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
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
RATIONALE: Drugs used in chemotherapy, such as bendamustine hydrochloride, work in different
 ways to stop the growth of cancer cells, either by killing the cells or by stopping them from
 dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different
 ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and
 help kill them or carry cancer-killing substances to them. Bortezomib may stop the growth of
 cancer cells by blocking some of the enzymes needed for cell growth. Biological therapies,
 such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells
 from growing. It is not yet known whether giving bendamustine hydrochloride and rituximab
 together alone is more effective than giving bendamustine hydrochloride and rituximab
 together with bortezomib or lenalidomide in treating follicular lymphoma.

 PURPOSE: This randomized phase II trial is studying giving bendamustine hydrochloride and
 rituximab together with or without bortezomib followed by rituximab with or without
 lenalidomide to see how well they work in treating patients with high-risk stage II, stage
 III, or stage IV follicular lymphoma.
OBJECTIVES:

 Primary

 -  To compare the complete remission rate in patients with high-risk follicular lymphoma
 receiving induction therapy comprising bendamustine hydrochloride and rituximab with vs
 without bortezomib.

 -  To compare the 1-year post-induction disease-free survival rate in patients receiving
 continuation therapy comprising rituximab with vs without lenalidomide.

 Secondary

 -  To determine the 3-year progression-free survival and the 5-year overall survival of
 these patients.

 -  To evaluate patient-reported outcomes at baseline and during treatment to determine
 differences in symptom palliation, treatment-related symptoms, and overall
 health-related quality of life.

 -  To examine the association between baseline Follicular Lymphoma International Prognostic
 Index (FLIPI) information and outcome of these patients.

 -  To examine the association between baseline and end-of-treatment patient comorbidities
 assessed by the Cumulative Illness Rating Scale (CIRS) and outcome.

 -  To create an image and tissue bank including serial PET/CT scans, diagnostic
 paraffin-embedded tissue, germline DNA, and serial blood and bone marrow samples
 sufficient to support proposed and future studies of tumor and host characteristics that
 may predict for clinical outcome, including treatment arm effects, and enhance existing
 prognostic indices. (exploratory)

 -  To evaluate the rate of peripheral neuropathy associated with subcutaneous and
 intravenous bortezomib.

 OUTLINE: Patients are stratified according to FLIPI-1score (0-2 vs 3 vs 4-5) and Groupe
 d'Etude des Lymphomes Folliculaires (GELF) tumor burden (low vs high). Patients are
 randomized to 1 of 3 treatment arms.

 -  Arm A then Arm D

 -  Arm A (induction): Patients receive rituximab intravenously (IV) on day 1 and
 bendamustine hydrochloride IV over 1 hour on days 1 and 2. Treatment repeats every
 28 days for 6 courses in the absence of disease progression or unacceptable
 toxicity.

 -  Arm D (continuation): Beginning 4 weeks after the completion of induction therapy,
 patients who have stable disease or better at time of post-induction restaging
 receive rituximab IV on day 1. Treatment repeats every 8 weeks for 2 years in the
 absence of disease progression or unacceptable toxicity.

 -  Arm B then Arm E

 -  Arm B (induction): Patients receive rituximab IV on day 1; bortezomib IV on days 1,
 4, 8, and 11; and bendamustine hydrochloride IV over 1 hour on days 1 and 4.
 Treatment repeats every 28 days for 6 courses in the absence of disease progression
 or unacceptable toxicity.

 -  Arm E (continuation): Beginning 4 weeks after the completion of induction therapy,
 patients who have stable disease or better at time of post-induction restaging
 receive rituximab as in arm D.

 -  Arm C then Arm F

 -  Arm C (induction): Patients receive rituximab IV on day 1 and bendamustine
 hydrochloride IV over 1 hour on days 1 and 2. Treatment repeats every 28 days for 6
 courses in the absence of disease progression or unacceptable toxicity.

 -  Arm F (continuation): Immediately after completing induction therapy, patients who
 have stable disease or better at time of post-induction restaging receive oral
 lenalidomide on days 1-21. Treatment repeats every 4 weeks for 13 courses in the
 absence of disease progression or unacceptable toxicity. Beginning 4 weeks after
 the completion of induction therapy, these patients receive rituximab IV on day 1.
 Treatment repeats every 8 weeks for 2 years in the absence of disease progression
 or unacceptable toxicity.

 Quality of life (including fatigue, neurotoxicity, anxiety, and depression) is assessed by
 questionnaire at baseline and periodically during study therapy.

 Blood, bone marrow, and tissue samples may be collected periodically for correlative studies
 and for a repository.

 After completion of study therapy, patients are followed up periodically for 15 years.
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 < 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 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 < 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

 -  ECOG performance status 0-2

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

 -  Platelet count ≥ 100,000/mm³

 -  Creatinine ≤ 2.0 mg/dL

 -  Aspartate aminotransferase (AST) and alanine transaminase (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)

 -  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

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

 Exclusion Criteria (Induction):

 -  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

 -  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

 -  Pregnant or nursing

 -  Active, uncontrolled infections (afebrile for > 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 or to practice complete abstinence from heterosexual
 intercourse during the following time periods related to this study/lenalidomide:
 1) for at least 28 days before starting lenalidomide; 2) while participating in
 the study; and 3) for at least 28 days after discontinuation/stopping
 lenalidomide. The two methods of reliable contraception must include one highly
 effective method (i.e. intrauterine device (IUD), hormonal [birth control pills,
 injections, or implants], tubal ligation, partner's vasectomy) and one additional
 effective (barrier) method (i.e. latex condom, diaphragm, cervical cap). FCBP
 must be referred to a qualified provider of contraceptive methods if needed.

 -  Patient must agree to abstain from donating blood during study participation and
 for at least 28 days after discontinuation from protocol treatment.

 -  All males, regardless of whether they have undergone a successful vasectomy, must
 agree to use a latex condom during sexual contact with a female of childbearing
 potential, or to practice complete abstinence from heterosexual intercourse with
 any female of childbearing potential during the cycles of continuation therapy of
 which lenalidomide are taken and for at least 28 days after
 discontinuation/stopping lenalidomide. Patient must agree to abstain from
 donating blood, semen, or sperm during study participation and for at least 28
 days after discontinuation from protocol treatment.

 -  Must register into the mandatory RevAssist® program and be willing and able to
 comply with the requirements of RevAssist®

 Exclusion Criteria (Continuation):

 -  Active, uncontrolled infections (afebrile for > 48 hours off antibiotics)

 -  ≥ grade 2 neuropathy

 -  Additional requirements for Arm C induction patients registering to arm F:

 -  Not pregnant or breast-feeding