Lymphoma, Mantle Cell Lymphoma
Conditions
Keywords
Lymphoma, Mantle Cell Lymphoma
Brief summary
RATIONALE: Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some find cancer cells and help kill them or carry cancer-killing substances to them. Others interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as bendamustine hydrochloride, also work in different ways to kill cancer cells or stop them from dividing. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Lenalidomide may stop the growth of mantle cell lymphoma by blocking blood flow to the cancer. It is not yet known whether giving rituximab together with bendamustine and bortezomib is more effective than rituximab and bendamustine, followed by rituximab alone or with lenalidomide in treating mantle cell lymphoma. PURPOSE: This randomized phase II trial studies rituximab, bortezomib, bendamustine, and lenalidomide in treating previously untreated older patients with mantle cell lymphoma.
Detailed description
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.
Interventions
BIOLOGICALrituximab
Given IV
DRUGBendamustine
Given IV
DRUGbortezomib
Given IV or SC
DRUGlenalidomide
Given PO
Sponsors
Eastern Cooperative Oncology Group
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) for Induction Phase | Assessed at baseline, every 3 months for 2.5 years, every 6 months up to 10 years from end of treatment, and then annually up to 10 years and 6 months | PFS is defined as time from randomization to lymphoma progression or death. Progression is defined as: * Appearance of any new lesion \>1.5 cm in any axis during or at the end of therapy * \>=50% increase from nadir in the sum of products of the diameters (SPD) of any previously involved nodes or extranodal masses, or in a single involved node or extranodal mass, or the size of other lesions. * \>=50% increase in the longest diameter of any single previously identified node or extranodal mass more than 1 cm in its short axis. * Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion was PET positive before therapy unless the lesion is too small to be detected with current PET systems |
| Progression-free Survival (PFS) for Maintenance Phase (Step 2) | Assessed at registration to step 2, cycles 6, 12, 18, treatment completion, then every 3 months for 2.5 years, every 6 months up to 10 years from end of treatment, and then annually up to 10 years and 6 months | PFS is defined as time from Step 2 registration to lymphoma progression or death. Progression is defined as: * Appearance of any new lesion \>1.5 cm in any axis during or at the end of therapy * \>=50% increase from nadir in the sum of products of the diameters (SPD) of any previously involved nodes or extranodal masses, or in a single involved node or extranodal mass, or the size of other lesions. * \>=50% increase in the longest diameter of any single previously identified node or extranodal mass more than 1 cm in its short axis. * Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion was PET positive before therapy unless the lesion is too small to be detected with current PET systems |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response for Induction Phase (Step 1) | Assessed at baseline and 24 weeks (end of cycle 6) | Objective response is defined as either complete response (CR) or partial response (PR). CR is defined as disappearance of all detectable clinical evidence of disease, and disease-related symptoms if present prior to therapy. PR is defined as: * ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or extranodal masses * No increase in the size of other nodes, liver or spleen. * Bone marrow assessment is irrelevant for determination of a PR if the sample was positive prior to treatment. However, if positive, the cell type should be specified, e.g. large-cell lymphoma or small cleaved cell lymphoma. * No new sites of disease. * Patients who achieve a CR but have persistent morphologic bone marrow involvement will be considered partial responders. * When the bone marrow was involved before therapy and a clinical CR was achieved, but with no bone marrow assessment after treatment, patients are considered partial responders. |
| PET-documented Complete Response for Induction Phase (Step 1) | Assessed at baseline and 24 weeks (end of cycle 6) | Complete response is defined as disappearance of all detectable clinical evidence of disease. |
| Overall Survival (OS) Rate at 5 Years Since Maintenance (Step 2) | Assessed every 3 months for 2.5 years, every 6 months for years 2.5-5 | OS is defined as the time from registration of Step 2 (maintenance) until death from any cause or last know alive. The Kaplan-Meier estimate of 5-year OS rate is reported. |
| Objective Response for Maintenance (Step 2) Among Patients Without PET-documented CR at the End of Induction | Assessed at baseline and every 4 months for 2 years | Objective response is defined as either complete response (CR) or partial response (PR). CR is defined as disappearance of all detectable clinical evidence of disease, and disease-related symptoms if present prior to therapy. PR is defined as: * ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or extranodal masses * No increase in the size of other nodes, liver or spleen. * Bone marrow assessment is irrelevant for determination of a PR if the sample was positive prior to treatment. However, if positive, the cell type should be specified, e.g. large-cell lymphoma or small cleaved cell lymphoma. * No new sites of disease. * Patients who achieve a CR but have persistent morphologic bone marrow involvement will be considered partial responders. * When the bone marrow was involved before therapy and a clinical CR was achieved, but with no bone marrow assessment after treatment, patients are considered partial responders. |
Countries
Canada, United States
Contacts
PRINCIPAL_INVESTIGATORMitchell R. Smith, MD, PhD
Fox Chase Cancer Center
Participant flow
Recruitment details
From 2012 to 2016, 373 patients were enrolled in this trial.
