Lymphoma
Conditions
Keywords
contiguous stage II grade 1 follicular lymphoma, contiguous stage II grade 2 follicular lymphoma, contiguous stage II grade 3 follicular lymphoma, noncontiguous stage II grade 1 follicular lymphoma, noncontiguous stage II grade 2 follicular lymphoma, noncontiguous stage II grade 3 follicular lymphoma, stage III grade 1 follicular lymphoma, stage III grade 2 follicular lymphoma, stage III grade 3 follicular lymphoma, stage IV grade 1 follicular lymphoma, stage IV grade 2 follicular lymphoma, stage IV grade 3 follicular lymphoma
Brief summary
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.
Detailed description
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.
Interventions
BIOLOGICALrituximab
Given IV
DRUGBendamustin
Given IV
DRUGbortezomib
Given IV
DRUGlenalidomide
Given orally
Sponsors
National Cancer Institute (NCI)
ECOG-ACRIN Cancer Research Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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®
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Remission (CR) Rate | Assessed every 4 weeks during induction treatment and every 8 weeks during continuation treatment, up to 2 years | Complete remission is defined as complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present prior to therapy. This analysis was conducted among 222 evaluable patients for the primary analysis. The purpose of this analysis is to compare the complete remission rate of rituximab + bendamustine vs. bortezomib + rituximab + bendamustine as induction therapy, therefore, the proportion of patients with complete remission was compared between Arm B (bortezomib + rituximab + bendamustine) and Arms A and C combined (rituximab + bendamustine). |
| 1-year Post-induction Disease-free Survival (DFS) Rate | Assessed at 1 year post-induction, approximately 1.5 years | 1-year post induction disease-free survival rate is defined as the proportion of patients achieving complete remission during induction treatment and are alive and maintaining complete remission at 1 year after induction completion. The purpose of this analysis is to compare the 1-year post-induction disease-free survival (DFS) rate with rituximab plus lenalidomide to rituximab alone as continuation therapy following induction treatment of bendamustine+rituximab, therefore, patients with induction treatment of bendamustine + rituximab + bortezomib were not included in this analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Remission (CR) Rate | Assessed every 4 weeks during induction treatment and every 8 weeks during continuation treatment, up to 2 years | Complete remission is defined as complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present prior to therapy. This analysis was conducted among 222 evaluable patients. The proportion of patients with complete remission was compared between patients with Follicular Lymphoma International Prognostic Index (FLIPI) of 3-5 and patients with FLIPI of 0-2/unknown. The FLIPI was developed in order to predict prognosis of patients with newly diagnosed follicular lymphoma (FL). The five FLIPI risk factors were: age \> 60 years, Ann Arbor stage III-IV, hemoglobin level \< 12 gm/dL, \>4 nodal areas, and serum LDH level above normal. The FLIPI score was calculated by summing the number of risk factors. The higher the FLIPI score, the worse the prognosis. |
| 1-year Disease-free Survival (DFS) Rate | Assessed at 1 year post-induction, approximately 1.5 years | 1-year post induction disease-free survival rate is defined as the proportion of patients achieving complete remission during induction treatment and are alive and maintaining complete remission at 1 year after induction completion. This analysis was conducted among 203 evaluable patients in the continuation treatment portion of the study. The 1-year post induction disease-free survival rate was compared between patients with FLIPI of 3-5 and patients with FLIPI of 0-2/unknown. The FLIPI was developed in order to predict prognosis of patients with newly diagnosed follicular lymphoma (FL). The five FLIPI risk factors were: age \> 60 years, Ann Arbor stage III-IV, hemoglobin level \< 12 gm/dL, \>4 nodal areas, and serum LDH level above normal. The FLIPI score was calculated by summing the number of risk factors. The higher the FLIPI score, the worse the prognosis. |
| Progression-free Survival | Assessed every cycle during treatment and every 6 months between 2 and 5 years from study entry | Progression-free survival is defined as the time from registration of induction treatment to progression, relapse or death, whichever occurs first. Patients alive without documented progression are censored at last disease assessment. Progression/relapse is defined as appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, \>=50% increase from nadir in the SPD of any previously involved nodes or extranodal masses or the size of other lesions, or \>=50% increase in the longest diameter of any single previously identified node or extranodal mass more than 1 cm in its short axis. The five FLIPI risk factors were: age \> 60 years, Ann Arbor stage III-IV, hemoglobin level \< 12 gm/dL, \>4 nodal areas, and serum LDH level above normal. The FLIPI score was calculated by summing the number of risk factors. The higher the FLIPI score, the worse the prognosis. |
| Proportion of Patients With Grade 3 or Higher Peripheral Neuropathy | Assessed every cycle during treatment and for 30 days after discontinuation of treatment, up to 15 years | Peripheral neuropathy was assessed using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Proportion of patients with grade 3 or higher peripheral neuropathy was compared between patients with subcutaneous bortezomib and patients with intravenous bortezomib. |
