E1411: Intergroup Randomized Phase II Four Arm Study In Patients With Previously Untreated Mantle Cell Lymphoma Of Therapy With: Arm A = Rituximab+ Bendamustine Followed By Rituximab Consolidation (RB [?] R); Arm B = Rituximab + Bendamustine + Bortezomib Followed By Rituximab Consolidation (RBV[?] R), Arm C = Rituximab + Bendamustine Followed By Lenalidomide + Rituximab Consolidation (RB [?] LR) or Arm D = Rituximab + Bendamustine + Bortezomib Followed By Lenalidomide + Rituximab Consolidation (RBV [?] LR)

Summary

arm a:
rituximab 375 mg/m2 iV day 1
bendamustine 90 mg/m2/d iV days 1, 2
Repeat every 28 days x 6 cyclesrituximab

arm B:
rituximab 375 mg/m2 iV day 1
bendamustine 90 mg/m2/d iV days 1, 2
bortezomib 1.6 mg/m2/day SC or iV days 1 and 8
Repeat every 28 days x 6 cycles

arm C:
rituximab 375 mg/m2 iV day 1
bendamustine 90 mg/m2/d iV days 1, 2
Repeat every 28 days x 6 cyclesrituximab

arm D:
rituximab 375 mg/m2 iV day 1
bendamustine 90 mg/m2/d iV days 1, 2
bortezomib 1.6 mg/m2/day SC or iV days 1 and 8
Repeat every 28 days x 6 cycles

arm e:
rituximab 375 mg/m2 iV day 1 (odd numbered cycles 1, 3, 5[?]) Total[?] 12 doses of rituximab over 24 months.

arm F:
rituximab 375 mg/m2 iV day 1 (odd numbered cycles 1, 3, 5[?]) Total[?] 12 doses of rituximab over 24 months.

arm G:
lenalidomide 15 mg po daily days 1-21 every 28 days x 24 cycles
+
rituximab 375 mg/m2 iV day 1 (odd numbered cycles 1, 3, 5[?]) Total[?] 12 doses of rituximab over 24 months.

arm H:
lenalidomide 15 mg po daily days 1-21 every 28 days x 24 cycles
+
rituximab 375 mg/m2 iV day 1 (odd numbered cycles 1, 3, 5[?]) Total[?] 12 doses of rituximab over 24 months.

Participant Eligibility

Step 1 Registration:
1. Age >= 18 years.
2. Negative blood or urine pregnancy test (female patient of childbearing potential only) performed within 2 weeks prior to registration.
3. Patients must have at least one objective measurable disease parameter. Baseline measurements and evaluations must be obtained within 4 weeks of registration to the study. 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. If the only radiographically assessable disease is splenomegaly (without discrete measurable nodules), the patient can be enrolled, but for such patients CR cannot be differentiated from PR, while the spleen will be considered nodal with respect to criteria for PD.
4. Histologically confirmed untreated mantle cell lymphoma, with documented cyclin D1 (BCL1) by immunohistochemical stains and/or t(11;14) by cytogenetics or FISH.
5. Patients must have measurable disease.
6. ECOG performance status between 0-2.
7. Hematologic parameters (unless due to marrow involvement) obtained within 4 weeks prior to registration.
- ANC >= 1500/ mcL (1.5 x 109/L)
- Platelets >= 100,000/mcL (100 x 109/L)
8. Liver/Renal function, obtained within 4 weeks prior to registration
- AST/ALT <= 2 x upper limit of normal (ULN)
- Bilirubin <= 2 x upper limit of normal (ULN)
- Calculated creatinine clearance by Cockroft-Gault formula > 30 ml/min
9. No evidence of prior malignancy except adequately treated nonmelanoma skin cancer, adequately treated in situ carcinoma or any surgically- or radiation-cured malignancy continuously disease free for >= 3 years so as not to interfere with interpretation of radiographic response.
10. No prior therapy for MCL, except < 1 week of steroid therapy for symptom control.
11. Patient must have no known CNS involvement.
12. 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 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 x 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).
13. HIV positive patients 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.

Step 2 Registration:
1. ECOG performance status between 0-2.
2. CR, PR or SD after Step 1.
3. Prior to beginning consolidation, patients must meet the following criteria:
Hematologic parameters:
- ANC >= 1000 cells/mm3 (1.0 x 109/L)
- Platelets >= 75,000 cells/mm3 (75 x 109/L)
- AST/ALT <= 2 x upper limit of normal (ULN)
- Bilirubin <= 2 x upper limit of normal (ULN)
- Calculated creatinine clearance by Cockroft-Gault formula > 30 ml/min
3. 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.
4. 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.
*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)
5. 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 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[Single Quote]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.
6. 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.
7. Women must agree to abstain from donating blood during study participation and for at least 28 days after discontinuation from protocol treatment.
8. 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.
9. 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 therapeutic doses of low molecular weight heparin or warfarin to maintain an INR between 2.0 x 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.
- 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, which ever occurs later.