Bendamustine Hydrochloride and Rituximab With or Without Bortezomib Followed by Rituximab With or Without Lenalidomide in Treating Patients With High-Risk Stage II, Stage III, or Stage IV Follicular Lymphoma

• Sponsor: ECOG-ACRIN Cancer Research Group (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT01216683
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 289
• Locations: 227
• Arms: 3
• Anticipated Duration (Months): 232.8
• Patients Per Site: 1.3
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma	Biological: rituximab; Drug: Bendamustin; Drug: bortezomib; Drug: lenalidomide	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 289 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A 3-Arm Randomized Phase II Trial of Bendamustine-Rituximab (BR) Followed by Rituximab vs Bortezomib-BR (BVR) Followed by Rituximab vs BR Followed by Lenalidomide/Rituximab in High Risk Follicular Lymphoma
• Actual Study Start Date: Dec 13, 2010
• Actual Primary Completion Date: Dec 2, 2019
• Anticipated Study Completion Date: May 8, 2030

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Biological: rituximab; Given IV; Other Names: IDEC-C2B8 Chimeric anti-CD20 monoclonal antibody Rituxan ; Drug: Bendamustin; Given IV; Other Names: Bendamustine hydrochloride CEP-18083 TREANDA
Experimental: 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.	Biological: rituximab; Given IV; Other Names: IDEC-C2B8 Chimeric anti-CD20 monoclonal antibody Rituxan ; Drug: Bendamustin; Given IV; Other Names: Bendamustine hydrochloride CEP-18083 TREANDA ; Drug: bortezomib; Given IV; Other Names: MLN341 LDP-341 Velcade® PS-341
Experimental: 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.	Biological: rituximab; Given IV; Other Names: IDEC-C2B8 Chimeric anti-CD20 monoclonal antibody Rituxan ; Drug: Bendamustin; Given IV; Other Names: Bendamustine hydrochloride CEP-18083 TREANDA ; Drug: lenalidomide; Given orally; Other Names: IMiD compound CC-5013 Revlimid®

Outcome Measures

Primary Outcome Measures

1. 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).

2. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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. 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.

7. 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 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.

8. 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 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.

9. 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. 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.

10. 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. 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.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

17. 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.

18. 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.

19. 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.

20. 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.

21. 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.

22. 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.

23. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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®

Exclusion Criteria (Continuation):

• Active, uncontrolled infections (afebrile for > 48 hours off antibiotics)

• ≥ grade 2 neuropathy

• Additional requirements for Arm C induction patients registering to arm F:

• Not pregnant or breast-feeding

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Marin Cancer Care Inc	Greenbrae	California	United States	94904
2	Salinas Valley Memorial	Salinas	California	United States	93901
3	Stanford University Hospitals and Clinics	Stanford	California	United States	94305
4	The Medical Center of Aurora	Aurora	Colorado	United States	80012
5	Boulder Community Hospital	Boulder	Colorado	United States	80301
6	Rocky Mountain Cancer Centers-Boulder	Boulder	Colorado	United States	80304
7	Penrose-Saint Francis Healthcare	Colorado Springs	Colorado	United States	80907
8	Porter Adventist Hospital	Denver	Colorado	United States	80210
9	Exempla Saint Joseph Hospital	Denver	Colorado	United States	80218
10	Presbyterian - Saint Lukes Medical Center - Health One	Denver	Colorado	United States	80218
11	Rocky Mountain Cancer Centers-Midtown	Denver	Colorado	United States	80218
12	Rocky Mountain Cancer Centers-Rose	Denver	Colorado	United States	80220
13	Rose Medical Center	Denver	Colorado	United States	80220
14	Colorado Cancer Research Program CCOP	Denver	Colorado	United States	80224-2522
15	Colorado Blood Cancer Institute	Denver	Colorado	United States	80907
16	Comprehensive Cancer Care and Research Institute of Colorado LLC	Englewood	Colorado	United States	80113
17	Swedish Medical Center	Englewood	Colorado	United States	80113
18	Poudre Valley Hospital	Fort Collins	Colorado	United States	80524
19	Mountain Blue Cancer Care Center	Golden	Colorado	United States	80401
20	North Colorado Medical Center	Greeley	Colorado	United States	80631
21	Rocky Mountain Cancer Centers-Greenwood Village	Greenwood Village	Colorado	United States	80111
22	Rocky Mountain Cancer Centers-Lakewood	Lakewood	Colorado	United States	80228
23	Saint Anthony Hospital	Lakewood	Colorado	United States	80228
24	Littleton Adventist Hospital	Littleton	Colorado	United States	80122
25	Rocky Mountain Cancer Centers-Sky Ridge	Lone Tree	Colorado	United States	80124
26	Sky Ridge Medical Center	Lone Tree	Colorado	United States	80124
27	Longmont United Hospital	Longmont	Colorado	United States	80501
28	McKee Medical Center	Loveland	Colorado	United States	80539
29	Parker Adventist Hospital	Parker	Colorado	United States	80138
30	Rocky Mountain Cancer Centers-Parker	Parker	Colorado	United States	80138
31	Saint Mary Corwin Medical Center	Pueblo	Colorado	United States	81004
32	North Suburban Medical Center	Thornton	Colorado	United States	80229
33	Exempla Lutheran Medical Center	Wheat Ridge	Colorado	United States	80033
34	Christiana Care Health System-Christiana Hospital	Newark	Delaware	United States	19718
35	Emory University/Winship Cancer Institute	Atlanta	Georgia	United States	30322
36	Georgia Regents University Medical Center	Augusta	Georgia	United States	30912
37	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho	United States	83706
38	Rush - Copley Medical Center	Aurora	Illinois	United States	60504
39	Illinois CancerCare-Bloomington	Bloomington	Illinois	United States	61701
40	Saint Joseph Medical Center	Bloomington	Illinois	United States	61701
41	Graham Hospital Association	Canton	Illinois	United States	61520
42	Illinois CancerCare-Canton	Canton	Illinois	United States	61520
43	Illinois CancerCare-Carthage	Carthage	Illinois	United States	62321
44	Memorial Hospital	Carthage	Illinois	United States	62321
45	Centralia Oncology Clinic	Centralia	Illinois	United States	62801
46	Northwestern University	Chicago	Illinois	United States	60611
47	Rush University Medical Center	Chicago	Illinois	United States	60612
48	Carle on Vermilion	Danville	Illinois	United States	61832
49	Cancer Care Center of Decatur	Decatur	Illinois	United States	62526
50	Decatur Memorial Hospital	Decatur	Illinois	United States	62526
51	Carle Physician Group-Effingham	Effingham	Illinois	United States	62401
52	Crossroads Cancer Center	Effingham	Illinois	United States	62401
53	Eureka Hospital	Eureka	Illinois	United States	61530
54	Illinois CancerCare-Eureka	Eureka	Illinois	United States	61530
55	Illinois CancerCare Galesburg	Galesburg	Illinois	United States	61401
56	Mason District Hospital	Havana	Illinois	United States	62644
57	Hinsdale Hematology Oncology Associates Incorporated	Hinsdale	Illinois	United States	60521
58	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois	United States	61443
59	North Shore Hematology Oncology	Libertyville	Illinois	United States	60048
60	Illinois CancerCare-Macomb	Macomb	Illinois	United States	61455
61	Mcdonough District Hospital	Macomb	Illinois	United States	61455
62	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois	United States	61938
63	Illinois CancerCare-Monmouth	Monmouth	Illinois	United States	61462
64	Illinois Cancer Specialists-Niles	Niles	Illinois	United States	60714
65	Bromenn Regional Medical Center	Normal	Illinois	United States	61761
66	Community Cancer Center Foundation	Normal	Illinois	United States	61761
67	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois	United States	61350
68	Ottawa Regional Hospital and Healthcare Center	Ottawa	Illinois	United States	61350
69	Illinois CancerCare-Pekin	Pekin	Illinois	United States	61554
70	Pekin Cancer Treatment Center	Pekin	Illinois	United States	61554
71	Methodist Medical Center of Illinois	Peoria	Illinois	United States	61603
72	Proctor Hospital	Peoria	Illinois	United States	61614
73	Illinois CancerCare-Peoria	Peoria	Illinois	United States	61615
74	Illinois Oncology Research Association CCOP	Peoria	Illinois	United States	61615
75	OSF Saint Francis Medical Center	Peoria	Illinois	United States	61637
76	Illinois CancerCare-Peru	Peru	Illinois	United States	61354
77	Illinois Valley Hospital	Peru	Illinois	United States	61354
78	Illinois CancerCare-Princeton	Princeton	Illinois	United States	61356
79	Perry Memorial Hospital	Princeton	Illinois	United States	61356
80	SwedishAmerican Regional Cancer Center/ACT	Rockford	Illinois	United States	61107
81	Memorial Medical Center	Springfield	Illinois	United States	62781-0001
82	Carle Cancer Center	Urbana	Illinois	United States	61801
83	The Carle Foundation Hospital	Urbana	Illinois	United States	61801
84	IU Health Arnett Cancer Care	Lafayette	Indiana	United States	47904
85	Franciscan Saint Anthony Health-Michigan City	Michigan City	Indiana	United States	46360
86	McFarland Clinic PC-William R Bliss Cancer Center	Ames	Iowa	United States	50010
87	Ottumwa Regional Health Center	Ottumwa	Iowa	United States	52501
88	Siouxland Hematology Oncology Associates	Sioux City	Iowa	United States	51101
89	Mercy Medical Center-Sioux City	Sioux City	Iowa	United States	51104
90	Saint Luke's Regional Medical Center	Sioux City	Iowa	United States	51104
91	Lawrence Memorial Hospital	Lawrence	Kansas	United States	66044
92	Wesley Medical Center	Wichita	Kansas	United States	67214
93	Ochsner Health Center-Summa	Baton Rouge	Louisiana	United States	70809
94	Ochsner Baptist Medical Center	New Orleans	Louisiana	United States	70115
95	Ochsner Medical Center Jefferson	New Orleans	Louisiana	United States	70121
96	Greater Baltimore Medical Center	Baltimore	Maryland	United States	21204
97	Tufts Medical Center	Boston	Massachusetts	United States	02111
98	Dana-Farber Harvard Cancer Center	Boston	Massachusetts	United States	02115
99	University of Massachusetts Medical School	Worcester	Massachusetts	United States	01655
100	Saint Joseph Mercy Hospital	Ann Arbor	Michigan	United States	48106-0995
101	Saint John Hospital and Medical Center	Detroit	Michigan	United States	48236
102	Green Bay Oncology - Escanaba	Escanaba	Michigan	United States	49431
103	Green Bay Oncology - Iron Mountain	Iron Mountain	Michigan	United States	49801
104	Allegiance Health	Jackson	Michigan	United States	49201
105	Borgess Medical Center	Kalamazoo	Michigan	United States	49001
106	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
107	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007
108	Saint Joseph Mercy Oakland	Pontiac	Michigan	United States	48341
109	Saint Mary's of Michigan	Saginaw	Michigan	United States	48601
110	Saint John Macomb-Oakland Hospital	Warren	Michigan	United States	48093
111	Sanford Clinic North-Bemidgi	Bemidji	Minnesota	United States	56601
112	Essentia Health Saint Joseph's Medical Center	Brainerd	Minnesota	United States	56401
113	Fairview Ridges Hospital	Burnsville	Minnesota	United States	55337
114	Mercy Hospital	Coon Rapids	Minnesota	United States	55433
115	Essentia Health Cancer Center	Duluth	Minnesota	United States	55805
116	Essentia Health Saint Mary's Medical Center	Duluth	Minnesota	United States	55805
117	Miller-Dwan Hospital	Duluth	Minnesota	United States	55805