| Functional Assessment of Cancer Therapy - General (FACT-G) Total Score at Baseline | Assessed at baseline | The Functional Assessment of Cancer Therapy - General (FACT-G) is a 27-item questionnaire that has four areas of measurements (physical well-being, social/family well-being, emotional well-being and functional well-being) with a scale of 0-4. The FACT-G total score ranges between 0 and 108. The higher the score, the better the quality of life. |
| Functional Assessment of Cancer Therapy - General (FACT-G) Total Score at Mid-treatment | Assessed at cycle 3 or cycle 4, approximately 3 or 4 months | The Functional Assessment of Cancer Therapy - General (FACT-G) is a 27-item questionnaire that has four areas of measurements (physical well-being, social/family well-being, emotional well-being and functional well-being) with a scale of 0-4. The FACT-G total score ranges between 0 and 108. The higher the score, the better the quality of life. FACT-G total score at cycle 3 is considered as mid-treatment score. If FACT-G total score at cycle 3 is not available, the score at cycle 4 will be used as the mid-treatment score. |
| Functional Assessment of Cancer Therapy - General (FACT-G) Total Score at End of Induction Treatment | Assessed at cycle 6, approximately 6 months | The Functional Assessment of Cancer Therapy - General (FACT-G) is a 27-item questionnaire that has four areas of measurements (physical well-being, social/family well-being, emotional well-being and functional well-being) with a scale of 0-4. The FACT-G total score ranges between 0 and 108. The higher the score, the better the quality of life. |
| Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Subscale Score at Baseline | Assessed at baseline | The Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) is a 15-item questionnaire that evaluates disease-related symptoms and concerns specific to lymphoma with a scale of 0-4. The FACT-Lym subscale score ranges between 0 and 60. The higher the score, the better the quality of life. |
| 3-year Progression-free Survival Rate | Assessed every cycle during treatment and every 6 months between 2 and 5 years from study entry | Progression-free survival is defined as the time from registration of induction treatment to progression, relapse or death, whichever occurs first. Patients alive without documented progression are censored at last disease assessment. 3-year progression-free survival rate is the proportion of patients who were progression-free and alive at 3 years estimated using the method of Kaplan-Meier. Progression/relapse is defined as appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, \>=50% increase from nadir in the SPD of any previously involved nodes or extranodal masses or the size of other lesions, or \>=50% increase in the longest diameter of any single previously identified node or extranodal mass more than 1 cm in its short axis. |
| Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Subscale Score at End of Induction Treatment | Assessed at cycle 6, approximately 6 months | The Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) is a 15-item questionnaire that evaluates disease-related symptoms and concerns specific to lymphoma with a scale of 0-4. The FACT-Lym subscale score ranges between 0 and 60. The higher the score, the better the quality of life. |
| Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) Subscale Score at Baseline | Assessed at baseline | The Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) is comprised of 13 items that assess fatigue and its impact with a scale of 0-4. The FACIT-Fatigue subscale score ranges between 0 and 52. The higher the score, the better the quality of life. |
| Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) Subscale Score at Mid-induction Treatment | Assessed at cycle 3 or cycle 4, approximately 3 or 4 months | The Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) is comprised of 13 items that assess fatigue and its impact with a scale of 0-4. The FACIT-Fatigue subscale score ranges between 0 and 52. The higher the score, the better the quality of life. FACIT-Fatigue subscale score at cycle 3 is considered as mid-treatment score. If FACIT-Fatigue subscale score at cycle 3 is not available, the score at cycle 4 will be used as the mid-treatment score. |
| Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) Subscale Score at End of Induction Treatment | Assessed at cycle 6, approximately 6 months | The Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) is comprised of 13 items that assess fatigue and its impact with a scale of 0-4. The FACIT-Fatigue subscale score ranges between 0 and 52. The higher the score, the better the quality of life. |
| Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT-GOG-NTX) Subscale Score at Baseline | Assessed at baseline | The Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT-GOG-NTX) subscale is comprised of 11 items that assess neurotoxicity with a scale of 0-4. The FACT-GOG-NTX subscale score ranges between 0 and 44. The higher the score, the better the quality of life. |
| Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT-GOG-NTX) Subscale Score at Mid-induction Treatment | Assessed at cycle 3, approximately 3 months | The Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT-GOG-NTX) subscale is comprised of 11 items that assess neurotoxicity with a scale of 0-4. The FACT-GOG-NTX subscale score ranges between 0 and 44. The higher the score, the better the quality of life. |
| Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT-GOG-NTX) Subscale Score at the End of Induction Treatment | Assessed at end of induction treatment (cycle 6), approximately 6 months | The Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT-GOG-NTX) subscale is comprised of 11 items that assess neurotoxicity with a scale of 0-4. The FACT-GOG-NTX subscale score ranges between 0 and 44. The higher the score, the better the quality of life. |
| Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Subscale Score at Mid-induction Treatment | Assessed at cycle 3 or cycle 4, approximately 3 or 4 months | The Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) is a 15-item questionnaire that evaluates disease-related symptoms and concerns specific to lymphoma with a scale of 0-4. The FACT-Lym subscale score ranges between 0 and 60. The higher the score, the better the quality of life. FACT-Lym subscale score at cycle 3 is considered as mid-treatment score. If FACT-Lym subscale score at cycle 3 is not available, the score at cycle 4 will be used as the mid-treatment score. |
| 5-year Overall Survival Rate | Assessed every cycle during treatment and every 6 months between 2 and 5 years from study entry | Overall survival is defined as the time from randomization to death or date last known alive. 5-year overall survival rate is the proportion of patients who were alive at 5 years estimated using the method of Kaplan-Meier. |
Countries
United States
Participant flow
Recruitment details
This study was activated on December 13, 2010, accrued its first patient on February 9, 2011, and closed on May 13, 2015, with final accrual of 289 patients
Participants by arm
| Arm | Count |
|---|---|
| Arm A Then Arm D (Induction With Bendamustine + Rituximab; Continuation With Rituximab) 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. | 59 |
| Arm B Then Arm E (Induction With Bendamustine + Rituximab + Bortezomib; Continuation With Rituximab) 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. | 85 |
| Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab) 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. | 114 |
| Total | 258 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Continuation | Adverse Event | 5 | 3 | 16 |
| Continuation | Death | 1 | 0 | 2 |
| Continuation | Insurance change | 0 | 1 | 0 |
| Continuation | Lack of Efficacy | 3 | 2 | 7 |
| Continuation | Mistakenly stayed on treatment for longer than expected | 0 | 1 | 0 |
| Continuation | Never started treatment | 0 | 1 | 5 |
| Continuation | Non-compliance | 1 | 0 | 1 |
| Continuation | Not reported | 0 | 0 | 1 |
| Continuation | Other diseases | 0 | 2 | 1 |
| Continuation | Physician Decision | 1 | 0 | 1 |
| Continuation | Withdrawal by Subject | 4 | 5 | 9 |
| Induction | Adverse Event | 0 | 5 | 5 |
| Induction | Death | 0 | 0 | 2 |
| Induction | Lack of Efficacy | 4 | 3 | 7 |
| Induction | Never started treatment | 0 | 6 | 3 |
| Induction | Other disease | 0 | 1 | 2 |
| Induction | Withdrawal by Subject | 0 | 4 | 2 |
Baseline characteristics
| Characteristic | Arm A Then Arm D (Induction With Bendamustine + Rituximab; Continuation With Rituximab) | Total | Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab) | Arm B Then Arm E (Induction With Bendamustine + Rituximab + Bortezomib; Continuation With Rituximab) |
|---|---|---|---|---|
| Age, Continuous | 59 years | 61 years | 61 years | 60 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 9 Participants | 5 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 55 Participants | 244 Participants | 107 Participants | 82 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 5 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 5 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 11 Participants | 6 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 8 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) White | 53 Participants | 233 Participants | 102 Participants | 78 Participants |
| Sex: Female, Male Female | 26 Participants | 116 Participants | 56 Participants | 34 Participants |
| Sex: Female, Male Male | 33 Participants | 142 Participants | 58 Participants | 51 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 |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 65 | 9 / 99 | 12 / 125 | 6 / 59 | 7 / 71 | 10 / 94 |
| other Total, other adverse events | 64 / 65 | 92 / 93 | 122 / 122 | 59 / 59 | 70 / 70 | 88 / 89 |
| serious Total, serious adverse events | 51 / 65 | 78 / 93 | 96 / 122 | 39 / 59 | 44 / 70 | 77 / 89 |
Outcome results
Primary
1-year Post-induction Disease-free Survival (DFS) Rate
1-year post induction disease-free survival rate is defined as the proportion of patients achieving complete remission during induction treatment and are alive and maintaining complete remission at 1 year after induction completion. The purpose of this analysis is to compare the 1-year post-induction disease-free survival (DFS) rate with rituximab plus lenalidomide to rituximab alone as continuation therapy following induction treatment of bendamustine+rituximab, therefore, patients with induction treatment of bendamustine + rituximab + bortezomib were not included in this analysis.
Time frame: Assessed at 1 year post-induction, approximately 1.5 years
Population: All eligible and treated patients in the continuation phase of arm A + D and arm C + F.~The purpose of this analysis is to compare the 1-year post-induction disease-free survival (DFS) rate with rituximab plus lenalidomide to rituximab alone as continuation therapy following induction treatment of bendamustine+rituximab, therefore, patients with induction treatment of bendamustine + rituximab + bortezomib were not included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A and Arm C (Induction With Bendamustine + Rituximab) | 1-year Post-induction Disease-free Survival (DFS) Rate | 0.85 proportion of participants |
| Arm B (Induction With Bendamustine + Rituximab + Bortezomib) | 1-year Post-induction Disease-free Survival (DFS) Rate | 0.67 proportion of participants |
p-value: 0.02Cochran-Mantel-Haenszel
Primary
Complete Remission (CR) Rate
Complete remission is defined as complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present prior to therapy. This analysis was conducted among 222 evaluable patients for the primary analysis. The purpose of this analysis is to compare the complete remission rate of rituximab + bendamustine vs. bortezomib + rituximab + bendamustine as induction therapy, therefore, the proportion of patients with complete remission was compared between Arm B (bortezomib + rituximab + bendamustine) and Arms A and C combined (rituximab + bendamustine).