Participants by arm
| Arm | Count |
|---|---|
| Induction: Bendamustine + Rituximab Then Maintenance: Rituximab 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. Patients then proceed to maintenance treatment.
Patients receive maintenance therapy comprising rituximab IV on day 1. Courses repeat every 8 weeks for 2 years in the absence of disease progression or unacceptable toxicity. | 94 |
| Induction: Bendamustine + Rituximab + Bortezomib Then Maintenance: Rituximab Patients receive induction therapy comprising rituximab IV on day 1, bendamustine hydrochloride IV over 60 minutes on days 1-2 and bortezomib IV subcutaneously (SC) on days 1 and 8. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then proceed to maintenance treatment.
Patients receive maintenance therapy comprising rituximab IV on day 1. Courses repeat every 8 weeks for 2 years in the absence of disease progression or unacceptable toxicity. | 93 |
| Induction: Bendamustine + Rituximab Then Maintenance: Lenalidomide + Rituximab 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. Patients then proceed to maintenance treatment. Patients then proceed to maintenance treatment.
Patients receive maintenance 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. | 93 |
| Induction: Bendamustine + Rituximab + Bortezomib Then Maintenance: Lenalidomide + Rituximab Patients receive induction therapy comprising rituximab IV on day 1, bendamustine hydrochloride IV over 60 minutes on days 1-2 and bortezomib IV subcutaneously (SC) on days 1 and 8. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then proceed to maintenance treatment.
Patients receive maintenance 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. | 93 |
| Total | 373 |
Baseline characteristics
| Characteristic | Induction: Bendamustine + Rituximab Then Maintenance: Rituximab | Induction: Bendamustine + Rituximab + Bortezomib Then Maintenance: Rituximab | Induction: Bendamustine + Rituximab Then Maintenance: Lenalidomide + Rituximab | Induction: Bendamustine + Rituximab + Bortezomib Then Maintenance: Lenalidomide + Rituximab | Total |
|---|---|---|---|---|---|
| Age, Continuous | 67 years | 69 years | 68 years | 66 years | 67 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 3 Participants | 1 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 89 Participants | 90 Participants | 88 Participants | 91 Participants | 358 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 1 Participants | 2 Participants | 1 Participants | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 4 Participants | 1 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 2 Participants | 0 Participants | 4 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 0 Participants | 4 Participants | 2 Participants | 10 Participants |
| Race (NIH/OMB) White | 86 Participants | 88 Participants | 85 Participants | 84 Participants | 343 Participants |
| Sex: Female, Male Female | 26 Participants | 26 Participants | 25 Participants | 21 Participants | 98 Participants |
| Sex: Female, Male Male | 68 Participants | 67 Participants | 68 Participants | 72 Participants | 275 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 11 / 94 | 16 / 93 | 11 / 93 | 11 / 93 | 22 / 75 | 20 / 68 | 26 / 76 | 17 / 74 |
| other Total, other adverse events | 92 / 93 | 88 / 92 | 93 / 93 | 92 / 92 | 71 / 74 | 64 / 68 | 73 / 73 | 73 / 73 |
| serious Total, serious adverse events | 75 / 93 | 80 / 92 | 70 / 93 | 83 / 92 | 50 / 74 | 41 / 68 | 62 / 73 | 65 / 73 |
Outcome results
Primary
Progression-free Survival (PFS) for Induction Phase
PFS is defined as time from randomization to lymphoma progression or death. Progression is defined as: * Appearance of any new lesion \>1.5 cm in any axis during or at the end of therapy * \>=50% increase from nadir in the sum of products of the diameters (SPD) of any previously involved nodes or extranodal masses, or in a single involved node or extranodal mass, or the size of other lesions. * \>=50% increase in the longest diameter of any single previously identified node or extranodal mass more than 1 cm in its short axis. * Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion was PET positive before therapy unless the lesion is too small to be detected with current PET systems
Time frame: Assessed at baseline, every 3 months for 2.5 years, every 6 months up to 10 years from end of treatment, and then annually up to 10 years and 6 months
