Conditions: Lymphoid Leukemia Small Lymphocytic Lymphoma Lymphoma, Non-Hodgkin
Keywords: Lymphoid Leukemia Bendamustine Rituximab Small Lymphocytic Lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 36
Healthy volunteers: no

Brief summary:
The investigators propose a treatment strategy where patients are treated with induction chemoimmunotherapy consisting of rituximab + bendamustine for 6 cycles, followed by initiation of maintenance rituximab and lenalidomide among patients achieving an objective response (i.e., at least stable disease with some tumor shrinkage) to induction therapy. The goal of maintenance therapy will be to capitalize on the cytoreduction following induction chemotherapy with a maintenance regimen that has also shown promising activity in CLL, in order to allow for improved PFS in this population.

Detailed description:
This is a phase II single arm, open-label, multicenter study evaluating the efficacy and safety of the combination of induction chemoimmunotherapy with bendamustine and rituximab followed by maintenance therapy with rituximab and lenalidomide in subjects with CLL or SLL who have not received any prior cytotoxic chemotherapy for their disease (i.e., prior single-agent rituximab is permitted). The study will be carried out at the University of Wisconsin Carbone Cancer Center (UWCCC).

The subject participation will include a screening period, treatment period, and a follow-up period. The treatment period will extend from the first dose of study drug treatment (day 1, cycle 1 of induction chemoimmunotherapy) until any of the following: completion of the entire course of induction and maintenance therapy; progressive disease (PD); an unacceptable adverse event (AE); the initiation of alternate anti-neoplastic therapy; or a decision by the subject or by the investigator to discontinue treatment; or death. The induction chemoimmunotherapy regimen consists of bendamustine and rituximab for 6 cycles, followed by initiation of maintenance therapy with rituximab and lenalidomide among subjects achieving an objective response to induction therapy (i.e., complete or partial response; stable disease with objective evidence of tumor shrinkage). Subjects with objective response after 4 cycles of bendamustine + rituximab (BR) are eligible to proceed to maintenance therapy if toxicities are limiting further BR induction therapy, or if the treating physician determines that further BR induction therapy would be associated with excessive risk for additional toxicities.

To minimize toxicity with induction chemotherapy, we have chosen a dose of bendamustine at 90 mg/m2/day on days 1 \& 2 every 28 days for a total of 6 cycles. Rituximab will be administered at a dose of 500 mg/m2 IV on day 1 of each cycle of induction chemoimmunotherapy (375 mg/m2 cycle 1 only); however, patients at high-risk for cytokine release syndrome may receive rituximab on day 2 of induction therapy. In select circumstances in subjects at high risk for cytokine release syndrome and/or tumor lysis syndrome, rituximab may be administered as late as day 5 of cycle 1 (this alternative dosing of rituximab applies to cycle 1 of induction therapy only). Lenalidomide and rituximab maintenance will be initiated 6-12 weeks after the 6th cycle of chemotherapy, and continued for a total of 24 cycles. Maintenance therapy will continue for a maximum of 24 cycles or until unacceptable toxicity or progression of disease.

Maintenance therapy will begin once there has been adequate hematologic recovery (ANC ≥1000/µL and platelets ≥50,000/µL) and other criteria as outlined in Section 7.5 have been met. Rituximab will be administered at a dose of 375 mg/m2 IV on day 1 of every odd-numbered 28 day cycle (cycles 1,3,5,7,9,11,13,15,17,19,21,23) for a maximum of 12 doses during the maintenance phase. Subjects will receive concurrent lenalidomide 5 mg orally daily on days 1-21 of cycles 1-24 (28 day cycles). If subjects do not experience adverse effects from lenalidomide, dose escalation up to 10 mg orally daily on days 1-21 of each 28 day cycle will be allowed at the start of cycle 2 or at the start of any subsequent cycle (see Section 9.2.3 and 9.2.5 for criteria required to escalate the dose of lenalidomide to 10 mg/day on days 1-21). Lenalidomide dose escalation is only allowed at the start of a new cycle to a maximum dose of 10 mg/day on days 1-21. Subjects entering maintenance with reduced renal function (i.e., creatinine clearance ≥40 but \<60 mL/min) will start lenalidomide at a dose of 5 mg every other day. There is no dose modification of rituximab based on reduced renal function. Among subjects without excessive toxicity or evidence of progression, treatment with lenalidomide will continue for up to 24 cycles (cycle 1-24) and treatment with rituximab will continue for up to 12 doses (administered every odd-numbered cycle during cycles 1,3,5,7,9,11,13,15,17,19,21,23). If subjects have excessive toxicity from lenalidomide, ongoing maintenance therapy with rituximab alone is permitted after lenalidomide is discontinued. After completing 24 cycles of maintenance therapy, subjects will then be observed for evidence of PD with clinical assessments every 3 months for at least 2 years.

Arms:
arm 1: INDUCTION: Bendamustine 90mg/m2 IV D1\&2 and rituximab IV D1 (up to day 5 of course 1) every 28 days for 6 cycles. Patients with objective response move to maintenance therapy. Patients with objective response after 4 courses are eligible to for maintenance therapy if ongoing induction therapy is associated w/unacceptable toxicity.

MAINTENANCE: At 6-12 wks post induction therapy, patients receive rituximab IV on day 1 of odd-numbered cycles for 24 cycles; lenalidomide 5mg PO daily on days 1-21 of each cycle (28 day cycles). Dose escalation to 10mg daily on days 1-21 allowed at start of cycle 2 or at start of subsequent cycles in subjects w/acceptable toxicities. Lenalidomide dose escalation only allowed at start of a new cycle up to a max dose of 10 mg/day on days 1- 21. Subjects entering maintenance with CrCl ≥40 \& \<60mL/min will begin dosing at 5mg every other day on days 1-21. Patients with excessive toxicity from lenalidomide may continue maintenance therapy with rituximab alone.

Interventions: intervention 1: Bendamustine intervention 2: Rituximab intervention 3: Lenalidomide
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given PO

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bendamustine and Rituximab Induction Therapy and 
Maintenance Rituximab and Lenalidomide in Previously 
Untreated CLL/SLL 
 
NCT01754857 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PI: Julie Chang, MD 
03/01/2020 
 


Protocol HO11414                               Confidential                                 Page 2 of 121 
 
 
    
 
Version 03/01/2020 
 
 
Phase II Study of Bendamustine and Rituximab 
Induction Chemoimmunotherapy Followed by 
Maintenance Rituximab (Rituxan®) and Lenalidomide 
(Revlimid®) in Previously Untreated Chronic 
Lymphocytic Leukemia (CLL) and Small Lymphocytic 
Lymphoma (SLL) 
 
 
 
SPONSOR:   
University of Wisconsin Carbone 
Comprehensive 
Cancer 
Center 
(UWCCC)  
Sponsor Protocol #:  
HO11414 
Celgene Tracking #:  
RV-CLL/ -PI-0689 
Genentech Tracking #: 
IND #:  
 
ML28201 
117210 
VERSION DATE:  
03/01/2020 
 
 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to 
the extent necessary to obtain informed consent, may not be disclosed to another party 
unless law or regulations require such disclosure.  Persons to whom the information is 
disclosed must be informed that the information is confidential and may not be further 
disclosed by them. 


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Version 03/01/2020 
INVESTIGATOR SIGNATURE PAGE 
 
Phase II Study of Bendamustine and Rituximab Induction 
Chemoimmunotherapy Followed by Maintenance Rituximab (Rituxan®) and 
Lenalidomide (Revlimid®) in Previously Untreated Chronic Lymphocytic 
Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) 
 
The signature below confirms that I have read this protocol and provides the necessary 
assurances that this trial will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and ICH guidelines. 
 
Site Name: ____________________________________________________________ 
 
Investigator Signature: ______________________________________ Date: ________ 


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STUDY PERSONNEL 
Industry 
collaborators/ 
Supporters: 
 
 
Celgene Corporation 
86 Morris Ave 
Summit, NJ   07901 
1-800-742-3107 
 
Genentech, Inc 
1 DNA Way 
South San Francisco, CA 94080-4990 
 
Study Location: 
 
 
University of Wisconsin Carbone Cancer Center (UWCCC),  
Madison, Wisconsin 
 
Principal Investigator/ 
Sponsor-Investigator: 
 
 
Julie E. Chang, MD 
Phone: 608-262-3970 
Fax: 608-262-4598 
jc2@medicine.wisc.edu 
 
Study CRA:  
 
 
Mitch Howard 
Phone:608-265-5749 
Fax: 608-406-2034 
mvhoward@wisc.edu 
 
Statistician: 
 
 
KyungMann Kim, Ph.D. 
Phone: 608-265-6380 
kmkim@biostat.wisc.edu 
 


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Version 03/01/2020 
  
Table of Contents 
 
1   Schema ................................................................................................................... 9 
2   Protocol Synopsis ................................................................................................ 10 
3   Schedule of Study Assessments ......................................................................... 16 
4 Glossary of Abbreviations ..................................................................................... 19 
4  Background and Rationale ................................................................................... 21 
4.1 
Introduction ..................................................................................................... 21 
4.1.1 Diagnosis and natural history of CLL/SLL ..................................................... 21 
4.1.2 Current treatment for CLL/SLL ........................ Error! Bookmark not defined. 
4.2 
Experience with Bendamustine ..................................................................... 22 
4.2.1 Bendamustine biochemistry: in vitro and in vivo studies ............................... 22 
4.2.2 Clinical activity of bendamustine in relapsed and refractory CLL/SLL .......... 22 
Table 1. Bendamustine + rituximab in relapsed, refractory indolent NHL and CLL . 24 
4.2.3 Bendamustine in previously untreated CLL/SLL ........................................... 25 
Table 2. Bendamustine ± rituximab in previously untreated CLL ............................. 25 
4.2.4 FDA approval of bendamustine for CLL/SLL................................................. 26 
4.3 
Experience with Lenalidomide ...................................................................... 27 
4.3.1 Lenalidomide pharmacology and in vitro experience .................................... 27 
4.3.2 Clinical experience in multiple myeloma ....................................................... 27 
4.3.3 Clinical experience in myelodysplastic syndromes (MDS) ............................ 28 
4.3.4 Clinical experience in leukemia and lymphoma with lenalidomide ................ 28 
Table 3. Outcomes of lenalidomide in relapsed/refractory lymphoma subtypes† .... 30 
4.3.5 Lenalidomide Adverse Events ....................................................................... 31 
4.4 
Maintenance Therapy with Rituximab + Lenalidomide ............................... 31 
4.4.1 Experience with rituximab maintenance therapy in indolent NHL ................. 31 
Table 4. Maintenance rituximab in indolent NHL subtypes ...................................... 32 
4.4.2 Rationale for lenalidomide maintenance ....................................................... 32 
4.4.3 Secondary malignancy risk with lenalidomide maintenance ......................... 32 
4.4.4 Lenalidomide + rituximab combination therapy ............................................. 34 
4.4.5 Rationale for maintenance rituximab + lenalidomide in previously untreated 
CLL/SLL ................................................................................................................... 34 
4.5 
Investigational Rationale ............................................................................... 36 
5 ................................................................................ Study Objectives and Endpoints
 ................................................................................................................................... 37 
5.1 
Primary Objective ........................................................................................... 37 
5.2 
Secondary Objectives .................................................................................... 37 


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6 ..................................................................................................... Investigational Plan
 ................................................................................................................................... 38 
6.1 
Overall Design ................................................................................................. 38 
6.1.1 Induction chemoimmunotherapy ................................................................... 38 
6.1.2 Maintenance therapy ..................................................................................... 39 
6.1.3 Follow-up phase ............................................................................................ 40 
6.1.4 Discontinuation of Study Treatment .............................................................. 41 
6.2 
Screening and Eligibility ................................................................................ 41 
6.2.1 Induction Inclusion criteria ............................................................................. 41 
6.2.2 Induction Exclusion criteria ........................................................................... 43 
6.3 
Registration ..................................................................................................... 43 
6.4 
Visit Schedule and Assessment .................................................................... 44 
6.5 
Criteria for Initiation of Rituximab and Lenalidomide Maintenance Therapy
 
44 
6.5.1 Inclusion criteria for initiation of rituximab and lenalidomide maintenance 
therapy ..................................................................................................................... 44 
6.5.2 Exclusion criteria for initiation of lenalidomide maintenance therapy ............ 45 
7 ............................................... Drug Administration, Formulation, and Procurement
 ................................................................................................................................... 46 
7.1 
Drug Administration ....................................................................................... 46 
7.1.1 Rituximab ...................................................................................................... 46 
7.1.2 Bendamustine ............................................................................................... 47 
7.1.3 Lenalidomide ................................................................................................. 47 
7.2 
Record of Administration and Treatment Compliance ................................ 48 
8 ........................................................................ Dose Modifications and Interruptions
 ................................................................................................................................... 49 
8.1 
Induction Dose Modification Guidelines ...................................................... 49 
8.1.1 Rituximab Dose Modifications During Induction ............................................ 49 
8.1.2 Bendamustine Dose Modifications During Induction ..................................... 49 
Table 5. Bendamustine Dose Reduction Steps† ...................................................... 50 
Table 6. Bendamustine Dose Modification guidelines ............................................. 50 
8.2 
Maintenance Dose Modification Guidelines ................................................. 51 
8.2.1 Lenalidomide ................................................................................................. 51 
8.2.2 Rituximab ...................................................................................................... 59 
8.3 
Concomitant Therapy ..................................................................................... 60 
8.3.1 Tumor lysis syndrome (TLS) prophylaxis ...................................................... 60 
8.3.2 Tumor flare reaction (TFR) prophylaxis......................................................... 61 
8.3.3 Hematopoietic Growth Factors ...................................................................... 61 
8.3.4 Prophylactic anti-coagulation ........................................................................ 61 
8.3.5 Prohibited concomitant therapy ..................................................................... 61 


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9 ....................................................................................... Data Safety Monitoring Plan
 ................................................................................................................................... 62 
9.1 
Oversight and Monitoring Plan...................................................................... 62 
9.1.1 Monitoring and Reporting Guidelines ............................................................ 62 
9.1.2 Protocol Summary Reports ........................................................................... 63 
9.2 
Safety Reconciliation ..................................................................................... 63 
10 .................................................................. Adverse Event Reporting Requirements
 ................................................................................................................................... 64 
10.1 Adverse Event Reporting Period ................................................................... 64 
10.2 Assessment of Adverse Events .................................................................... 64 
10.2.1 
Procedures for Eliciting, Recording, and Reporting Adverse Events ......... 66 
10.3 Expedited Adverse Event Reporting ............................................................. 69 
10.3.1 
SAE Reporting ........................................................................................... 69 
10.3.2 
Determine the reporting time line for the SAE in question by using the 
following table 13. Serious Adverse Event (SAE) Definition .................................... 69 
Table 13. Reporting Requirements for Serious Adverse Events (UW Carbone 
Cancer Center requirements) .................................................................................. 70 
10.3.3 
Additional Protocol-Specific Instructions, Requirements, and Exceptions to 
Expedited Reporting ................................................................................................ 70 
10.3.4 
General procedures for SAE reporting ...................................................... 73 
10.3.5 
Expedited Reporting of Serious Adverse Events ....................................... 74 
10.4 Sponsor-Investigator Adverse Event Reporting Responsibilities ............. 76 
10.4.1 
Sponsor-Investigator AE reporting to the FDA .......................................... 77 
Figure 1: Reporting responsibilities of Sponsor-Investigators to the FDA under 21 
CFR 312.64(b) for serious and unexpected suspected adverse events. ................. 79 
10.4.2 
Sponsor-Investigator AE Reporting to Celgene ......................................... 79 
10.4.3 
Sponsor-Investigator AE Reporting to Genentech..................................... 80 
10.4.4 
Product complaints to Genentech.............................................................. 81 
10.4.5 
Sponsor-Investigator AE Reporting to the Institutional Review Board (IRB) 
and Institutional Data Safety Monitoring Board (DSMB) .......................................... 81 
10.4.6 
Adverse event updates/IND safety reports ................................................ 81 
11 ............................................. Sponsor-Investigator Responsibilities and Oversight
 ................................................................................................................................... 83 
11.1 Reporting Responsibilities to FDA ................................................................ 83 
11.2 Protocol Deviations ........................................................................................ 83 
12 ...................................................................................................... Response Criteria
 ................................................................................................................................... 83 
13 ............................................................................ Protocol Amendments/Deviations
 ................................................................................................................................... 85 
13.1 Protocol Amendments ................................................................................... 85 


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13.2 Protocol Deviations ........................................................................................ 85 
14 ......................................................................................... Statistical Considerations
 ................................................................................................................................... 86 
14.1 Overview .......................................................................................................... 86 
14.2 Sample Size Calculation ................................................................................ 86 
14.3 Statistical Analysis Plan ................................................................................ 87 
14.3.1 
Primary endpoint ....................................................................................... 87 
14.3.2 
Secondary endpoints ................................................................................. 87 
14.4 Accrual Rate .................................................................................................... 87 
15 ....................................................................................... Regulatory Considerations
 ................................................................................................................................... 87 
15.1 Investigator Responsibilities with Study Monitoring and Auditing ........... 88 
15.2 Study Records Requirements........................................................................ 88 
15.3 Institutional Review Board/Ethics Committee Approval ............................. 88 
15.4 Informed Consent ........................................................................................... 89 
15.5 Subject Confidentiality ................................................................................... 89 
15.6 Premature Discontinuation of Study ............................................................. 89 
16 .................................................................................................................References
 ................................................................................................................................... 91 
Appendix A – ECOG Performance Status Scale ...................................................... 97 
Appendix B: Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods ........................................................................... 98 
Appendix C: Body Surface Area Calculations ....................................................... 102 
Appendix D: Rituximab Formulation, Preparation, and Adverse Effects ............. 103 
Appendix E: Bendamustine Formulation, Preparation, and Adverse Effects ...... 106 
Appendix F: Lenalidomide Formulation, Preparation, and Adverse Effects ........ 110 
Appendix G:  Guidelines on Reporting Suspected or Confirmed Pregnancies ... 113 
Appendix H:  Assessment of Response ................................................................ 114 
Appendix I:  Cairo-Bishop Definition of Tumor Lysis Syndrome108 ...................... 119 
Appendix J:  Cockcroft-Gault estimation of CrCl: ................................................. 121 
 
 
 


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1 Schema 
 
 
1Induction chemoimmunotherapy with bendamustine 90 mg/m2/day IV days 1 & 2 every 28 
days; rituximab 500 mg/m2 day 1 (375 mg/m2 cycle 1) every 28 days (1 cycle = 28 
days). Rituximab may be given cycle 1, day 2-5 in subjects at high risk for the cytokine 
release syndrome. A total of 6 cycles will be administered, with disease assessment 
after cycles 3 and 6 of induction therapy. Subjects with objective response after 4 
cycles of bendamustine + rituximab (BR) are eligible to proceed to maintenance 
therapy if toxicities are limiting further BR induction therapy, or if the treating physician 
determines that further BR induction therapy would be associated with excessive risk 
for additional toxicities. 
2Subjects with progressive disease (PD) at any time during induction or maintenance 
therapy will discontinue protocol therapy. Formal disease assessments are performed 
after cycles 3 and 6 of induction therapy and every 4 cycles during maintenance 
lenalidomide. 
3Subjects with stable disease (SD) and evidence of objective response may continue to 
maintenance at investigator discretion. 
4Rituximab maintenance administered as 375 mg/m2 IV on day 1 of odd-numbered cycles 
(cycles 1,3,5,7,9,11,13,15,17,19,21,23) of each 28-day cycle for a total of 12 doses. 
5Lenalidomide maintenance administered as 5 mg/day on days 1-21 of cycles 1-24 (28-
day cycles), with dose escalation up to 10 mg/day on days 1-21 allowed (see Sections 
9.2.1.5 and 9.2.1.6 for criteria required to escalate the dose of lenalidomide). 
Registration
Bendamustine + Rituximab induction 
chemotherapy1
CR, PR,SD3
Rituximab4 + Lenalidomide5
maintenance
Long-term follow-up
PD2
Discontinue protocol 
therapy
Discontinue protocol 
therapy
PD2


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2 Protocol Synopsis 
PROTOCOL TITLE: Phase II study of bendamustine and rituximab induction 
chemoimmunotherapy followed by maintenance rituximab (Rituxan®) and lenalidomide 
(Revlimid®) in previously untreated chronic lymphocytic leukemia (CLL) and small 
lymphocytic lymphoma (SLL). 
UWCCC PROTOCOL NUMBER: 
HO11414 
 
DATE PROTOCOL FINAL: 
10/17/13 
INDICATION: 
Chronic lymphocytic leukemia (CLL) and small 
lymphocytic lymphoma (SLL), previously untreated 
with cytotoxic chemotherapy. 
STUDY PHASE: 
Phase II 
BACKGROUND AND RATIONALE:   
Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) represent different 
clinical manifestations of a shared hematologic disorder with a typically indolent but incurable 
course.1 Multiple treatments have proven beneficial in CLL/SLL, including alkylating agents, 
nucleoside analogues, anthracyclines, and various combinations of these agents. Multiple 
combination chemotherapy regimens in CLL/SLL employing the monoclonal anti-C20 antibody 
rituximab have demonstrated a probable synergistic benefit related to potential chemo-
sensitization properties of rituximab.2-4 Recent data in indolent non-Hodgkin lymphoma (NHL) 
have also shown a role for rituximab in treating minimum residual disease in the setting of 
maintenance therapy following induction chemotherapy.5-10  
Standard therapy options for patients requiring treatment who are healthy enough to tolerate 
chemotherapy are typically fludarabine-based regimens. However, regimens such as FCR 
chemotherapy (fludarabine, cyclophosphamide, rituximab) are often too toxic for older adults to 
tolerate, and have significant short-term as well as long-term toxicities (i.e., myelodysplasia, 
prolonged cytopenias). Bendamustine is an agent receiving FDA approval in 2008 for treatment 
of chronic lymphocytic leukemia and more recently receiving FDA approval in indolent NHL that 
has progressed within 6 months of rituximab or a rituximab-containing regimen. Multiple reports 
suggest that bendamustine may have a toxicity profile that is more tolerable than other standard 
chemotherapy regimens including CHOP chemotherapy (cyclophosphamide, doxorubicin, 
vincristine, prednisone) or fludarabine-based regimens.11-13 Previous experience with 
bendamustine with or without rituximab in indolent NHL histologies and CLL has demonstrated 
response rates from 40-90%.11,13-16 However, progression-free survival (PFS) with this 
combination has been variable, although outcomes are improved in the setting of rituximab-
sensitive disease.13,15,17-19 
The response rates and acceptable toxicity profile of bendamustine have generated interest in its 
use for front-line therapy of CLL and SLL. A prospective, multicenter randomized phase III trial 
compared bendamustine with chlorambucil for treatment of symptomatic CLL that had not 
previously received therapy.20 Patients were treated with bendamustine 100 mg/m2 IV days 1 & 2 
of 28 day cycles for up to 6 treatment cycles. Among the 319 enrolled patients, PFS favored 
bendamustine (21.6 months versus 8.3 months). Objective response rates were also higher for 
bendamustine compared with chlorambucil (68% versus 31%).20 A report from the German CLL 