Time frame: Assessed every 4 weeks during induction treatment and every 8 weeks during continuation treatment, up to 2 years
Population: This analysis was conducted among 222 evaluable patients for the primary analysis. The purpose of this analysis is to compare the complete remission rate of rituximab + bendamustine vs. bortezomib + rituximab + bendamustine as induction therapy, therefore, the proportion of patients with complete remission was compared between Arm B (bortezomib + rituximab + bendamustine) and Arms A and C combined (rituximab + bendamustine).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A and Arm C (Induction With Bendamustine + Rituximab) | Complete Remission (CR) Rate | 0.62 proportion of participants |
| Arm B (Induction With Bendamustine + Rituximab + Bortezomib) | Complete Remission (CR) Rate | 0.75 proportion of participants |
Comparison: The study was designed to detect a 16% difference in CR rate from 50% in the Bendamustine + Rituximab arms to 66% in the Bendamustine + Rituximab + Bortezomib arm, with 90% power at the one-sided alpha 0.15 level.p-value: 0.02Cochran-Mantel-Haenszel
Secondary
1-year Disease-free Survival (DFS) Rate
1-year post induction disease-free survival rate is defined as the proportion of patients achieving complete remission during induction treatment and are alive and maintaining complete remission at 1 year after induction completion. This analysis was conducted among 250 evaluable patients with Cumulative Illness Rating Scale (CIRS) data available. The proportion of patients disease-free and alive at 1 year post induction treatment was compared between patients with CIRS \<10 and patients with CIRS \>=10. Higher CIRS scores indicate higher severity with max score of 56 points.
Time frame: Assessed at 1 year post-induction, approximately 1.5 years
Population: This analysis was conducted among 250 evaluable patients with baseline Cumulative Illness Rating Scale (CIRS) data available. The proportion of patients disease-free and alive at 1 year post induction treatment was compared between patients with CIRS \<10 and patients with CIRS \>=10.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A and Arm C (Induction With Bendamustine + Rituximab) | 1-year Disease-free Survival (DFS) Rate | 0.62 proportion of participants |
| Arm B (Induction With Bendamustine + Rituximab + Bortezomib) | 1-year Disease-free Survival (DFS) Rate | 0.65 proportion of participants |
Secondary
1-year Disease-free Survival (DFS) Rate
1-year post induction disease-free survival rate is defined as the proportion of patients achieving complete remission during induction treatment and are alive and maintaining complete remission at 1 year after induction completion. This analysis was conducted among 203 evaluable patients in the continuation treatment portion of the study. The 1-year post induction disease-free survival rate was compared between patients with FLIPI of 3-5 and patients with FLIPI of 0-2/unknown. The FLIPI was developed in order to predict prognosis of patients with newly diagnosed follicular lymphoma (FL). The five FLIPI risk factors were: age \> 60 years, Ann Arbor stage III-IV, hemoglobin level \< 12 gm/dL, \>4 nodal areas, and serum LDH level above normal. The FLIPI score was calculated by summing the number of risk factors. The higher the FLIPI score, the worse the prognosis.
Time frame: Assessed at 1 year post-induction, approximately 1.5 years
Population: This analysis was conducted among 203 evaluable patients in the continuation treatment portion of the study. The 1-year post induction disease-free survival rate was compared between patients with FLIPI of 3-5 and patients with FLIPI of 0-2/unknown.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A and Arm C (Induction With Bendamustine + Rituximab) | 1-year Disease-free Survival (DFS) Rate | 0.84 proportion of participants |
| Arm B (Induction With Bendamustine + Rituximab + Bortezomib) | 1-year Disease-free Survival (DFS) Rate | 0.74 proportion of participants |
Secondary
3-year Progression-free Survival Rate
Progression-free survival is defined as the time from registration of induction treatment to progression, relapse or death, whichever occurs first. Patients alive without documented progression are censored at last disease assessment. 3-year progression-free survival rate is the proportion of patients who were progression-free and alive at 3 years estimated using the method of Kaplan-Meier. Progression/relapse is defined as appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, \>=50% increase from nadir in the SPD of any previously involved nodes or extranodal masses or the size of other lesions, or \>=50% increase in the longest diameter of any single previously identified node or extranodal mass more than 1 cm in its short axis.
Time frame: Assessed every cycle during treatment and every 6 months between 2 and 5 years from study entry
Population: This analysis was conducted among 222 evaluable patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A and Arm C (Induction With Bendamustine + Rituximab) | 3-year Progression-free Survival Rate | 0.77 proportion of participants |
| Arm B (Induction With Bendamustine + Rituximab + Bortezomib) | 3-year Progression-free Survival Rate | 0.82 proportion of participants |
| Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab) | 3-year Progression-free Survival Rate | 0.76 proportion of participants |
Secondary
3-year Progression-free Survival Rate
Progression-free survival is defined as the time from registration of induction treatment to progression, relapse or death, whichever occurs first. Patients alive without documented progression are censored at last disease assessment. 3-year progression-free survival rate is the proportion of patients who were progression-free and alive at 3 years estimated using the method of Kaplan-Meier. Progression/relapse is defined as appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, \>=50% increase from nadir in the SPD of any previously involved nodes or extranodal masses or the size of other lesions, or \>=50% increase in the longest diameter of any single previously identified node or extranodal mass more than 1 cm in its short axis. The 3-year progression-free survival rate is reported by Cumulative Illness Rating Scale (CIRS) score (\<10 vs. \>=10). Higher CIRS scores indicate higher severity with max score of 56 points.