Population: Eligible and treated patients at Step 1 (induction)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Induction: Bendamustine + Rituximab (RB; Arms A + C) | Progression-free Survival (PFS) for Induction Phase | 5.5 years |
| Induction: Bendamustine + Rituximab + Bortezomib (RBV; Arms B + D) | Progression-free Survival (PFS) for Induction Phase | 6.4 years |
p-value: 0.25Log Rank
Primary
Progression-free Survival (PFS) for Maintenance Phase (Step 2)
PFS is defined as time from Step 2 registration to lymphoma progression or death. Progression is defined as: * Appearance of any new lesion \>1.5 cm in any axis during or at the end of therapy * \>=50% increase from nadir in the sum of products of the diameters (SPD) of any previously involved nodes or extranodal masses, or in a single involved node or extranodal mass, or the size of other lesions. * \>=50% increase in the longest diameter of any single previously identified node or extranodal mass more than 1 cm in its short axis. * Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion was PET positive before therapy unless the lesion is too small to be detected with current PET systems
Time frame: Assessed at registration to step 2, cycles 6, 12, 18, treatment completion, then every 3 months for 2.5 years, every 6 months up to 10 years from end of treatment, and then annually up to 10 years and 6 months
Population: Eligible and treated patients at Step 2 (maintenance)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Induction: Bendamustine + Rituximab (RB; Arms A + C) | Progression-free Survival (PFS) for Maintenance Phase (Step 2) | 5.9 years |
| Induction: Bendamustine + Rituximab + Bortezomib (RBV; Arms B + D) | Progression-free Survival (PFS) for Maintenance Phase (Step 2) | 7.2 years |
p-value: 0.178Log Rank
Secondary
Objective Response for Induction Phase (Step 1)
Objective response is defined as either complete response (CR) or partial response (PR). CR is defined as disappearance of all detectable clinical evidence of disease, and disease-related symptoms if present prior to therapy. PR is defined as: * ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or extranodal masses * No increase in the size of other nodes, liver or spleen. * Bone marrow assessment is irrelevant for determination of a PR if the sample was positive prior to treatment. However, if positive, the cell type should be specified, e.g. large-cell lymphoma or small cleaved cell lymphoma. * No new sites of disease. * Patients who achieve a CR but have persistent morphologic bone marrow involvement will be considered partial responders. * When the bone marrow was involved before therapy and a clinical CR was achieved, but with no bone marrow assessment after treatment, patients are considered partial responders.
Time frame: Assessed at baseline and 24 weeks (end of cycle 6)
Population: Eligible and treated patients at Step 1 (induction)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Induction: Bendamustine + Rituximab (RB; Arms A + C) | Objective Response for Induction Phase (Step 1) | Objective response | 158 Participants |
| Induction: Bendamustine + Rituximab (RB; Arms A + C) | Objective Response for Induction Phase (Step 1) | No objective response | 21 Participants |
| Induction: Bendamustine + Rituximab + Bortezomib (RBV; Arms B + D) | Objective Response for Induction Phase (Step 1) | Objective response | 158 Participants |
| Induction: Bendamustine + Rituximab + Bortezomib (RBV; Arms B + D) | Objective Response for Induction Phase (Step 1) | No objective response | 21 Participants |
Secondary
Objective Response for Maintenance (Step 2) Among Patients Without PET-documented CR at the End of Induction
Objective response is defined as either complete response (CR) or partial response (PR). CR is defined as disappearance of all detectable clinical evidence of disease, and disease-related symptoms if present prior to therapy. PR is defined as: * ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or extranodal masses * No increase in the size of other nodes, liver or spleen. * Bone marrow assessment is irrelevant for determination of a PR if the sample was positive prior to treatment. However, if positive, the cell type should be specified, e.g. large-cell lymphoma or small cleaved cell lymphoma. * No new sites of disease. * Patients who achieve a CR but have persistent morphologic bone marrow involvement will be considered partial responders. * When the bone marrow was involved before therapy and a clinical CR was achieved, but with no bone marrow assessment after treatment, patients are considered partial responders.
