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 (RB) improves progression-free survival (PFS) compared to RB alone in patients 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.

Laboratory

• 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).

Quality of Life

• 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.

Imaging

• 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.

Residual Disease Assessment by Molecular and 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.

Step 1 (Induction) Inclusion Criteria:

• Mantle Cell Lymphoma International Prognostic Index (MIPI) score must be calculated and entered in OPEN
• 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
• Negative pregnancy test
• Women of childbearing potential and sexually active males use an accepted and effective method of contraception
• ECOG performance status 0-2
• Absolute neutrophil count (ANC) ≥ 1,500/mcL (1.5 x 10^9/L)
• Platelets ≥ 100,000/mcL (100 x 10^9/L)
• Aspartate transaminase (AST)/alanine transaminase (ALT) ≤ 2 times upper limit of normal (ULN)
• Bilirubin ≤ 2 times ULN
• Calculated creatinine clearance by Cockroft-Gault formula ≥ 30 mL/min
• Patient agrees that if randomized to Arms C or D, and proceeding 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, DVT prophylaxis as all patients registering to the lenalidomide/rituximab Arms G and H will be required to have deep vein thrombosis (DVT) prophylaxis. Patients randomized to Arms G or H who have 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. 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 or another accepted full anticoagulation regimen. Ways to minimize risk of DVT should be discussed with patients, including, but not limited to, avoiding smoking, minimizing prothrombotic hormone replacement, avoiding prolonged periods of inactivity (e.g. uninterrupted long car or plane trips).
• 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
• CD4 count at screening >= 300 cells/mm³
• 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

Step 1 (Induction) Exclusion Criteria:

• Women (sexually mature female) must not be pregnant or breast-feeding
• Evidence of prior malignancy except adequately treated non-melanoma skin cancer, in situ cervical carcinoma, low grade prostate carcinoma (Gleason grade ≤ 6) managed with observation that has been stable for at least 6 months, or any malignancy treated with curative intent continuously disease free for >=3 years so as not to interfere with interpretation of radiographic response
• Prior therapy for MCL, except: < 2 weeks of steroid therapy for symptom control or local radiation therapy for symptom control if there is measurable disease outside the radiation portal. Patients may be on chronic steroids for non-malignant disease if on a stable dose equivalent to ≤ 20 mg prednisone per day.
• CNS involvement
• History of AIDS-defining conditions
• Grade 2 or greater peripheral neuropathy.
• NYHA Class III or IV heart failure, uncontrolled angina severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia
• Hypersensitivity to bortezomib, boron or mannitol
• A serious medical or psychiatric illness likely to interfere with study participation
• Participating in any other therapeutic clinical trial or taking any other experimental medications within 14 days prior to registration.

Step 2 (Maintenance) Inclusion Criteria:

• ECOG performance status between 0-2
• Complete response, partial response or stable disease after Step 1
• ANC >= 1000 cells/mm3 (1.0 x 10^9/L)
• Platelets >= 75,000 cells/mm3 (75 x 10^9/L)
• AST/ALT <= 2 x upper limit of normal (ULN)
• Total bilirubin <= 2 x upper limit of normal (ULN) or, if total elevated, direct bilirubin <= 2 x upper limit of normal (ULN)
• Calculated creatinine clearance by Cockroft-Gault formula >= 30 ml/min
• Patient agrees that if randomized to Arms C or D, and proceeding onto Arms G or H, they must register into the mandatory REMS program, and be willing and able to comply with the requirements of REMS.

• Pregnancy tests must occur within 10 - 14 days and again within 24 hours prior to initiation of Cycle 1 of lenalidomide.
• Females of childbearing potential (FCBP)* with regular or no menstruation must have a pregnancy test weekly for the first 28 days and then every 28 days while on lenalidomide therapy (including breaks in therapy); at discontinuation of lenalidomide and at Day 28 post the last dose of lenalidomide. Females with irregular menstruation must have a pregnancy test weekly for the first 28 days and then every 14 days while on lenalidomide therapy (including breaks in therapy), at discontinuation of lenalidomide and at Day 14 and Day 28 post the last dose of lenalidomide (see Appendix VI: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods).
• Females of childbearing potential (FCBP)* must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 - 14 days and again within 24 hours prior to starting Cycle 1 of lenalidomide and 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 she starts taking 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. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure.
• A female of childbearing potential is any sexually mature female, regardless of sexual orientation of whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
• 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/lenaliomide: 1) for at least 28 days before starting lenalidomide; 2) while participating in the study including interruptions in therapy; 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.
• 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. 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 all cycles of study treatment and for at least 28 days following discontinuation of protocol treatment
• Patients must have no medical contra-indications to, and be willing to take, DVT prophylaxis as all patients registering to the lenalidomide/rituximab Arms G and H will be required to have deep vein thrombosis (DVT) prophylaxis. Patients randomized to Arms G or H who have full anticoagulation, 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, or any other accepted full anticoagulation regimen (e.g. direct thrombin inhibitors or Factor Xa inhibitors) with appropriate monitoring for that agent. 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 or another accepted full anticoagulation regimen. Ways to minimize risk of DVT should be discussed with patients, including, but not limited to, avoiding smoking, minimizing pro-thrombotic hormone replacement, avoiding prolonged periods of inactivity (e.g. uninterrupted long car or plane trips).