Time frame: Assessed every cycle during treatment and every 6 months between 2 and 5 years from study entry
Population: This analysis was conducted among 250 evaluable patients with baseline Cumulative Illness Rating Scale (CIRS) data available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A and Arm C (Induction With Bendamustine + Rituximab) | 3-year Progression-free Survival Rate | 0.83 proportion of participants |
| Arm B (Induction With Bendamustine + Rituximab + Bortezomib) | 3-year Progression-free Survival Rate | 0.68 proportion of participants |
Secondary
5-year Overall Survival Rate
Overall survival is defined as the time from randomization to death or date last known alive. 5-year overall survival rate is the proportion of patients who were alive at 5 years estimated using the method of Kaplan-Meier. The 5-year overall survival rate is reported by Cumulative Illness Rating Scale (CIRS) score (\<10 vs. \>=10). Higher CIRS scores indicate higher severity with max score of 56 points.
Time frame: Assessed every cycle during treatment and every 6 months between 2 and 5 years from study entry
Population: This analysis was conducted among 250 evaluable patients with baseline Cumulative Illness Rating Scale (CIRS) data available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A and Arm C (Induction With Bendamustine + Rituximab) | 5-year Overall Survival Rate | 0.87 proportion of participants |
| Arm B (Induction With Bendamustine + Rituximab + Bortezomib) | 5-year Overall Survival Rate | 0.80 proportion of participants |
Secondary
5-year Overall Survival Rate
Overall survival is defined as the time from randomization to death or date last known alive. 5-year overall survival rate is the proportion of patients who were alive at 5 years estimated using the method of Kaplan-Meier.
Time frame: Assessed every cycle during treatment and every 6 months between 2 and 5 years from study entry
Population: This analysis was conducted among 222 evaluable patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A and Arm C (Induction With Bendamustine + Rituximab) | 5-year Overall Survival Rate | 0.87 proportion of participants |
| Arm B (Induction With Bendamustine + Rituximab + Bortezomib) | 5-year Overall Survival Rate | 0.86 proportion of participants |
| Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab) | 5-year Overall Survival Rate | 0.83 proportion of participants |
Secondary
5-year Overall Survival Rate
Overall survival is defined as the time from randomization to death or date last known alive. 5-year overall survival rate is the proportion of patients who were alive at 5 years estimated using the method of Kaplan-Meier. The FLIPI was developed in order to predict prognosis of patients with newly diagnosed follicular lymphoma (FL). The five FLIPI risk factors were: age \> 60 years, Ann Arbor stage III-IV, hemoglobin level \< 12 gm/dL, \>4 nodal areas, and serum LDH level above normal. The FLIPI score was calculated by summing the number of risk factors. The higher the FLIPI score, the worse the prognosis.
Time frame: Assessed every cycle during treatment and every 6 months between 2 and 5 years from study entry
Population: This analysis was conducted among 222 evaluable patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A and Arm C (Induction With Bendamustine + Rituximab) | 5-year Overall Survival Rate | 0.90 proportion of participants |
| Arm B (Induction With Bendamustine + Rituximab + Bortezomib) | 5-year Overall Survival Rate | 0.81 proportion of participants |
Secondary
Complete Remission (CR) Rate
Complete remission is defined as complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present prior to therapy. This analysis was conducted among 250 evaluable patients with Cumulative Illness Rating Scale (CIRS) data available. The proportion of patients with complete remission was compared between patients with CIRS \<10 and patients with CIRS \>=10. Higher CIRS scores indicate higher severity with max score of 56 points.
Time frame: Assessed every 4 weeks during induction treatment and every 8 weeks during continuation treatment, up to 2 years
Population: This analysis was conducted among 250 evaluable patients with baseline CIRS data available. The proportion of patients with complete remission was compared between baseline CIRS \<10 and baseline CIRS \>=10.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A and Arm C (Induction With Bendamustine + Rituximab) | Complete Remission (CR) Rate | 0.70 proportion of participants |
| Arm B (Induction With Bendamustine + Rituximab + Bortezomib) | Complete Remission (CR) Rate | 0.70 proportion of participants |
Secondary
Complete Remission (CR) Rate
Complete remission is defined as complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present prior to therapy. This analysis was conducted among 222 evaluable patients. The proportion of patients with complete remission was compared between patients with Follicular Lymphoma International Prognostic Index (FLIPI) of 3-5 and patients with FLIPI of 0-2/unknown. The FLIPI was developed in order to predict prognosis of patients with newly diagnosed follicular lymphoma (FL). The five FLIPI risk factors were: age \> 60 years, Ann Arbor stage III-IV, hemoglobin level \< 12 gm/dL, \>4 nodal areas, and serum LDH level above normal. The FLIPI score was calculated by summing the number of risk factors. The higher the FLIPI score, the worse the prognosis.