Time frame: Assessed at baseline and every 4 months for 2 years
Secondary
Overall Survival (OS) Rate at 5 Years Since Maintenance (Step 2)
OS is defined as the time from registration of Step 2 (maintenance) until death from any cause or last know alive. The Kaplan-Meier estimate of 5-year OS rate is reported.
Time frame: Assessed every 3 months for 2.5 years, every 6 months for years 2.5-5
Population: Eligible and treated patients for the maintenance phase (Step 2)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Induction: Bendamustine + Rituximab (RB; Arms A + C) | Overall Survival (OS) Rate at 5 Years Since Maintenance (Step 2) | 0.866 Proportion of participants |
| Induction: Bendamustine + Rituximab + Bortezomib (RBV; Arms B + D) | Overall Survival (OS) Rate at 5 Years Since Maintenance (Step 2) | 0.828 Proportion of participants |
| Induction: (C) Bendamustine + Rituximab Then Maintenance: (G) Lenalidomide + Rituximab | Overall Survival (OS) Rate at 5 Years Since Maintenance (Step 2) | 0.727 Proportion of participants |
| Induction: (D) Bendamustine + Rituximab + Bortezomib Then Maintenance: (H) Lenalidomide + Rituximab | Overall Survival (OS) Rate at 5 Years Since Maintenance (Step 2) | 0.853 Proportion of participants |
Secondary
PET-documented Complete Response for Induction Phase (Step 1)
Complete response is defined as disappearance of all detectable clinical evidence of disease.
Time frame: Assessed at baseline and 24 weeks (end of cycle 6)
Other Pre-specified
Assessment of the Correlation of Interim FDG-PET/CT Imaging With Response Rate and PFS Both During Induction and Consolidation Therapy
Among patients with interim 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.
Time frame: Assessed at baseline and every 4 months for 2 years and every 6 months for years 3-10 and then annually up to 15 years
Other Pre-specified
Correlation Between FDG-PET/CT Response and Residual Disease
To determine whether there is a correlation between FDG-PET/CT response and residual disease assessment by molecular and/or flow cytometric techniques
Time frame: Assessed at baseline and every 4 months for 2 years and every 6 months for years 3-10 and then annually up to 15 years
Other Pre-specified
Difference in MRD Levels by Molecular Techniques and Flow Cytometry
MRD levels will be evaluated using two different methods, molecular techniques and flow cytometry. The difference in MRD levels between the two methods will be assessed.
Time frame: Assessed at baseline, end of cycles 3 and 6, every 4 months during 1st year of maintenance, every 6 months during 2nd year of maintenance and 12 months after completion of maintenance
Other Pre-specified
Difference in Overall Response Rates Between Deauville and International Harmonization Project FDG-PET/CT Interpretation Criteria
To assess differences in overall and complete response rates when using Deauville vs. International Harmonization Project FDG-PET/CT interpretation criteria.
Time frame: Assessed at baseline and every 4 months for 2 years
Other Pre-specified
Functional Assessment of Cancer Therapy - General (FACT-G) Score
FACT-G subscale has 27 items and the score ranges from 0 to 108. The higher the score, the better the quality of life.
Time frame: Assessed at baseline, 6, 12, 30, 36, 48 and 60 months
Other Pre-specified
Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT/GOG-Ntx Subscale) Score
FACT/GOG-Ntx subscale has 11 items and the score ranges from 0 to 44. The higher the score, the better the quality of life.
Time frame: Assessed at baseline, 6, 12, 30, 36, 48 and 60 months
Other Pre-specified
Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lymphoma) Subscale Score
FACT-Lymphoma has 15 items and the score ranges from 0 to 60. The higher the score, the better the quality of life.
