Rituximab, Bendamustine Hydrochloride, and Bortezomib Followed by Rituximab and Lenalidomide in Treating Older Patients With Previously Untreated Mantle Cell Lymphoma

OBJECTIVES:

Primary

- To determine whether the addition of bortezomib (RBV) to an induction regimen of
rituximab-bendamustine hydrochloride (RB) improves progression-free survival (PFS)
compared to RB alone in patients ≥ 60 years of age with previously untreated mantle cell
lymphoma.

- To determine whether the addition of lenalidomide to a consolidation regimen of
rituximab following an induction regimen of RB or RBV improves PFS compared to
consolidation rituximab alone in this patient population.

Secondary

- To determine whether the addition of bortezomib to induction therapy improves the
positron emission tomography (PET)-documented complete response (CR) rate compared to RB
alone.

- To determine the objective response rate (ORR) for RB and RBV.

- Among patients who do not have PET-documented CR at the end of induction, to determine
whether the addition of lenalidomide to consolidation therapy improves CR and ORR
compared with rituximab alone.

- To determine overall survival (OS) in the treatment arms.

- To determine safety, with attention to the addition of bortezomib in the induction
regimen and lenalidomide-rituximab (LR) as consolidation therapy.

- To collect paraffin-embedded tissue for creation of tissue microarray.

- To collect and bank serum and blood mononuclear cells for future studies.

- To collect formalin-fixed paraffin-embedded (FFPE) tissue to analyze potential
prognostic factors (Ki-67 proliferation index by immunohistochemistry and correlation
with proposed 5-gene set of proliferation markers analyzed by RNA PCR; SOX 11 expression
by immunohistochemistry; and Micro-RNA levels by microarray).

- Using patient-reported outcomes data, to determine the extent and severity of neuropathy
associated with the addition of bortezomib to induction treatment.

- Using patient-reported outcomes data, to determine the extent and severity of fatigue
associated with the addition of lenalidomide to consolidation treatment.

- To evaluate the effects of the addition of bortezomib and lenalidomide on
patient-reported health-related quality of life.

- To evaluate the effects of bortezomib-related neuropathy on patient-reported
health-related quality of life.

- To evaluate the response of lymphoma-specific symptoms to treatment.

- Using longitudinal patient-reported outcomes data, to describe the trajectory of
lymphoma symptoms, neuropathy, fatigue, and overall health-related quality of life prior
to, during, and following treatment among older adults with MCL.

Tertiary

- To assess the proportion of patients up and down staging when fludeoxyglucose F 18-
(FDG) PET/CT is added to standard Ann Arbor staging.

- To assess the ability of pre-treatment FDG-PET/CT (SUVmax) to predict response rate and
PFS.

- Among patients with interim (post-cycle 3) FDG-PET/CT imaging, to assess the correlation
of interim FDG-PET/CT imaging with response rate and PFS both during induction and
consolidation therapy.

- To assess standard FDG-PET/CT metrics including SUVmax, tumor metabolic burden, total
tumor burden, and association with pathology features (blastoid variant vs other, and
Ki67) in the setting of MCL.

- To assess differences in overall and CR rates when using Deauville vs International
Harmonization Project FDG-PET/CT interpretation criteria.

- To determine whether there is a correlation between FDG-PET/CT response and residual
disease assessment by molecular and/or flow cytometric techniques.

- To determine whether the number of malignant cells in circulation predict the number of
cells in marrow.

- To determine whether the number of malignant cells in circulation/in marrow at the end
of induction correlate with CR and 2-year PFS.

- To determine whether there is a higher rate of minimal residual disease (MRD) negativity
among patients randomized to RBV as compared with RB, and among patients treated with LR
maintenance compared with rituximab.

- To compare the two methods of MRD detection - molecular techniques and flow cytometry -
as prognostic markers for outcome.

OUTLINE: This is a multicenter study. Patients are stratified according to mantle cell
lymphoma International Prognostic Index risk score (low vs intermediate vs high). Patients
are randomized to 1 of 4 treatment arms.

- Arm A: Patients receive induction therapy comprising rituximab IV on day 1 and
bendamustine hydrochloride IV over 60 minutes on days 1-2. Treatment repeats every 4
weeks for 6 courses in the absence of disease progression or unacceptable toxicity.

- Arm E: Patients receive consolidation therapy comprising rituximab IV on day 1.
Courses repeat every 8 weeks for 2 years in the absence of disease progression or
unacceptable toxicity.

- Arm B: Patients receive induction therapy comprising bortezomib IV or subcutaneously
(SC) on days 1, 4, 8, and 11 and rituximab and bendamustine hydrochloride as patients in
arm A. Treatment repeats every 4 weeks for 6 courses in the absence of disease
progression or unacceptable toxicity.

- Arm F: Patients receive consolidation therapy comprising rituximab IV on day 1.
Courses repeat every 8 weeks for 2 years in the absence of disease progression or
unacceptable toxicity.