Time frame: Assessed every 4 weeks during induction treatment and every 8 weeks during continuation treatment, up to 2 years
Population: This analysis was conducted among 222 evaluable patients that were enrolled before activation of addendum #8. The proportion of patients with complete remission was compared between FLIPI 0-2/unknown and FLIPI 3-5 at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A and Arm C (Induction With Bendamustine + Rituximab) | Complete Remission (CR) Rate | 0.71 proportion of participants |
| Arm B (Induction With Bendamustine + Rituximab + Bortezomib) | Complete Remission (CR) Rate | 0.64 proportion of participants |
Secondary
Functional Assessment of Cancer Therapy - General (FACT-G) Total Score at Baseline
The Functional Assessment of Cancer Therapy - General (FACT-G) is a 27-item questionnaire that has four areas of measurements (physical well-being, social/family well-being, emotional well-being and functional well-being) with a scale of 0-4. The FACT-G total score ranges between 0 and 108. The higher the score, the better the quality of life.
Time frame: Assessed at baseline
Population: All enrolled patients with baseline FACT-G total score available
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A and Arm C (Induction With Bendamustine + Rituximab) | Functional Assessment of Cancer Therapy - General (FACT-G) Total Score at Baseline | 83.9 score on a scale | Standard Deviation 14.2 |
| Arm B (Induction With Bendamustine + Rituximab + Bortezomib) | Functional Assessment of Cancer Therapy - General (FACT-G) Total Score at Baseline | 84.7 score on a scale | Standard Deviation 15.5 |
| Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab) | Functional Assessment of Cancer Therapy - General (FACT-G) Total Score at Baseline | 86.0 score on a scale | Standard Deviation 16 |
Secondary
Functional Assessment of Cancer Therapy - General (FACT-G) Total Score at End of Induction Treatment
The Functional Assessment of Cancer Therapy - General (FACT-G) is a 27-item questionnaire that has four areas of measurements (physical well-being, social/family well-being, emotional well-being and functional well-being) with a scale of 0-4. The FACT-G total score ranges between 0 and 108. The higher the score, the better the quality of life.
Time frame: Assessed at cycle 6, approximately 6 months
Population: All enrolled patients with cycle 6 FACT-G total score available
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A and Arm C (Induction With Bendamustine + Rituximab) | Functional Assessment of Cancer Therapy - General (FACT-G) Total Score at End of Induction Treatment | 86.0 score on a scale | Standard Deviation 17.7 |
| Arm B (Induction With Bendamustine + Rituximab + Bortezomib) | Functional Assessment of Cancer Therapy - General (FACT-G) Total Score at End of Induction Treatment | 86.5 score on a scale | Standard Deviation 13.9 |
| Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab) | Functional Assessment of Cancer Therapy - General (FACT-G) Total Score at End of Induction Treatment | 84.9 score on a scale | Standard Deviation 18.2 |
Secondary
Functional Assessment of Cancer Therapy - General (FACT-G) Total Score at Mid-treatment
The Functional Assessment of Cancer Therapy - General (FACT-G) is a 27-item questionnaire that has four areas of measurements (physical well-being, social/family well-being, emotional well-being and functional well-being) with a scale of 0-4. The FACT-G total score ranges between 0 and 108. The higher the score, the better the quality of life. FACT-G total score at cycle 3 is considered as mid-treatment score. If FACT-G total score at cycle 3 is not available, the score at cycle 4 will be used as the mid-treatment score.
Time frame: Assessed at cycle 3 or cycle 4, approximately 3 or 4 months
Population: All enrolled patients with cycle 3 or cycle 4 FACT-G total score available
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A and Arm C (Induction With Bendamustine + Rituximab) | Functional Assessment of Cancer Therapy - General (FACT-G) Total Score at Mid-treatment | 85.5 score on a scale | Standard Deviation 15.7 |
| Arm B (Induction With Bendamustine + Rituximab + Bortezomib) | Functional Assessment of Cancer Therapy - General (FACT-G) Total Score at Mid-treatment | 84.2 score on a scale | Standard Deviation 16.4 |
| Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab) | Functional Assessment of Cancer Therapy - General (FACT-G) Total Score at Mid-treatment | 85.2 score on a scale | Standard Deviation 15.9 |
Secondary
Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT-GOG-NTX) Subscale Score at Baseline
The Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT-GOG-NTX) subscale is comprised of 11 items that assess neurotoxicity with a scale of 0-4. The FACT-GOG-NTX subscale score ranges between 0 and 44. The higher the score, the better the quality of life.