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study group (protocol CLL2M) addressed the activity of bendamustine + rituximab (BR) in 
previously untreated CLL. A total of 117 patients received bendamustine 90 mg/m2 + rituximab 375 
mg/m2 every 28 days X 6 cycles. An overall RR of 90.9% was observed, with 32.7% achieving 
complete responses (CRs), 2.7% with nodular partial responses and 55.5% with partial responses 
(PRs). At 18 months, 75.8% remained with durable remissions.21 Toxicity of BR was reasonable, 
with <10% of treatment courses complicated by grade ≥3 anemia or thrombocytopenia, and grade 
≥3 infections observed in only 5.1% of courses. Recent data have also shown response rates, PFS, 
and toxicity with BR are superior to the standard regimen of rituximab + CHOP chemotherapy in 
indolent NHL.12 An ongoing German CLL Study Group trial is comparing FCR versus BR in newly 
diagnosed CLL (clinicaltrials.gov, NCT00769522). 
The German CLL Study Group CLL10 trial compared the efficacy of BR versus FCR for newly 
diagnosed CLL.22 The results from the CLL10 trial have been recently published, and demonstrated 
more severe neutropenia and infections with FCR chemotherapy. Although median PFS was 
improved in the overall population with FCR (55.2 months versus 41.7 months), there was no 
difference in median progression-free survival with FCR versus BR chemotherapy in 
patients older than age 65. One strategy of interest in improving PFS after induction therapy is 
the incorporation of maintenance therapy. The benefit of maintenance rituximab has already been 
established in other NHL histologies.5-8,10,23 In addition, several reports have shown benefit of 
lenalidomide in multiple NHL histologies, with a trend for improved benefit in the setting of lower 
tumor burden.24,25 Two additional studies (CALGB 10404 and the German CLLM1 trial) have 
reported improvement in PFS when lenalidomide maintenance is administered to patients with 
higher-risk, previously untreated CLL.26,27 There are additional data showing good efficacy and 
acceptable toxicity profile with the combination of rituximab and lenalidomide in relapsed/refractory 
CLL.28 
Given the minimal toxicities and proven activity of rituximab in the maintenance setting for 
treatment of indolent NHL,5-10 rituximab appears to be an ideal agent for use in combination 
therapy following induction chemotherapy in CLL/SLL. In addition, safety data exist to support 
maintenance therapy with rituximab for at least 2 years following induction chemotherapy.5-10 
Lenalidomide is also an appealing option for maintenance therapy in this setting based on recent 
data showing its activity in CLL and the convenience of its oral dosing. Lenalidomide is an 
immunomodulatory drug that has already received FDA approval for treatment of multiple 
myeloma and myelodysplastic syndrome with presence of the 5q deletion. In general, 
lenalidomide has been observed to be well tolerated, with common toxicities including 
neutropenia, thrombocytopenia, rash, constipation, diarrhea, and fatigue. Preliminary data show 
significant activity of lenalidomide in CLL, with response rates in relapsed/refractory CLL and 
NHL ranging from 25% to 70%, including responses in patients who have fludarabine-refractory 
disease.29,30 There are additional data demonstrating an association between increased 
likelihood of objective response in NHL and low tumor burden.24,25  
More recent data have suggested improved efficacy and an acceptable toxicity profile with the 
combination of rituximab and lenalidomide. A report of the activity of lenalidomide (dosed at 10 mg 
daily on days 9-28 of each 28-day treatment cycle) combined with rituximab for up to 12 therapy 
cycles found promising response rates in patients with relapsed and refractory CLL. All patients 
had received prior fludarabine-based chemotherapy, and 59 patients were evaluable for response. 
An ORR of 64% was observed, including 8% CRs and 5% CRs with incomplete hematologic 
recovery.31 In a single institution phase II study of rituximab 375 mg/m2 on day 1 and lenalidomide 
20 mg/day orally days 1-21 every 28 days for up to 6 treatment cycles, outcomes on 30 patients 
with previously untreated CLL were reported. Of 28 patients evaluable for response, an overall 
response rate of 85% was observed with an impressive 79% achieving CRs.32,33  These data 
suggest that lenalidomide + rituximab have promising response rates and appear to +have 


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improved efficacy compared with single-agent lenalidomide.29,30We propose a treatment strategy 
where patients are treated with induction chemoimmunotherapy consisting of rituximab + 
bendamustine for 6 cycles, followed by initiation of maintenance rituximab and lenalidomide among 
patients achieving an objective response (i.e., at least stable disease with some tumor shrinkage) 
to induction therapy. The goal of maintenance therapy will be to capitalize on the cytoreduction 
following induction chemotherapy with a maintenance regimen that has also shown promising 
activity in CLL, in order to allow for improved PFS in this population. 
A completed clinical protocol through the Wisconsin Oncology Network (WON) investigated the 
activity of lenalidomide as a single-agent in maintenance therapy administered after induction 
chemoimmunotherapy with bendamustine/rituximab in relapsed and refractory CLL/SLL 
(HO08405, RV-CLL/SLL-PI-397), and is now a published manuscript.34This study ultimately 
showed no improvement in median PFS at 18.3 months compared with previously reported activity 
of bendamustine + rituximab chemotherapy without maintenance therapy in the relapsed/refractory 
CLL/SLL setting (median PFS 15.2 reported by the German CLL Study Group).35 Progressive 
disease and toxicities were the primary reasons for discontinuation of protocol therapy, and only 6 
subjects were able to complete the entire 12 months of maintenance therapy per protocol. The 
small number of patients able to receive the full maintenance therapy likely limited the ability to 
assess the activity of maintenance lenalidomide after BR induction. 
 
Three recent large, multicenter, randomized, placebo controlled trials of maintenance lenalidomide 
have been reported in previously untreated high-risk CLL and relapsed/refractory CLL. These 
studies demonstrated improvement in PFS with maintenance lenalidomide compared with 
placebo.36,37 This previous experience with maintenance lenalidomide lends further support for 
investigating lenalidomide-based maintenance therapy in the previously untreated setting of 
CLL/SLL. Given the improved activity in relapsed CLL with the combination of rituximab + 
lenalidomide compared with single-agent lenalidomide, the combination of rituximab + 
lenalidomide in the maintenance setting is of particular interest as a novel means of improving upon 
remissions after first-line chemotherapy. 
STUDY DESIGN: 
This is a phase II single arm, open-label study evaluating the efficacy and safety of the 
combination of induction chemoimmunotherapy with bendamustine and rituximab followed by 
maintenance therapy with rituximab and lenalidomide in subjects with CLL or SLL who have not 
received any prior cytotoxic chemotherapy for their disease (i.e., prior single-agent rituximab is 
permitted). The study will be carried out at the University of Wisconsin Carbone Cancer Center 
(UWCCC)..  
 
The subject participation will include a screening period, treatment period, and a follow-up 
period. The treatment period will extend from the first dose of study drug treatment (day 1, 
cycle 1 of induction chemoimmunotherapy) until any of the following: completion of the entire 
course of induction and maintenance therapy; progressive disease (PD); an unacceptable 
adverse event (AE); the initiation of alternate anti-neoplastic therapy; or a decision by the 
subject or by the investigator to discontinue treatment; or death. The induction 
chemoimmunotherapy regimen consists of bendamustine and rituximab for 6 cycles, followed 
by initiation of maintenance therapy with rituximab and lenalidomide among subjects achieving 
an objective response to induction therapy (i.e., complete or partial response; stable disease 
with objective evidence of tumor shrinkage). Subjects with objective response after 4 cycles of 
bendamustine + rituximab (BR) are eligible to proceed to maintenance therapy if toxicities are 
limiting further BR induction therapy, or if the treating physician determines that further BR 
induction therapy would be associated with excessive risk for additional toxicities. 
 


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To minimize toxicity with induction chemotherapy, we have chosen a dose of bendamustine at 90 
mg/m2/day on days 1 & 2 every 28 days for a total of 6 cycles. Rituximab will be administered at a 
dose of 500 mg/m2 IV on day 1 of each cycle of induction chemoimmunotherapy (375 mg/m2 cycle 
1 only); however, patients at high-risk for cytokine release syndrome may receive rituximab on day 
2 of induction therapy. In select circumstances in subjects at high risk for cytokine release 
syndrome and/or tumor lysis syndrome, rituximab may be administered as late as day 5 of cycle 1 
(this alternative dosing of rituximab applies to cycle 1 of induction therapy only). Lenalidomide and 
rituximab maintenance will be initiated 6-12 weeks after the 6th cycle of chemotherapy, and 
continued for a total of 24 cycles. Maintenance therapy will continue for a maximum of 24 cycles 
or until unacceptable toxicity or progression of disease. 
 
Maintenance therapy will begin once there has been adequate hematologic recovery (ANC 
≥1000/µL and platelets ≥50,000/µL) and other criteria as outlined in Section 7.5 have been met. 
Rituximab will be administered at a dose of 375 mg/m2 IV on day 1 of every odd-numbered 28 day 
cycle (cycles 1,3,5,7,9,11,13,15,17,19,21,23) for a maximum of 12 doses during the maintenance 
phase. Subjects will receive concurrent lenalidomide 5 mg orally daily on days 1-21 of cycles 1-24 
(28 day cycles). If subjects do not experience adverse effects from lenalidomide, dose escalation 
up to 10 mg orally daily on days 1-21 of each 28 day cycle will be allowed at the start of cycle 2 or 
at the start of any subsequent cycle (see Section 9.2.1.5 and 9.2.1.6 for criteria required to escalate 
the dose of lenalidomide to 10 mg/day on days 1-21).  Lenalidomide dose escalation is only allowed 
at the start of a new cycle to a maximum dose of 10 mg/day on days 1-21. Subjects entering 
maintenance with reduced renal function (i.e., creatinine clearance ≥40 but <60 mL/min) will start 
lenalidomide at a dose of 5 mg every other day on days 1-21. There is no dose modification of 
rituximab based on reduced renal function.  Among subjects without excessive toxicity or evidence 
of progression, treatment with lenalidomide will continue for up to 24 cycles (cycle 1-24) and 
treatment with rituximab will continue for up to 12 doses (administered every odd-numbered cycle 
during cycles 1,3,5,7,9,11,13,15,17,19,21,23). If subjects have excessive toxicity from 
lenalidomide, ongoing maintenance therapy with rituximab alone is permitted after lenalidomide is 
discontinued. After completing 24 cycles of maintenance therapy, subjects will then be observed 
for evidence of PD with clinical assessments every 3 months for at least 2 years.  
 
STUDY ENDPOINTS 
 
Primary: 
• 
The primary objective is progression-free survival (PFS). Tumor measurements and 
disease assessments will be performed at the time of screening, following cycles 3 and 
6 of induction chemotherapy, every 4 cycles during the maintenance portion of treatment, 
and at the end of treatment (EOT). Subjects with clinical evidence of progression prior 
to a planned disease assessment will be evaluated at the time of clinically suspected 
progression. Follow-up visits for disease assessment will occur every 3 months after the 
EOT visit until PD, initiation of alternate anti-neoplastic therapy, decision by the subject 
to withdraw from the study, or death. The follow-up period will begin after the EOT visit, 
and all subjects will be followed for at least 2 years after completion of therapy or until 
death or progression and until the last patient has been followed for at least 1 year 
following completion of therapy. 
 
 
 
Secondary: 


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Version 03/01/2020 
• 
To determine objective response rates (CR + PR). As described in the primary objective, 
formal disease assessments including imaging will be performed after cycles 3 and 6 of 
induction chemotherapy and every 4 cycles during the maintenance portion of treatment. 
Response and progression in cases of SLL will be evaluated using the International 
Working Group Criteria38 for response in lymphoma. Response and progression in cases 
of CLL will be evaluated in this study using the Revised IWCLL Criteria39 for response in 
CLL. Radiological methodologies, techniques and/or physical examination, established 
at baseline for the assessment and measurement of each identified lesion will be used 
for all subsequent assessments. 
• 
To determine toxicities observed with induction chemotherapy and maintenance therapy. 
Safety evaluations will be based on the incidence, intensity, and type of adverse events 
(AEs) and clinical laboratory results. Drug doses will be modified as required based on 
toxicity as assessed using the National Cancer Institute Common Terminology Criteria 
for Adverse Events (CTCAE), version 4.0. 
• 
To determine overall survival. Overall survival will be determined from the date of 
enrollment until death from any cause. 
• 
STUDY DURATION:  Anticipated accrual 
period of 30 months, with a follow-up 
period of at least 2 years after completion 
of therapy or until death or progression 
and until the last subject has been 
followed for at least 1 year following 
completion of therapy. 
 
TOTAL SAMPLE SIZE:  Approximately 36 
subjects are planned for enrollment.   
DOSING REGIMEN(S): 
Induction chemoimmunotherapy: 
• 
Bendamustine 90 mg/m2 IV days 1 & 2 
every 28 days X 6 cycles 
• 
Rituximab 500 mg/m2 IV day 1 every 28 
days X 6 cycles (375 mg/m2 IV cycle 1 
only, day 1-5) 
 
Maintenance phase: 
• 
Rituximab 375 mg/m2 IV on day 1 of 
every 
odd-numbered 
28-day 
cycle 
(cycles 1,3,5,7,9,11,13,15,17,19,21,23) 
for a maximum of 12 doses during the 
maintenance phase.  
Lenalidomide 5 mg orally daily on days 1-21 
of each 28-day cycle for 24 cycles 
(maintenance cycles 1-24); dose escalation 
to 10 mg orally daily on days 1-21 will be 
allowed at the start of cycle 2 or at the start of 
any subsequent cycle in subjects with 
acceptable toxicities (see Section 9.2.1.5 and 
9.2.1.6 for criteria needed to escalate the 
dose of lenalidomide to 10 mg/day on days 1-
21).  Lenalidomide dose escalation is only 
STUDY DRUG SUPPLIES: 
Bendamustine 
is 
commercially 
available. 
 
For study participants, rituximab will 
be provided by Genentech, Inc. at no 
charge.  
 
For 
study 
participants, 
Celgene 
Corporation will provide lenalidomide 
at no charge through the Revlimid 
REMS® program.   


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allowed at the start of a new cycle up to a 
maximum dose of 10 mg/day on days 1-21. 
Subjects entering maintenance with a CrCl 
≥40 and <60 mL/min will begin dosing at 5 mg 
every other day on days 1-21. 


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3 Schedule of Study Assessments 
 
Baseline assessments will be within 28 days of C1D1. 
 
 
Baseline1 
 
C1-6 Induction 
chemotherapy 
 
 
Maintenance 
cycles 1-6 
rituximab + 
lenalidomide 
(28-day cycles, 
+/- 10 days) 
 
Maintenance 
cycles 7-24 
rituximab + 
lenalidomide 
(28-day 
cycles, +/- 
10 days) 
 
 
End of 
treatment20 
 
Follow-up 
phase2 
 
Every 3 
months for 2 
years 
( ±  3 weeks) 
 
 
D1 (±4 days) 
 
 
Informed consent 
X 
 
 
 
 
 
Medical history & 
medications3 
X1 
 
 
 
 
 
Physical exam, vital 
signs, weight, 
height,4 ECOG 
performance status 
X1 
X 
X5 
(D1 each 
cycle) 
X5 
(D1 each 
odd-
numbered 
cycle) 
X 
X 
Bone marrow 
aspirate & biopsy 
X6 
 
X6 
 
 
 
CLL cytogenetic 
analysis 
X7 
 
 
 
 
 
Hematology profile8 
X1 
X8 
X8 
X8 
X 
X 
Chemistry profile9 
X1,9 
X9 
X9 
X9 
X 
X 
Beta-2 microglobulin 
level 
X 
 
 
 
 
 
Tumor lysis 
syndrome (TLS) 
assessment10 
 
X10 
X10 
X10 
 
 
Immunoglobulin 
levels11 
X 
X11 
X11 
X11 
X 
X11 
Hepatitis screening19 
X 
 
 
 
 
 
Thyroid Function12 
X 
 
X12 
X12 
X 
X12 
Pregnancy testing13 
X 
 
X13 
X13 
 
 
CT of the chest & 
abdomen / pelvis14 
X14 
X14 
X14 
X14 
X14,20 
X14 
PET imaging15 
X15 
X15 
X15 
X15 
X15,20 
X15 
Formal Disease 
assessment (CT 
scans, palpated 
disease, and other 
assessable 
disease)14 
X1 
X14 
X14 
Every 4 cycles 
X14 
Every 4 
cycles 
 
X14 
 
Record adverse 
events 
X 
X 
X 
X 
X 
X16 
Allopurinol 
prophylaxis 
 
X17 
X17 
X17 
 
 
Bendamustine 
infusion 
 
X 
 
 
 
 
Rituximab infusion 
 
X 
X 
X 
 
 


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Version 03/01/2020 
(cycles 1,3, 5) 
(cycles 
7,9,11 
13,15, 
17,19,21,23) 
Register subject into 
Revlimid REMS ® 
program 
 
X18 
 
 
 
 
Lenalidomide 
administration 
 
 
X 
(cycles 1-6) 
X  
(cycles 7-24) 
 
 
1 If screening assessments (i.e., baseline history, physical exam, laboratory evaluations) were done within 7 days of C1D1, they do not 
need to be repeated at study day 1. The exception to this is baseline disease assessments; baseline CT scans and bone marrow 
biopsy/aspirate may be performed within 6 weeks of C1D1. 
2The follow-up phase of therapy will begin 30 days after the last dose of lenalidomide is administered and will continue for up to 2 years 
or until death, progression of disease, or start of a new anti-cancer therapy. After 2 years of follow-up, subjects will be followed 
annually for 5 years for survival and disease progression. 
3Include all prior anti-cancer therapies and pre-existing medical conditions. 
4Start of protocol only. 
5Clinical assessments to be performed on day 1 of each 28-day cycle during cycles 1-6 of maintenance rituximab + lenalidomide, then 
day 1 of each odd-numbered cycle during maintenance rituximab + lenalidomide cycles 7-24. In subjects who discontinue 
lenalidomide but continue receiving maintenance rituximab per protocol, clinical assessments may be performed on day 1 of odd-
numbered cycles even prior to cycle 7. 
 6BM aspirate and biopsy to be done within 6 weeks prior to C1D1. A repeat BM biopsy is required after cycle 6 of chemotherapy in 
subjects with BM involvement at enrollment who have achieved a possible CR to induction chemotherapy based on imaging studies 
and improvement in hematologic parameters. In subjects being evaluated with CLL response criteria, investigators should note that 
2 bone marrow biopsies performed ≥ 2 months apart are required to confirm a complete response. In subjects who appear to have 
improved their objective response (i.e., partial to complete response) with maintenance lenalidomide, a BM biopsy may be indicated 
to confirm the CR. 
7CLL cytogenetic analysis should include analysis for presence of 11q-, ATM/Cen11; 17p-, p53/Cen17; 13q-, D13S319/LAMP1; and 
trisomy 12, D1273/MDM2 by fluorescence in situ hybridization (FISH). Baseline assessment of IgVH gene mutation status by ZAP70 
and/or CD38 positivity is preferred, but not mandatory. If CLL mutation analysis has been performed within 12 months prior to 
enrollment, repeat analysis is not required. Cytogenetic analyses may be performed on bone marrow aspirate or on peripheral blood. 
8Hematology profile (CBC, differential, platelets) is required within 48 hours of cycles 2-6 of induction chemotherapy (hematology profile 
prior cycle 1, day 1 may be performed within 7 days.  Hematology profiles are required within 48 hours prior to day 1 of each 
maintenance cycle during cycles 1-24. Hematology profiles are required weekly (±48 hours) during cycle 1 of maintenance 
lenalidomide. In addition, in any maintenance cycle where the lenalidomide dose is escalated or re-escalated or treatment is 
interrupted for more than 4 weeks, subjects will have weekly (±48 hours) hematology profiles performed for at least 4 consecutive 
weeks.  Subjects who are on a stable lenalidomide dose (without escalation or interruption) for ≥1 cycle of maintenance will require 
hematology profiles every 4 weeks. In study subjects who discontinue lenalidomide but continue receiving rituximab per protocol, 
labs are not required on even cycles, including those prior to cycle 7.  
9Chemistry profile includes sodium, potassium, chloride, CO2 (bicarbonate) calcium, magnesium, phosphorus, blood urea nitrogen 
(BUN), creatinine, glucose, albumin, total protein, alkaline phosphatase, total bilirubin, AST/SGOT, ALT/SGPT, lactate 
dehydrogenase (LDH), and uric acid.  Chemistry profile is to be obtained at screening, within 7 days of cycle 1, day 1 of induction, 
and within 48 hours prior to day 1 of induction cycles 2-6 and maintenance cycles 1-24. In study subjects who discontinue 
lenalidomide but continue receiving rituximab per protocol, labs are not required on even cycles, including those prior to cycle 7.  
10Tumor lysis syndrome (TLS) assessment will consist of sodium, potassium, chloride, CO2 (bicarbonate), calcium, magnesium, 
phosphorus, BUN, creatinine, LDH, and uric acid. In subjects at high-risk for TLS (see Section 9.3.1 for definition of subjects at high-
risk), TLS assessments must be repeated on cycle 1, day 2 of induction therapy. Subsequent TLS laboratory monitoring during the 
first week of induction therapy beyond cycle 1, day 2 will be at investigator discretion depending on clinical status and change in 
laboratory values (see Appendix I: Cairo-Bishop definition of tumor lysis syndrome). TLS assessments are required on day 1 of 
maintenance cycle 1, in any cycles where lenalidomide dosing is escalated/re-escalated, or if lenalidomide dosing is held for >4 
weeks. Refer to Section 9.3.1 for guidelines on use of allopurinol and/or rasburicase for TLS prophyalxis during induction and 
maintenance therapy. 
11Immunoglobulin levels (quantitative serum levels of IgA, IgG, IgM) should be evaluated at baseline, at the end of induction 
chemotherapy (at least 4 weeks after C6D1 of induction chemotherapy but prior to C1D1 of maintenance therapy), and before 
maintenance cycles 5, 9, 13, 17, 21, and the EOT. Please note that the schedule for immunoglobulin level evaluation corresponds 
to the schedule for disease assessments (i.e., CT imaging and/or PET imaging) after every 4 cycles of maintenance therapy. During 
the follow-up phase after completion of maintenance therapy, immunoglobulin levels should be monitored approximatelyevery 6 
months. 
12Thyroid Stimulating Hormone (TSH) level is required at screening, within 48 hours prior to cycle 1, day 1 of maintenance therapy, and  
within 48 hours prior to  maintenance cycles 5, 9, 13, 17, 21, and the EOT. T3 and T4 levels may be assessed as clinically indicated. 
Please note that the schedule for thyroid function evaluation corresponds to the schedule for disease assessments after every 4 
cycles of maintenance therapy. During the follow-up phase after completion of maintenance therapy, TSH levels should be monitored 
approximately every 6 months. 
13Pregnancy tests for females of childbearing potential.  A female of childbearing potential (FCBP) is a sexually mature female who: 
1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 


