Lenalidomide With or Without Idelalisib in Treating Patients With Relapsed or Refractory Mantle Cell Lymphoma

1. Documentation of Disease: 1. Histologically documented mantle cell lymphoma, with the following immunophenotypic characteristics: cluster of differentiation (CD)5+, (CD)23-, cyclin D1+; this may be from an initial diagnostic biopsy, or one obtained at time of relapse 2. Institutional flow cytometry or immunohistochemistry must confirm CD5 antigen expression, lack of CD23 antigen expression, and expression of cyclin D1. 3. Variant cases of mantle cell lymphoma will be eligible to participate after discussion and joint agreement between the PI, the Pathology Committee Chair, and the Lymphoma Committee Chair. Variant cases may include (but are not limited to) lack of Cyclin D1 expression (ie cases with Cyclin D2 or Cyclin D3 expression), CD23 negativity (if all other criteria are met), or alternative translocations leading to Cyclin D1 expression. 2. Prior Treatment - Patients must have prior treatment with at least one regimen, which may have been single agent or multi-agent, and consisted of traditional cytotoxic agents and/or biologic agents. Patient must not have received prior idelalisib or lenalidomide therapy. Patient must have progressive disease or refractory disease. Refractory disease will be defined as stable disease (SD) or progressive disease (PD) as best response to prior therapy. Progressive disease will be defined as complete response (CR) or partial response (PR) as initial response to prior therapy followed by disease progression within 6 months. Prior autologous, but not allogeneic, stem cell transplant is allowed. No corticosteroids within two weeks prior to study, except for maintenance therapy for a non-malignant disease. Maintenance therapy dose may not exceed 20 mg/day prednisone or equivalent. 3. Eastern Cooperative Oncology Group (ECOG) Performance Status - Patients must have ECOG performance status of 0-2. 4. Measurable Disease must be present either on imaging studies. Non-measurable disease alone is not acceptable. Any tumor mass \> 1 cm by computed tomography (CT), magnetic resonance imaging (MRI), or conventional radiograph is acceptable. Lesions that are considered non-measurable include the following: 1. Bone lesions (lesions, if present, should be noted) 2. Ascites 3. Pleural/pericardial effusion 4. Lymphangitis cutis/pulmonis 5. Bone marrow (involvement by non-Hodgkin lymphoma should be noted) 5. Central Nervous System (CNS) Involvement - Patients must have no known CNS involvement by lymphoma. 6. Human Immunodeficiency Virus (HIV) Infection - Patients with HIV infection are eligible, provided they meet the following: 1. CD4+ cell count \> 350/mm3 2. Treatment sensitive HIV and, if on anti-HIV therapy, HIV viral load \< 50 copies/mm3 3. No history of Acquired Immune Deficiency Syndrome (AIDS)-defining conditions or other HIV related illness 4. No concurrent zidovudine or stavudine because of overlapping toxicities with protocol therapy 5. Patients with known HIV positivity must have CD4 assessment and viral load at baseline and every 6 months while on study. 7. Pregnancy and Nursing Status - Patients must be non-pregnant and non-nursing. 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 prior to registration. Further, they 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 starting lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP, even if they have had a successful vasectomy. A FCBP is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy, or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time preceding 24 consecutive months). 8. Deep Vein Thrombosis/Pulmonary Embolism (DVT/PE) - Patients with a recent history (within 3 months of study entry) of DVT/PE are not eligible. Patients with a distant history (greater than 3 months before study entry) of DVT/PE are eligible, but must receive either prophylactic aspirin or low molecular weight heparin, unless contraindicated. 9. Congestive Heart Failure - Patients must have no New York Heart Association (NYHA) Class III or Class IV congestive heart failure at study entry. 10. Myocardial Infarction - Patients must have no myocardial infarction within 6 months prior to study entry. 11. Hepatitis - Patients must not have known positivity for hepatitis B, as evidenced by + HBsAg or +anti-HBc, and must not have known history of hepatitis C. 12. Patients must be ≥ 18 years of age. 13. Cytochrome P450 3A4 (CYP3A4) Strong Inducers and Inhibitors - Patients must not be on strong CYP3A4 inhibitors and/or inducers. 1. The following strong inhibitors are prohibited: indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole,nefazodone 2. The following strong inducers are prohibited: carbamazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John's Wort, troglitazone 14. Required Initial Laboratory Values: 1. ANC ≥ 1,000/µL, ≥ 500/µL if marrow involvement 2. Platelets ≥ 75,000/µL 3. Creatinine ≤ 1.5 x ULN, and estimated creatinine clearance ≥ 60 mL/min (patients on dialysis not eligible), unless attributable to non-Hodgkin lymphoma 4. Total bilirubin ≤ 2 x ULN, unless attributable to non-Hodgkin lymphoma or Gilbert's disease