Time frame: Assessed at baseline
Population: All enrolled patients with baseline FACT-GOG-NTX subscale score available
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A and Arm C (Induction With Bendamustine + Rituximab) | Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT-GOG-NTX) Subscale Score at Baseline | 39.9 score on a scale | Standard Deviation 4.3 |
| Arm B (Induction With Bendamustine + Rituximab + Bortezomib) | Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT-GOG-NTX) Subscale Score at Baseline | 38.7 score on a scale | Standard Deviation 6 |
| Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab) | Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT-GOG-NTX) Subscale Score at Baseline | 38.8 score on a scale | Standard Deviation 5.5 |
Secondary
Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT-GOG-NTX) Subscale Score at Mid-induction Treatment
The Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT-GOG-NTX) subscale is comprised of 11 items that assess neurotoxicity with a scale of 0-4. The FACT-GOG-NTX subscale score ranges between 0 and 44. The higher the score, the better the quality of life.
Time frame: Assessed at cycle 3, approximately 3 months
Population: All enrolled patients with cycle 3 FACT-GOG-NTX subscale score available
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A and Arm C (Induction With Bendamustine + Rituximab) | Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT-GOG-NTX) Subscale Score at Mid-induction Treatment | 40.0 score on a scale | Standard Deviation 4.6 |
| Arm B (Induction With Bendamustine + Rituximab + Bortezomib) | Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT-GOG-NTX) Subscale Score at Mid-induction Treatment | 38.6 score on a scale | Standard Deviation 5.1 |
| Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab) | Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT-GOG-NTX) Subscale Score at Mid-induction Treatment | 39.1 score on a scale | Standard Deviation 5.2 |
Secondary
Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT-GOG-NTX) Subscale Score at the End of Induction Treatment
The Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT-GOG-NTX) subscale is comprised of 11 items that assess neurotoxicity with a scale of 0-4. The FACT-GOG-NTX subscale score ranges between 0 and 44. The higher the score, the better the quality of life.
Time frame: Assessed at end of induction treatment (cycle 6), approximately 6 months
Population: All enrolled patients with cycle 6 FACT-GOG-NTX subscale score available
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A and Arm C (Induction With Bendamustine + Rituximab) | Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT-GOG-NTX) Subscale Score at the End of Induction Treatment | 39.8 score on a scale | Standard Deviation 4 |
| Arm B (Induction With Bendamustine + Rituximab + Bortezomib) | Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT-GOG-NTX) Subscale Score at the End of Induction Treatment | 36.1 score on a scale | Standard Deviation 6.5 |
| Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab) | Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT-GOG-NTX) Subscale Score at the End of Induction Treatment | 39.0 score on a scale | Standard Deviation 5.9 |
Secondary
Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Subscale Score at Baseline
The Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) is a 15-item questionnaire that evaluates disease-related symptoms and concerns specific to lymphoma with a scale of 0-4. The FACT-Lym subscale score ranges between 0 and 60. The higher the score, the better the quality of life.
Time frame: Assessed at baseline
Population: All enrolled patients with baseline FACT-Lym subscale score available
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A and Arm C (Induction With Bendamustine + Rituximab) | Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Subscale Score at Baseline | 43.8 score on a scale | Standard Deviation 8.7 |
| Arm B (Induction With Bendamustine + Rituximab + Bortezomib) | Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Subscale Score at Baseline | 44.3 score on a scale | Standard Deviation 9.3 |
| Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab) | Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Subscale Score at Baseline | 44.9 score on a scale | Standard Deviation 10.6 |
Secondary
Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Subscale Score at End of Induction Treatment
The Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) is a 15-item questionnaire that evaluates disease-related symptoms and concerns specific to lymphoma with a scale of 0-4. The FACT-Lym subscale score ranges between 0 and 60. The higher the score, the better the quality of life.
Time frame: Assessed at cycle 6, approximately 6 months
Population: All enrolled patients with cycle 6 FACT-Lym subscale score available
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A and Arm C (Induction With Bendamustine + Rituximab) | Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Subscale Score at End of Induction Treatment | 48.9 score on a scale | Standard Deviation 7.5 |
| Arm B (Induction With Bendamustine + Rituximab + Bortezomib) | Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Subscale Score at End of Induction Treatment | 48.4 score on a scale | Standard Deviation 8.5 |
| Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab) | Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Subscale Score at End of Induction Treatment | 47.2 score on a scale | Standard Deviation 9.9 |
Secondary
Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Subscale Score at Mid-induction Treatment
The Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) is a 15-item questionnaire that evaluates disease-related symptoms and concerns specific to lymphoma with a scale of 0-4. The FACT-Lym subscale score ranges between 0 and 60. The higher the score, the better the quality of life. FACT-Lym subscale score at cycle 3 is considered as mid-treatment score. If FACT-Lym subscale score at cycle 3 is not available, the score at cycle 4 will be used as the mid-treatment score.
