A 3-Arm Randomized Phase II Trial of Bendamustine-Rituximab (BR) Followed by Rituximab vs Bortezomib-BR (BVR) Followed by Rituximab vs BR Followed by Lenalidomide/Rituximab in High Risk Follicular Lymphoma

Inclusion Criteria

DISEASE CHARACTERISTICS:

- 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 < 1.0 X 10^9/L, hemoglobin < 10
g/dL, and/or platelets < 100 x 10^9/L)

- Patient must have a FLIPI-1 score of 3, 4, or 5 (1 point per criterion below):

- Age ≥ 60 years

- Stage III-IV disease

- Hemoglobin level < 12 g/dL

- > 4 nodal areas

- Serum 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

PATIENT CHARACTERISTICS:

- See Disease Characteristics

- ECOG performance status 0-2

- ANC ≥ 1,500/mm³ (includes neutrophils and bands)

- Platelet count ≥ 100,000/mm³

- Creatinine ≤ 2.0 mg/dL

- AST and ALT ≤ 5 x upper limit of normal (ULN)

- Alkaline phosphatase ≤ 5 x ULN

- Total bilirubin ≤ 1.5 x ULN (patients with known Gilbert disease should contact the
study PI)

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use 2 effective methods (1 highly effective and 1 additional
effective method) of contraception ≥ 28 days before, during, and for ≥ 28 days after
completing study treatment

- 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 < 300 cells/mm³ prior to or at the time of lymphoma diagnosis

- No history of AIDS-defining conditions

- If on antiretroviral therapy, must not be taking zidovudine or stavudine

- Must be willing to take prophylaxis for Pneumocystis jiroveci pneumonia (PCP)
during therapy and ≥ 2 months following completion of study therapy or until the
CD4 cells recover to over 250 cells/mm³

- No recent history of malignancy except for adequately treated basal cell or squamous
cell skin cancer, in situ cervical cancer, or other cancer for which the patient has
been disease-free for ≥ 2 years

- No active, uncontrolled infections (afebrile for > 48 hours off antibiotics)

- No ≥ grade 2 neuropathy

- No myocardial infarction within the past 6 months

- No NYHA class III-IV heart failure, uncontrolled angina, severe uncontrolled
ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active
conduction system abnormalities

- No serious medical or psychiatric illness likely to interfere with participation in
this clinical study

- No known hypersensitivity to boron or mannitol

- No chronic carriers of hepatitis B virus (HBV) with positive hepatitis surface
antigen (HBsAg +)

- 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

- Must register into the mandatory RevAssist® program and be willing and able to comply
with the requirements of RevAssist® (for patients randomized to arm III)

PRIOR CONCURRENT THERAPY:

- No prior chemotherapy, radiotherapy, or immunotherapy for lymphoma

- Prednisone or other corticosteroids used for non-lymphomatous conditions will
not be considered as prior chemotherapy

- A prior/recent short course (< 2 weeks) of steroids for symptom relief of
lymphoma-related symptoms is allowed