118	Fairview-Southdale Hospital	Edina	Minnesota	United States	55435
119	Unity Hospital	Fridley	Minnesota	United States	55432
120	Hutchinson Area Health Care	Hutchinson	Minnesota	United States	55350
121	Minnesota Oncology Hematology PA-Maplewood	Maplewood	Minnesota	United States	55109
122	Saint John's Hospital - Healtheast	Maplewood	Minnesota	United States	55109
123	Abbott-Northwestern Hospital	Minneapolis	Minnesota	United States	55407
124	Hennepin County Medical Center	Minneapolis	Minnesota	United States	55415
125	North Memorial Medical Health Center	Robbinsdale	Minnesota	United States	55422
126	Mayo Clinic	Rochester	Minnesota	United States	55905
127	Metro-Minnesota CCOP	Saint Louis Park	Minnesota	United States	55416
128	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota	United States	55416
129	Regions Hospital	Saint Paul	Minnesota	United States	55101
130	United Hospital	Saint Paul	Minnesota	United States	55102
131	Saint Francis Regional Medical Center	Shakopee	Minnesota	United States	55379
132	Lakeview Hospital	Stillwater	Minnesota	United States	55082
133	Ridgeview Medical Center	Waconia	Minnesota	United States	55387
134	Rice Memorial Hospital	Willmar	Minnesota	United States	56201
135	Minnesota Oncology and Hematology PA-Woodbury	Woodbury	Minnesota	United States	55125
136	Saint Francis Medical Center	Cape Girardeau	Missouri	United States	63703
137	Veterans Adminstration New Jersey Health Care System	East Orange	New Jersey	United States	07018-1095
138	Hunterdon Medical Center	Flemington	New Jersey	United States	08822
139	Cancer Institute of New Jersey At Hamilton	Hamilton	New Jersey	United States	08690
140	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey	United States	08903
141	UMDNJ - New Jersey Medical School	Newark	New Jersey	United States	07103
142	New York University Langone Medical Center	New York	New York	United States	10016
143	Essentia Health Cancer Center-South University Clinic	Fargo	North Dakota	United States	58103
144	Roger Maris Cancer Center	Fargo	North Dakota	United States	58122
145	Sanford Clinic North-Fargo	Fargo	North Dakota	United States	58122
146	Sanford Medical Center-Fargo	Fargo	North Dakota	United States	58122
147	Summa Akron City Hospital/Cooper Cancer Center	Akron	Ohio	United States	44304
148	Toledo Clinic Cancer Centers-Bowling Green	Bowling Green	Ohio	United States	43402
149	Mercy Medical Center	Canton	Ohio	United States	44708
150	Geaugra Hospital	Chardon	Ohio	United States	44024
151	Case Western Reserve University	Cleveland	Ohio	United States	44106
152	MetroHealth Medical Center	Cleveland	Ohio	United States	44109
153	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
154	Ireland Cancer Center Landerbrook Health Center	Mayfield Heights	Ohio	United States	44124
155	Lake University Ireland Cancer Center	Mentor	Ohio	United States	44060
156	Southwest General Health Center Ireland Cancer Center	Middleburg Heights	Ohio	United States	44130
157	UHHS-Chagrin Highlands Medical Center	Orange Village	Ohio	United States	44122
158	Toledo Clinic Cancer Centers-Oregon	Oregon	Ohio	United States	43616
159	Ireland Cancer Center at Firelands Regional Medical Center	Sandusky	Ohio	United States	44870
160	Flower Hospital	Sylvania	Ohio	United States	43560
161	Toledo Community Hospital Oncology Program CCOP	Toledo	Ohio	United States	43617
162	Toledo Clinic Cancer Centers-Toledo	Toledo	Ohio	United States	43623
163	University Hospitals Sharon Health Center	Wadsworth	Ohio	United States	44281
164	UH-Seidman Cancer Center at Saint John Medical Center	Westlake	Ohio	United States	44145
165	UHHS-Westlake Medical Center	Westlake	Ohio	United States	44145
166	Abington Memorial Hospital	Abington	Pennsylvania	United States	19001
167	Geisinger Medical Center	Danville	Pennsylvania	United States	17822
168	Geisinger Medical Center-Cancer Center Hazleton	Hazleton	Pennsylvania	United States	18201
169	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania	United States	17033-0850
170	Geisinger Medical Oncology at Evangelical Community Hospital	Lewisburg	Pennsylvania	United States	17837
171	Lewistown Hospital	Lewistown	Pennsylvania	United States	17044
172	Pennsylvania Hospital	Philadelphia	Pennsylvania	United States	19107
173	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania	United States	19107
174	Aria Health-Torresdale Campus	Philadelphia	Pennsylvania	United States	19114
175	Geisinger Medical Oncology-Pottsville	Pottsville	Pennsylvania	United States	17901
176	Hematology and Oncology Associates of North East Pennsylvania	Scranton	Pennsylvania	United States	18508
177	Geisinger Medical Group	State College	Pennsylvania	United States	16801
178	Mount Nittany Medical Center	State College	Pennsylvania	United States	16803
179	Reading Hospital	West Reading	Pennsylvania	United States	19611
180	Geisinger Wyoming Valley	Wilkes-Barre	Pennsylvania	United States	18711
181	Sanford Cancer Center-Oncology Clinic	Sioux Falls	South Dakota	United States	57104
182	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota	United States	57117-5134
183	Vanderbilt-Ingram Cancer Center Cool Springs	Franklin	Tennessee	United States	37067
184	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232
185	Parkland Memorial Hospital	Dallas	Texas	United States	75235
186	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
187	West Virginia University Charleston	Charleston	West Virginia	United States	25304
188	West Virginia University Healthcare	Morgantown	West Virginia	United States	26506
189	Langlade Hospital and Cancer Center	Antigo	Wisconsin	United States	54409
190	Fox Valley Hematology and Oncology	Appleton	Wisconsin	United States	54911
191	Marshfield Clinic-Chippewa Center	Chippewa Falls	Wisconsin	United States	54729
192	Marshfield Clinic Cancer Center at Sacred Heart	Eau Claire	Wisconsin	United States	54701
193	Green Bay Oncology at Saint Vincent Hospital	Green Bay	Wisconsin	United States	54301-3526
194	Bellin Memorial Hospital	Green Bay	Wisconsin	United States	54301
195	Saint Vincent Hospital	Green Bay	Wisconsin	United States	54301
196	Green Bay Oncology Limited at Saint Mary's Hospital	Green Bay	Wisconsin	United States	54303
197	Saint Mary's Hospital	Green Bay	Wisconsin	United States	54303
198	Aurora BayCare Medical Center	Green Bay	Wisconsin	United States	54311-6519
199	UW Cancer Center Johnson Creek	Johnson Creek	Wisconsin	United States	53038
200	Gundersen Lutheran Medical Center	La Crosse	Wisconsin	United States	54601
201	Dean Hematology and Oncology Clinic	Madison	Wisconsin	United States	53717
202	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792
203	Vince Lombardi Cancer Clinic-Marinette	Marinette	Wisconsin	United States	54143
204	Marshfield Clinic	Marshfield	Wisconsin	United States	54449
205	Saint Joseph's Hospital	Marshfield	Wisconsin	United States	54449
206	Froedtert and the Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
207	Marshfield Clinic-Minocqua Center	Minocqua	Wisconsin	United States	54548
208	Oconomowoc Memorial Hospital-ProHealth Care Inc	Oconomowoc	Wisconsin	United States	53066-3896
209	Green Bay Oncology - Oconto Falls	Oconto Falls	Wisconsin	United States	54154
210	Vince Lombardi Cancer Clinic - Oshkosh	Oshkosh	Wisconsin	United States	54904
211	Marshfield Clinic at James Beck Cancer Center	Rhinelander	Wisconsin	United States	54501
212	Saint Mary's Hospital	Rhinelander	Wisconsin	United States	54501
213	Marshfield Clinic-Rice Lake Center	Rice Lake	Wisconsin	United States	54868
214	Saint Nicholas Hospital	Sheboygan	Wisconsin	United States	53081
215	Vince Lombardi Cancer Clinic-Sheboygan	Sheboygan	Wisconsin	United States	53081
216	Marshfield Clinic Cancer Care at Saint Michael's Hospital	Stevens Point	Wisconsin	United States	54481
217	Saint Michael's Hospital	Stevens Point	Wisconsin	United States	54481
218	Green Bay Oncology - Sturgeon Bay	Sturgeon Bay	Wisconsin	United States	54235
219	Aurora Medical Center in Summit	Summit	Wisconsin	United States	53066
220	Vince Lombardi Cancer Clinic	Two Rivers	Wisconsin	United States	54241
221	Waukesha Memorial Hospital - ProHealth Care	Waukesha	Wisconsin	United States	53188
222	Aspirus Regional Cancer Center	Wausau	Wisconsin	United States	54401
223	Aurora Cancer Care-Milwaukee West	Wauwatosa	Wisconsin	United States	53226
224	Diagnostic and Treatment Center	Weston	Wisconsin	United States	54476
225	Marshfield Clinic - Weston Center	Weston	Wisconsin	United States	54476
226	Marshfield Clinic - Wisconsin Rapids Center	Wisconsin Rapids	Wisconsin	United States	54494
227	Riverview Hospital	Wisconsin Rapids	Wisconsin	United States	54494