Time frame: Assessed at cycle 3 or cycle 4, approximately 3 or 4 months
Population: All enrolled patients with cycle 3 or cycle 4 FACT-Lym subscale score available
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A and Arm C (Induction With Bendamustine + Rituximab) | Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Subscale Score at Mid-induction Treatment | 47.9 score on a scale | Standard Deviation 7.4 |
| Arm B (Induction With Bendamustine + Rituximab + Bortezomib) | Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Subscale Score at Mid-induction Treatment | 46.8 score on a scale | Standard Deviation 8.7 |
| Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab) | Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Subscale Score at Mid-induction Treatment | 46.5 score on a scale | Standard Deviation 9.5 |
Secondary
Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) Subscale Score at Baseline
The Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) is comprised of 13 items that assess fatigue and its impact with a scale of 0-4. The FACIT-Fatigue subscale score ranges between 0 and 52. The higher the score, the better the quality of life.
Time frame: Assessed at baseline
Population: All enrolled patients with baseline FACIT-Fatigue subscale score available
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A and Arm C (Induction With Bendamustine + Rituximab) | Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) Subscale Score at Baseline | 38.6 score on a scale | Standard Deviation 10.5 |
| Arm B (Induction With Bendamustine + Rituximab + Bortezomib) | Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) Subscale Score at Baseline | 37.9 score on a scale | Standard Deviation 11.4 |
| Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab) | Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) Subscale Score at Baseline | 38.1 score on a scale | Standard Deviation 12.1 |
Secondary
Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) Subscale Score at End of Induction Treatment
The Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) is comprised of 13 items that assess fatigue and its impact with a scale of 0-4. The FACIT-Fatigue subscale score ranges between 0 and 52. The higher the score, the better the quality of life.
Time frame: Assessed at cycle 6, approximately 6 months
Population: All enrolled patients with cycle 6 FACIT-Fatigue subscale score available
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A and Arm C (Induction With Bendamustine + Rituximab) | Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) Subscale Score at End of Induction Treatment | 39.9 score on a scale | Standard Deviation 10.1 |
| Arm B (Induction With Bendamustine + Rituximab + Bortezomib) | Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) Subscale Score at End of Induction Treatment | 39.1 score on a scale | Standard Deviation 9.8 |
| Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab) | Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) Subscale Score at End of Induction Treatment | 36.3 score on a scale | Standard Deviation 12.2 |
Secondary
Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) Subscale Score at Mid-induction Treatment
The Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) is comprised of 13 items that assess fatigue and its impact with a scale of 0-4. The FACIT-Fatigue subscale score ranges between 0 and 52. The higher the score, the better the quality of life. FACIT-Fatigue subscale score at cycle 3 is considered as mid-treatment score. If FACIT-Fatigue subscale score at cycle 3 is not available, the score at cycle 4 will be used as the mid-treatment score.
Time frame: Assessed at cycle 3 or cycle 4, approximately 3 or 4 months
Population: All enrolled patients with cycle 3 or cycle 4 FACIT-Fatigue subscale score available
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A and Arm C (Induction With Bendamustine + Rituximab) | Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) Subscale Score at Mid-induction Treatment | 39.2 score on a scale | Standard Deviation 9 |
| Arm B (Induction With Bendamustine + Rituximab + Bortezomib) | Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) Subscale Score at Mid-induction Treatment | 34.5 score on a scale | Standard Deviation 10.9 |
| Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab) | Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) Subscale Score at Mid-induction Treatment | 36.3 score on a scale | Standard Deviation 12.3 |
Secondary
Progression-free Survival
Progression-free survival is defined as the time from registration of induction treatment to progression, relapse or death, whichever occurs first. Patients alive without documented progression are censored at last disease assessment. Progression/relapse is defined as appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, \>=50% increase from nadir in the SPD of any previously involved nodes or extranodal masses or the size of other lesions, or \>=50% increase in the longest diameter of any single previously identified node or extranodal mass more than 1 cm in its short axis. The five FLIPI risk factors were: age \> 60 years, Ann Arbor stage III-IV, hemoglobin level \< 12 gm/dL, \>4 nodal areas, and serum LDH level above normal. The FLIPI score was calculated by summing the number of risk factors. The higher the FLIPI score, the worse the prognosis.
Time frame: Assessed every cycle during treatment and every 6 months between 2 and 5 years from study entry
Population: This analysis was conducted among 222 evaluable patients that were enrolled before activation of addendum #8.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A and Arm C (Induction With Bendamustine + Rituximab) | Progression-free Survival | 6.1 years |
| Arm B (Induction With Bendamustine + Rituximab + Bortezomib) | Progression-free Survival | 6.2 years |
Secondary
Proportion of Patients With Grade 3 or Higher Peripheral Neuropathy
Peripheral neuropathy was assessed using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Proportion of patients with grade 3 or higher peripheral neuropathy was compared between patients with subcutaneous bortezomib and patients with intravenous bortezomib.
Time frame: Assessed every cycle during treatment and for 30 days after discontinuation of treatment, up to 15 years
Population: This analysis was conducted among 99 patients who received bortezomib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A and Arm C (Induction With Bendamustine + Rituximab) | Proportion of Patients With Grade 3 or Higher Peripheral Neuropathy | 0.06 proportion of participants |
| Arm B (Induction With Bendamustine + Rituximab + Bortezomib) | Proportion of Patients With Grade 3 or Higher Peripheral Neuropathy | 0.12 proportion of participants |