- Arm C: Patients receive induction therapy comprising rituximab and bendamustine
hydrochloride as patients in arm A. Treatment repeats every 4 weeks for 6 courses in the
absence of disease progression or unacceptable toxicity.

- Arm G: Patients receive consolidation therapy comprising lenalidomide orally (PO)
daily on days 1-21 every 4 weeks and rituximab IV every 8 weeks for 2 years in the
absence of disease progression or unacceptable toxicity.

- Arm D: Patients receive bortezomib, rituximab, and bendamustine hydrochloride as
patients in arm B. Treatment repeats every 4 weeks for 6 courses in the absence of
disease progression or unacceptable toxicity.

- Arm H: Patients receive consolidation therapy comprising lenalidomide PO daily on
days 1-21 every 4 weeks and rituximab IV every 8 weeks for 2 years in the absence
of disease progression or unacceptable toxicity.

Patients may undergo blood and bone marrow sample collection at baseline and during treatment
for correlative studies.

Patients complete the Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym), the
FACT/GOG-Neurotoxicity scale (FACT/GOG-Ntx), FACT-Fatigue, and FACT-General questionnaires at
baseline and periodically during study and follow up.

After completion of study treatment, patients are followed up every 3 months for 2 years,
every 6 months for 3 years, and then annually for 10 years.

DISEASE CHARACTERISTICS:

- Histologically confirmed untreated mantle cell lymphoma (MCL), with documented cyclin
D1 by immunohistochemical stains and/or t(11;14) by cytogenetics or fluorescence in
situ hybridization (FISH)

- Patients must have at least one objective measurable disease parameter

- Abnormal PET scans will not constitute evaluable disease, unless verified by CT
scan or other appropriate imaging

- Measurable disease in the liver is required if the liver is the only site of
lymphoma

- Patient must have no CNS involvement

PATIENT CHARACTERISTICS:

- ECOG performance status 0-2

- ANC ≥ 1,500/mcL (1.5 x 10^9/L)*

- Platelets ≥ 100,000/mcL (100 x 10^9/L)* NOTE: *Unless due to marrow involvement.

- AST/ALT ≤ 2 times upper limit of normal (ULN)

- Bilirubin ≤ 2 times ULN

- Calculated creatinine clearance by Cockroft-Gault formula ≥ 30 mL/min

- Women (sexually mature female) must not be pregnant or breast-feeding

- Negative pregnancy test

- Women of childbearing potential and sexually active males use an accepted and
effective method of contraception

- Men must agree to use a latex condom during sexual contact with a female of
child-bearing potential, even if they have had a successful vasectomy

- All patients must be counseled at a minimum of every 28 days about pregnancy
precautions and risks of fetal exposure

- No evidence of prior malignancy except adequately treated non-melanoma skin cancer, in
situ cervical carcinoma, or any surgically or radiation-cured malignancy continuously
disease free for ≥ 5 years so as not to interfere with interpretation of radiographic
response

- Patient agrees that if randomized to Arms C or D, and proceed onto Arms G or H, they
must register into the mandatory RevAssist® program, and be willing and able to comply
with the requirements of RevAssist®

- Patients must have no medical contra-indications to, and be willing to take, deep
vein thrombosis (DVT) prophylaxis as all patients registering to the
lenalidomide/rituximab Arms G and H will be required to have DVT prophylaxis

- Patients randomized to Arms G or H who have a history of a thrombotic
vascular event will be required to have therapeutic doses of low-molecular
weight heparin or warfarin to maintain an INR between 2.0 - 3.0

- Patients on Arms G and H without a history of a thromboembolic event are
required to take a daily aspirin (81 mg or 325 mg) for DVT prophylaxis

- Patients who are unable to tolerate aspirin should receive low
molecular weight heparin therapy or warfarin treatment

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

- Males must agree to abstain from donating blood, semen, or sperm during study
participation and for at least 28 days after discontinuation from protocol
treatment

- HIV-positive patients are not excluded but, to enroll, must meet all of the below
criteria:

- HIV is sensitive to antiretroviral therapy

- Must be willing to take effective antiretroviral therapy, if indicated

- No history of CD4 prior to or at the time of lymphoma diagnosis < 300 cells/mm³

- 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 until at least 2 months following the completion of therapy or
until the CD4 cells recover to over 250 cells/mm³, whichever occurs later

- Patients must not have grade 2 or greater peripheral neuropathy

- Patients must not have NYHA Class III or IV heart failure, uncontrolled angina, severe
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
ischemia

- Patients must not have hypersensitivity to bortezomib, boron, or mannitol

- Patients must not have a serious medical or psychiatric illness likely to interfere
with study participation

PRIOR CONCURRENT THERAPY:

- No prior therapy for MCL, except < 1 week of steroid therapy for symptom control

- HIV-positive patients are not excluded, but to enroll, must meet all of the below
criteria:

- Must be willing to take effective antiretroviral therapy if indicated

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

- Patients must not be participating in any other clinical trial or taking any other
experimental medications within 14 days prior to registration