Sponsors and Collaborators

• ECOG-ACRIN Cancer Research Group
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Andrew M. Evens, DO, MS, Robert H. Lurie Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 15, 2016

More Information

Publications

None provided.

• Responsible Party: ECOG-ACRIN Cancer Research Group
• ClinicalTrials.gov Identifier: NCT01216683
• Other Study ID Numbers: E2408; E2408; NCI-2011-02644; CDR0000683312
• First Posted: Oct 7, 2010
• Last Update Posted: Mar 9, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by ECOG-ACRIN Cancer Research Group: 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
• Additional relevant MeSH terms: Lymphoma; Lymphoma, Follicular; Rituximab; Lenalidomide; Bortezomib; Bendamustine Hydrochloride

Study Results

Participant Flow

Recruitment Details	This study was activated on December 13, 2010, and closed on May 13, 2015, with final accrual of 289 patients

Arm/Group Title	Arm A Then Arm D (Induction With Bendamustine + Rituximab; Continuation With Rituximab)	Arm B Then Arm E (Induction With Bendamustine + Rituximab + Bortezomib; Continuation With Rituximab)	Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab)
Arm/Group Description	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. rituximab: Given IV Bendamustin: Given IV	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. rituximab: Given IV Bendamustin: Given IV bortezomib: Given IV	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. rituximab: Given IV Bendamustin: Given IV lenalidomide: Given orally
Period Title: Induction
STARTED	65	99	125
Received Treatment and Assessed for Toxicities	65	93	122
Eligible and Treated	59	85	114
Included in the Primary Analysis of Complete Remission Rate During Induction Treatment	48	85	89
COMPLETED	61	80	104
NOT COMPLETED	4	19	21
Period Title: Induction
STARTED	59	71	94
Received Continuation Treatment	59	70	89
COMPLETED	44	56	51
NOT COMPLETED	15	15	43

Baseline Characteristics

Arm/Group Title	Arm A Then Arm D (Induction With Bendamustine + Rituximab; Continuation With Rituximab)	Arm B Then Arm E (Induction With Bendamustine + Rituximab + Bortezomib; Continuation With Rituximab)	Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab)	Total
Arm/Group Description	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 (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 (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.	Total of all reporting groups
Overall Participants	59	85	114	258
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	59	60	61	61
Sex: Female, Male (Count of Participants)
Female	26 44.1%	34 40%	56 49.1%	116 45%
Male	33 55.9%	51 60%	58 50.9%	142 55%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 3.4%	2 2.4%	5 4.4%	9 3.5%
Not Hispanic or Latino	55 93.2%	82 96.5%	107 93.9%	244 94.6%
Unknown or Not Reported	2 3.4%	1 1.2%	2 1.8%	5 1.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 1.2%	0 0%	1 0.4%
Asian	1 1.7%	3 3.5%	1 0.9%	5 1.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	4 6.8%	1 1.2%	6 5.3%	11 4.3%
White	53 89.8%	78 91.8%	102 89.5%	233 90.3%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	1 1.7%	2 2.4%	5 4.4%	8 3.1%

Outcome Measures

1. Primary Outcome

Title	Complete Remission (CR) Rate
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Arm A and Arm C (Induction With Bendamustine + Rituximab)	Arm B (Induction With Bendamustine + Rituximab + Bortezomib)
Arm/Group Description	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.	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.
Measure Participants	137	85
Number (95% Confidence Interval) [proportion of participants]	0.62 1.1%	0.75 0.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A and Arm C (Induction With Bendamustine + Rituximab), Arm B (Induction With Bendamustine + Rituximab + Bortezomib)
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments	one-sided p-value
	Method	Cochran-Mantel-Haenszel
	Comments

2. Primary Outcome

Title	1-year Post-induction Disease-free Survival (DFS) Rate
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Arm A Then Arm D (Induction With Bendamustine + Rituximab; Continuation With Rituximab)	Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab)
Arm/Group Description	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 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.
Measure Participants	53	84
Number (95% Confidence Interval) [proportion of participants]	0.85 1.4%	0.67 0.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A and Arm C (Induction With Bendamustine + Rituximab), Arm B (Induction With Bendamustine + Rituximab + Bortezomib)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test stratified on Groupe d'Etude des Lymphomes Folliculaires status and Follicular Lymphoma International Prognostic Index

3. Secondary Outcome

Title	3-year Progression-free Survival Rate
Description	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

Outcome Measure Data

Analysis Population Description

This analysis was conducted among 222 evaluable patients.

