV or hepatitis type B or C. Seropositive HBV patients are eligible if they are negative for HBV DNA by PCR and receive concomitant antiviral therapy during treatment and for additional six months after coming off study.
* Prior history of malignancies other than MCL unless the patient has been disease free for ≥ 5 years from the signing of the ICF. Exceptions include basal cell carcinoma or squamous cell carcinoma of the skin; carcinoma in situ of cervix; carcinoma in situ of breast, or localized prostate cancer
* Active uncontrolled systemic fungal, bacterial or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy and/or other treatment)
* Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification.
* Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass.
* Active bleeding or history of bleeding diathesis (e.g., hemophilia or von Willebrand disease).
* Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic purpura).
* Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer. Patients on moderate CYP3A inhibitors can be considered for study after a washout period of at least 7 days.
* Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days of first dose of study drug.
* Prothrombin time (PT)/INR or aPTT (in the absence of lupus anticoagulant) \>2x ULN.
* Requires treatment with proton pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study.
* History of significant cerebrovascular disease/event, including stroke or intracranial hemorrhage, within 6 months before the first dose of study drug.
* Major surgical procedure within 28 days of first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug.
* Patients with a history of toxic epidermal necrolysis or Stevens-Johnson syndrome
* Patients that are pregnant or breast feeding
* Known hypersensitivity to any study drug or excipients
* Patient on corticosteroids within two weeks prior to study entry, except for prednisone ≤ 20 mg/day or equivalent for purposes other than treating MCL
* Use of any other experimental drug or therapy within 28 days of baseline
* Patient at high risk for deep vein thrombosis not willing to take DVT prophylaxis
* Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
* Known prior exposure to BTK inhibitor