Time frame: Assessed at baseline, 6, 12, 30, 36, 48 and 60 months
Other Pre-specified
Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) Scale Score
FACIT-Fatigue scale has 14 items and the score ranges from 0 to 56. The higher the score, the better the quality of life.
Time frame: Assessed at baseline, 6, 12, 30, 36, 48 and 60 months
Other Pre-specified
Proportion of Patients With Minimal Residual Disease (MRD)
Minimal residual disease (MRD) will be evaluated using blood samples and bone marrow samples collected on this study.
Time frame: Assessed at baseline, end of cycles 3 and 6, every 4 months during 1st year of maintenance, every 6 months during 2nd year of maintenance and 12 months after completion of maintenance
Other Pre-specified
The Association Between the Number of Malignant Cells in Circulation or Marrow at the End of Induction and Clinical Outcomes
To determine whether the number of malignant cells in circulation/in marrow at the end of induction correlate with CR and 2 year PFS
Time frame: Assessed at baseline and every 4 months for 2 years
Other Pre-specified
The Trajectory of Overall Health-related Quality of Life
The overall health-related quality of life is evaluated using FACT-G. FACT-G subscale has 27 items and the score ranges from 0 to 108. The higher the score, the better the quality of life.
Time frame: Assessed at baseline, 6, 12, 30, 36, 48 and 60 months
Other Pre-specified
To Assess Standard FDG-PET/CT Metrics and Association With Pathology Features
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.
Time frame: Assessed at baseline and every 4 months for 2 years and every 6 months for years 3-10 and then annually up to 15 years
Other Pre-specified
To Assess the Ability of Pre-treatment FDG-PET/CT Semi Quantitative Parameters Including SUVmax and Metabolic Measurements to Predict Response Rate and PFS.
To assess the ability of pre-treatment FDG-PET/CT semi quantitative parameters including SUVmax and metabolic measurements to predict response rate and PFS.
Time frame: Assessed at baseline and every 4 months for 2 years and every 6 months for years 3-10 and then annually up to 15 years
Other Pre-specified
To Assess the Proportion of Patients up and Down Staging When FDGPET/CT is Added to Standard Ann Arbor Staging.
Assessment of the proportion of patients up and down staging when FDGPET/CT is added to standard Ann Arbor staging will be performed.
Time frame: Assessed at baseline and every 4 months for 2 years and every 6 months for years 3-10 and then annually up to 15 years
Other Pre-specified
To Collect and Bank Serum and Blood Mononuclear Cells for Future Studies
Collecting and banking serum and blood mononuclear cells for future studies
Time frame: Assessed at baseline, end of cycle 3, end of cycle 6, every 4 months during first year of maintenance, every 6 months during 2nd year of maintenance, and 12 months after completion of maintenance
Other Pre-specified
To Collect Formalin Fixed Paraffin Embedded (FFPE) Tissue to Analyze Potential Prognostic Factors
Collection of formalin fixed paraffin embedded (FFPE) tissue for future analysis of potential prognostic factors
Time frame: Assessed at baseline
Other Pre-specified
To Collect Paraffin Embedded Tissue for Creation of Tissue Microarray
Collection of paraffin embedded tissue for creation of tissue microarray
Time frame: Assessed at baseline
Other Pre-specified
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 predict the number of cells in marrow
Time frame: Assessed at baseline and end of cycle 6
Other Pre-specified
To Evaluate the Effects of Bortezomib-related Neuropathy (FACT/GOG-Ntx Subscale Score) on Patient Reported Health-related Quality of Life (FACT-G Score).
FACT/GOG-Ntx subscale has 11 items and the score ranges from 0 to 44. FACT-G has 27 items and the score ranges from 0 to 108. The higher the score, the better the quality of life for both scales.
Time frame: Assessed at baseline, 6, 12, 30, 36, 48 and 60 months
Other Pre-specified
To Evaluate the Response of Lymphoma-specific Symptoms to Treatment.
FACT-Lymphoma has 15 items and the score ranges from 0 to 60. The higher the score, the better the quality of life.
Time frame: Assessed at baseline, 6, 12, 30, 36, 48 and 60 months