Arm/Group Title	Arm A Then Arm D (Induction With Bendamustine + Rituximab; Continuation With Rituximab)	Arm B Then Arm E (Induction With Bendamustine + Rituximab + Bortezomib; Continuation With Rituximab)	Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab)
Arm/Group Description	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 (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 (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.
Measure Participants	48	85	89
Number (95% Confidence Interval) [proportion of participants]	0.77 1.3%	0.82 1%	0.76 0.7%

4. Secondary Outcome

Title	5-year Overall Survival Rate
Description	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

Outcome Measure Data

Analysis Population Description

This analysis was conducted among 222 evaluable patients.

Arm/Group Title	Arm A Then Arm D (Induction With Bendamustine + Rituximab; Continuation With Rituximab)	Arm B Then Arm E (Induction With Bendamustine + Rituximab + Bortezomib; Continuation With Rituximab)	Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab)
Arm/Group Description	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 (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 (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.
Measure Participants	48	85	89
Number (95% Confidence Interval) [proportion of participants]	0.87 1.5%	0.86 1%	0.83 0.7%

5. Secondary Outcome

Title	Complete Remission (CR) Rate
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	FLIPI 0-2/Unknown	FLIPI 3-5
Arm/Group Description	Patients with baseline follicular lymphoma international prognostic index (FLIPI) score of 0-2 or unknown.	Patients with baseline follicular lymphoma international prognostic index (FLIPI) score of 3-5.
Measure Participants	101	121
Number (95% Confidence Interval) [proportion of participants]	0.71 1.2%	0.64 0.8%

6. Secondary Outcome

Title	1-year Disease-free Survival (DFS) Rate
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	FLIPI 0-2/Unknown	FLIPI 3-5
Arm/Group Description	Patients with baseline follicular lymphoma international prognostic index (FLIPI) score of 0-2 or unknown.	Patients with baseline follicular lymphoma international prognostic index (FLIPI) score of 3-5.
Measure Participants	91	112
Number (95% Confidence Interval) [proportion of participants]	0.84 1.4%	0.74 0.9%

7. Secondary Outcome

Title	Progression-free Survival
Description	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

Outcome Measure Data

Analysis Population Description

This analysis was conducted among 222 evaluable patients that were enrolled before activation of addendum #8.

Arm/Group Title	FLIPI 0-2/Unknown	FLIPI 3-5
Arm/Group Description	Patients with baseline follicular lymphoma international prognostic index (FLIPI) score of 0-2 or unknown.	Patients with baseline follicular lymphoma international prognostic index (FLIPI) score of 3-5.
Measure Participants	101	121
Median (95% Confidence Interval) [years]	6.1	6.2

8. Secondary Outcome

Title	5-year Overall Survival Rate
Description	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

Outcome Measure Data

Analysis Population Description

This analysis was conducted among 222 evaluable patients.

Arm/Group Title	FLIPI 0-2/Unknown	FLIPI 3-5
Arm/Group Description	Patients with baseline follicular lymphoma international prognostic index (FLIPI) score of 0-2 or unknown.	Patients with baseline follicular lymphoma international prognostic index (FLIPI) score of 3-5.
Measure Participants	101	121
Number (95% Confidence Interval) [proportion of participants]	0.90 1.5%	0.81 1%

9. Secondary Outcome

Title	Complete Remission (CR) Rate
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	CIRS <10	CIRS >=10
Arm/Group Description	Patients with baseline Cumulative Illness Rating Scale (CIRS) score <10	Patients with baseline Cumulative Illness Rating Scale (CIRS) score >=10
Measure Participants	207	43
Number (95% Confidence Interval) [proportion of participants]	0.70 1.2%	0.70 0.8%

10. Secondary Outcome

Title	1-year Disease-free Survival (DFS) Rate
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	CIRS <10	CIRS >=10
Arm/Group Description	Patients with baseline Cumulative Illness Rating Scale (CIRS) score <10	Patients with baseline Cumulative Illness Rating Scale (CIRS) score >=10.
Measure Participants	207	43
Number (95% Confidence Interval) [proportion of participants]	0.62 1.1%	0.65 0.8%

11. Secondary Outcome

Title	3-year Progression-free Survival Rate
Description	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

Outcome Measure Data

Analysis Population Description

This analysis was conducted among 250 evaluable patients with baseline Cumulative Illness Rating Scale (CIRS) data available.

Arm/Group Title	CIRS <10	CIRS >=10
Arm/Group Description	Patients with baseline Cumulative Illness Rating Scale (CIRS) score <10	Patients with baseline Cumulative Illness Rating Scale (CIRS) score >=10
Measure Participants	207	43
Number (95% Confidence Interval) [proportion of participants]	0.83 1.4%	0.68 0.8%

12. Secondary Outcome

Title	5-year Overall Survival Rate
Description	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

Outcome Measure Data

Analysis Population Description

This analysis was conducted among 250 evaluable patients with baseline Cumulative Illness Rating Scale (CIRS) data available.

Arm/Group Title	CIRS <10	CIRS >=10
Arm/Group Description	Patients with baseline Cumulative Illness Rating Scale (CIRS) score <10	Patients with baseline Cumulative Illness Rating Scale (CIRS) score >=10
Measure Participants	207	43
Number (95% Confidence Interval) [proportion of participants]	0.87 1.5%	0.80 0.9%

13. Secondary Outcome

Title	Proportion of Patients With Grade 3 or Higher Peripheral Neuropathy
Description	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

Outcome Measure Data

Analysis Population Description

This analysis was conducted among 99 patients who received bortezomib.

Arm/Group Title	Subcutaneous Bortezomib	Intravenous Bortezomib
Arm/Group Description	Patients who received subcutaneous bortezomib.	Patients who received intravenous bortezomib. Patients who received both subcutaneous and intravenous bortezomib are included in the intravenous bortezomib group.
Measure Participants	17	82
Number (95% Confidence Interval) [proportion of participants]	0.06 0.1%	0.12 0.1%

14. Secondary Outcome

Title	Functional Assessment of Cancer Therapy - General (FACT-G) Total Score at Baseline
Description	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

Outcome Measure Data

Analysis Population Description

All enrolled patients with baseline FACT-G total score available

Arm/Group Title	Arm A Then Arm D (Induction With Bendamustine + Rituximab; Continuation With Rituximab)	Arm B Then Arm E (Induction With Bendamustine + Rituximab + Bortezomib; Continuation With Rituximab)	Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab)
Arm/Group Description	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 (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 (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.
Measure Participants	63	91	119
Mean (Standard Deviation) [score on a scale]	83.9 (14.2)	84.7 (15.5)	86.0 (16.0)

15. Secondary Outcome

Title	Functional Assessment of Cancer Therapy - General (FACT-G) Total Score at Mid-treatment
Description	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