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consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). Pregnancy testing must be 
performed with a method of serum or urine testing with a sensitivity of at least 50 mIU/mL. Pregnancy testing in FCBP will occur at 
baseline and prior to maintenance as follows:  Pregnancy tests must occur within 10 – 14 days and again within 24 hours prior to 
prescribing lenalidomide cycle 1 (prescriptions must be filled within 7 days).  The patient may not receive lenalidomide until the 
Investigator has verified that the results of these pregnancy tests are negative. FCBP with regular or no menstruation must have a 
pregnancy test weekly for the first 28 days and then every 28 days while on therapy (including breaks in therapy); at discontinuation 
of lenalidomide and at day 28 post the last dose of lenalidomide.  Females with irregular menstruation must have a pregnancy test 
weekly for the first 28 days and then every 14 days while on therapy (including breaks in therapy), at discontinuation of lenalidomide 
and at day 14 and day 28 post the last dose of lenalidomide (see Appendix B: Risks of fetal exposure, pregnancy testing guidelines 
and acceptable birth control methods). 
14Formal disease assessment to be repeated after cycles 3 and 6 of induction therapy, then after every 4 cycles during the maintenance 
phase of treatment (i.e., after maintenance cycles 4, 8, 12, 16, 20, and 24). CT imaging of the abdomen and pelvis is must include 
oral and IV contrast; CT imaging of the chest does not require IV contrast. During the follow-up phase of treatment, use of CT 
imaging is at the treating physician’s discretion, and may or may not be used as part of the disease assessment. CT imaging (and 
PET imaging, if clinically indicated) must be performed within 6 weeks of enrollment. Subjects with CLL and without clinically significant 
lymphadenopathy (defined as lymph nodes measuring ≤ 1.5 cm in greatest dimension) at baseline will not require repeat CT imaging 
as part of ongoing disease assessments. All PRs and CRs in cases of CLL evaluated by the Revised IWCLL 2008 (Appendix H) must 
be confirmed by repeat scans at least 2 months after the criteria for response are first met. Timing of alternate cycle efficacy 
assessments will be reset following a confirmation or response assessment.  Confirmatory scans can be done 4 months after initial 
response is noted, investigators do not have to schedule a separate scan at the 2 month interval for confirmation of response. If 
investigators perform 2 month confirmatory scan for response, then timing of alternate cycle efficacy assessments will be reset 
following a confirmation of response assessment (see section 7.1.1). In cases of CLL, bone marrow biopsy and flow cytometry of both 
bone marrow and blood are required to confirm a CR  
15PET imaging is required at the end of treatment only for subjects being evaluated with small lymphocytic lymphoma response criteria 
who have residual masses on CT imaging or in subjects with areas of increased uptake on baseline PET imaging who require re-
assessment to determine CR status; subsequent PET scans are only required if clinically indicated as part of disease assessment. 
16An additional safety assessment will be done 30 days (+/- 2 days) following the last dose of study drug. 
17Subjects who are determined to be at high-risk for TLS (see Section 9.3.1 for definition of TLS risk) are required to 
receive allopurinol 300 mg orally daily or twice daily for 14 days at the start of induction chemotherapy. Subjects must 
receive their first day of allopurinol prophylaxis on C1D1 of induction chemotherapy, but preferably 1-2 days prior to 
C1D1. Alternatively, subjects at high-risk for TLS with intolerance to allopurinol or judged to be at increased risk for 
TLS even with allopurinol prophylaxis, should be considered for treatment with rasburicase. For all other subjects (i.e., 
not meeting high-risk criteria for TLS), use of allopurinol during induction therapy is at the discretion of the investigator. 
Subjects not meeting criteria for a partial or complete response after induction therapy should receive allopurinol 
prophylaxis 300 mg orally daily for 10 days beginning 2 days prior to the start of cycle 1 of maintenance therapy.  
18Subjects must be registered into Revlimid REMS® program prior to prescribing lenalidomide. Ideally, this should occur prior to cycle 6 
of induction therapy. All physicians who prescribe lenalidomide for research subjects enrolled in to this trial, and all research subjects 
enrolled into this trial, must be registered in, and must comply with, all requirements of the Revlimid REMS® program.  Drug will be 
shipped on a per patient basis by contract pharmacy to the clinic site. Only enough lenalidomide for one cycle of therapy will be 
supplied to the patient each cycle. 
19Hepatitis screening to include hepatitis B surface antigen, hepatitis B core antibody, and hepatitis C antibody 
screening. 
20For subjects who discontinue lenalidomide early and continue with rituximab, the EOT visit may occur 30 days (+/- 2  
days) after cycle 23, day 1 dosing of rituximab, and also be inclusive of the 30-day safety visit. For these subjects 
completing 23 cycles of rituximab (stopping lenalidomide early), restaging will occur after cycle 23 of rituximab. For 
subjects stopping all maintenance or induction cycles prematurely, the EOT visit may occur 30 days (+/-2 days) after 
the last dose of study drug, to also be inclusive of the 30-day safety visit. Subjects are allowed to have restaging imaging 
up to 8 weeks after the final dose of study drug.  
 
 
 
 
 
 
 
 
 


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4.0 Glossary of Abbreviations  
 
Abbreviation  
Term 
5-HT3  
 
5-hydroxytryptamine (serotonin) 
AE 
 
 
Adverse event 
ANC 
 
 
Absolute neutrophil count 
B-ALL  
 
B-cell acute lymphoblastic leukemia 
BM 
 
 
Bone marrow 
BSA 
 
 
Body surface area 
CLL 
 
 
Chronic lymphocytic leukemia 
CR 
 
 
Complete response 
CRC 
 
 
Clinical Research Committee 
CRF 
 
 
Case report form 
CRCO  
 
Central Research Coordinating Office 
CT 
 
 
Computed tomography 
CTCAE 
 
Common terminology criteria for adverse events 
DLBCL 
 
Diffuse large B cell lymphoma 
DOT 
 
 
Disease Oriented Team 
DSMB  
 
Data Safety Monitoring Board 
EC 
 
 
Ethics committee 
ECOG  
 
Eastern Cooperative Oncology Group 
EMEA  
 
European Medicines Agency 
EOT   
 
End of treatment 
FCBP  
 
Females of childbearing potential 
FCR 
 
 
Fludarabine, cyclophosphamide, rituximab 
FDA 
 
 
United States Food and Drug Administration 
FISH  
 
Fluorescence in situ hybridization  
G-CSF  
 
Granulocyte colony stimulating factor 
GCLLSG 
 
German CLL study group 


Protocol HO11414                               Confidential                                 Page 20 of 121 
 
 
    
 
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GCP 
 
 
Good clinical practice 
ICH 
 
 
International Conference on Harmonization 
IND 
 
 
Investigational New Drug 
IRB 
 
 
Institutional Review Board 
IV 
 
 
Intravenous/intravenously 
MCL 
 
 
Mantle cell lymphoma 
MDS  
 
Myelodysplastic syndrome 
MM 
 
 
Multiple myeloma 
MRN  
 
Medical record number 
NCI 
 
 
National Cancer Institute 
NCI-CTCAE 
National Cancer Institute Common Toxicity Criteria for Adverse 
Events 
NHL 
Non-Hodgkin lymphoma 
OS 
 
 
Overall survival 
PFS 
 
 
Progression-free survival 
PD 
 
 
Progressive disease 
PET   
 
Positron-emission tomography 
PR 
 
 
Partial response 
SAE 
 
 
Serious adverse events 
SD 
 
 
Stable disease 
SLL 
 
 
Small lymphocytic lymphoma 
SOP 
 
 
Standard operating procedure 
SPM 
 
 
Second primary malignancy  
TLS 
 
 
Tumor lysis syndrome 
TPD 
 
 
Therapeutic Products Directorate (Canada) 
ULN 
 
 
Upper limit of laboratory normal 
UWCCC 
 
University of Wisconsin Carbone Cancer Center 
WON  
 
Wisconsin Oncology Network 
WWDSS 
 
Celgene Corporation Worldwide Drug Safety Surveillance 


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5 Background and Rationale 
 Introduction 
5.1.1 Diagnosis and natural history of CLL/SLL 
Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) represent 
different clinical manifestations of a shared hematologic disorder with a typically indolent 
but incurable course. Generally, a peripheral blood lymphocyte count >5000 monoclonal 
B-cell lymphocytes/microliter is defined as the threshold to separate CLL from SLL.1 
Despite the relatively arbitrary division between CLL and SLL, clinical trials often strictly 
separate these diagnoses. Only diseases meeting criteria for CLL are included in studies 
that are typically limited to CLL as a single entity. In contrast, SLL is often excluded from 
trials focusing on CLL, and equally as frequently is excluded from trials of indolent non-
Hodgkin lymphoma (NHL) because of its traditionally lower rates of response compared 
with other indolent NHL subtypes. Unfortunately, this has led to limited progress in 
developing new treatment modalities for SLL and has limited options for clinical trial 
participation in patients with SLL. A recent report from M.D. Anderson Cancer Center 
focused on comparing outcomes in patients with CLL and SLL, with data from 2126 
patients retrospectively identified from 1985 until 2005. Rates of response, survival, and 
failure-free survival were ultimately found to be no different between patients classified as 
CLL or SLL.1 Based on these factors collectively, the clinical trial design we propose will 
focus on the populations of CLL and SLL together, recognizing the commonalities between 
these diagnoses. 
 
5.1.2 Current treatment for CLL/SLL 
Although CLL/SLL is typically an indolent disease with a multiply relapsing course after 
response to various treatments, CLL/SLL remains incurable in the majority of cases. 
Although some patients achieve long-term remissions with potentially curative options 
such as allogeneic stem cell transplantation, the older age of most patients at diagnosis 
and availability of a suitable donor makes this approach impractical for most patients.2 
Therefore, for the overwhelming majority of patients with CLL/SLL, the goal of disease 
management is palliation of symptoms and optimization of disease control with intermittent 
therapeutic intervention.  
Multiple treatments have proven beneficial in CLL/SLL, including alkylating agents, 
nucleoside analogues, anthracyclines, and various combinations of these agents.2 
Rituximab, a monoclonal antibody directed against CD20, has shown limited activity as a 
single-agent in CLL/SLL presumably due to the generally weak expression of CD20 in 
CLL/SLL. However, multiple combination chemotherapy regimens in CLL/SLL employing 
rituximab have demonstrated a probable synergistic benefit related to potential chemo-
sensitization properties of rituximab.2-4  Standard therapy options for patients requiring 
treatment who are healthy enough to tolerate chemotherapy are typically fludarabine-
based regimens. However, regimens such as FCR chemotherapy (fludarabine, 
cyclophosphamide, rituximab) are often too toxic for older adults to tolerate, and have 
significant short-term as well as long-term toxicities (i.e., myelodysplasia, prolonged 


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cytopenias). Bendamustine is an agent receiving FDA approval in 2008 for treatment of 
chronic lymphocytic leukemia and more recently receiving FDA approval in indolent NHL 
that has progressed within 6 months of rituximab or a rituximab-containing regimen. 
Multiple reports suggest that bendamustine may have a toxicity profile that is more 
tolerable than other standard chemotherapy regimens including CHOP chemotherapy 
(cyclophosphamide, 
doxorubicin, 
vincristine, 
prednisone) 
or 
fludarabine-based 
regimens.11-13 
 
 Experience with Bendamustine 
5.2.1 Bendamustine biochemistry: in vitro and in vivo studies 
Bendamustine is a promising chemotherapy agent for treatment of CLL/SLL with a 
substantial record of activity in indolent NHL and CLL. Bendamustine has been available 
for several decades in Europe, with evidence of activity in several hematologic and solid 
tumors.40 Following its development in 1963 in the German Democratic Republic, 
bendamustine was initially available in Europe from 1971 until 1992 under the name 
Cytostasan®. Then in 1993, bendamustine was marketed by Ribosepharm GmbH as 
Ribomustin® and more recently has been made available for investigation in the United 
States through Cephalon, Inc. as Treanda™. The anti-neoplastic effects of bendamustine 
are related to its dual functional properties of both an alkylating agent and a nitrogen 
mustard.40 Through these unique cytostatic properties, bendamustine is able to inhibit 
DNA transcription, replication, and repair. In addition, some data have suggested that 
bendamustine’s improved chemical stability compared with other nitrogen mustards may 
enable the compound to have more efficient DNA alkylating properties. These unique 
properties of bendamustine also enable it to exhibit only partial cross-resistance with other 
alkylating agents.40,41   
 
Bendamustine has demonstrated in vitro activity in multiple tumor cell lines, including drug-
resistant human breast cancer,41,42  CLL,42,43 indolent NHL,44,45 and myeloid leukemia.46 
More recently, in vitro studies have investigated the effect of the monoclonal antibody 
rituximab on the activity of bendamustine. For example, studies using the cell lines DOHH-
2 and WSU-NHL (cell lines derived from CD20+ lymphomas) and cells freshly isolated 
from humans with B-CLL demonstrated a significant reduction in the dose of 
bendamustine required to induce apoptosis with the addition of rituximab, supporting a 
syngergistic effect between bendamustine and rituximab.4,47 
 
5.2.2 Clinical activity of bendamustine in relapsed and refractory CLL/SLL 
The clinical activity of bendamustine has been reported in Hodgkin lymphoma,48 
NHL,11,15,17,18 CLL,20,21,49,50 myeloma,51 breast cancer,52 and lung cancer.53 Several of the 
earlier reports showing significant activity in NHL were predominantly European studies in 
relapsed indolent NHL, with bendamustine given as monotherapy or in combination with 
other agents. In this setting, objective response rates between 50-90% were observed in 
these studieswhich often included patients with heavily pretreated disease.45,54,55 More 
recently reported experience in indolent NHL and CLL with single-agent bendamustine 


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doses ranging from 50-120 mg/m2 given for 2 consecutive days every 3-4 weeks yielded 
response rates ranging from 40-75%.19,50,56,57 Notably, single agent bendamustine for 
treatment of relapsed CLL was associated with the lower rates of response compared with 
other indolent NHL subtypes, which is consistent with experience in other 
chemotherapeutic trials. Bendamustine at a dose of 90 mg/m2/day IV on days 1 and 2 in 
combination with rituximab has shown response rates exceeding 70-90%, but with 
CLL/SLL comprising the minority of patients and many patients either not refractory to 
rituximab or rituximab-naϊve.11,14,58-60  In comparison, other regimens combining rituximab 
with nucleoside analogues in relapsed and refractory CLL and indolent NHL have shown 
similar response rates of 70-75%.61,62 
Despite the high objective response rates with bendamustine when combined with 
rituximab in relapsed and refractory indolent NHL, the observed durations of remission 
have been quite variable (Table 1). Although several reports of bendamustine 
monotherapy or bendamustine + rituximab have reported PFS exceeding 1 to 2 years, 
many of these studies include less heavily pretreated patients and patients who are not 
refractory to rituximab or are rituximab-naϊve.11,55,58-60 In a report by Rummel et al among 
63 patients with relapsed/refractory non-Hodgkin lymphoma, a PFS of 30 months was 
reported with the combination of rituximab and bendamustine, but with none of the patients 
having received prior rituximab.11,60 Another study by Robinson et al in 66 patients with 
relapsed, refractory NHL found high overall response rates of 92% with bendamustine + 
rituximab, with a median PFS of 23 months. However, this study excluded patients who 
were rituximab-refractory.15 A recently reported multicenter study treating 78 patients with 
relapsed and refractory CLL (28% refractory to fludarabine) reported an overall response 
rate of 59%, and median PFS of 14.7 months.13 In a multi-center study of 76 patients 
reported by Friedberg et al, response rates and PFS were reported among a less favorable 
subgroup of NHL patients with relapsed and rituximab-refractory disease treated with 
bendamustine monotherapy. Among these patients, the objective response rate was quite 
high at 77%, but the median duration of response was only 6.7 months.19  Similarly, Kahl 
et al reported a high objective response rate of 75% among 100 patients with relapsed, 
rituximab-refractory indolent NHL (21% with SLL). However, the observed median PFS 
was 9.3 months.18 These results provide conflicting information about the use of 
bendamustine in relapsed/refractory NHL; primarily, that response rates are high with 
bendamustine but with a disappointing duration of remission when patients are refractory 
to rituximab. 
 
 
 
 
 
 
 
 
 


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Table 1. Bendamustine + rituximab in relapsed, refractory indolent NHL 
and CLL 
 
N 
Regimen 
Response rate 
PFS 
Overall 
CR/ 
CRu 
PR 
Rummel et al11,60 
 
Relapsed; no prior R 
63 
FL 38% 
MCL 25% 
B 90 mg/m2 D1,2 
R 375 mg/m2 D1 
Cycles q4 weeks 
(max 4 cycles) 
90% 
60% 
30% 
24, 30 
mos 
van der Jagt et al59 
 
Relapsed; not        
R-refractory (37% 
with prior R)  
MPT= 1 
66 
FL 61% 
SLL 15% 
MCL 18%  
B 90 mg/m2 D2,3 
R 375 mg/m2 D1 
Cycles q4 weeks 
(max 6 cycles) 
94% 
41% 
53% 
Not yet 
reached 
Weide R et al14 
 
Relapsed, refractory 
disease 
MPT= 2 
54 
CLL 39% 
FL 26% 
Transformed 
11% 
B 90 mg/m2 D1,2 
M10 mg/m2 D1 
R 375 mg/m2 
weekly (cycle 1) 
Cycles q4 weeks 
(max 6 cycles) 
96% 
41% 
55% 
CLL: 17 
months 
 
Indolent 
NHL: NR 
 
Robinson et al15 
 
Relapsed; not        
R-refractory 
MPT= 1 
(56% with prior R) 
 
67 
FL 61% 
SLL 15% 
MCL 18% 
 
B 90 mg/m2 D2,3 
R 375 mg/m2 D1 
Cycles q4 weeks 
(max 4-6 cycles) 
 
92% 
41%/ 
14% 
38% 
23 mos 
Friedberg et al19 
(bendamustine 
monotherapy) 
 
Relapsed, R-
refractory, 
MPT= 2 
76 
61% follicular 
16% SLL 
20% 
Transformed 
disease 
B 120 mg/m2 D1,2  
Cycles q3 weeks 
(median 5 cycles) 
77% 
15%/ 
19% 
43% 
6.7 mos 
Kahl et al18 
(bendamustine 
monotherapy) 
 
Relapsed, R-
refractory 
MPT = 2 
100 
62% FL 
21% SLL 
16% MZL 
B 120 mg/m2 D1,2  
Cycles q3 weeks 
(max 6-8 cycles) 
75% 
14%/3% 
58% 
9.3 mos 
Fischer et al13 
 
Relapsed, refractory 
CLL 
78  
All with CLL 
 
28% 
fludarabine-
refractory 
B 70 mg/m2 D1,2 
R 500 mg/m2 D1 
(max 6 cycles) 
59% 
9% 
47.4% 
(+ 2.6% 
with 
nodular 
PR) 
Median 
EFS  
14.7 mos 
Abbreviations: B=bendamustine, CR=complete response, CRu=unconfirmed complete response, FL=follicular lymphoma, 
M=mitoxantrone, MCL=mantle cell lymphoma, MPT=median prior therapies, MZL=marginal zone lymphoma, NR=not 
reported, PR=partial response, R=rituximab. 
 
 


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5.2.3 Bendamustine in previously untreated CLL/SLL 
 
The response rates and acceptable toxicity profile of bendamustine have generated 
interest in its use for front-line therapy of CLL and SLL (Table 2). A prospective, multicenter 
randomized phase III trial compared bendamustine with chlorambucil for treatment of 
symptomatic CLL that had not previously received therapy.20 Patients were treated with 
bendamustine 100 mg/m2 IV days 1 & 2 of 28-day cycles for up to 6 treatment cycles. 
Among the 319 enrolled patients, PFS favored bendamustine (21.6 months versus 8.3 
months). Objective response rates were also higher for bendamustine compared with 
chlorambucil (68% versus 31%).20 A report from the German CLL study group (protocol 
CLL2M) addressed the activity of bendamustine + rituximab (BR) in previously untreated 
CLL. A total of 117 patients received bendamustine 90 mg/m2 IV on days 1 & 2 and 
rituximab 500 mg/m2 IV on day 1 every 28 days X 6 cycles. An ORR of 90.9% was 
observed, with 32.7% CRs, 2.7% with nodular PRs, and 55.5% with PRs. At 18 months, 
75.8% remained in ongoing remission.21 Toxicity of BR was reasonable, with <10% of 
treatment courses complicated by grade ≥3 anemia or thrombocytopenia, and grade ≥3 
infections were observed in only 5.1% of courses.21 Recent data have also shown 
response rates, PFS, and toxicity with BR is superior to the standard regimen rituximab + 
CHOP chemotherapy in indolent NHL.12  The German SLL Study Group CLL10 trial 
compared FCR versus BR in newly diagnosed CLL.22 The median PFS for patient treated 
with BR chemotherapy was 41.7 months, and there was no difference in PFS between 
patients treated with FCR versus BR chemotherapy among the subgroup of adults aged 
>65 years. In addition, there were significantly more infectious complications among adults 
aged >65 years treated with FCR. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 2. Bendamustine ± rituximab in previously untreated CLL 
 
N 
Regimen 
Response rate 
PFS 


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Overall 
CR/CRu 
PR 
Fischer et al 21 
GCLLSG CLL2M 
 
Median age 64 
117 
B 90 mg/m2 D1,2 
R 375 mg/m2 C1D1 
R 500 mg/m2 C2-6  
 
Cycles q4 weeks 
(max 6 cycles) 
 
90.9% 
32.7% 
55.5% 
75.8% in 
remission at >18 
months 
 
Median PFS NR 
Knauf et al20 
319 
B 100 mg/m2 D1,2 
        versus 
Chlorambucil (Chl) 
 
Cycles q4 weeks 
(max 6 cycles B) 
B 68% 
 
Chl 31% 
B 31% 
 
Chl 2% 
 
B = 21.6 months 
 
Chl = 8.3 months 
GCLLSG CLL10 trial 
 
 
FCR vs BR 
FCR 
95% 
 
BR 96% 
FCR 40% 
 
BR 31% 
 
BR = 41.7 
months 
 
FCR = 55.2 
months 
Abbreviations: B=bendamustine; BR=bendamustine + rituximab; Chl=chlorambucil; CR=complete response; 
CRu=unconfirmed complete response; FCR=fludarabine, cyclophosphamide, rituximab; GCLLSG=German CLL study 
group; NR=not reached; PR=partial response; R=rituximab. 
 
