Bendamustine Hydrochloride and Rituximab With or Without Bortezomib Followed by Rituximab With or Without Lenalidomide in Treating Patients With High-Risk Stage II, Stage III, or Stage IV Follicular Lymphoma

Inclusion Criteria (Induction):

• Histologically confirmed (biopsy-proven) diagnosis of follicular B-cell non-Hodgkin lymphoma with no evidence of transformation to large cell histology
• Patients having both diffuse and follicular architectural elements are eligible if the histology is predominantly follicular (i.e., ≥ 50% of the cross-sectional area) and there is no evidence of transformation to a large cell histology
• Diagnostic confirmation (i.e., core needle or excisional lymph node biopsy) required if the interval since tissue diagnosis of low-grade malignant lymphoma is > 24 months
• Bone marrow biopsy alone not acceptable
• Stage II, III, or IV AND grade 1, 2, or 3a disease
• Must meet criteria for High Tumor Burden (higher risk) as defined by either the Groupe D'Etude des Lymphomes Follicularies (GELF) criteria OR the follicular lymphoma international prognostic index (FLIPI) as defined below:
• Patient must meet ≥ 1 of the following GELF criteria:
• Nodal or extranodal mass ≥ 7 cm
• At least 3 nodal masses > 3.0 cm in diameter
• Systemic symptoms due to lymphoma or B symptoms
• Splenomegaly with spleen > 16 cm by CT scan
• Evidence of compression syndrome (e.g., ureteral, orbital, gastrointestinal) or pleural or peritoneal serous effusion due to lymphoma (irrespective of cell content)
• Leukemic presentation (≥ 5.0 x 10^9/L malignant circulating follicular cells)
• Cytopenias (polymorphonuclear leukocytes 4 nodal areas
• Serum lactate dehydrogenase (LDH) level above normal
• At least 1 objective measurable disease parameter
• Baseline measurements and evaluations (PET and CT) obtained within 6 weeks of randomization
• Measurable disease in the liver is required if the liver is the only site of lymphoma
• HIV-positive patients must meet all of the following criteria:
• HIV is sensitive to antiretroviral therapy
• Must be willing to take effective antiretroviral therapy if indicated
• No history of CD4 48 hours off antibiotics)
• ≥ grade 2 neuropathy
• Myocardial infarction within the past 6 months
• NYHA class III-IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
• Serious medical or psychiatric illness likely to interfere with participation in this clinical study
• Known hypersensitivity to boron or mannitol
• Chronic carriers of hepatitis B virus (HBV) with positive hepatitis surface antigen (HBsAg +)

Inclusion Criteria (Continuation):

• Patient must have improved their response or have had no interval change in their tumor measurements with restaging from Induction cycle 3 to 6 as determined at Cycle 6 restaging.
• Adequate organ function
• ECOG performance status 0-2
• Patients with a prior history of HBV infection, but immune, with only IgG hepatitis core antibody positive (HBcAb+), must receive antiviral prophylaxis (e.g., lamivudine 100 mg po daily) for ≥ 1 week prior to course 1 and throughout induction and continuation therapy and for ≥ 12 months after the last rituximab dose
• Additional requirements for Arm C induction patients registering to arm F:
• Patients must be willing to take deep vein thrombosis (DVT) prophylaxis. Subjects with a history of a thrombotic vascular event will be required to have full anticoagulation, therapeutic doses of low molecular weight heparin or warfarin to maintain an INR between 2.0 - 3.0, or any other accepted full anticoagulation regimen (e.g. direct thrombin inhibitors or Factor Xa inhibitors) with appropriate monitoring for that agent. Subjects without a history of a thromboembolic event are required to take a daily aspirin (81 mg or 325 mg) for DVT prophylaxis. Subjects who are unable to tolerate aspirin should receive low molecular weight heparin therapy or warfarin treatment or another accepted full anticoagulation regimen.
• Females of childbearing potential (FCBP) must agree to use two reliable forms of contraception simultaneously