Outcome Measure Data

Analysis Population Description

All enrolled patients with cycle 3 or cycle 4 FACT-G total score available

Arm/Group Title	Arm A Then Arm D (Induction With Bendamustine + Rituximab; Continuation With Rituximab)	Arm B Then Arm E (Induction With Bendamustine + Rituximab + Bortezomib; Continuation With Rituximab)	Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab)
Arm/Group Description	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 (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 (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.
Measure Participants	55	74	107
Mean (Standard Deviation) [score on a scale]	85.5 (15.7)	84.2 (16.4)	85.2 (15.9)

16. Secondary Outcome

Title	Functional Assessment of Cancer Therapy - General (FACT-G) Total Score at End of Induction Treatment
Description	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

Outcome Measure Data

Analysis Population Description

All enrolled patients with cycle 6 FACT-G total score available

Arm/Group Title	Arm A Then Arm D (Induction With Bendamustine + Rituximab; Continuation With Rituximab)	Arm B Then Arm E (Induction With Bendamustine + Rituximab + Bortezomib; Continuation With Rituximab)	Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab)
Arm/Group Description	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 (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 (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.
Measure Participants	54	71	101
Mean (Standard Deviation) [score on a scale]	86.0 (17.7)	86.5 (13.9)	84.9 (18.2)

17. Secondary Outcome

Title	Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Subscale Score at Baseline
Description	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

Outcome Measure Data

Analysis Population Description

All enrolled patients with baseline FACT-Lym subscale score available

Arm/Group Title	Arm A Then Arm D (Induction With Bendamustine + Rituximab; Continuation With Rituximab)	Arm B Then Arm E (Induction With Bendamustine + Rituximab + Bortezomib; Continuation With Rituximab)	Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab)
Arm/Group Description	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 (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 (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.
Measure Participants	63	91	120
Mean (Standard Deviation) [score on a scale]	43.8 (8.7)	44.3 (9.3)	44.9 (10.6)

18. Secondary Outcome

Title	Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Subscale Score at Mid-induction Treatment
Description	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

Outcome Measure Data

Analysis Population Description

All enrolled patients with cycle 3 or cycle 4 FACT-Lym subscale score available

Arm/Group Title	Arm A Then Arm D (Induction With Bendamustine + Rituximab; Continuation With Rituximab)	Arm B Then Arm E (Induction With Bendamustine + Rituximab + Bortezomib; Continuation With Rituximab)	Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab)
Arm/Group Description	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 (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 (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.
Measure Participants	55	75	108
Mean (Standard Deviation) [score on a scale]	47.9 (7.4)	46.8 (8.7)	46.5 (9.5)

19. Secondary Outcome

Title	Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Subscale Score at End of Induction Treatment
Description	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

Outcome Measure Data

Analysis Population Description

All enrolled patients with cycle 6 FACT-Lym subscale score available

Arm/Group Title	Arm A Then Arm D (Induction With Bendamustine + Rituximab; Continuation With Rituximab)	Arm B Then Arm E (Induction With Bendamustine + Rituximab + Bortezomib; Continuation With Rituximab)	Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab)
Arm/Group Description	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 (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 (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.
Measure Participants	54	71	101
Mean (Standard Deviation) [score on a scale]	48.9 (7.5)	48.4 (8.5)	47.2 (9.9)

20. Secondary Outcome

Title	Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) Subscale Score at Baseline
Description	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

Outcome Measure Data

Analysis Population Description

All enrolled patients with baseline FACIT-Fatigue subscale score available

Arm/Group Title	Arm A Then Arm D (Induction With Bendamustine + Rituximab; Continuation With Rituximab)	Arm B Then Arm E (Induction With Bendamustine + Rituximab + Bortezomib; Continuation With Rituximab)	Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab)
Arm/Group Description	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 (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 (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.
Measure Participants	63	91	120
Mean (Standard Deviation) [score on a scale]	38.6 (10.5)	37.9 (11.4)	38.1 (12.1)

21. Secondary Outcome

Title	Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) Subscale Score at Mid-induction Treatment
Description	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

Outcome Measure Data

Analysis Population Description

All enrolled patients with cycle 3 or cycle 4 FACIT-Fatigue subscale score available

Arm/Group Title	Arm A Then Arm D (Induction With Bendamustine + Rituximab; Continuation With Rituximab)	Arm B Then Arm E (Induction With Bendamustine + Rituximab + Bortezomib; Continuation With Rituximab)	Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab)
Arm/Group Description	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 (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 (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.
Measure Participants	55	75	108
Mean (Standard Deviation) [score on a scale]	39.2 (9.0)	34.5 (10.9)	36.3 (12.3)

22. Secondary Outcome

Title	Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) Subscale Score at End of Induction Treatment
Description	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

Outcome Measure Data

Analysis Population Description

All enrolled patients with cycle 6 FACIT-Fatigue subscale score available

Arm/Group Title	Arm A Then Arm D (Induction With Bendamustine + Rituximab; Continuation With Rituximab)	Arm B Then Arm E (Induction With Bendamustine + Rituximab + Bortezomib; Continuation With Rituximab)	Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab)
Arm/Group Description	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 (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 (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.
Measure Participants	54	71	100
Mean (Standard Deviation) [score on a scale]	39.9 (10.1)	39.1 (9.8)	36.3 (12.2)

23. Secondary Outcome

Title	Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT-GOG-NTX) Subscale Score at Baseline
Description	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

Outcome Measure Data

Analysis Population Description

All enrolled patients with baseline FACT-GOG-NTX subscale score available

Arm/Group Title	Arm A Then Arm D (Induction With Bendamustine + Rituximab; Continuation With Rituximab)	Arm B Then Arm E (Induction With Bendamustine + Rituximab + Bortezomib; Continuation With Rituximab)	Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab)
Arm/Group Description	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 (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 (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.
Measure Participants	46	65	90
Mean (Standard Deviation) [score on a scale]	39.9 (4.3)	38.7 (6.0)	38.8 (5.5)

24. Secondary Outcome

Title	Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT-GOG-NTX) Subscale Score at Mid-induction Treatment
Description	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

Outcome Measure Data

Analysis Population Description

All enrolled patients with cycle 3 FACT-GOG-NTX subscale score available

Arm/Group Title	Arm A Then Arm D (Induction With Bendamustine + Rituximab; Continuation With Rituximab)	Arm B Then Arm E (Induction With Bendamustine + Rituximab + Bortezomib; Continuation With Rituximab)	Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab)
Arm/Group Description	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 (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 (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.
Measure Participants	58	80	109
Mean (Standard Deviation) [score on a scale]	40.0 (4.6)	38.6 (5.1)	39.1 (5.2)

25. Secondary Outcome

Title	Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT-GOG-NTX) Subscale Score at the End of Induction Treatment
Description	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

Outcome Measure Data

Analysis Population Description

All enrolled patients with cycle 6 FACT-GOG-NTX subscale score available

Arm/Group Title	Arm A Then Arm D (Induction With Bendamustine + Rituximab; Continuation With Rituximab)	Arm B Then Arm E (Induction With Bendamustine + Rituximab + Bortezomib; Continuation With Rituximab)	Arm C Then Arm F (Induction With Bendamustine+Rituximab; Continuation With Lenalidomide + Rituximab)
Arm/Group Description	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 (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 (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.
Measure Participants	52	69	96
Mean (Standard Deviation) [score on a scale]	39.8 (4.0)	36.1 (6.5)	39.0 (5.9)