 
 
5.2.4 FDA approval of bendamustine for CLL/SLL 
Bendamustine received FDA approval for treatment of CLL in March of 2008 based on the 
promising results of 2 clinical studies.20,63 A large international phase III randomized clinical 
trial of bendamustine versus chlorambucil in previously untreated CLL patients (n=319) 
demonstrated a significant improvement in objective response rates and median PFS 
favoring bendamustine (Table 2).20 In this study, bendamustine was given as a dose of 100 
mg/m2/day IV days 1 and 2 every 28 days for a total of up to 6 cycles. Within the 
bendamustine-treated group, the overall response rate was 68% (31% of all responses 
were CRs) compared with 31% in the chlorambucil treated group (2% of all responses were 
CRs). Median PFS of 21.6 months was observed with bendamustine versus 8.3 months 
with chlorambucil (p<.0001).20 In another multicenter phase II study of bendamustine in 
patients with relapsed CLL, bendamustine again demonstrated good efficacy but with more 
toxicity in this relatively heavily pretreated population. Patients received bendamustine 70 
mg/m2/day IV days 1 and 2 every 28 days in combination with rituximab for up to 6 cycles. 
The efficacy data in 23 patients treated with bendamustine and rituximab demonstrated an 
overall response rate of 65.2% and a CR rate of 13%. Toxicity primarily consisted of 
myelosuppression and infections, with grade 3 or 4 hematologic toxicities occurring in 10-
15% of all treatment cycles. In addition, 6 events of grade 3 or 4 infections occurred, as 
well as 3 deaths from pneumonia and urosepsis.63 


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 Experience with Lenalidomide 
5.3.1 Lenalidomide pharmacology and in vitro experience  
Lenalidomide is a proprietary IMiD® compound of Celgene Corporation.   IMiD® 
compounds have both immunomodulatory and anti-angiogenic properties which could 
confer anti-tumor and anti-metastatic effects.  Lenalidomide has been demonstrated to 
possess anti-angiogenic activity through inhibition of bFGF, VEGF and TNF-alpha induced 
endothelial cell migration, due at least in part to inhibition of Akt phosphorylation response 
to bFGF.1 In addition, lenalidomide has a variety of immunomodulatory effects.  
Lenalidomide stimulates T-cell proliferation, and the production of IL-2, IL-10 and IFN-
gamma, inhibits IL-1 beta and IL-6 and modulates IL-12 production.2  Upregulation of T-
cell derived IL-2 production is achieved at least in part through increased AP-1 activity.64  
Increased production of IL-2 and IFN-gamma also leads to augmentation of natural killer 
cell number and function.65 Previous experience in multiple myeloma cell lines has 
demonstrated the direct ability of lenalidomide to induce apoptosis and G1 growth arrest.3 
5.3.2 Clinical experience in multiple myeloma 
Revlimid® (lenalidomide) is FDA approved in combination with dexamethasone for the 
treatment of patients with multiple myeloma who have received at least one prior therapy. 
Based on phase I studies with lenalidomide and the observed myelosuppression beyond 
day 28 at the 25 mg and 50 mg daily dose levels, the dose schedule most widely used in 
recent phase II and III studies has been lenalidomide doses up to 25 mg daily on days 1-
21, repeated every 28 days.66,67  
A multicenter, randomized phase II trial compared 2 syncopated dose schedules of 
lenalidomide used alone or in combination with dexamethasone in the treatment of 
relapsed or refractory multiple myeloma, with all patients receiving treatment on days 1-
21 of a 28-day cycle.  Patients treated with 15 mg twice daily experienced more 
myelosuppression and dose reductions compared with patients treated with 30 mg once 
daily.  Anti-myeloma activity was observed with each dose and schedule of single-agent 
lenalidomide.  The addition of dexamethasone to lenalidomide yielded responses in some 
patients who had not responded to lenalidomide alone.68 A phase II trial utilizing 
lenalidomide plus dexamethasone for newly diagnosed multiple myeloma patients was 
reported by the Mayo Clinic, with lenalidomide given orally 25 mg daily on days 1-21 and 
dexamethasone given orally 40 mg daily on days 1-4, 9-12, and 17-20 of each 28 day 
cycle. Thirty-one of 34 patients achieved an objective response, including 2 (6%) 
achieving a CR, and 11 (32%) meeting criteria for both very good partial response and 
near CR, resulting in an overall objective response rate of 91%. Forty-seven percent of 
patients experienced grade 3 or higher non-hematologic toxicity, most commonly fatigue 
(15%), muscle weakness (6%), anxiety (6%), pneumonitis (6%) and rash (6%).69  
Celgene Corporation sponsored 2 multicenter, randomized, double-blinded, placebo-
controlled phase III trials [1 U.S. (MM-009) and 1 international (MM-010)] trial in patients 
with relapsed or refractory multiple myeloma], enrolling more than 350 patients.70 Patients 
could not be refractory to dexamethasone, and were randomized to receive 
dexamethasone with lenalidomide or dexamethasone + placebo. Patients received 


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dexamethasone 40 mg orally daily on days 1-4, 9-12 and 17-20, and lenalidomide or 
placebo at a dose of 25 mg daily on days 1-21 of each 28 days cycle. After 4 cycles, there 
was a pre-determined reduction of the dexamethasone dose to 40 mg daily on days 1-4 
repeated every 28 days.  In both studies, a pre-specified interim analysis conducted by an 
Independent Data Monitoring Committee demonstrated that patients receiving the 
combination of lenalidomide and dexamethasone had significantly longer times to 
progression and higher response rates than those treated with single-agent 
dexamethasone.70  These studies led to the FDA approval of lenalidomide in combination 
with dexamethasone for the treatment of multiple myeloma in patients that have received 
at least one prior therapy.  
5.3.3 Clinical experience in myelodysplastic syndromes (MDS)  
Revlimid® (lenalidomide) is also approved for the treatment of patients with transfusion-
dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes 
associated with a deletion 5q cytogenetic abnormality with or without additional 
cytogenetic abnormalities.  An exploratory trial in 43 MDS patients with transfusion-
dependent or symptomatic anemia was conducted at the University of Arizona.71 Patients 
received lenalidomide at doses of 10 mg or 25 mg per day on days 1-21, repeated every 
28 days.  All enrolled patients had achieved no response to erythropoietin or had a high 
endogenous erythropoietin level.  Response rates were similar across the different dose 
schedules used.  Responses were observed in 24 patients overall (56%) including 21 
patients with a major response and 20 patients with sustained transfusion independence. 
After a median follow-up of 81 weeks, the median duration of major response had not 
been reached after more than 48 weeks. Neutropenia and thrombocytopenia were the 
most common adverse events, and resulted in dose delays or reductions in 25 patients 
(58%). 
Celgene Corporation sponsored a multicenter trial (MDS-003) of 148 MDS patients with a 
clonal interstitial deletion involving chromosome 5q31.1.  Lenalidomide was given at a 
dose of 10 mg on days 1-21 (repeated every 28 days) to 44 patients, and at a dose of 10 
mg daily to the other 104 patients.  Transfusion-independence was achieved in 93 patients 
(64%), with a median hemoglobin increase of 3.9 g/dL. Cytogenetic response was 
achieved in 76% of transfusion-independent patients with 55% achieving a cytogenetic 
complete response. With a median follow-up of 9.3 months, the median response duration 
had not been reached.  Neutropenia (39%) and thrombocytopenia (35%) were the most 
common adverse events requiring dose delays or reductions.72 Another Celgene 
sponsored trial (MDS-002) included patients with low- to intermediate-1 risk MDS (n=215). 
Among the 166 patients with documented low- to intermediate-1 risk MDS, 84 patients 
(51%) responded to treatment.  Transfusion-independence was achieved in 54 patients 
(33%) and 30 patients (18%) achieved a minor response (defined as a ≥50% decrease in 
blood transfusion requirements).  The median duration of transfusion-independence was 
41 weeks.72 These data collectively led to the FDA approval of lenalidomide for MDS with 
the 5q chromosomal deletion. 
5.3.4 Clinical experience in leukemia and lymphoma with lenalidomide   
Preliminary data show significant activity of lenalidomide in CLL, with response rates in 
relapsed/refractory CLL and indolent and aggressive NHL ranging from 25% to 70% 


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(Table 3).24,25,29,73-75 These results with single-agent lenalidomide were particularly 
impressive given that 36% and 51% of patients in 2 of the larger CLL studies had disease 
which was fludarabine-refractory.29,30  Additional data have demonstrated an association 
between increased likelihood of objective response in NHL and low tumor burden (<50 
cm2 of measurable disease).24,25  
 
A recent report of lenalidomide in previously untreated CLL demonstrated clinically 
significant single-agent activity.76 In the original study design, patients were treated with 
lenalidomide 10 mg daily on days 1-21 of each 28 day cycle, with 5 mg weekly dose 
escalations to the target dose of 25 mg/day. However, severe toxicities (tumor lysis 
syndrome and fatal sepsis) in the first 2 patients enrolled led to amendment of the 
treatment protocol to a lenalidomide starting dose of 2.5 mg/day on the same dosing 
schedule followed by monthly dose escalations to target dose of 10 mg/day. A total of 25 
patients were treated on the amended dosing schedule, with 56% of patients achieving a 
partial response. Of the 14 responders, the duration of response was 16.6 months (range 
5-28.7 months). Toxicities observed most commonly were tumor flare (88% of patients 
with some degree of tumor flare) but all were grade 1-2. Grade 3 and 4 neutropenia 
occurred in 72% of patients, but with only 5 episodes of febrile neutropenia.76 Interestingly, 
rebound lymphocytosis was noted during the 1 week break from drug therapy, further 
supporting the potential benefit of a continuous dosing scheduling as proposed in the 
study protocol.  
 


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Table 3. Outcomes of lenalidomide in relapsed/refractory lymphoma subtypes† 
 
 
N 
 
ORR 
 
 
PFS 
 
Ferrajoli et al30 
 
Phase II, R/R CLL 
(27% FB-refractory) 
 
 
44 
 
MPT 5 
 
32% 
3 CR, 11 PR 
 
NR 
 
73% alive with median 
follow-up time of 14 months 
 
Chanan-Khan et al29 
 
Phase II, R/R CLL 
(51% FB-refractory) 
 
 
45 
 
MPT 3 
 
47% 
4 CR, 17 PR 
 
NR 
 
Witzig et al74 
 
Phase II, indolent 
NHL 
 
 
43 
SLL 18 
FL 22 
 
MPT 3 
 
23% 
2 CR, 1 CRu, 7 PR 
 
 
4.4 mos 
(>16.5 mos in responders) 
 
Tuscano et al24 
 
Phase II, MCL 
 
 
 
15 
 
MPT 4 
 
53% 
 
All responses in patients 
with tumor burden <50 cm2 
and time since last RB of 
≥230 days 
 
5.7+ mos 
 
Wiernik et al77 
 
Phase II, aggressive 
NHL 
 
 
49 
 
MPT 4 
 
35% 
 
2 CR, 4 CRu, 11 PR 
 
7.5 mos versus 1.9 mos  
 
(longer PFS in patients with 
low tumor burden and ≥230 
days since last RB)  
 
Lossos et al25 
 
Phase II, DLBCL 
 
 
 
26 
 
MPT 3 
 
19% 
1 CR, 2 CRu, 2 PR 
 
50% in subset with lower 
disease burden, longer time 
since prior RB 
 
7.4 mos versus 1.9 mos  
 
(longer PFS in patients with 
low tumor burden and ≥230 
days since last RB) 
 
Wang et al75 
 
Phase I/II study of RB 
+ LD in MCL (all with 
prior RB) 
 
 
10‡ 
 
MPT 1-4 
 
 
70%‡ 
3 CR, 4 PR 
 
NR 
 
Abbreviations: CR=complete response, CRu=unconfirmed complete response, DLBCL=diffuse large B-cell lymphoma, 
FB=fludarabine, FL=follicular lymphoma, LD=lenalidomide, MCL=mantle cell lymphoma, MPT=median prior therapies, 
NR=not reported/not yet reached, PR=partial response, RB=rituximab, R/R=relapsed/refractory. 
†All patients treated with lenalidomide 20-25 mg/day days 1-21 every 28 days. 
‡Includes 7 patients treated at maximum tolerated LD dose of 20 mg/day as determined in phase I portion of study and 3 
patients treated at 20 mg/day dose level in phase II portion of study; no responses observed at the 10 mg and 15 mg 
dose levels. 


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 Lenalidomide Adverse Events 
Most frequently reported adverse events observed during clinical studies with 
lenalidomide in oncologic and non-oncologic indications, regardless of presumed 
relationship to study medication include: anemia, neutropenia, thrombocytopenia and 
pancytopenia, abdominal pain, nausea, vomiting, diarrhea, dehydration, rash, itching, 
infections, sepsis, pneumonia, urinary tract infection, upper respiratory infection, cellulitis, 
atrial fibrillation, congestive heart failure, myocardial infarction, chest pain, weakness, 
hypotension, hypercalcemia, hyperglycemia, back pain, bone pain, fractures, generalized 
pain, dizziness, mental status changes, syncope, renal failure, dyspnea, pleural effusion, 
pulmonary embolism, deep vein thrombosis, stroke, convulsions, dizziness, spinal cord 
compression, syncope, disease progression, and death not otherwise specified.72 
 Maintenance Therapy with Rituximab + Lenalidomide 
 Experience with rituximab maintenance therapy in indolent NHL 
One strategy to improve the durations of remission in CLL and SLL is the use of 
maintenance therapy for treatment of minimal residual disease following cytoreductive 
induction chemotherapy. This method has already demonstrated benefit in improving PFS 
in indolent lymphomas, although with the majority of data limited to follicular lymphoma 
(Table 4).5-7,9,10 ECOG 1496 did include approximately 15% of enrolled patients as SLL, 
although limited conclusions about the specific added benefit of rituximab maintenance 
are difficult to extrapolate from this subgroup.5 These data with maintenance rituximab 
collectively led to FDA approval in January 2011 of rituximab maintenance therapy for 
patients with previously untreated CD-20 positive follicular B-cell non-Hodgkin lymphoma 
who achieve a response to rituximab in combination with induction chemotherapy.  
Given the minimal toxicities and proven activity of rituximab in the maintenance setting, 
rituximab appears to be an ideal agent for use in combination therapy following induction 
chemotherapy in CLL/SLL. In addition, safety data exist to support maintenance therapy 
with rituximab for at least 2 years following induction chemotherapy. 
 
 
 
 


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Table 4. Maintenance rituximab in indolent NHL subtypes 
 
 
N 
 
MR dosing 
 
PFS 
 
PRIMA6  
 
Induction chemo 
(R-CHOP, R-CVP, 
R-FCM) followed 
by MR versus OBS 
 
 
N=1217 
 
All with FL  
Previously untreated 
FL 
 
375 mg/m2 IV every 8 weeks 
for 2 years  
 
(total 12 doses) 
 
3 year PFS 
MR 74.9% 
OBS 57.6% 
 
(p<.0001) 
 
EORTC 209819 
 
R-CHOP or CHOP 
induction followed 
by MR versus OBS 
 
 
N=465 
 
All with FL 
Relapsed/refractory 
FL 
 
375 mg/m2 IV every 3 months 
for 2 years  
 
(total 8 doses) 
 
Median PFS 
MR 3.7 years 
OBS 1.3 years 
 
(p<.001) 
 
ECOG 14965 
 
CVP → OBS 
CVP → MR  
 
 
 
N= 387 
 
FL 282 
SLL 57 (15%) 
 
Previously untreated 
NHL 
 
375 mg/m2 IV weekly X 4 
every 6 mos for 2 years 
 
(total 16 doses) 
 
3 year PFS: 
MR 68% 
OBS 33% 
 
(p<.0001) 
 
Abbreviations: CHOP=cyclophosphamide, doxorubicin, vincristine, prednisone chemotherapy; CVP=cyclophosphamide, 
vincristine, prednisone chemotherapy; FCM=fludarabine, cyclophosphamide, mitoxantrone chemotherapy; FL=follicular 
lymphoma; MR=maintenance rituximab; NHL=non-Hodgkin lymphoma; OBS=observation; PFS=progression-free survival; 
SLL=small lymphocytic lymphoma. 
 
 Rationale for lenalidomide maintenance 
As described in Section 5.3.4, existing data show significant activity of lenalidomide in 
CLL, with response rates in relapsed/refractory CLL and indolent and aggressive NHL 
ranging from 25% to 70% (Table 2).24,25,29,73-75 More recent data have also demonstrated 
the activity of lenalidomide in previously untreated CLL.76 Previous reports have 
demonstrated an association between increased likelihood of objective response in NHL 
and low tumor burden (<50 cm2 of measurable disease).24,25 Given the anticipated minimal 
residual disease expected after induction chemotherapy with bendamustine and 
rituximab, lenalidomide further emerges as an appealing maintenance therapy option.  
 Secondary malignancy risk with lenalidomide maintenance  
A possible small increased risk of second primary malignancy (SPM) has been described 
with lenalidomide therapy in clinical trials involving treatment of a broad range of 
hematologic malignances. A summary of the available data to date for SPM with 
lenalidomide was recently distributed to investigators in a confidential notice from Celgene 
Corporation dated March 15, 2011. An updated confidential safety notice from Celgene 
Corporation dated January 5, 2018 provides additional data supporting that overall rates 
of invasive SPMs have been similar for patients receiving versus not receiving 


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lenalidomide in randomized CLL/lymphoma trials. However, this updated safety notice 
from January 2018 described what may be a signal of an increased risk of B-cell 
neoplasms (particularly B-cell acute lymphoblastic leukemia, B-ALL) in CLL patients 
exposed to lenalidomide. 
 
 
Data are available on rates of SPM in subjects with CLL and other non-Hodgkin lymphoma 
histologies treated with lenalidomide. Nine Celgene-sponsored studies in non-Hodgkin 
lymphoma (including indolent B-cell histologies, aggressive B-cell histologies, mantle cell 
lymphoma, and mature T-cell lymphomas), noted 9 of 527 subjects have experienced a 
reported SPM (1.7%), including 8 solid tumors and 1 new primary hematologic 
malignancy. Among 4 Celgene-sponsored clinical studies in subjects with CLL, 2 of 184 
(1.1%) of lenalidomide-treated subjects experienced a SPM (Celgene safety notice, 
3.15.2011).  
 
As mentioned previously, there may be an increased trend for a potential causal 
relationship between lenalidomide exposure and risk for B-cell neoplasms. A detailed 
review of safety data from 3 Celgene sponsored studies (CLL-002, CLL-008 and CLL-009) 
identified 4 cases of B-ALL among 484 lenalidomide-exposed subjects (0.8% risk). In the 
CLL-002 (CONTINUUM) study,37 randomizing subjects to lenalidomide versus placebo 
maintenance following induction therapy for relapsed/refractory CLL, there were 3 cases 
of B-cell neoplasms among 157 lenalidomide-treated patients. These 3 cases included 1 
event of B-ALL (0.6%), 1 event of Hodgkin lymphoma, and 1 event of diffuse large B-cell 
lymphoma. No events of B-ALL of other B-cell neoplasms were reported in the placebo 
group (n=154). In the CLL-008 (ORIGIN) study,78 elderly patients with previously untreated 
CLL were randomized to lenalidomide versus chlorambucil. Three cases of B-cell 
neoplasms (1.3%) were reported among 224 subjects treated with lenalidomide; these 
events included B-ALL (n=2) and Hodgkin lymphoma (n=1).  
 
A recent report of the CLLM1 trial randomized 89 high-risk patients with measurable 
minimal residual disease in a 2:1 fashion to lenalidomide (n=60) versus placebo (n=29), 
with lenalidomide administration until disease progression.27 After a median observation 
time of 17.9 months, the hazard ration for progression-free survival was 0.168 (95% CI 
0.074-0.379). Recently 2 events of B-ALL in the lenalidomide arm led to discontinuation 
of the lenalidomide treatment arm of the study. There were no events of B-ALL in the 
smaller placebo arm of the trial.  
 
Results from CALGB 10404 administered lenalidomide on days 1-21 of each 28-day cycle 
following fludarabine-based induction therapy. In this large trial of 342 patients, no 
increased rate of secondary primary malignancies or second primary hematologic 
malignancies were observed.26 This study limited duration of maintenance to 6 months. 
 
In conclusion, the risk for development of SPM and especially hematologic SPM remains 
an area of uncertainty and for which careful monitoring is required. Dose modification of 
lenalidomide to allow periods of marrow recovery may provide benefit in decreasing risk 
of second malignancies (i.e., comparing dosing strategy of CLL M1 with CALGB 10404). 
To maximum benefit of maintenance and improve safety of the described risks, 
lenalidomide dosing will be modified to days 1-21 of each 28 day cycle.  


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 Lenalidomide + rituximab combination therapy 
Promising efficacy and an acceptable toxicity profile have been reported with the 
combination of rituximab and lenalidomide. A report of the activity of lenalidomide (dosed 
at 10 mg daily on days 9-28 of each 28-day treatment cycle) combined with rituximab for 
up to 12 therapy cycles found promising response rates in patients with relapsed and 
refractory CLL. All patients had received prior fludarabine-based chemotherapy, and 59 
patients were evaluable for response. An ORR of 64% was observed, including 8% CRs 
and 5% CRs with incomplete hematologic recovery.31 In a single institution phase II study 
of rituximab 375 mg/m2 on day 1 and lenalidomide 20 mg/day orally days 1-21 every 28 
days for up to 6 treatment cycles, outcomes in 30 patients with previously untreated CLL 
were reported. Of 28 patients evaluable for response, an overall response rate of 85% 
was observed with an impressive 79% achieving CRs.32,33  These data suggest that the 
combination of lenalidomide + rituximab has promising response rates and appears to 
have improved efficacy compared with single-agent lenalidomide.29,30  
 Rationale for maintenance rituximab + lenalidomide in previously 
untreated CLL/SLL  
Patients with CLL/SLL harboring mutations that result in dysfunction of the p53 tumor 
suppressor gene are associated with higher rates of chemotherapy-resistance and poorer 
survivals.79-84 Although de novo p53 mutations have been reported in CLL/SLL, the 
majority of functional losses of p53 in CLL/SLL occur in the setting of 17p or 11q deletions. 
The tumor suppressor gene p53 maps to 17p13.1, and up to two-thirds of CLL/SLL 
patients with 17p deletions are found to harbor p53 mutations.84-90 The ataxia 
telangiectasia gene (ATM) is the principal activator upstream of the p53 protein in 
response to DNA double-strand breaks. Mutations of ATM occurring in a subset of 
CLL/SLL patients with 11q deletions may lead to functional loss of p53, resulting in higher 
rates of chemotherapy-resistance in patients with 11q- CLL/SLL.91-94   
 
At least 3 separate large multicenter randomized trials (i.e., German CLL Study Group 
CLL4,95 United Kingdom Leukemia Research Foundation CLL4,96 US intergroup E299797) 
have demonstrated poorer outcomes for patients harboring the 17p deletion, with shorter 
durations of remission and in some cases, significantly inferior overall survival. Based on 
the innate chemotherapy-resistance of CLL/SLL with 11q and 17p deletions, considering 
a novel immunomodulatory therapy approach with maintenance rituximab + lenalidomide 
following induction chemotherapy is a rationale first-line approach, even in younger 
patients who may be fit enough to tolerate up-front FCR chemotherapy. In older patients 
or patients with co-morbidities in the setting of newly diagnosed CLL/SLL requiring 
therapy, the high rates of toxicity with FCR chemotherapy makes a rituximab + 
bendamustine induction regimen an appealing option regardless of cytogenetic risk 
profile.  
 
FCR chemotherapy has been associated with the longest progression-free survival to 
date, although the toxicity of this regimen often precludes its use in older patient 
populations or patients with medical comorbidities. A prospective phase II trial of 300 
previously untreated CLL patients reported from MD Anderson Cancer Center found a 6 
year failure-free survival of 51% and 6 year overall survival of 77% with FCR 


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chemotherapy. The median time to progression was 80 months.98 Cytogenetic studies 
were available in 222 of the enrolled patients, but with only 8 patients demonstrating a 17p 
deletion. Of these patients with 17p deletions, only 2 achieved a completed response. The 
toxicity of this regimen is highlighted by the risks of acute and delayed myelosuppression 
and infections with this regimen, with 10% rate and 4% rate of serious grade ≥3 
opportunistic post-treatment infections in the first 1 and 2 years post-chemotherapy, 
respectively.98 Relevant pretreatment characteristics independently associated with 
inferior response and outcomes were age ≥70 years and presence of 17p deletion. 
Although these data reported by MD Anderson demonstrate impressive durations of 
remission, the number of older adults were small (only 14% of patients age 70 or older) 
with a relatively small fraction of patients with the adverse 17p deletion. 98 Despite the 
small number of enrolled patients with the 17p deletion, it was highlighted that this 
subgroup fared poorly in terms of chemotherapy response and duration of response with 
FCR chemotherapy. 
For younger, fit patients, FCR remains a recommended first-line chemotherapy in many 
cases. However, the above data from MD Anderson reports a single-institution 
experience, and superiority of FCR over FR (fludarabine + rituximab) or BR (bendamustine 
+ rituximab) chemotherapy has not been proven. A randomized trial comparing FCR and 
FR is underway in the US intergroup (CALGB 10404). In phase II trials, overall survival 
rates appear to be similar with these regimens, but toxicity is lower with FR.99 A recent 
report by the German CLL Study Group of BR in previously untreated CLL reported an 
overall response rate of 88% and CR rate of 23.1%. This study included 25.6% of patients 
age 70 or older, and also included 26% of patients with the adverse cytogenetics 17p or 
11q deletions. Although the median observation is relatively brief at 27.0 months, 90.5% 
of patients are alive with median EFS of 33.9 months.35 The German CLL Study Group 
CLL10 trial compared the efficacy of BR versus FCR for newly diagnosed CLL.22 The 
results from the CLL10 trial have been recently published, and demonstrated more severe 
neutropenia and infections with FCR chemotherapy. Although median PFS was improved 
in the overall population with FCR (55.2 months versus 41.7 months), there was no 
difference in median progression-free survival with FCR versus BR chemotherapy 
in patients older than age 65.  
However, there is sufficient data regarding the efficacy and favorable toxicity of 
bendamustine + rituximab to consider this regimen as a standard upfront therapy for 
CLL/SLL in all patient groups, regardless of age, fitness, or ability to tolerate even more 
toxic regimens (i.e., FCR or other fludarabine-containing regimens). Bendamustine has 
received an FDA approved indication for treatment of CLL, both in upfront treatment of 
disease and in the relapsed/refractory setting based on the compelling data supporting its 
efficacy in this disease. As cited above, the German CLL Study Group report reported a 
median PFS of 33.9 months in a population treated with BR that included >25% of patients 
older than age 70.35 In addition, this was a multicenter trial including over 40 sites, further 
lending to the strength of the data.35 In contrast, the data reported from MD Anderson with 
an impressive median time to progression of 80 months with FCR chemotherapy was a 
single-institution trial (e.g., inherent selection bias) with only 13% of enrolled patients older 
than age 70.98,100 As described above, the long-term report of outcomes from this study 
independently identified older age as an adverse prognostic indicator in this study 
population.98 The German CLL Study Group CLL10 trial (FCR versus BR chemotherapy 


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as front-line therapy in CLL) reported a favorable median PFS of 41.7 months in patients 
treated with front-line BR, although notably this study excluded patients with the high-risk 
17p deletion.22  
 
The conclusions from these data are: 1.) BR is a highly active induction regimen in CLL in 
the first-line setting, 2.) Randomized data show no benefit with FCR versus BR in adults 
older than age 65 in the CLL10 trial,22, 3.) Both short-term and long-term toxicities were 
more favorable with BR chemotherapy compared with reported toxicities with FCR; this 
was further verified by the CLL10 trial.22  Therefore, standard clinical practice at the 
University of Wisconsin is to offer both BR or fludarabine-based regimens to all patients 
as reasonable first-line strategies, with physicians collaborating with patients to guide the 
final decision based on the probable risk-to-benefit ratio of treatment depending on their 
individual health issues, clinical behavior and biological features of their CLL/SLL, and 
concerns regarding toxicities. 
 
In all populations with adverse cytogenetic risk disease, consideration of a novel therapy 
approach with the combination of the biologic agents rituximab + lenalidomide is a 
reasonable consideration. A recent report by Ferrajoi and colleagues reported their 
experience with rituximab + lenalidomide in 59 patients with relapsed/refractory CLL (all 
had received prior fludarabine, 88% had received prior FCR), including 25% of enrolled 
patients having 17p deletions. An impressive 64% response rate was observed, with a 
treatment failure rate of 42% after a median follow-up of 14 months. Most interestingly, 
there was no difference in objective response rate and time to treatment failure for patients 
with the 17p deletion versus those with other baseline cytogenetic risk disease. Given the 
poor outcomes associated with FCR chemotherapy in 17p deletion CLL, consideration of 
a less toxic induction chemotherapy regimen following by therapy with the novel biologic 
combination of rituximab + lenalidomide is particularly promising for younger and fitter 
patients with poor cytogenetic risk factors at baseline. This role maintenance therapy 
containing lenalidomide is further strengthened by 2 recent randomized, placebo-
controlled trials of single-agent lenalidomide maintenance after induction 
chemotherapy in both previously untreated and relapsed/refractory CLL. Both 
studies showed significant improvement in PFS with lenalidomide with acceptable 
toxicity and tolerability.36,37 
 Investigational Rationale  
Bendamustine is a recently FDA-approved agent with activity in CLL/SLL, including 
significant activity in the setting of fludarabine-refractory disease. The efficacy of 
bendamustine with a favorable toxicity profile has been demonstrated in previously 
untreated CLL/SLL, and ongoing studies are comparing up-front use of bendamustine 
versus fludarabine-based chemotherapy regimens. As the majority of patients with newly-
diagnosed CLL/SLL are over the age of 60 and more at risk from significant toxicity from 
fludarabine-based regimens, evaluation of a bendamustine-based regimen in this 
population may offer the possibility of improved PFS with lesser toxicity. It is notable to 
emphasize that there was no difference in PFS between patients >65 years of age treated 
with FCR versus BR in the CLL10 trial of first-line CLL therapy; however, there was 
significantly more neutropenia and infections with FCR.22 In younger patients, the 
presence of 11q and 17p deletions that confer increased risk of chemotherapy resistance 


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further supports the potential advantageous role for a novel immunomodulatory 
maintenance therapy after initial cytoreduction. 
The incorporation of a maintenance therapy to overcome the shorter remission durations 
that are typical for this patient population is a reasonable and feasible option. In 
considering potential options for treatment of CLL/SLL as a maintenance strategy 
following induction chemotherapy, lenalidomide and rituximab are appealing options 
based on their convenient dosing schedules and recent evidence of acceptable toxicity 
and promising efficacy in combination therapy.  
 
6. Study Objectives and Endpoints 
6.1    Primary Objective 
• 
The primary objective is progression-free survival for patients entering the 
maintenance therapy phase with rituximab and lenalidomide after induction 
therapy with bendamustine and rituximab (beginning cycle 1, day 1 of 
maintenance chemotherapy): 
o Progression is defined as radiographic or clinical progression as defined 
by the specified standard response criteria for CLL/SLL or initiation of a 
new anti-neoplastic therapy in the absence of progression.  
o Tumor measurements and disease assessments will be performed at the 
time of screening, following cycles 3 and 6 of induction chemotherapy, 
every 4 cycles during the maintenance portion of treatment, and at the 
end of treatment (EOT).  
o Subjects with clinical evidence of progression prior to a planned disease 
assessment will be evaluated at the time of clinically suspected 
progression. 
o Follow-up visits for disease assessment will occur every 3 months after 
the EOT visit until PD, initiation of alternate anti-neoplastic therapy, 
decision by the subject to withdraw from the study, or death. 
6.2 
Secondary Objectives 
• 
To determine objective response rates (CR + PR):  
o Disease assessments including imaging will be performed after cycles 3 
and 6 of induction chemotherapy and every 4 cycles during the 
maintenance portion of treatment.  
o Response and progression in cases of SLL will be evaluated using the 
International Working Group Criteria for response in lymphoma.38 
Response and progression in cases of CLL will be evaluated in this study 
using the Revised IWCLL 2008 Criteria for Response in CLL (see Appendix 
H: Assessment of response).39  
o Radiological methodologies, techniques and/or physical examination, 
established at baseline for the assessment and measurement of each 
identified lesion will be used for all subsequent assessments. 


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• 
To determine toxicities observed with induction chemotherapy and maintenance 
therapy:  
o Safety evaluations will be based on the incidence, intensity, and type of 
adverse events (AEs) and clinical laboratory results.  
o Drug doses will be modified as required based on toxicity as assessed 
using the National Cancer Institute Common Terminology Criteria for 
Adverse Events (CTCAE), version 4.0. 
• 
To determine overall survival:  
o Overall survival will be determined from the date of enrollment until death 
from any cause. 
 
7  Investigational Plan 
7.1  Overall Design 
Subjects meeting eligibility criteria will begin treatment as described below. All subjects 
will undergo bone marrow biopsy, CT imaging, and/or PET imaging within 6 weeks prior 
to enrollment. CLL FISH panel (as described in Section 3.0, Schedule of study 
assessments) must be completed within at least 12 months prior to enrollment. 
 Induction chemoimmunotherapy 
• 
Bendamustine 90 mg/m2/day IV days 1 and 2, administered every 28 days for a 
total of 6 cycles. 
• 
Rituximab 500 mg/m2 IV day 1 administered  every 28 days (cycle 1 only, rituximab 
administered at a dose of 375 mg/m2 IV, which may be given on day 2 of cycle 1 
for subjects with significant lymphocytosis at risk for the cytokine release 
syndrome). In select circumstances, in subjects at high risk for cytokine release 
syndrome and/or tumor lysis syndrome, rituximab may be administered as late as 
day 5 of cycle 1 (this alternative dosing of rituximab applies to cycle 1 of induction 
therapy only). 
• 
Cycles of induction chemoimmunotherapy are repeated every 28 days for a 
maximum of 6 cycles. 
All subjects will undergo CT imaging and bone marrow biopsy within 6 weeks prior to 
enrollment. CLL FISH panel (as described in Section 3.0, Schedule of study assessments) 
must be completed within at least 12 months prior to enrollment. During induction 
chemotherapy, repeat disease assessments will be performed following cycles 3 and 6 of 
therapy. Treatment will be discontinued for progressive disease, excessive toxicity, or the 
subject’s decision to discontinue therapy. At completion of induction therapy, subjects with 
CT imaging consistent with possible complete response (CR) will undergo bone marrow 
evaluation to verify a CR. Subjects with possible CR with residual masses of undetermined 
significance at the end of induction therapy will undergo PET imaging to evaluate their 
remission status. Responses to therapy in subjects with leukemic manifestations of 
disease as CLL will be assessed by the Revised IWCLL 2008 criteria for CLL.39 Subjects 


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with primarily lymphomatous manifestation of disease as SLL will be assessed according 
to the revised Cheson criteria for NHL.38 All PRs and CRs in cases of CLL will be confirmed 
by repeat scans at the next scheduled assessment, as outlined in the study calendar. A 
bone marrow biopsy is required in cases of CLL to confirm CR at least 2 months after the 
other clinical and laboratory criteria for response are met.  Confirmation of complete or 
partial responses is not required in SLL. Timing of alternate cycle efficacy assessments 
will be reset following a confirmation of response assessment. In subjects who discontinue 
induction treatment after 4 cycles, a formal disease assessment does not need to be 
repeated prior to beginning maintenance therapy.  
 
Subjects achieving an objective response (i.e., PR, CR, or stable disease with tumor 
shrinkage not meeting criteria for PR) to bendamustine and rituximab induction 
chemotherapy will begin maintenance therapy with rituximab and lenalidomide 6-12 
weeks following the last cycle of induction chemotherapy (i.e., 6-12 weeks from cycle 
6, day 1, of induction therapy). Subjects achieving stable disease following induction 
therapy with an objective response may proceed to maintenance therapy at the 
discretion of the treating physician. Subjects with objective response after 4 cycles of 
bendamustine + rituximab (BR) induction therapy are eligible to proceed to 
maintenance therapy if toxicities are limiting further BR induction therapy, or if the 
treating physician determines that further BR induction therapy would be associated 
with excessive risk for additional toxicities. 
 Maintenance therapy 
• 
Rituximab 375 mg/m2 IV on day 1 of every odd-numbered cycle X 24 cycles (cycles 
1,3,5,7,9,11,13,15,17,19,21,23) for total of 12 doses. 
• 
Lenalidomide 5 mg orally daily on days 1-21 of each 28-day cycle X 24 cycles 
(cycles 1-24 of maintenance therapy): 
o Subjects entering maintenance with CrCl ≥40 and <60 mL/min will begin 
dosing at 5 mg every other day on days 1-21.  If subjects tolerate treatment 
without requiring dose modifications, interruptions, or delays due to toxicity, 
they may, at investigator discretion, escalate in a step-wise manner during 
subsequent cycles to: 5 mg daily on days 1-21, and then to 10 mg daily on 
days 1-21.   
• 
At the start of cycle 2 of maintenance (or at the start of a subsequent cycle), 
lenalidomide may be escalated to 10 mg/day on days 1-21 if toxicity allows (see 
Sections 9.2.1.5 and 9.2.1.6 for criteria needed to escalate the dose of 
lenalidomide to 10 mg/day on days 1-21).   
Maintenance therapy will begin within 6-12 weeks after the last dose of induction 
chemotherapy (i.e., 6-12 weeks from cycle 6, day 1 of induction chemotherapy) once there 
has been recovery of the neutrophils to ≥1000/μL and recovery of platelets to ≥50,000/μL, 
and the other criteria in Section 7.5 have been met. Subjects are allowed to dose de-
escalate and re-escalate lenalidomide during the course of maintenance therapy based 
on the criteria described in Sections 9.2.1.2, 9.2.1.5, and 9.2.1.6. If lenalidomide must 
be held for >12 weeks due to toxicity, subjects must discontinue lenalidomide but 
are eligible to continue maintenance rituximab as defined by the treatment protocol. 


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If rituximab therapy must be held for >12 weeks due to toxicities, subjects will 
discontinue rituximab but may continue lenalidomide maintenance therapy as 
defined by the treatment protocol. If subjects are not able to resume either rituximab 
or lenalidomide maintenance for >12 weeks due to toxicities or issues unrelated to 
protocol therapy (e.g., other medical complications, surgery, ect), the subject must 
withdraw from protocol therapy.  
Subjects will undergo reassessment of disease after every 4 cycles of maintenance 
therapy, and at the end of treatment (EOT). However, subjects who have findings on 
clinical or laboratory exam suggesting progression of disease must undergo CT imaging 
at the time of suspected progression to reassess their disease status.  
 Follow-up phase 
At the time of treatment discontinuation for any reason, subjects will undergo end of 
treatment (EOT) evaluations. Whenever possible, restaging CT scans (with or without 
repeat PET imaging) and a clinical assessment of any other sites of evaluable disease 
should be performed within 30 days of treatment discontinuation. In addition, a safety 
assessment will be done approximately 30 days following the last dose of study drug.   
Subjects who complete the full course of maintenance therapy will immediately begin the 
follow-up phase of the protocol. During this period of long-term follow-up, subjects will be 
evaluated at 3 month intervals for 2 years with a physical examination and repeat imaging 
as indicated to evaluate for evidence of disease progression.  After 2 years of long-term 
follow-up in the absence of progression, the frequency of ongoing care and assessment 
will be at the discretion of the subject’s treating physician. However, it is recommended 
that reassessment of the subject’s disease status be performed by repeat imaging at least 
every 6 months. Information on the subject’s survival and progression status will be 
updated annually for up to 5 years following completion of therapy. 
For subjects who discontinue therapy due to progression, information on the subject’s 
survival will be updated annually for up to 5 years following the time of progression.  
Subjects who discontinue treatment early due to toxicity or the subject’s decision to 
discontinue treatment (but not to withdraw consent from the protocol), follow-up with 
clinical and/or radiographic reassessment approximately every 3 months will be continued 
until evidence of progression or up to 2 years.  After 2 years of follow-up, the frequency of 
ongoing care and assessment will be at the discretion of the subject’s treating physician, 
although it is recommended that reassessment of the subject’s disease status be 
performed by repeat imaging at least every 6 months. Information on the subject’s survival 
and progression status will be updated annually for up to 5 years after discontinuation of 
therapy. 
 


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 Discontinuation of Study Treatment  
Treatment will continue until completion of the protocol therapy (6 months of induction 
therapy and 24 cycles of maintenance therapy) or the occurrence of any of the following 
events:  
• 
Disease progression, defined as clinical, laboratory, or radiographic criteria for 
progression as defined in the response criteria (Appendix H). 
• 
Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of the treatment regimen. 
• 
Discontinuation of protocol treatment for any reason. 
• 
Initiation of alternative anti-cancer therapy, even in the absence of progression. 
• 
Major violation of the study protocol. 
• 
Withdrawal of consent. 
• 
Lost to follow up. 
• 
Death. 
• 
Suspected pregnancy 
 
 Screening and Eligibility 
The investigator is responsible for keeping a record of all subjects who sign an Informed 
Consent Form for entry into the study.  All subjects will be screened for eligibility.  
Screening procedures are outlined in Section 3.0, Schedule of study assessments, and 
unless otherwise specified, must take place within 28 days prior to initiation of therapy.  
Approximately 36 subjects with CLL/SLL will be screened for enrollment and must meet 
the eligibility criteria below. 
 Induction Inclusion criteria 
1. Histologically confirmed CLL/SLL. 
2. No prior cytotoxic chemotherapy for their disease; prior therapy with single-agent 
rituximab is permitted. 
3. Understand and voluntarily sign an informed consent document. 
4. Age 18 years at the time of signing the informed consent document. 
5. In cases of SLL, subjects must have at least one bidimensionally measurable 
lesion; one of the measurements must be ≥1.5 cm in one dimension. 
6. ECOG performance status of 2 at study entry (see Appendix A). 
7. Laboratory test results within these ranges: 
• 
Absolute neutrophil count 1500/μL 


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• 
Platelet count 100,000/μL 
• 
Subjects with neutrophils <1500/μL or platelets <100,000/μL with 
splenomegaly or extensive bone marrow involvement as the etiology for 
their cytopenias are eligible 
• 
Subjects must have adequate renal function with a creatinine clearance of 
≥40 mL/min as determined by the Cockcroft-Gault calculation 
• 
Total bilirubin 2X upper limit laboratory normal (ULN); subjects with non-
clinically significant elevations of bilirubin due to Gilbert’s disease are not 
required to meet these criteria 
• 
Serum transaminases AST (SGOT) and ALT (SGPT) 5X ULN 
• 
Serum alkaline phosphatase ≤5X ULN 
8. Disease-free of prior malignancies for ≥2 years with the exception of basal or 
squamous cell skin carcinoma, carcinoma “in situ” of the breast or cervix, or 
localized prostate cancer (treated definitively with hormone therapy, radiotherapy, 
or surgery). 
9. Life expectancy of at least 3 months. 
10. All study participants must be willing to be registered into the mandatory Revlimid 
REMS® program after completion of induction chemoimmunotherapy and prior to 
maintenance therapy, and be willing and able to comply with the requirements of 
the Revlimid REMS® program. 
11. Subjects must not have a known history of hypersensitivity to mannitol. 
12. Prior therapy with rituximab is permitted, even in the setting of rituximab-refractory 
disease.  
13. Females of reproductive potential must adhere to the scheduled pregnancy testing 
as required in the Revlimid REMS® program. 
14. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (subjects 
intolerant to aspirin may use warfarin or low molecular weight heparin) if clinically 
indicated. 
15. Females of childbearing potential (FCBP)† must have a negative serum or urine 
pregnancy test with a sensitivity of at least 50 mIU/mL within 10 – 14 days and 
again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions 
must be filled within 7 days as required by the Revlimid REMS® program) and 
must either commit to continued abstinence from heterosexual intercourse or begin 
TWO acceptable methods of birth control, one highly effective method and one 
additional effective method AT THE SAME TIME, at least 28 days before she starts 
taking lenalidomide.  FCBP must also agree to ongoing pregnancy testing.  Men 
must agree to use a latex condom during sexual contact with a FCBP even if they 
 
 
 


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have had a successful vasectomy.  See Appendix B: Risks of Fetal Exposure, 
Pregnancy Testing Guidelines and Acceptable Birth Control Methods. 
 Induction Exclusion criteria 
1.  Any serious medical condition, laboratory abnormality, or psychiatric illness that 
would prevent the subject from signing the informed consent document or 
complying with the protocol treatment.  
2.  Pregnant or breast-feeding females. Lactating females must agree not to breast-
feed while taking lenalidomide. 
3.  Any condition, including the presence of laboratory abnormalities, which places the 
subject at unacceptable risk if he/she were to participate in the study or confounds 
the ability to interpret data from the study. 
4.  Subjects are not eligible if there is a prior history or current evidence of central 
nervous system or leptomeningeal involvement. 
5.   Known hypersensitivity to thalidomide. 
6.   Concurrent use of other anti-cancer agents or treatments. 
7.   Known to be positive for HIV or infectious hepatitis (type B or C). 
8.  Prior malignancy, except for adequately treated basal cell or squamous cell skin 
cancer, in situ cervical or breast cancer, or other cancer from which the subject 
has been disease free for at least 2 years. 
 9.  Severe or life-threatening anaphylaxis or hypersensitivity reaction when previously 
exposed to rituximab or other monoclonal antibody therapy. 
10. Chronic hepatitis B or hepatitis C infection. 
11. New York Heart Association class 3-4 heart failure. 
12. More than one grade 2 or higher transaminase elevation. 
7.3  
Registration  
 
Each subject enrolled in the study is to be registered with the UWCCC OnCore database 
at study entry.  
At the time of registration, the following will be verified in OnCore:  
• 
IRB approval at the registering institution  
• 
Subject eligibility  
• 
Existence of a signed informed consent form  
• 
Existence of a signed authorization for use and disclosure of protected 
health information  
• 
Accrual assessed for subject to enter study 
 


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Treatment cannot begin prior to registration and must begin within ≤7 days 
following registration. Baseline tests must be completed within the guidelines as 
outlined in Section 3.0, Schedule of study assessments. All required baseline symptoms 
must be documented and graded. 
 
 Visit Schedule and Assessment 
Screening assessments and study visits and assessments are outlined in Section 3.0, 
Schedule of study assessments.   
A description and schedule of planned disease assessments during protocol therapy are 
outlined in Section 7.1.1, Induction chemoimmunotherapy and Section 7.1.2, Maintenance 
therapy above. At treatment discontinuation, subjects will undergo EOT evaluations as 
described in Section 7.1.3, Follow-up phase. A safety assessment will be done 
approximately 30 days following the last dose of study drug.   
 
 Criteria for Initiation of Rituximab and Lenalidomide Maintenance 
Therapy 
After receiving 6 cycles of induction therapy with bendamustine and rituximab, subjects 
may proceed to maintenance therapy with rituximab and lenalidomide. Subjects with 
objective response after 4 cycles of bendamustine + rituximab (BR) are eligible to proceed 
to maintenance therapy if toxicities are limiting further BR induction therapy, or if the 
treating physician determines that further BR induction therapy would be associated with 
excessive risk for additional toxicities. Maintenance therapy with lenalidomide must begin 
6-12 weeks following the last dose of induction chemotherapy (i.e., 6-12 weeks following 
cycle 6, day 1 of bendamustine + rituximab).  The following inclusion and exclusion criteria 
must be met prior to initiating maintenance therapy with lenalidomide. 
 