Adverse Events

Time Frame	Assessed every 4 weeks while on treatment and for 30 days after the end of treatment, up to 5 years
Adverse Event Reporting Description	Serious Adverse Events include post-baseline adverse events of grade 3 and higher that are definitely, probably or possibly related to protocol treatment based on the case report forms (CRFs). Only patients who started protocol therapy are included in the analysis of adverse events. All registered patients are included in the analysis of all-cause mortality. Deaths were counted in Step 1 (Arms A, B and C) for patients who did not registered to Step 2 continuation treatment.
Arm/Group Title	Arm A		Arm B		Arm C		Arm D		Arm E		Arm F
Arm/Group Description	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 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 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 D (continuation after Arm A): Beginning 4 weeks after the completion of Arm A 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 E (continuation after Arm B): Beginning 4 weeks after the completion of Arm B induction therapy, patients who have stable disease or better at time of post-induction restaging receive rituximab as in arm D.		Arm F (continuation after Arm C): Immediately after completing Arm C 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.
All Cause Mortality
	Arm A		Arm B		Arm C		Arm D		Arm E		Arm F
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/65 (3.1%)		9/99 (9.1%)		12/125 (9.6%)		6/59 (10.2%)		7/71 (9.9%)		10/94 (10.6%)
Serious Adverse Events
	Arm A		Arm B		Arm C		Arm D		Arm E		Arm F
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	51/65 (78.5%)		78/93 (83.9%)		96/122 (78.7%)		39/59 (66.1%)		44/70 (62.9%)		77/89 (86.5%)
Blood and lymphatic system disorders
Anemia	2/65 (3.1%)		3/93 (3.2%)		5/122 (4.1%)		0/59 (0%)		1/70 (1.4%)		7/89 (7.9%)
Febrile neutropenia	4/65 (6.2%)		3/93 (3.2%)		6/122 (4.9%)		1/59 (1.7%)		2/70 (2.9%)		9/89 (10.1%)
Hemolysis	0/65 (0%)		0/93 (0%)		1/122 (0.8%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Blood and lymphatic disorders - Other	0/65 (0%)		0/93 (0%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		1/89 (1.1%)
Cardiac disorders
Heart failure	0/65 (0%)		1/93 (1.1%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Restrictive cardiomyopathy	0/65 (0%)		0/93 (0%)		1/122 (0.8%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Gastrointestinal disorders
Abdominal pain	1/65 (1.5%)		1/93 (1.1%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Colitis	0/65 (0%)		1/93 (1.1%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Constipation	0/65 (0%)		0/93 (0%)		1/122 (0.8%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Diarrhea	0/65 (0%)		6/93 (6.5%)		2/122 (1.6%)		1/59 (1.7%)		0/70 (0%)		3/89 (3.4%)
Dysphagia	0/65 (0%)		0/93 (0%)		1/122 (0.8%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Enterocolitis	0/65 (0%)		0/93 (0%)		0/122 (0%)		0/59 (0%)		1/70 (1.4%)		0/89 (0%)
Hemorrhoids	0/65 (0%)		0/93 (0%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		1/89 (1.1%)
Mucositis oral	0/65 (0%)		0/93 (0%)		1/122 (0.8%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Nausea	0/65 (0%)		4/93 (4.3%)		1/122 (0.8%)		0/59 (0%)		1/70 (1.4%)		0/89 (0%)
Small intestinal obstruction	0/65 (0%)		1/93 (1.1%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Vomiting	1/65 (1.5%)		3/93 (3.2%)		2/122 (1.6%)		0/59 (0%)		1/70 (1.4%)		0/89 (0%)
Gastrointestinal disorders - Other	0/65 (0%)		1/93 (1.1%)		1/122 (0.8%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
General disorders
Death NOS	0/65 (0%)		0/93 (0%)		1/122 (0.8%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Fatigue	2/65 (3.1%)		6/93 (6.5%)		9/122 (7.4%)		1/59 (1.7%)		0/70 (0%)		5/89 (5.6%)
Fever	0/65 (0%)		1/93 (1.1%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Infusion related reaction	0/65 (0%)		1/93 (1.1%)		3/122 (2.5%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Injection site reaction	1/65 (1.5%)		0/93 (0%)		1/122 (0.8%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Non-cardiac chest pain	1/65 (1.5%)		0/93 (0%)		2/122 (1.6%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Immune system disorders
Allergic reaction	0/65 (0%)		2/93 (2.2%)		1/122 (0.8%)		0/59 (0%)		0/70 (0%)		1/89 (1.1%)
Infections and infestations
Anorectal infection	0/65 (0%)		0/93 (0%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		1/89 (1.1%)
Bladder infection	0/65 (0%)		1/93 (1.1%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Lip infection	1/65 (1.5%)		0/93 (0%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Lung infection	1/65 (1.5%)		3/93 (3.2%)		0/122 (0%)		1/59 (1.7%)		0/70 (0%)		7/89 (7.9%)
Otitis media	0/65 (0%)		0/93 (0%)		1/122 (0.8%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Peripheral nerve infection	0/65 (0%)		1/93 (1.1%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Phlebitis infective	0/65 (0%)		0/93 (0%)		1/122 (0.8%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Sepsis	1/65 (1.5%)		0/93 (0%)		1/122 (0.8%)		1/59 (1.7%)		0/70 (0%)		3/89 (3.4%)
Sinusitis	0/65 (0%)		0/93 (0%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		2/89 (2.2%)
Skin infection	0/65 (0%)		0/93 (0%)		2/122 (1.6%)		0/59 (0%)		1/70 (1.4%)		0/89 (0%)
Tooth infection	0/65 (0%)		1/93 (1.1%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Upper respiratory infection	0/65 (0%)		1/93 (1.1%)		0/122 (0%)		1/59 (1.7%)		0/70 (0%)		0/89 (0%)
Urinary tract infection	1/65 (1.5%)		1/93 (1.1%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Infections and infestations - Other	0/65 (0%)		2/93 (2.2%)		1/122 (0.8%)		0/59 (0%)		0/70 (0%)		1/89 (1.1%)
Investigations
Alanine aminotransferase increased	0/65 (0%)		2/93 (2.2%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Alkaline phosphatase increased	1/65 (1.5%)		0/93 (0%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Aspartate aminotransferase increased	0/65 (0%)		2/93 (2.2%)		0/122 (0%)		1/59 (1.7%)		1/70 (1.4%)		0/89 (0%)
CD4 lymphocytes decreased	0/65 (0%)		0/93 (0%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		2/89 (2.2%)
Cholesterol high	0/65 (0%)		1/93 (1.1%)		0/122 (0%)		1/59 (1.7%)		0/70 (0%)		0/89 (0%)
Creatinine increased	0/65 (0%)		0/93 (0%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		1/89 (1.1%)
INR increased	1/65 (1.5%)		0/93 (0%)		0/122 (0%)		1/59 (1.7%)		0/70 (0%)		1/89 (1.1%)
Lipase increased	0/65 (0%)		1/93 (1.1%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Lymphocyte count decreased	44/65 (67.7%)		61/93 (65.6%)		77/122 (63.1%)		33/59 (55.9%)		35/70 (50%)		56/89 (62.9%)
Neutrophil count decreased	22/65 (33.8%)		33/93 (35.5%)		35/122 (28.7%)		12/59 (20.3%)		13/70 (18.6%)		58/89 (65.2%)
Platelet count decreased	2/65 (3.1%)		9/93 (9.7%)		7/122 (5.7%)		0/59 (0%)		2/70 (2.9%)		2/89 (2.2%)
Weight gain	0/65 (0%)		0/93 (0%)		0/122 (0%)		0/59 (0%)		1/70 (1.4%)		0/89 (0%)
Weight loss	0/65 (0%)		1/93 (1.1%)		2/122 (1.6%)		0/59 (0%)		1/70 (1.4%)		0/89 (0%)
White blood cell decreased	19/65 (29.2%)		32/93 (34.4%)		30/122 (24.6%)		14/59 (23.7%)		11/70 (15.7%)		52/89 (58.4%)
Metabolism and nutrition disorders
Anorexia	1/65 (1.5%)		0/93 (0%)		2/122 (1.6%)		0/59 (0%)		0/70 (0%)		1/89 (1.1%)
Dehydration	2/65 (3.1%)		3/93 (3.2%)		0/122 (0%)		0/59 (0%)		1/70 (1.4%)		0/89 (0%)
Hyperglycemia	3/65 (4.6%)		2/93 (2.2%)		3/122 (2.5%)		1/59 (1.7%)		0/70 (0%)		0/89 (0%)
Hyperkalemia	0/65 (0%)		0/93 (0%)		1/122 (0.8%)		0/59 (0%)		0/70 (0%)		1/89 (1.1%)
Hypokalemia	1/65 (1.5%)		3/93 (3.2%)		3/122 (2.5%)		0/59 (0%)		0/70 (0%)		3/89 (3.4%)
Hypomagnesemia	0/65 (0%)		0/93 (0%)		0/122 (0%)		1/59 (1.7%)		0/70 (0%)		0/89 (0%)
Hyponatremia	2/65 (3.1%)		1/93 (1.1%)		1/122 (0.8%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Hypophosphatemia	1/65 (1.5%)		1/93 (1.1%)		1/122 (0.8%)		0/59 (0%)		1/70 (1.4%)		1/89 (1.1%)
Tumor lysis syndrome	0/65 (0%)		1/93 (1.1%)		2/122 (1.6%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/65 (0%)		2/93 (2.2%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Arthritis	0/65 (0%)		1/93 (1.1%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Back pain	0/65 (0%)		2/93 (2.2%)		1/122 (0.8%)		0/59 (0%)		0/70 (0%)		1/89 (1.1%)
Bone pain	0/65 (0%)		0/93 (0%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		1/89 (1.1%)
Generalized muscle weakness	1/65 (1.5%)		1/93 (1.1%)		1/122 (0.8%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Muscle weakness lower limb	0/65 (0%)		0/93 (0%)		1/122 (0.8%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Myalgia	0/65 (0%)		3/93 (3.2%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Nervous system disorders
Dizziness	0/65 (0%)		0/93 (0%)		1/122 (0.8%)		0/59 (0%)		0/70 (0%)		1/89 (1.1%)
Headache	0/65 (0%)		1/93 (1.1%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Peripheral motor neuropathy	0/65 (0%)		1/93 (1.1%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Peripheral sensory neuropathy	0/65 (0%)		11/93 (11.8%)		1/122 (0.8%)		0/59 (0%)		3/70 (4.3%)		0/89 (0%)
Presyncope	1/65 (1.5%)		0/93 (0%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Stroke	0/65 (0%)		0/93 (0%)		1/122 (0.8%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Syncope	1/65 (1.5%)		2/93 (2.2%)		3/122 (2.5%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Psychiatric disorders
Agitation	0/65 (0%)		1/93 (1.1%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Anxiety	0/65 (0%)		0/93 (0%)		0/122 (0%)		0/59 (0%)		1/70 (1.4%)		0/89 (0%)
Confusion	0/65 (0%)		1/93 (1.1%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Depression	0/65 (0%)		0/93 (0%)		1/122 (0.8%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Renal and urinary disorders
Acute kidney injury	0/65 (0%)		0/93 (0%)		1/122 (0.8%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Chronic kidney disease	0/65 (0%)		1/93 (1.1%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/65 (0%)		0/93 (0%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		2/89 (2.2%)
Dyspnea	0/65 (0%)		2/93 (2.2%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Pleural effusion	0/65 (0%)		0/93 (0%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		1/89 (1.1%)
Pneumonitis	0/65 (0%)		0/93 (0%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		2/89 (2.2%)
Skin and subcutaneous tissue disorders
Dry skin	0/65 (0%)		0/93 (0%)		0/122 (0%)		0/59 (0%)		1/70 (1.4%)		0/89 (0%)
Pruritus	0/65 (0%)		0/93 (0%)		1/122 (0.8%)		0/59 (0%)		0/70 (0%)		2/89 (2.2%)
Rash maculo-papular	1/65 (1.5%)		1/93 (1.1%)		3/122 (2.5%)		0/59 (0%)		1/70 (1.4%)		3/89 (3.4%)
Urticaria	0/65 (0%)		0/93 (0%)		1/122 (0.8%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Vascular disorders
Flushing	0/65 (0%)		0/93 (0%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		1/89 (1.1%)
Hypertension	1/65 (1.5%)		2/93 (2.2%)		3/122 (2.5%)		2/59 (3.4%)		1/70 (1.4%)		2/89 (2.2%)
Hypotension	0/65 (0%)		2/93 (2.2%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		2/89 (2.2%)
Lymphedema	0/65 (0%)		0/93 (0%)		0/122 (0%)		0/59 (0%)		0/70 (0%)		1/89 (1.1%)
Thromboembolic event	1/65 (1.5%)		0/93 (0%)		1/122 (0.8%)		0/59 (0%)		1/70 (1.4%)		2/89 (2.2%)
Other (Not Including Serious) Adverse Events
	Arm A		Arm B		Arm C		Arm D		Arm E		Arm F
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	64/65 (98.5%)		92/93 (98.9%)		122/122 (100%)		59/59 (100%)		70/70 (100%)		88/89 (98.9%)
Blood and lymphatic system disorders
Anemia	39/65 (60%)		59/93 (63.4%)		67/122 (54.9%)		32/59 (54.2%)		35/70 (50%)		54/89 (60.7%)
Ear and labyrinth disorders
Tinnitus	0/65 (0%)		0/93 (0%)		0/122 (0%)		3/59 (5.1%)		1/70 (1.4%)		1/89 (1.1%)
Eye disorders
Blurred vision	0/65 (0%)		6/93 (6.5%)		2/122 (1.6%)		1/59 (1.7%)		4/70 (5.7%)		3/89 (3.4%)
Gastrointestinal disorders
Abdominal pain	5/65 (7.7%)		12/93 (12.9%)		7/122 (5.7%)		2/59 (3.4%)		4/70 (5.7%)		8/89 (9%)
Constipation	22/65 (33.8%)		45/93 (48.4%)		46/122 (37.7%)		7/59 (11.9%)		7/70 (10%)		27/89 (30.3%)
Diarrhea	20/65 (30.8%)		44/93 (47.3%)		27/122 (22.1%)		10/59 (16.9%)		11/70 (15.7%)		34/89 (38.2%)
Dry mouth	2/65 (3.1%)		7/93 (7.5%)		9/122 (7.4%)		0/59 (0%)		3/70 (4.3%)		9/89 (10.1%)
Dyspepsia	7/65 (10.8%)		8/93 (8.6%)		13/122 (10.7%)		5/59 (8.5%)		2/70 (2.9%)		6/89 (6.7%)
Mucositis oral	6/65 (9.2%)		7/93 (7.5%)		19/122 (15.6%)		1/59 (1.7%)		0/70 (0%)		6/89 (6.7%)
Nausea	37/65 (56.9%)		56/93 (60.2%)		74/122 (60.7%)		10/59 (16.9%)		8/70 (11.4%)		26/89 (29.2%)
Vomiting	11/65 (16.9%)		25/93 (26.9%)		28/122 (23%)		2/59 (3.4%)		3/70 (4.3%)		10/89 (11.2%)
Gastrointestinal disorders - Other	2/65 (3.1%)		7/93 (7.5%)		3/122 (2.5%)		0/59 (0%)		1/70 (1.4%)		5/89 (5.6%)
General disorders
Chills	3/65 (4.6%)		16/93 (17.2%)		8/122 (6.6%)		1/59 (1.7%)		1/70 (1.4%)		10/89 (11.2%)
Edema limbs	5/65 (7.7%)		14/93 (15.1%)		16/122 (13.1%)		6/59 (10.2%)		7/70 (10%)		15/89 (16.9%)
Fatigue	53/65 (81.5%)		74/93 (79.6%)		92/122 (75.4%)		38/59 (64.4%)		51/70 (72.9%)		67/89 (75.3%)
Fever	9/65 (13.8%)		20/93 (21.5%)		10/122 (8.2%)		3/59 (5.1%)		2/70 (2.9%)		5/89 (5.6%)
Infusion related reaction	12/65 (18.5%)		7/93 (7.5%)		13/122 (10.7%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Injection site reaction	3/65 (4.6%)		8/93 (8.6%)		3/122 (2.5%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Pain	2/65 (3.1%)		5/93 (5.4%)		1/122 (0.8%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Immune system disorders
Allergic reaction	4/65 (6.2%)		6/93 (6.5%)		8/122 (6.6%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Infections and infestations
Lung infection	0/65 (0%)		0/93 (0%)		0/122 (0%)		2/59 (3.4%)		5/70 (7.1%)		4/89 (4.5%)
Peripheral nerve infection	0/65 (0%)		0/93 (0%)		0/122 (0%)		3/59 (5.1%)		3/70 (4.3%)		1/89 (1.1%)
Sinusitis	0/65 (0%)		0/93 (0%)		0/122 (0%)		3/59 (5.1%)		6/70 (8.6%)		5/89 (5.6%)
Upper respiratory infection	3/65 (4.6%)		3/93 (3.2%)		7/122 (5.7%)		2/59 (3.4%)		3/70 (4.3%)		14/89 (15.7%)
Investigations
Alanine aminotransferase increased	12/65 (18.5%)		19/93 (20.4%)		13/122 (10.7%)		8/59 (13.6%)		13/70 (18.6%)		14/89 (15.7%)
Alkaline phosphatase increased	9/65 (13.8%)		12/93 (12.9%)		10/122 (8.2%)		3/59 (5.1%)		6/70 (8.6%)		11/89 (12.4%)
Aspartate aminotransferase increased	12/65 (18.5%)		20/93 (21.5%)		16/122 (13.1%)		8/59 (13.6%)		17/70 (24.3%)		14/89 (15.7%)
Blood bilirubin increased	4/65 (6.2%)		3/93 (3.2%)		3/122 (2.5%)		4/59 (6.8%)		3/70 (4.3%)		5/89 (5.6%)
Creatinine increased	5/65 (7.7%)		6/93 (6.5%)		7/122 (5.7%)		5/59 (8.5%)		4/70 (5.7%)		11/89 (12.4%)
Lymphocyte count decreased	35/65 (53.8%)		55/93 (59.1%)		62/122 (50.8%)		39/59 (66.1%)		54/70 (77.1%)		65/89 (73%)
Neutrophil count decreased	26/65 (40%)		46/93 (49.5%)		47/122 (38.5%)		25/59 (42.4%)		30/70 (42.9%)		61/89 (68.5%)
Platelet count decreased	26/65 (40%)		65/93 (69.9%)		65/122 (53.3%)		18/59 (30.5%)		21/70 (30%)		48/89 (53.9%)
Weight loss	10/65 (15.4%)		20/93 (21.5%)		24/122 (19.7%)		5/59 (8.5%)		8/70 (11.4%)		5/89 (5.6%)
White blood cell decreased	42/65 (64.6%)		60/93 (64.5%)		78/122 (63.9%)		39/59 (66.1%)		45/70 (64.3%)		78/89 (87.6%)
Investigations - Other, specify	4/65 (6.2%)		4/93 (4.3%)		5/122 (4.1%)		3/59 (5.1%)		11/70 (15.7%)		5/89 (5.6%)
Metabolism and nutrition disorders
Anorexia	17/65 (26.2%)		34/93 (36.6%)		46/122 (37.7%)		8/59 (13.6%)		6/70 (8.6%)		21/89 (23.6%)
Dehydration	3/65 (4.6%)		8/93 (8.6%)		7/122 (5.7%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Hyperglycemia	10/65 (15.4%)		14/93 (15.1%)		10/122 (8.2%)		9/59 (15.3%)		14/70 (20%)		12/89 (13.5%)
Hypoalbuminemia	5/65 (7.7%)		16/93 (17.2%)		13/122 (10.7%)		2/59 (3.4%)		2/70 (2.9%)		12/89 (13.5%)
Hypocalcemia	6/65 (9.2%)		14/93 (15.1%)		12/122 (9.8%)		2/59 (3.4%)		4/70 (5.7%)		10/89 (11.2%)
Hypokalemia	6/65 (9.2%)		12/93 (12.9%)		12/122 (9.8%)		4/59 (6.8%)		1/70 (1.4%)		10/89 (11.2%)
Hypomagnesemia	4/65 (6.2%)		4/93 (4.3%)		5/122 (4.1%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Hyponatremia	5/65 (7.7%)		13/93 (14%)		8/122 (6.6%)		0/59 (0%)		5/70 (7.1%)		9/89 (10.1%)
Hypophosphatemia	4/65 (6.2%)		0/93 (0%)		2/122 (1.6%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	5/65 (7.7%)		13/93 (14%)		8/122 (6.6%)		4/59 (6.8%)		8/70 (11.4%)		8/89 (9%)
Generalized muscle weakness	7/65 (10.8%)		8/93 (8.6%)		10/122 (8.2%)		2/59 (3.4%)		2/70 (2.9%)		5/89 (5.6%)
Myalgia	7/65 (10.8%)		12/93 (12.9%)		7/122 (5.7%)		5/59 (8.5%)		7/70 (10%)		10/89 (11.2%)
Pain in extremity	4/65 (6.2%)		18/93 (19.4%)		7/122 (5.7%)		2/59 (3.4%)		9/70 (12.9%)		4/89 (4.5%)
Musculoskeletal and connective - Other	0/65 (0%)		0/93 (0%)		0/122 (0%)		1/59 (1.7%)		1/70 (1.4%)		5/89 (5.6%)
Nervous system disorders
Dizziness	6/65 (9.2%)		13/93 (14%)		12/122 (9.8%)		2/59 (3.4%)		1/70 (1.4%)		9/89 (10.1%)
Dysgeusia	8/65 (12.3%)		14/93 (15.1%)		20/122 (16.4%)		1/59 (1.7%)		5/70 (7.1%)		11/89 (12.4%)
Headache	9/65 (13.8%)		21/93 (22.6%)		15/122 (12.3%)		3/59 (5.1%)		3/70 (4.3%)		11/89 (12.4%)
Memory impairment	0/65 (0%)		0/93 (0%)		0/122 (0%)		4/59 (6.8%)		2/70 (2.9%)		4/89 (4.5%)
Peripheral motor neuropathy	2/65 (3.1%)		8/93 (8.6%)		3/122 (2.5%)		3/59 (5.1%)		7/70 (10%)		3/89 (3.4%)
Peripheral sensory neuropathy	15/65 (23.1%)		61/93 (65.6%)		24/122 (19.7%)		15/59 (25.4%)		42/70 (60%)		22/89 (24.7%)
Psychiatric disorders
Insomnia	5/65 (7.7%)		11/93 (11.8%)		14/122 (11.5%)		4/59 (6.8%)		3/70 (4.3%)		8/89 (9%)
Renal and urinary disorders
Chronic kidney disease	0/65 (0%)		0/93 (0%)		0/122 (0%)		3/59 (5.1%)		0/70 (0%)		1/89 (1.1%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	0/65 (0%)		0/93 (0%)		0/122 (0%)		3/59 (5.1%)		1/70 (1.4%)		0/89 (0%)
Cough	6/65 (9.2%)		6/93 (6.5%)		11/122 (9%)		3/59 (5.1%)		8/70 (11.4%)		14/89 (15.7%)
Dyspnea	7/65 (10.8%)		15/93 (16.1%)		16/122 (13.1%)		5/59 (8.5%)		5/70 (7.1%)		14/89 (15.7%)
Productive cough	0/65 (0%)		0/93 (0%)		0/122 (0%)		2/59 (3.4%)		4/70 (5.7%)		4/89 (4.5%)
Skin and subcutaneous tissue disorders
Alopecia	0/65 (0%)		0/93 (0%)		0/122 (0%)		2/59 (3.4%)		3/70 (4.3%)		5/89 (5.6%)
Dry skin	4/65 (6.2%)		10/93 (10.8%)		15/122 (12.3%)		2/59 (3.4%)		3/70 (4.3%)		10/89 (11.2%)
Pruritus	8/65 (12.3%)		8/93 (8.6%)		12/122 (9.8%)		4/59 (6.8%)		2/70 (2.9%)		13/89 (14.6%)
Rash acneiform	0/65 (0%)		0/93 (0%)		0/122 (0%)		3/59 (5.1%)		0/70 (0%)		2/89 (2.2%)
Rash maculo-papular	10/65 (15.4%)		21/93 (22.6%)		24/122 (19.7%)		8/59 (13.6%)		2/70 (2.9%)		22/89 (24.7%)
Vascular disorders
Hypertension	1/65 (1.5%)		7/93 (7.5%)		2/122 (1.6%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Hypotension	3/65 (4.6%)		10/93 (10.8%)		4/122 (3.3%)		0/59 (0%)		0/70 (0%)		0/89 (0%)
Phlebitis	4/65 (6.2%)		1/93 (1.1%)		4/122 (3.3%)		0/59 (0%)		0/70 (0%)		0/89 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.