 Inclusion criteria for initiation of rituximab and lenalidomide 
maintenance therapy 
• 
Response evaluation at the completion of 6 cycles of induction therapy with 
bendamustine and rituximab must demonstrate a PR or CR. Subjects with SD but 
with evidence of an objective response to induction chemotherapy may proceed to 
maintenance therapy at investigator discretion. Subjects with objective response 
after 4 cycles of bendamustine + rituximab (BR) are eligible to proceed to 
maintenance therapy if toxicities are limiting further BR induction therapy, or if the 
treating physician determines that further BR induction therapy would be 
associated with excessive risk for additional toxicities. 
• 
ANC ≥ 1000/μL 
• 
Platelet count ≥ 50,000/μL  
• 
Calculated (method of Cockroft-Gault) creatinine clearance of ≥40 mL/min; 24 hour 
urine collection may also be performed to assess creatinine clearance. If creatinine 


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clearance is ≥40 mL/min and <60mL/min prior to cycle 1 of maintenance therapy, 
the starting dose of lenalidomide is dose level -1 (5 mg every other day on days 1-
21). 
• 
Any drug-related rash or neuropathy that may have occurred has resolved to 
≤grade 1 severity. 
• 
Tumor lysis syndrome (TLS) has not exceeded grade 1 severity during previous 
cycle (see Appendix I: Cairo-Bishop definition of tumor lysis syndrome). 
• 
If TLS ≥grade 2 during any previous cycle, electrolyte abnormalities have resolved 
to ≤grade 0 severity (see Appendix I: Cairo-Bishop Definition of Tumor Lysis 
Syndrome). 
• 
Any other drug-related non-hematologic toxicities that may have occurred have 
resolved to ≤grade 2 severity. 
• 
Females of childbearing potential (FCBP)† must have a negative serum or urine 
pregnancy test with a sensitivity of at least 50 mIU/mL within 10 – 14 days prior to 
and again within 24 hours of prescribing lenalidomide (prescriptions must be filled 
within 7 days) and must either commit to continued abstinence from heterosexual 
intercourse or begin TWO acceptable methods of birth control, one highly effective 
method and one additional effective method AT THE SAME TIME, at least 28 days 
before she starts taking lenalidomide.  FCBP must also agree to ongoing 
pregnancy testing.  Men must agree to use a latex condom during sexual contact 
with a FCBP even if they have had a successful vasectomy.  See Appendix B: 
Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth 
Control Methods. 
• 
All study participants must be registered into the mandatory Revlimid REMS® 
program, and be willing and able to comply with the requirements of the Revlimid 
REMS® program. 
 Exclusion criteria for initiation of lenalidomide maintenance therapy 
• 
Progressive disease following induction therapy with bendamustine and 
rituximab.  
• 
Uncontrolled hyperthyroidism or hypothyroidism. 
• 
Uncontrolled autoimmune hemolytic anemia or thrombocytopenia. 
• 
Disease transformation (active), i.e., Richter’s syndrome, prolymphocytic 
leukemia. 
 
 
† A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at 
any time in the preceding 24 consecutive months). 
 
 


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8 Drug Administration, Formulation, and Procurement 
 Drug Administration 
 Rituximab 
Rituximab will be provided by Genentech for participants in this study.  Rituximab will be 
administered at 500 mg/m2 IV on day 1 of each induction chemotherapy cycle (cycle 1 
only, rituximab administered at a dose of 375 mg/m2 IV), for a total of 6 induction 
chemotherapy cycles. Subjects with high circulating lymphocyte counts at high risk for the 
cytokine release syndrome may be given rituximab on day 2 of cycle 1. In select 
circumstances, in subjects at high risk for cytokine release syndrome and/or tumor lysis 
syndrome, rituximab may be administered as late as day 5 of cycle 1 (this alternative 
dosing of rituximab applies to cycle 1 of induction therapy only). Subjects demonstrating 
tumor lysis syndrome and receiving aggressive hydration for prophylaxis may have 
reduced physiologic reserve to tolerate any degree of cytokine release syndrome without 
risk for additional complications. In these circumstances, delaying rituximab as late as day 
5 of cycle 1 is acceptable to reduce additional complications. Given the long half-life of 
rituximab (median half-life of 32 days), this flexibility in dosing of rituximab during cycle 1 
only will not have a clinically significant impact on the response to induction 
chemoimmunotherapy. 
Rituximab should be administered by IV infusion, per the package insert instructions. 
The amount of drug to be administered will be based on body surface area (BSA). The 
preferred method for calculating body surface area is the Mosteller formula101 (see 
Appendix C) on cycle 1, day 1. At some participating community sites, the Dubois 
formula102 is the primary BSA calculation used as part of an electronic medical record and 
drug ordering template. In such cases, calculations using the Dubois formula are permitted 
as long as there is no more than a 10% difference in dosing between the Mosteller and 
Dubois calculations. If a >10% difference in drug dosing is observed, then the Mosteller 
calculation must be used. The drug doses calculated on cycle 1, day 1 of chemotherapy 
administration will be used at subsequent visits. However, if the subject experiences a 
>10% change in body weight from the weight used for the most recent BSA calculation, 
then drug doses must be recalculated with the more recent body weight. Rituximab 
dosing is permitted to be rounded according to institutional standard to ±5% of the 
calculated dose.  
 
At treating institutions with a rapid rituximab infusion protocol in place for eligible 
subjects, rituximab dosing may be administered per the treating institution’s rapid infusion 
protocol. Recommendations for eligibility to receive rituximab by a rapid infusion protocol 
are: 
• 
At least the 2nd or greater rituximab infusion of either the induction or maintenance 
phase of treatment. 
• 
Previous rituximab infusion not turned off due to symptoms of possible or probable 
rituximab-induced infusion reaction and/or cytokine release syndrome. 


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• 
Most recent circulating lymphocyte count <5000 lymphocytes/µL within 4-6 weeks 
of rituximab infusion. 
• 
Less than 6 months from last rituximab infusion. 
 
Subjects experiencing adverse events may need study treatment modifications (See 
Section 9). 
Complete information on drug formulation, preparation, and adverse effects of rituximab 
is outlined in Appendix D. 
 Bendamustine  
Bendamustine will be obtained commercially, and will not be supplied by the study 
supporters.  Available bendamustine products for use include Treanda®, generic 
bendamustine, and Bendeka™. Per institutional standards, bendamustine doses may be 
rounded within 10% of the calculated dose based on the subject’s BSA to accommodate 
at least half vial size increments (50 mg for bendamustine).  
 
The initial dose of bendamustine will be 90 mg/m2/day administered IV on days 1 and 2 of 
each induction chemotherapy cycle (total of 6 induction chemotherapy cycles). 
Bendamustine will be infused over ≈30-60 minutes for Treanda® and generic 
bendamustine, and will be infused over ≈10 minutes for the Bendeka™ product. The 
amount of drug to be administered will be based on BSA calculated using the Mosteller 
formula preferentially, although the Dubois calculation may be used as an alternative (see 
Appendix C; also refer to Section 8.1.1 above for complete details as to when the Dubois 
calculation may be an acceptable alternative). The same BSA will be used for each dose 
calculation unless the subject experiences a >10% change in body weight from the weight 
used for the most recent BSA calculation. Bendamustine dosing is permitted to be 
rounded according to institutional standard to ±5% of the calculated dose.  
Subjects experiencing adverse events may need study treatment modifications (See 
Section 9). 
Complete information on drug formulation, preparation, and adverse effects of 
bendamustine is outlined in Appendix E. 
 Lenalidomide 
Lenalidomide (Revlimid®) will be provided to research subjects for the duration of their 
participation in this trial at no charge to them or their insurance providers.  Lenalidomide 
will be provided in accordance with  Celgene Corporation’s Revlimid REMS® 
program.   Per standard Revlimid REMS® program  requirements, all physicians who 
prescribe lenalidomide for research subjects enrolled into this trial, and all research 
subjects enrolled into this trial, must be registered in and must comply with all 
requirements of the Revlimid REMS® program.  Prescriptions must be filled within 7 days 
for females of childbearing potential and 14 days for all other risk categories. Drug will be 


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shipped on a per patient basis by the contract pharmacy to the clinic site.  Only enough 
lenalidomide for one cycle of therapy will be supplied to the patient each cycle. 
After receiving 6 cycles of induction therapy with bendamustine and rituximab, subjects 
with objective response (i.e., CR, PR, or SD with objective improvement) may proceed to 
rituximab and lenalidomide maintenance therapy.  Maintenance therapy with lenalidomide 
must begin 6-12 weeks following the last dose of induction chemotherapy (i.e., 6-12 weeks 
following cycle 6, day 1 of bendamustine + rituximab).  The inclusion and exclusion criteria 
as outlined in Section 7.5 must be met prior to initiating maintenance therapy with 
rituximab and lenalidomide. 
The starting dose of lenalidomide maintenance for investigation is 5 mg/day, orally on 
days 1-21 of each 28-day cycle for up to 24 cycles. Subjects with CrCl ≥40 and <60 mL/min 
will initiate therapy at 5 mg every other day on days 1-21.  Dosing will be at approximately 
the same time each day.  Prescriptions must be filled within 7 days. If a dose of 
lenalidomide is missed, it should be taken as soon as possible on the same day.  If it is 
missed for the entire day, it should not be made up. Subjects who take more than the 
prescribed dose of lenalidomide should be instructed to seek emergency medical care if 
needed and contact study staff immediately. 
Subjects experiencing adverse events may need study treatment modifications (See 
Section 9).  
Complete information on drug formulation and adverse effects of lenalidomide is outlined 
in Appendix F. 
 
 Record of Administration and Treatment Compliance 
Accurate records will be kept of all study drug administration (including prescribing and 
dosing) and maintained in the source documents.  Clear documentation will be recorded 
of dose modifications made based on observed toxicities. 
Research center personnel will review the dosing instructions with subjects. Subjects will 
be asked to maintain a diary to record the drug administration. Subjects will be asked to 
bring any unused study drug and empty study drug containers to the research center at 
their next visit.  Research personnel will count and record the number of used and unused 
study drug capsules at each visit and reconcile with the subject diary.  Any unused 
Revlimid® (lenalidomide) should be returned to the study site for disposition in accordance 
with the Revlimid REMS® program. 
Females of childbearing potential should not handle or administer lenalidomide unless 
they are wearing gloves. 


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9 Dose Modifications and Interruptions  
 Induction Dose Modification Guidelines 
 Rituximab Dose Modifications During Induction 
The dose of rituximab will not change based upon hematologic toxicity. Rituximab 
administration and dose modification must follow labeling instructions and guidelines. 
Please refer to the approved product label for instructions. Subjects who develop severe 
infusion reactions should have the rituximab infusion discontinued and have supportive 
care measures instituted as medically indicated (e.g., IV fluids, vasopressors, oxygen, 
bronchodilators, diphenhydramine, and acetaminophen). In most cases, the infusion can 
be resumed at a 50% reduced rate, after symptoms have completely resolved. Subjects 
requiring close monitoring during first and all subsequent infusions include those with pre-
existing cardiac and pulmonary conditions, those with prior clinically significant 
cardiopulmonary events, and those with high numbers of circulating malignant cells 
(>25,000/mm3) with or without evidence of high tumor burden. In subjects who develop 
viral hepatitis, rituximab should be discontinued and appropriate treatment, including 
antiviral therapy, initiated. If a subject is unable to receive the entire dose of rituximab 
on day 1 due to a hypersensitivity reaction, the dose may be finished on day 2.  
In select circumstances, in subjects at high risk for cytokine release syndrome and/or 
tumor lysis syndrome, rituximab may be administered as late as day 5 of cycle 1 (this 
alternative dosing of rituximab applies to cycle 1 of induction therapy only). Subjects 
demonstrating tumor lysis syndrome and receiving aggressive hydration for prophylaxis 
may have reduced physiologic reserve to tolerate any degree of cytokine release 
syndrome without risk for additional complications. In these circumstances, delaying 
rituximab as late as day 5 of cycle 1 is acceptable to reduce additional complications. 
Given the long half-life of rituximab (median half-life of 32 days), this flexibility in dosing of 
rituximab during cycle 1 only will not have a clinically significant impact on the response 
to induction chemoimmunotherapy 
 Bendamustine Dose Modifications During Induction 
On the first day of each new treatment cycle and before each bendamustine dose, the 
subject will be evaluated for possible toxicities that may have occurred after the previous 
dose(s). Toxicities are to be assessed according to the CTCAE version 4.0. 
The following dose-reduction rules for bendamustine should be followed (Tables 5-
6): 
If toxicities occurred at 90 mg/m2, reduce to 70 mg/m2; if toxicity occurred at 70 mg/m2, 
reduce to 50 mg/m2; if toxicity occurred at 50 mg/m2, reduce to 40 mg/m2, if toxicity 
occurred at 40 mg/m2, discontinue bendamustine and withdraw the subject from the study 
protocol. If the dose of bendamustine is reduced due to toxicity, it will not be re-escalated 
later in the study. 
Note: If one drug is held during induction therapy, both drugs should be held. 


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Table 5. Bendamustine Dose Reduction Steps† 
Bendamustine dose level 
Bendamustine dose reduction 
Starting dose  
90 mg/m2 
-1 
70 mg/m2 
-2 
50 mg/m2 
-3 
40 mg/m2 
-4 
Discontinue bendamustine and withdraw 
from study protocol. 
 
†If subjects have disease-related splenomegaly or significant BM involvement as the etiology of cytopenias at enrollment, 
treatment may be continued without meeting the hematologic criteria for subsequent cycles of induction chemotherapy. In 
such cases, the decision to continue dosing of bendamustine at the current dose is at the investigator’s discretion. 
Table 6. Bendamustine Dose Modification guidelines 
NCI-CTCAE category 
Severity 
Dose modification 
Hematologic† 
Neutrophil <1000/μL on 
day 1 of cycles 2-6 
Initiation (day 1) of cycles 2-6 should be delayed until 
the neutrophil count is ≥1000/μL and the platelet 
count is ≥75,000/μL.† If day 1 is delayed by more than 
2 weeks, then bendamustine should be resumed at 
the next lower dose level. 
Platelets <75,000/μL on 
day 1 of cycles 2-6 
Grade 4 neutropenia 
with fever/infection 
Initiation (day 1) of cycles 2-6 should be delayed until 
the neutrophil count is ≥1000/μL without evidence of 
fever or infection and the platelet count is 
≥75,000/μL.† Bendamustine should then be resumed 
at the next lower dose level. 
Grade 4 neutropenia 
lasting ≥7 days 
Grade 4 platelets for ≥7 
days or a platelet count 
<10,000/μL at any time 
Nausea, emesis, or 
diarrhea in the 
absence of maximal 
prophylaxis 
 
≥Grade 3 
Continue treatment, but with institution of maximum 
prophylactic therapy, including a 5-HT3 antagonist for 
nausea and emesis, and loperamide, or a comparable 
antidiarrheal agent, for diarrhea. Events of grade 4 
toxicity require holding treatment until resolution of 
toxicity to ≤grade 2 with use of maximum prophylaxis. 
Nausea, emesis, or 
diarrhea with 
maximal prophylaxis 
≥Grade 3 
Hold bendamustine for up to 2 weeks or until the 
toxicity returns to ≤grade 2, and restart at the next 
lower dose. If treatment is delayed by more than 2 
weeks, treatment with bendamustine must be 
discontinued. 
 
All other non-
hematologic toxicities 
≥Grade 3 
†If subjects have disease-related splenomegaly or significant BM involvement as the etiology of cytopenias at enrollment, 
treatment may be continued without meeting the hematologic criteria for subsequent cycles of induction chemotherapy. In 
such cases, the decision to continue dosing of bendamustine at the current dose is at the investigator’s discretion. 


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 Maintenance Dose Modification Guidelines 
Maintenance therapy with lenalidomide and rituximab will begin concurrently (i.e., cycle 1, 
day 1 of maintenance therapy will include initiation of the first maintenance rituximab 
infusion and the first dose of lenalidomide).  
 Lenalidomide 
9.2.1.1 General Lenalidomide Dose Modification Guidelines 
On the first day of each new maintenance cycle, the subject will be evaluated for possible 
toxicities that may have occurred after the previous doses. Toxicities are to be assessed 
according to the CTCAE, version 4.0. 
The starting dose of lenalidomide for investigation is 5 mg orally daily on days 1-21 of 
each 28-day cycle (5 mg every other day on days 1-21for subjects with CrCl ≥40 and <60 
mL/min).  At the start of cycle 2 of maintenance (or at the start of a subsequent cycle), 
lenalidomide may be escalated to 10 mg/day on days 1-21 (or 5 mg daily on days 1-21, 
for subjects starting with every other day dosing) of each 28-day cycle if toxicity allows 
(see Sections 9.2.1.5 and 9.2.1.6).  Dose escalations may only occur at the start of a new 
cycle of therapy.  The following Sections outline additional specifics related to dose 
modifications during lenalidomide maintenance.  
The following dose-reduction rules should be followed (Tables 7-10) during lenalidomide 
maintenance therapy: 
 
Table 7. Lenalidomide Dose Reduction Steps.* 
Dose level 
Lenalidomide daily on days1-21 (28-day 
cycles) 
+1 
10 mg daily on days 1-21   
Starting dose (level 0) 
5 mg daily on days 1-21 
-1   
(starting dose for subjects with CrCl ≥40 
and <60 mL/min) 
5 mg every other day during days 1-21* 
-2 
Discontinue lenalidomide and withdraw 
subject from study protocol* 
* Lenalidomide 5 mg every other day on days 1-21 is the minimum lenalidomide dose.  Lenalidomide will be 
discontinued in subjects who cannot tolerate this dose.  However, subjects who experience toxicity requiring 
dose reduction while receiving lenalidomide 5 mg every other day on days 1-21 may, at the discretion of their 
physician, have their dose held until toxicity resolves as described in Tables8-10, and then restart lenalidomide 
5 mg every other day on days 1-21.  If the same toxicity recurs at lenalidomide 5 mg every other day on days 
1-21, strong consideration should be given to discontinuing lenalidomide. 
 
9.2.1.2 Instructions for Dose Modifications or Interruption During Lenalidomide 
Maintenance 
As the primary dose-limiting toxicity of lenalidomide is myelosuppression, a hematologic 
profile will be evaluated weekly during the first cycle of lenalidomide maintenance.  


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Hematologic toxicities will be evaluated at the time of every blood draw during 
lenalidomide maintenance according to the CTCAE version 4.0, and dose adjustments or 
interruptions will be made based on these hematologic profiles. Subjects who are on a 
stable lenalidomide dose (without escalation or interruption) for ≥ 1 cycle of maintenance 
will require hematologic surveys every 4 weeks.   Subjects will be monitored for tumor 
lysis syndrome risk with laboratory parameters on day 1 of each maintenance cycle as 
outlined in Section 3, Schedule of study assessments.  
 
At any time that dosing is escalated or re-escalated or lenalidomide dosing is interrupted 
for more than 4 weeks, at the time that lenalidomide is resumed subjects will undergo 
weekly hematologic surveys for 4 consecutive weeks. Subjects will be informed of 
potential adverse events associated with lenalidomide and will be instructed to report any 
adverse effects that occur during treatment. Subjects will be assessed with a clinical exam 
on day 1 of each cycle during cycles 1-6 of the maintenance phases of therapy. During 
cycles 7-23 of maintenance therapy, clinical exam is required on day 1 of odd-number 
cycles only (i.e., cycles 7,9,11,13,15,17,19,21,23) to coincide with dosing of rituximab.  
Dose adjustments will be made based on hematology and chemistry profiles, subject self-
reporting of symptoms and Tables 8, 9, and 10 below. 
 
If toxicities requiring dose reduction per Tables 8, 9, or 10 occur during lenalidomide 
maintenance therapy, subjects will be required to reduce dosing to the next lower dosing 
level (Table 7). For example, subjects experiencing toxicity at the starting dose of 5 mg/day 
on days 1-21 will not escalate up to 10 mg/day on days 1-21, but will reduce the dose to 
5 mg every other day on days 1-21. Re-escalation of lenalidomide dosing is allowed 
at the investigator’s discretion with the requirement that the criteria in Section 
9.2.1.5 and 9.2.1.6 are met at the time of an attempted dose re-escalation. 
 
There are some circumstances when toxicities not specifically addressed in Tables 8-10 
may require, in the opinion of the treating physician, temporary dose holding or dose 
reduction of lenalidomide to preserve patient safety (example: grade 2 rash that does not 
meet criteria for a dose hold per Table 10, but is progressive with possible attribution to 
lenalidomide). In such cases, dose interruption or dose reduction (by one dose level) of 
lenalidomide is permitted, provided it is clearly documented in the subject’s record the 
reason for the dose interruption or dose reduction. If subjects required dose interruption 
of lenalidomide for a toxicity at physician discretion (not specifically listed as requiring 
dose modification per Tables 8-10), the treating physician may resume lenalidomide 
dosing at the same dose level or lower dose level once the toxicity has improved to an 
acceptable level. However, subjects cannot resume dosing of lenalidomide following a 
dose interruption instituted per physician discretion until the patient is evaluated on day 1 
of the subsequent treatment cycle.  
 
Dose delay and dose reduction rules for lenalidomide maintenance are detailed in Tables 
8, 9, and 10 below, and also include:  
• 
Lenalidomide dose modification steps are outlined in Table 7 above.    
• 
For treatment interruptions during a cycle, the 28-day schedule of each cycle 
should continue to be followed.  Missed doses of lenalidomide are not made up.   


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• 
For treatment interruptions that delay the scheduled start of a new cycle of 
lenalidomide maintenance, when toxicity has resolved as required to allow the start 
of a new cycle (Section 9.2.1.4), the restart day of therapy becomes day 1 of the 
next cycle and treatment begins as planned for that new cycle. 
• 
A subject who cannot receive the next cycle of lenalidomide maintenance within 
12 weeks of the planned start of the next cycle due to persistence of lenalidomide-
related toxicity or non-drug related events (e.g., non-elective surgery) must 
discontinue lenalidomide. However, they are eligible to continue receiving 
maintenance rituximab as outlined per the study protocol. 
 
Table 8. Dose modification of lenalidomide for hematologic toxicities 
NCI-CTC Toxicity 
Dose modification 
 
Grade 3 neutropenia 
associated with fever 
(temperature ≥38.5º C) or 
Grade 4 neutropenia 
Hold (interrupt) lenalidomide dosing, and follow CBC weekly.  
• 
If the neutrophil count recovers to ≥750/μL without fever prior 
to day 21 of the cycle, restart lenalidomide at the next lower 
dose level and continue through day 21.  Otherwise, omit 
lenalidomide for remainder of cycle and reduce the dose of 
lenalidomide by 1 dose level at the start of the next cycle.  
Omitted doses are not made up. 
• 
G-CSF may be used at the investigator’s discretion. 
• 
If the neutrophil count has not recovered to ≥750/μL within 12 
weeks of holding lenalidomide (whether G-CSF is given or 
not), then lenalidomide must be discontinued. 
Note that grade 4 neutropenia during maintenance therapy with 
lenalidomide requires expedited reporting as a serious adverse 
event (Table 13, section 11.4). 
Thrombocytopenia, grade 3 
(platelet count ≥25,000/μL to  
< 50,000/μL)  
Hold prophylactic anti-coagulation, and follow CBC weekly.  
 
If the platelet count recovers to ≥ 50,000/μL, restart prophylactic anti-
coagulation  
Thrombocytopenia, ≥grade 4 
(platelet count <25,000/μL)  
 Hold (interrupt) lenalidomide dosing, and follow CBC weekly.  
• 
If the platelet count recovers to ≥25,000/μL (≤grade 3) prior to 
day 21 of the cycle, restart lenalidomide and continue through 
day 21.  Otherwise, omit lenalidomide for remainder of cycle 
and reduce the dose of lenalidomide by 1 dose level at the 
start of the next cycle.  Omitted doses are not made up. 
• 
If the platelet count has not recovered to ≥25,000/μL within 12 
weeks of holding lenalidomide, then lenalidomide must be 
discontinued. 
Note that grade 4 thrombocytopenia during maintenance therapy 
with lenalidomide requires expedited reporting as a serious 
adverse event (Table 13, section 11.4). 
If lenalidomide dosing is held for >12 continuous weeks due to hematologic toxicities, then 
lenalidomide must be discontinued. Subjects are eligible to continue receiving maintenance rituximab 
per the study protocol.  
 
 


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Table 9. Dose modifications of lenalidomide for tumor lysis syndrome and tumor 
flare reaction 
NCI-CTC Toxicity 
Dose modification 
Tumor lysis syndrome 
(TLS), ≥grade 2 
(see Section 9.3.1 for 
guidelines on prophylaxis 
and Appendix I for Cairo-
Bishop TLS grading scale) 
• 
Hold (interrupt) lenalidomide (missed doses are not made up). 
• 
First episode: restart lenalidomide at the current dose with 
appropriate TLS prophylaxis (Section 9.3.1) after resolution of 
electrolyte abnormalities to grade 0.   
• 
Subsequent episodes: restart lenalidomide with TLS 
prophylaxis (Section 9.3.1) after resolution of electrolyte 
abnormalities to grade 0.  At physician discretion, lenalidomide 
may be restarted at the current dose or be reduced by 1 dose 
level.   
• 
First or subsequent episodes: chemistry tests should be 
performed at a minimum on day 1, 3 and 8 (±1 day for the day 
3 and 8 laboratory assessments) following initiation of 
lenalidomide to monitor for TLS.  Subjects should be closely 
monitored for signs of TLS for at least 1 week after resuming 
treatment. 
TLS, grade 1 (see 
Appendix I for Cairo-Bishop 
TLS grading scale) or other 
laboratory abnormalities 
concerning for TLS 
• 
The following should be provided: vigorous intravenous 
hydration and increased dosing of allopurinol or initiation of 
rasburicase therapy as needed to reduce hyperuricemia and 
until correction of electrolyte abnormalities.   
• 
Lenalidomide maintenance will be continued at the same dose 
without interruption or dose reduction.   
Tumor flare reaction (TFR) 
(no recommended 
prophylaxis) 
TFR ≥grade 1: 
• 
May be treated with NSAIDs (i.e., ibuprofen 400-600 mg orally 
every 4-6 hours as needed).  
  
TFR ≥grade 2:  
• 
May be treated with corticosteroids, if desired. If corticosteroids 
are used, the following dosage schedule is recommended: 
prednisone 20 mg PO daily x 7 days followed by 10 mg PO 
daily x 7 days.  
• 
Narcotic analgesics may be added as needed for pain control.   
If lenalidomide dosing is held for >12 continuous weeks due to non-hematologic 
toxicities, then lenalidomide must be discontinued. Subjects are eligible to continue 
receiving maintenance rituximab per the study protocol. 
 
 
 
 
 


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Table 10. Dose modification of lenalidomide for non-hematologic toxicities 
NCI-CTC Toxicity 
Dose modification 
Non-blistering rash    
≥grade 3, possibly or likely 
attributable to 
lenalidomide 
 
 
 
If grade 3 non-blistering rash occurs: 
• 
Hold (interrupt) lenalidomide, follow with weekly clinical 
assessments. 
• 
When the toxicity resolves to ≤grade 1, restart lenalidomide at 
the next lower dose level. 
• 
If the rash has not recovered to ≤grade 1 within 12 weeks of 
holding lenalidomide, then lenalidomide must be discontinued 
and the subject must be removed from the study. 
 
If grade 4 non-blistering rash occurs: 
• 
Discontinue lenalidomide.   
• 
Remove subject from study. 
 
Desquamating (blistering) 
rash of any grade possibly 
attributable to 
lenalidomide 
Discontinue lenalidomide.  Remove subject from study. 
Neuropathy ≥grade 3 
 
If grade 3 neuropathy occurs: 
• 
Hold (interrupt) lenalidomide dose and follow at least weekly 
with clinical assessments. 
• 
If the toxicity resolves to ≤grade 1, restart lenalidomide at the 
next lower dose level.  
• 
If recovery of neuropathy to ≤grade 1 has not occurred within 12 
weeks of holding lenalidomide, the lenalidomide must be 
discontinued and the subject removed from the study. 
 
If grade 4 neuropathy occurs: 
• 
Discontinue lenalidomide. 
• 
Remove subject from study. 
 
Venous thrombosis, 
embolism (≥grade 3) 
 
Hold (interrupt) lenalidomide and start anticoagulation; restart 
lenalidomide at investigator’s discretion (maintain dose level). 
Other non-hematologic 
toxicity (≥grade 3) 
Hold (interrupt) lenalidomide dose.  Follow weekly with clinical 
assessment. At the discretion of the investigator, an assessment may be 
made over the phone and documented, rather than assessing the subject 
in clinic. 
 
If the toxicity resolves to ≤grade 2: 
• 
Restart lenalidomide at the next lowest dose level. 
• 
If the toxicity has not recovered to ≤grade 2 within 12 weeks of 
holding lenalidomide, then lenalidomide must be discontinued 
and the subject must be removed from the study. 
Any other clinically 
significant toxicity 
regardless of attribution to 
lenalidomide 
Dose interruption and/or reduction is permitted per MD discretion and 
must be clearly documented in the medical record.  See section 9.2.1.2 
for details. 


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9.2.1.3 Summary Criteria for Initiation of Maintenance Cycles and Dose 
Escalation 
Different hematologic and renal parameters are required for initiating the first cycle of 
maintenance, each subsequent cycle of lenalidomide maintenance, and for dose-
escalation of maintenance, Table 11 summarizes and compares these criteria for each 
phase of maintenance therapy.  This table is only a summary, see sections 9.2.1.4; 
9.2.1.5; 9.2.1.6 for additional cycle initiation and dose escalation criteria. 
Table 11.Summary Criteria for Lenalidomide Maintenance 
 
Criteria to Start 
Cycle 1 of 
Maintenance 
Criteria to Start 
Subsequent Cycles of  
Maintenance 
 
Criteria to Dose 
Escalate  
ANC/uL 
≥1000 
≥ 750 
≥ 1000 
Patelets/uL 
≥ 50,000 
≥ 25,000 
≥ 50,000 
CrCl (mL/min) 
≥ 40* 
≥ 40 
≥ 60* 
*If creatinine clearance is ≥40 mL/min and <60 mL/min the starting dose of lenalidomide is at a dose level -1 (5 mg 
every other day on days 1-21).Dose escalation is permitted for CrCl ≥ 40 and <60 mL/min if the prior treatment cycle 
was well tolerated without any dose modifications, interruptions, or delays due to toxicity.  Escalation will be done 
in a step-wise manner (one dose level per cycle).  
9.2.1.4 Criteria Required for Initiation of Subsequent Cycles of Lenalidomide 
Maintenance.  
Criteria required to begin day 1 of each new cycle of lenalidomide maintenance therapy 
(Table 11): 
• 
ANC ≥750/μL 
• 
Platelets ≥ 25,000/μL 
• 
Any drug-related rash or neuropathy that may have occurred has resolved to ≤ 
grade 1 severity. 
• 
Absence of laboratory TLS by Cairo-Bishop criteria (Appendix I).  Subjects may 
receive their first cycle or subsequent cycles of lenalidomide upon correction of 
electrolyte abnormalities.  
• 
If TLS ≥grade 2 during previous cycle (see Appendix I for Cairo-Bishop TLS 
grading scale), electrolyte abnormalities have resolved to ≤grade 0 severity. 
• 
Any other non-hematologic drug-related adverse events that may have occurred 
have resolved to ≤ grade 2 severity.  
• 
Calculated (method of Cockroft-Gault) creatinine clearance must be ≥40 mL/min 
(creatinine clearance may also be assessed by 24 hour urine collection).  


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• 
Any other clinically significant toxicity with a possible, probable, or definite 
attribution to lenalidomide requiring a physician discretion dose hold or reduction 
has been resolved. 
• 
Completed previous cycle without a dose hold >4 weeks for lenalidomide. 
If the above criteria are not met on day 1 of a maintenance cycle, lenalidomide should just 
be held and rituximab may be administered per the protocol schedule. It is recommended 
that patients be followed weekly with initiation of lenalidomide once above criteria are met. 
If hematologic criteria were not met on day 1 of a maintenance cycle, then only a CBC 
with differential needs to be repeated to verify eligibility to start a subsequent treatment 
cycle. If >3 weeks have passed with monitoring CBCs for maintenance cycle eligibility, 
then the entire panel of maintenance day 1 labs will need to be repeated.  If a lenalidomide 
dose reduction was taken during the previous cycle, and the cycle was completed without 
requiring further dose modification, then the next cycle will start at the same reduced dose 
of lenalidomide.  If lenalidomide dosing was omitted for the remainder of the previous 
cycle or if the new cycle is delayed due to toxicity newly encountered on the 
scheduled day 1, then the new cycle will be started with a one-level dose reduction of 
lenalidomide. 
9.2.1.5 Criteria Required for Lenalidomide Dose Escalation or to begin a new 
cycle after a dose hold of greater than 4 weeks   
Criteria required for initial dose escalation to lenalidomide 10 mg/day on days 1-21 from 
the starting dose of lenalidomide 5 mg/day on days 1-21, or to escalate from every other 
day dosing to daily dosing at 5 mg/day on days 1-21, or to begin a new cycle after a dose 
hold of ≥4 weeks must be met on day 1 of the cycle during which escalation is planned 
(Table 11): 
• 
ANC ≥1000/μL 
• 
Platelets ≥50,000/μL 
• 
Calculated (method of Cockroft-Gault) creatinine clearance must be ≥60 mL/min 
(creatinine clearance may also be assessed with 24 hour urine collection). In 
subjects with CrCl ≥40 and <60 mL/min, dose escalation of lenalidomide in a 
stepwise manner (e.g. 5 mg every other day to 5 mg daily on days 1-21; 5 mg daily 
to 10 mg daily on days 1-21) is permitted if the prior treatment cycle was well-
tolerated without requiring any dose modifications, interruptions, or delays due to 
toxicity.  
• 
The subject has completed at least one full cycle of lenalidomide maintenance 
without experiencing any toxicity that requires dose interruption or reduction if dose 
escalating. 
• 
The subject has not experienced ≥grade 1 TLS (see Appendix I for Cairo-Bishop 
TLS grading scale) during the previous cycle of lenalidomide maintenance. 
• 
The subject has not experienced ≥grade 1 tumor flare during the previous cycle of 
lenalidomide maintenance. 
• 
Dose escalations may only occur at the start of a new cycle of therapy. 


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• 
Subjects should be monitored for TLS, with the tumor lysis laboratory panel 
(Section 3, Schedule of study assessments) performed on day 1.   
• 
TLS prophylaxis with allopurinol and hydration as described in Section 9.3.1 must 
also be employed with lenalidomide dose escalation. 
• 
Any other clinically significant toxicity with a possible, probable, or definite 
attribution to lenalidomide requiring a physician discretion dose hold or reduction 
as described in section 9.2.1.2 has been resolved. 
 
When lenalidomide dosing is escalated to 10 mg/day on days 1-21, subjects must be 
dispensed 5 mg tablets during the first cycle to allow for dose modification mid-cycle if 
required. Thereafter, it is recommended but not required that subsequent cycles of 
lenalidomide at a dose of 10 mg/day on days 1-21 be dispensed as 5 mg tablets.  
In cycles where there is a proposed dose escalation or dose re-escalation, subjects 
must be seen for a clinical evaluation and physical exam on day 1 of the cycle, 
regardless of whether a study visit is pre-designated per the study calendar.  
9.2.1.6 Criteria Required for Dose Re-Escalation Following Dose Reductions due 
to Neutropenia, Thrombocytopenia, Tumor Lysis Syndrome, or Tumor 
Flare: 
• 
If a subject has had a lenalidomide dose reduction for neutropenia or 
thrombocytopenia, and has since completed one full cycle of lenalidomide 
maintenance without experiencing any toxicity that requires dose interruption or 
reduction, then lenalidomide dose re-escalation is permitted.  The lenalidomide 
dose may be increased by one dose level (Table 7) at the initiation of a new cycle 
of therapy. 
• 
If a subject has had a lenalidomide dose reduction for tumor lysis syndrome or 
tumor flare, and has since completed one full cycle of lenalidomide maintenance 
without experiencing a laboratory TLS or ≥grade 1 TLS or without experiencing 
≥grade 1 tumor flare, and without experiencing any toxicity that requires dose 
interruption or reduction, then lenalidomide dose re-escalation is permitted.  The 
lenalidomide dose may be increased by one dose level (Table 7) at the initiation 
of a new cycle of therapy. 
• 
Lenalidomide doses may be re-escalated in a step-wise fashion up to a maximum 
dose of 10 mg daily on days 1-21 of each 28-day cycle. 
• 
TLS prophylaxis with allopurinol and hydration as described in Section 9.3.1 should 
be considered if clinically indicated based on the discretion of the treating 
physician.  
In cycles where there is a proposed dose escalation or dose re-escalation, patients 
must be seen for a clinical evaluation and physical exam on day 1 of the cycle, 
regardless of whether a study visit is pre-designated per the study calendar.  


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 Rituximab 
9.2.2.1 Dose modification guidelines for rituximab maintenance therapy 
There are no hematologic criteria for initiation of maintenance rituximab. However, 
subjects must meet the hematologic and non-hematologic parameters as defined for 
dosing guidelines of lenalidomide above (Section 9.2.1) in order to receive rituximab 
concurrent with lenalidomide on day 1 of each odd-numbered cycle.  
The following guidelines (Table 12) will require consideration of delayed dosing or 
omission of rituximab during any cycle of maintenance therapy. If subjects have 
possible or probable rituximab-mediated recurrent toxicities with maintenance therapy, 
they are eligible to complete lenalidomide maintenance as defined by the study protocol. 
Table 12. Dose modification of rituximab for toxicities 
NCI-CTC Toxicity 
Dose modification 
 
 
≥Grade 3 infusion reaction 
and/or cytokine release 
syndrome possibly or likely 
attributable to rituximab 
 
• 
If grade 3 infusion reaction and/or cytokine release syndrome 
occurs, consider increasing steroid and anti-histamine 
prophylaxis with subsequent infusions. If grade 3 infusion 
reaction and/or cytokine release syndrome recurs, may 
consider discontinuation of rituximab. 
• 
If grade 4 infusion reaction and/or cytokine release syndrome 
occurs (e.g., anaphylactic shock, severe hypotension), 
rituximab must be discontinued.  
≥Grade 3 toxicity likely 
attributable to rituximab 
• 
If recurrent ≥grade 3 toxicity is observed that, in the opinion of 
the investigator, is likely attributable to rituximab, 
consideration should be made for discontinuation of rituximab. 
Patients who discontinue rituximab are eligible to complete 
lenalidomide per the protocol schedule. 
Neutropenia, particularly in 
setting of severe and 
unexplained nadir in 
neutrophil count with 
relative stability in 
hemoglobin and platelet 
counts 
• 
Consider possibility of delayed immune-mediated rituximab-
induced neutropenia, which may be observed at any time 
during an extended treatment course with rituximab.  
• 
Immuned-mediated rituximab-induced neutropenia is not a 
contra-indication to ongoing rituximab therapy. However, 
administration of growth factor is recommended to increase 
ANC > 1000/µL prior to next rituximab dose if this etiology for 
neutropenia is suspected.  
Hypogammaglobulinemia 
• 
Levels of serum immune globulins below the lower limits of 
normal in the setting of clinically significant and recurrent 
infections (i.e., sinusitis, upper respiratory infections, 
pneumonia, cellulitis, colitis, etc.) may warrant discontinuation 
of rituximab. Patients who discontinue rituximab are eligible to 
complete lenalidomide per the protocol schedule. 
 
Subjects who discontinue rituximab are permitted to complete maintenance cycles 
with lenalidomide per the protocol schedule. 
 
 
 


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 Concomitant Therapy 
Subjects should receive full supportive care, including transfusions of blood products, 
antibiotics, and anti-emetics when appropriate.  
 Tumor lysis syndrome (TLS) prophylaxis  
 
Tumor lysis syndrome (TLS) may be a risk in subjects with high-tumor burden CLL/SLL 
initiating induction chemotherapy with bendamustine and rituximab. Tumor lysis syndrome 
has been reported in patients with CLL treated with bendamustine.103 
 
Allopurinol prophylaxis is to beconsidered for subjects during induction 
chemotherapy based on the risk for tumor lysis syndrome. In high-risk subjects 
allopurinol is mandatory during induction phase of therapy.  In non high-risk 
subjects, allopurinol is at the discretion of treating physicians.    
 
Subjects who are determined to be at high-risk for TLS are required to receive allopurinol 
300 mg orally daily or twice daily for 14 days at the start of induction chemotherapy. 
Subjects must receive their first day of allopurinol prophylaxis on the day of induction 
chemotherapy, but preferably 1-2 days prior to initiation of chemotherapy. Alternatively, 
subjects at high-risk for TLS with intolerance to allopurinol or judged to be at increased 
risk for TLS even with allopurinol prophylaxis, should be considered for treatment with 
rasburicase for TLS prophylaxis. 
 
Subjects will be defined as high-risk for TLS if they meet any of the following:  
• 
Baseline uric acid ≥7.5 mg/dL 
• 
Bulky disease (one or more masses >10 cm), measuring >10 cm in at least one 
direction of a bimensionally measurable lesion) 
• 
Elevated LDH (> 2X/ULN)  
• 
Elevated WBC (>100,000/µL)  
• 
Serum creatinine >1.5X/ULN 
 
For all other subjects (i.e., not meeting high-risk criteria for TLS), use of allopurinol during 
induction therapy is at the discretion of the investigator.  
 
Fatal TLS and life-threatening TLS have been associated with the use of lenalidomide in 
CLL.104  Although the majority of TLS cases have occurred during the first or second cycle 
of lenalidomide, subjects may be at higher risk for TLS when lenalidomide is re-started 
after treatment interruptions or when the lenalidomide dose is escalated or re-escalated.  
 
Allopurinol prophylaxis (300 mg/day for 10 days; starting 2 days prior to day 1 of 
maintenance) should be considered in subjects not meeting criteria for a partial or 
complete response prior to the start of cycle 1 of maintenance therapy.  
 
Subjects should be instructed to maintain adequate hydration and maintain urinary output 
during lenalidomide maintenance.  To maintain fluid intake, subjects should be instructed 
to drink 8-10 eight ounce glasses of water each day for the first 14 days of cycle 1.  
Hydration levels should be adjusted according to age and clinical status, and lowered if 


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the subject’s cardiovascular status indicates the possibility of volume overload.  Additional 
oral hydration should be considered after treatment interruptions or when the lenalidomide 
dose is escalated or re-escalated.   
 Tumor flare reaction (TFR) prophylaxis 
There is no recommended prophylactic therapy for tumor flare reaction during 
lenalidomide maintenance. 
 Hematopoietic Growth Factors 
Subjects are allowed to receive G-CSF to maintain the neutrophil count during both the 
induction and maintenance portion of therapy. Prophylactic G-CSF is permitted during 
cycle 1 of induction and maintenance therapy in subjects with prior history of treatment-
related neutropenia or possible increased risk of treatment-related neutropenia. 
 Prophylactic anti-coagulation  
Lenalidomide increases the risk of thrombotic events in subjects who are at high risk or 
with a history of thrombosis, in particular when combined with other drugs known to cause 
thrombosis. When lenalidomide is combined with other agents such as steroids (e.g. 
dexamethasone, prednisone) and erythropoietin, the risk of thrombosis is increased. 
Based on previous experience in multiple myeloma, this thrombotic risk appears to be 
highest in the setting of high-volume disease that has not achieved a remission. In this 
population those that will have achieved an objective response prior to receiving 
lenalidomide, the thrombotic risk is hypothesized to be low enough not to warrant required 
empiric thromboembolic prophylaxis. However, in individual subjects who are felt to be at 
higher risk for thromboembolic events, empiric anticoagulation is allowed with warfarin, 
low-molecular weight heparin, or anti-factor Xa inhibitors.  If prophylactic anti-coagulation 
is used, it should be held for platelets counts <50,000/μL and resumed once platelet 
counts are ≥50,000/μL. 
 Prohibited concomitant therapy 
Concomitant use of other anti-cancer therapies, including radiation or other investigational 
agents is not permitted while subjects are receiving study drug during the treatment phase 
of the study. 


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10 Data Safety Monitoring Plan 
 Oversight and Monitoring Plan  
The UWCCC Data and Safety Monitoring Committee (DSMC) is responsible for the 
regular review and monitoring of all ongoing clinical research in the UWCCC.  A 
summary of DSMC activities are as follows: 
• 
Reviews all clinical trials conducted at the UWCCC for subject safety, protocol 
compliance, and data integrity. 
• 
Reviews all Serious Adverse Events (SAE) requiring expedited reporting, as 
defined in the protocol, for all clinical trials conducted at the UWCCC, and studies 
conducted at external sites for which UWCCC acts as an oversight body. 
• 
Reviews all reports generated through the UWCCC DSMS elements (Internal 
Audits, Quality Assurance Reviews, Response Reviews, Compliance Reviews, 
and Protocol Summary Reports). 
• 
Notifies the protocol Principal Investigator of DSMC decisions and, if applicable, 
any requirements for corrective action related to data or safety issues. 
• 
Notifies the CRC of DSMC decisions and any correspondence from the DSMC to 
the protocol Principal Investigator. 
• 
Works in conjunction with the UW Health Sciences IRB in the review of relevant 
safety information as well as protocol deviations, non-compliance, and 
unanticipated problems reported by the UWCCC research staff.  
• 
Ensures that notification is of SAEs requiring expedited reporting is provided to 
external sites participating in multi-institutional clinical trials coordinated by the 
UWCCC. 
 Monitoring and Reporting Guidelines 
UWCCC quality assurance and monitoring activities are determined by study 
sponsorship and risk level of the protocol as determined by the PRMC.  All protocols 
(including Intervention Trials, Non-Intervention Trials, Behavioral and Nutritional Studies, 
and trials conducted under a Training Grant) are evaluated by the PRMC at the time of 
committee review.  UWCC monitoring requirements for trials without an acceptable 
external DSMB are as follows: 
 
a.) Intermediate monitoring 
 
Protocols subject to intermediate monitoring generally include UW Institutional 
Phase I/II and Phase II Trials. These protocols undergo review of subject safety 
at regularly scheduled DOT meetings where the results of each subject’s 
treatment are discussed and the discussion is documented in the DOT meeting 
minutes. The discussion includes the number of subjects enrolled, significant 
toxicities, dose adjustments, and responses observed. Protocol Summary 
Reports are submitted on a semi-annual basis by the study team for review by 
the DSMC. Subjects being treated in this study protocol will be monitored 
according to this intermediate monitoring category. 
 


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 Protocol Summary Reports 
Protocol Summary Reports (PSR) are required to be submitted to the DSMC in the 
timeframe determined by the risk level of the study (semi-annually). The PSR provides a 
cumulative report of SAEs, as well as instances of non-compliance, protocol deviations, 
and unanticipated problems, toxicities and responses that have occurred on the protocol 
in the timeframe specified.  PSRs for those protocols scheduled for review are reviewed 
at each DSMC meeting. 
Protocol Summary Reports enable DSMC committee members to assess whether 
significant benefits or risks are occurring that would warrant study suspension or closure. 
This information is evaluated by the DSMC in conjunction with other reports of quality 
assurance activities (e.g., reports from Internal Audits, Quality Assurance Reviews, etc.) 
occurring since the prior review of the protocol by the DSMC.  Additionally, the DSMC 
requires the study team to submit external DSMB or DSMC reports, external monitoring 
findings for industry-sponsored studies, and any other pertinent study-related 
information.  
In the event that there is significant risk warranting study suspension or closure, the 
DSMC will notify the PI of the DSMC findings and ensure the appropriate action is taken 
for the protocol (e.g., suspension or closure).  The DSMC ensures that the PI reports 
any temporary or permanent suspension of a clinical trial to the sponsor (e.g., NCI 
Program Director, Industry Sponsor Medical Monitor, Cooperative Group Study Chair, 
etc.) and other appropriate agencies. DSMC findings and requirements for follow-up 
action are submitted to the CRC.   
 Safety Reconciliation 
The Sponsor agrees to conduct reconciliation for the product. Genentech and the 
Sponsor will agree to the reconciliation periodicity and format, but agree at minimum to 
exchange quarterly line listings of cases received by the other party. If discrepancies are 
identified, the Sponsor and Genentech will cooperate in resolving the discrepancies. The 
responsible individuals for each party shall handle the matter on a case-by-case basis 
until satisfactory resolution. Following Case Transmission Verification, single case 
reports which have not been received by Genentech shall be forwarded by Sponsor to 
Genentech within five (5) calendar days from request by Genentech. 
 
 
 
 
 


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11 Adverse Event Reporting Requirements 
 Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after the 
initiation of study treatment and ends 30 days following the last administration of study 
treatment or study discontinuation/termination (prior to completing all protocol-directed 
therapy), whichever is earlier. After this period, investigators should only report SAEs that 
are possibly, probably, or definitely attributed to prior study treatment. 
 Assessment of Adverse Events 
An adverse event is any unfavorable and unintended sign, symptom, or disease 
temporally associated with the use of an investigational medicinal product or other 
protocol-imposed intervention, regardless of attribution.  
 
This includes the following: 
• 
AEs not previously observed in the subject that emerge during the protocol-
specified AE reporting period, including signs or symptoms associated with 
CLL/SLL that were not present prior to the AE reporting period. 
• 
Complications that occur as a result of protocol-mandated interventions 
(e.g., invasive procedures such as cardiac catheterizations). 
• 
Preexisting medical conditions (other than the condition being studied) 
judged by the investigator to have worsened in severity or frequency or 
changed in character during the protocol-specified AE reporting period. 
• 
Changes in vital signs are considered to be adverse events only if they 
result in discontinuation from the study, necessitate therapeutic medical 
intervention or if the investigator considers them to be adverse events. 
• 
Clinically Significant Laboratory Abnormalities:  The investigator must 
appraise and document all abnormal laboratory results for their clinical 
significance.  If an abnormal laboratory result is considered clinically 
significant, the value must be recorded in the research chart on the Adverse 
Events Log. 
 
 


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Attribution 
 
To ensure consistency of AE and SAE causality assessments, investigators should apply 
the following general guideline: 
 
RELATIONSHIP 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to treatment. 
A clinical event in which a relationship to the study drug 
seems 
improbable 
because 
of 
factors 
such 
as 
inconsistency with known effects of the study drug; lack of 
a temporal association with study drug administration; lack 
of association of the event with study drug withdrawal or 
rechallenge; and/or presence of alternative explanations for 
the event.  Alternative explanations might include a known 
relationship of the adverse event to a concomitant drug, 
past medical history of a similar event, the patient’s disease 
state, intercurrent illness, or environmental factors. 
Unlikely 
The AE is doubtfully related to treatment. 
A clinical event with a temporal relationship to study drug 
administration that makes a causal relationship improbable 
and for which other factors suggesting an alternative 
etiology exist.  Such factors might include a known 
relationship of the adverse event to a concomitant drug, 
past medical history of a similar event, the patient’s disease 
state, intercurrent illness, or environmental factors. 
Possible 
The AE may be related to treatment. 
A clinical event with a reasonable temporal association with 
administration of the study drug, and that is not likely to be 
explained by concurrent disease or other drugs or 
chemicals.  Information on drug withdrawal may be lacking. 
Probable 
The AE is likely related to treatment. 
A clinical event in which a relationship to the study drug 
seems probable because of such factors as consistency 
with known effects of the drug; a reasonable temporal 
association with the use of the drug; lack of alternative 
explanations for the event; and improvement upon 
withdrawal of the drug (de-challenge). 
Definite 
The AE is clearly related to treatment. 
A clinical event in which a relationship to the use of the 
study drug seems definite because of such factors as 
consistency with known effects of the drug; a clear temporal 
association with the use of the drug; lack of alternative 
explanations for the event; improvement upon withdrawal of 
the drug (de-challenge); and recurrence upon resumption of 
the drug (rechallenge). 
 
 
 


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Expectedness of Adverse Events 
 
Expected adverse events are those adverse events that are listed or characterized in the 
Package Insert or current Investigator Brochure.  
 
Unexpected adverse events are those not listed in the Package Insert (P.I.) or current 
Investigator Brochure (I.B.) or not identified. This includes adverse events for which the 
specificity or severity is not consistent with the description in the P.I. or I.B. For example, 
under this definition, hepatic necrosis would be unexpected if the P.I. or I.B. only referred 
to elevated hepatic enzymes or hepatitis. 
 
Celgene, Genentech and the UWCCC all have specific language regarding Adverse Event 
assessment and reporting.  This protocol requires additional reporting to the FDA based 
on the Investigational New Drug (IND) designation of the study (please refer to section 
11.4.1). Participating investigators should review the following information carefully, and if 
an event meets criteria for reporting for any one of these entities, the event should be 
reported following the guidelines in Section 11.4.1 and 11.4.   
 Procedures for Eliciting, Recording, and Reporting Adverse Events 
11.2.1.1 Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all subject evaluation timepoints should be 
adopted. Examples of non-directive questions include:  
• 
“How have you felt since your last clinical visit?” 
• 
“Have you had any new or changed health problems since you were last 
here?”  
11.2.1.2 Protocol Specific Instructions for Recording Adverse Events 
Toxicities and adverse events will be scored using CTCAE, version 4.0.  A copy of the 
CTCAE, 
version 
4.0 
can 
be 
downloaded 
from 
the 
CTEP 
homepage 
(HTTP://CTEP.INFO.NIH.GOV).  All appropriate treatment areas should have access to a 
copy of the CTCAE version 4.0.  All adverse clinical experiences, whether observed by 
the investigator or reported by the subject, must be recorded, with details about the 
duration and intensity of each episode, the action taken with respect to the test drug, and 
the subject’s outcome.  The investigator must evaluate each adverse experience for its 
relationship to the study drug(s) and for its seriousness. 
 
Investigators should use correct medical terminology/concepts when reporting AEs or 
SAEs. Avoid colloquialisms and abbreviations. 
 
a. Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather 
than jaundice, asterixis, and elevated transaminases). However, if a constellation 
of signs and/or symptoms cannot be medically characterized as a single 


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diagnosis or syndrome at the time of reporting, it is ok to report the information 
that is currently available. If a diagnosis is subsequently established, it should be 
reported as follow-up information. 
b. Deaths 
All deaths that occur during the protocol-specified AE reporting period (see 
Section 11.1), regardless of attribution, will be reported to the appropriate parties. 
When recording a death, the event or condition that caused or contributed to the 
fatal outcome should be reported as the single medical concept. If the cause of 
death is unknown and cannot be ascertained at the time of reporting, report 
“Unexplained Death”. 
c. Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. 
Such conditions should be reported as medical and surgical history. A preexisting 
medical condition should be re-assessed throughout the trial and reported as an 
AE or SAE only if the frequency, severity, or character of the condition worsens 
during the study. When reporting such events, it is important to convey the 
concept that the preexisting condition has changed by including applicable 
descriptors (e.g., “more frequent headaches”). 
d. Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be 
documented and reported as an SAE. If a subject is hospitalized to undergo a 
medical or surgical procedure as a result of an AE, the event responsible for the 
procedure, not the procedure itself, should be reported as the SAE. For example, 
if a subject is hospitalized to undergo coronary bypass surgery, record the heart 
condition that necessitated the bypass as the SAE. 
Hospitalizations for the following reasons do not require reporting: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions 
• Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study or 
• Hospitalization or prolonged hospitalization for scheduled therapy of the target 
disease of the study. 
e. Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a subject 
has completed or discontinued study participation if possibly, probably, or 
definitely attributed to prior study drug exposure per section 11.3. If the 
investigator should become aware of the development of cancer or a congenital 
anomaly in a subsequently conceived offspring of a female subject who 
participated in the study, this should be reported as an SAE per section 11.3.2 
and 11.3.  


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11.2.1.3 Protocol Specific Instructions for Reporting Adverse Events 
a) General Adverse Event Reporting 
 
All AEs and SAEs will be recorded in the research chart on the Adverse Event Log, 
regardless of whether volunteered by the subject, discovered by study personnel 
during questioning, or detected through physical examination, laboratory test, or 
other means. Each reported AE or SAE will be described by its duration (i.e., start 
and end dates), seriousness criteria if applicable, suspected relationship 
(attribution) to the study drugs (see following guidance), and actions taken.  A 
trained investigator should review each event. 
 
Only the worst grade toxicity for a specific AE should be reported on the electronic 
case report form (eCRF) within each reporting period. A reporting period is defined 
as each treatment cycle, or the interval between each follow-up visit. 
 
Anticipated grade 1 toxicities that are excluded from reporting on the electronic 
case report form (must be recorded on AE log if deemed clinically significant): 
• 
Leukopenia (WBC decreased) 
• 
Lymphopenia (Absolute lymphocyte count decreased) 
• 
Neutropenia (Absolute neutrophil count decreased) 
• 
Anemia (decreased hemoglobin) 
 
b) Expedited Adverse Event Reporting 
 
Serious Adverse Events: See section 11.3 for details. 
 
Non-Serious Expedited Reporting Requirements: See section 11.3.3.1 for details. 
 
Pregnancy: See section 11.3.3.1 for details. 
 
Second Primary Malignancies: See section 11.3.3.1 for details. 


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 Expedited Adverse Event Reporting 
 SAE Reporting 
Depending on the nature, severity, and attribution of the serious adverse event an SAE 
report will be phoned in, submitted in writing, or both according to Table 13 below. All 
serious adverse events must also be reported to the UWCCC Data and Safety 
Monitoring Committee Chair.  All serious adverse events must also be reported to the 
UW IRB (if applicable), and any sponsor/funding agency not already included in the list. 
 Determine the reporting time line for the SAE in question by using the 
following table 13. Serious Adverse Event (SAE) Definition  
A serious adverse event is one that at any dose (including overdose): 
• 
Results in death. 
• 
Is life-threatening, meaning that the subject was at immediate risk of death at the 
time of the serious adverse event; it does not refer to a serious adverse event that 
hypothetically might have caused death if it were more severe. 
• 
Requires subject hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability or incapacity, which is defined as a 
substantial disruption of a subject’s ability to carry out normal life functions. 
• 
Is a congenital anomaly or birth defect. 
• 
Is an important (significant) medical event, with medical and scientific judgment 
exercised in deciding whether expedited reporting is appropriate in situations 
where none of the outcomes listed above has occurred.  
• 
Important medical events that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the subject or may require intervention 
to prevent one of the other outcomes listed in the definition above should also 
usually be considered serious.  
• 
Examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that 
do not result in inpatient hospitalization, or the development of drug dependency 
or drug abuse.  A new diagnosis of cancer during the course of a treatment should 
be considered as medically important.  
• 
Suspected pregnancy. 
• 
A secondary primary malignancy in a patient who has received lenalidomide. 
 


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Table 13. Reporting Requirements for Serious Adverse Events (UW 
Carbone Cancer Center requirements) 
 
NOTE: Investigators MUST immediately report to the UWCCC and any other parties outlined in the 
protocol ANY Serious Adverse Events, whether or not they are considered related to the investigational 
agent(s)/intervention (21 CFR 312.64). 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) 
Death. 
2) 
A life-threatening adverse event. 
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours. 
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions. 
5) 
A congenital anomaly/birth defect. 
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition (FDA 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
UWCCC within the timeframes detailed in the table below: 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
hospitalization  ≥ 
24 hrs 
10 Calendar Days 
24-Hour; 5 
Calendar Days 
Not resulting in 
Hospitalization ≥ 
24 hrs 
Not required 
10 Calendar Days 
NOTE: See section 11.3.3 for additional protocol-specific exceptions to and requirements of 
expedited reporting 
 
Expedited AE reporting timelines are defined as: 
• 
24-Hour; 5 Calendar Days – The AE must initially be reported within 24 hours of learning of the 
AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
• 
10 Calendar Days – A complete expedited report on the AE must be submitted within 10 
calendar days of learning of the AE 
1 Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows: 
 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4 and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization 
• 
Grade 3 events 
 
 Additional Protocol-Specific Instructions, Requirements, and 
Exceptions to Expedited Reporting 
11.3.3.1 Protocol-Specific Expedited Reporting Requirements 
A. Non-Serious Expedited Reporting Requirements 


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The following toxicities must be reported expeditiously, irrespective of regulatory 
seriousness criteria: 
 
Maintenance 
• 
Grade 4 Neutrophil count decreased 
• 
Grade 4 Platelet count decreased 
 
Report to the UWCCC (saenotify@uwcarbone.wisc.edu): 
Follow the SAE 24 hour reporting directions in section 11.3.4 
 
B. Pregnancy 
 
If a female subject becomes pregnant or is suspected to be pregnant while 
receiving investigational therapy, within 28 days of last dose of lenalidomide, or 
within 90 days after the last dose of RITUXAN, a report should be completed and 
expeditiously submitted as an SAE. Follow-up to obtain the outcome of the 
pregnancy should also occur. Abortion, whether accidental, therapeutic, or 
spontaneous, should always be classified as serious, and expeditiously reported 
as an SAE. Similarly, any congenital anomaly/birth defect in a child born to a 
female subject exposed to RITUXAN and/or lenalidomide should be reported as 
an SAE.  See appendix B for information on risks, pregnancy, testing, and 
acceptable birth control methods with the use of lenalidomide.  See appendix G 
for guidelines on reporting pregnancies to Celgene. 
 
Report to the UWCCC (saenotify@uwcarbone.wisc.edu): 
Follow the SAE 24 hour reporting directions in section 11.3.4 
 
C. Second Primary Malignancies 
 
A possible small increased risk of second primary malignancy (SPM) has been 
described with lenalidomide therapy in clinical trials involving treatment of a broad 
range of hematologic malignances. A summary of the available data to date for 
SPM with lenalidomide was recently distributed to investigators in a confidential 
notice from Celgene Coporation dated March 15, 2011.105 Based on these data 
provided, Celgene requires that events of second primary malignancies 
documented during the course of protocol treatment and during the study follow-
up period be reported as SAEs.  
 
Report to the UWCCC (saenotify@uwcarbone.wisc.edu): 
Follow the SAE 24 hour reporting directions in section 11.3.4 
11.3.3.2 Protocol-Specific Exceptions to Expedited Reporting 
The following toxicities are anticipated and will NOT require expedited reporting: 
 
Any Time Point 
• 
Grade 1 – 4 Myelosuppression 


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• 
Grade 3 – 4 Lymphocyte count decreased 
• 
Grade 3 – 4 While blood cell count decreased 
 
Induction 
• 
Grade 3 – 4 Neutrophil count decreased 
• 
Grade 3 – 4 Platelet count decreased 
 
Maintenance 
• 
Grade 3 Neutrophil count decreased 
• 
Grade 3 Platelet count decreased 
 
 


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 General procedures for SAE reporting 
Serious adverse event – reported within 24 hours 
Serious Adverse Events requiring reporting within 24 hours (as described in the protocol) 
must also be reported to the Data and Safety Monitoring Committee (DSMC) Chair via 
an email to saenotify@uwcarbone.wisc.edu within one business day.  The OnCore SAE 
Details Report must be submitted along with other report materials as appropriate (FDA 
Medwatch Form #3500 and/or any other documentation available at that time of initial 
reporting). The DSMC Chair will review the information and determine if immediate 
action is required. Within 5 calendar days a final initial report is required to be submitted, 
all available subsequent SAE documentation must be submitted electronically along with 
a completed UWCCC SAE Routing Form to saenotify@uwcarbone.wisc.edu. Follow up 
reports should be submitted, as needed, when additional information becomes available.  
All information is entered and tracked in the UWCCC database. 
As applicable, the Sponsor-Investigator notifies all investigators involved with the study 
at the UWCCC, the IRB, the sponsor, and the funding agency and provides 
documentation of these notifications to the DSMC. 
If the SAE occurs on a clinical trial in which the UW PI serves as the sponsor-
investigator, the sponsor-investigator reviews the event to determine whether the SAE 
requires reporting to the FDA and other participating investigators (see section 11.4.1).   
For a multiple-institutional clinical trial the sponsor-investigator is responsible for 
ensuring SAEs are reported to the FDA as well as to all participating investigators. 
 
See Section 11.3.5 for detailed instructions on SAE reporting. 
 
 
Serious adverse event – reported within 10 days 
Serious Adverse Events requiring reporting within 10 days (as described in the protocol) 
must also be reported to the Data and Safety Monitoring Committee (DSMC) Chair via an 
email to saenotify@uwcarbone.wisc.edu.  The OnCore SAE Details Report must be 
submitted along with other report materials as appropriate (FDA Medwatch Form #3500 
and/or any other documentation available at that time of initial reporting). The DSMC Chair 
will review the information and determine if further action is required. Follow up reports 
should be submitted, as needed, when additional information becomes available.  All 
information is entered and tracked in the UWCCC database. 
The Principal Investigator notifies all investigators involved with the study at the UWCCC, 
the IRB, the industry collaborators, and the FDA (if applicable)and provides documentation 
of these notifications to the DSMC. 
If the SAE occurs on a clinical trial in which the UW PI serves as the sponsor-investigator, 
the sponsor-investigator reviews the event to determine whether the SAE requires 
reporting to the FDA (see section 11.4.1) and other participating investigators.   
For a multiple-institutional clinical trial the sponsor-investigator is responsible for ensuring 
SAEs are reported to the FDA as well as to all participating investigators. 


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See Section 11.3.5 for detailed instructions on SAE reporting. 
 Expedited Reporting of Serious Adverse Events  
• 
Complete the following for all reports, regardless of reporting period: 
• 
FDA MedWatch Form 3500A 
• 
OnCore SAE Details Report 
• 
Serious Adverse Event Routing Form 
 
Complete the following for all SAE reports:: 
• 
Sponsor-Investigator Determination Form for FDA Reporting of Safety Events 
Form (Sponsor-Investigator Review) 
• 
Genentech Safety Reporting Fax Cover Sheet 
 
A. SAE Requiring 24 Hour Reporting Occurs at UWCCC: 
  
1. Report to the UWCCC: 
 
Reference the SAE SOP (Standard Operating Procedure) and the SAE 
Reporting Workflow for DOTs on the UWCCC website, Data and Safety 
Monitoring page (https://kb.wisc.edu/uwccc/internal/41020) for specific 
instructions on how and what to report to the UWCCC for 24 hour initial and 
follow-up reports.  A final initial report is required to be submitted within 
5 calendar days of the initial 24 hour report.   
 
For this protocol, the following UWCCC entities are required to be notified: 
 
a) saenotify@uwcarbone.wisc.edu 
b) Julie Chang, MD (Study Chair) jc2@medicine.wisc.edu 
c) Any other appropriate parties listed on the SAE Routing Form  
 
2. Report to Industry Collaborators:  
 
Submit the following items to Celgene: 
• 
FDA MedWatch Form 3500A 
• 
Source documentation as applicable  
 
Celgene Corporation 
Global Safety and Risk Management 
Connell Corporate Park 
300 Connell Dr. Suite 6000 
Berkeley Heights, NJ  07922  
 
Fax:(908) 673-9115 
e-mail: drugsafety@celgene.com 
Please reference Protocol  RV-CLL/-PI-0689.   
 


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Submit the following items to Genentech: 
• 
Genentech Safety Reporting Fax Cover Sheet 
• 
FDA MedWatch Form 3500A  
• 
Source documentation as applicable 
 
Genentech Safety 
Fax: 650-225-4682 
Alternate Fax: 650-225-5288 
Phase: 888-835-2555 
 
3. Report to the IRB: 
 
Consult the UW-IRB website (kb.wisc.edu/hsirbs) for reporting guidelines.  
     
B. 
SAE Requiring 10 Day Reporting Occurs at UWCCC:  
 
  
1. Report to the UWCCC: 
 
Reference the SAE SOP and the SAE Reporting Workflow for DOTs on the 
UWCCC website, Data and Safety Monitoring page 
(https://kb.wisc.edu/uwccc/internal/41020) for specific instructions on how 
and what to report to the UWCCC for 10 day reports.   
 
For this protocol, the following UWCCC entities are required to be notified: 
 
a) saenotify@uwcarbone.wisc.edu 
b) Julie Chang, MD (Study Chair) jc2@medicine.wisc.edu 
c) Any other appropriate parties listed on the SAE Routing Form  
 
2. Report to Industry Collaborators:  
 
Submit the following items to Celgene: 
• 
FDA MedWatch Form 3500A 
• 
Source documentation as applicable 
 
Celgene Corporation 
Global Drug Safety and Risk Management 
Connell Corporate Park 
300 Connell Dr. Suite 6000 
Berkeley Heights, NJ  07922  
 
Fax:(908) 673-9115 
e-mail: drugsafety@celgene.com 
Please reference Protocol  RV-CLL/-PI-0689.   
 


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Submit the following items to Genentech: 
• 
Genentech Safety Reporting Fax Cover Sheet 
• 
FDA MedWatch Form 3500A 
• 
Source documentation as applicable 
 
Genentech Safety 
Fax: 650-225-4682 
Alternate Fax: 650-225-5288 
Phase: 888-835-2555 
 
3.  Report to the IRB: 
 
       
       Consult the UW-IRB website (kb.wisc.edu/hsirbs) for reporting guidelines.   
 
 
C. 
Other Reporting Requirements: 
 
Reporting to the FDA 
Serious Adverse Events occurring on studies on which a UW PI is acting as 
sponsor-investigator must be reported to the FDA within the appropriate time 
frame.  Mandatory and voluntary reporting guidelines and instructions are 
outlined on the FDA website: 
http://www.fda.gov/Safety/MedWatch/HowToReport/default.htm 
 
See section 11.4 for details on how to report. 
 
The Sponsor-investigator reviews the SAE for possible requirement for reporting 
to the FDA, as described in detail in section 11.4.1. The Sponsor-investigator is 
responsible for the final determination of adverse event attribution to study drug. 
The Sponsor-investigator will assess the adverse event for appropriate need for 
reporting to the FDA (see section 11.4.1).  
 Sponsor-Investigator Adverse Event Reporting Responsibilities 
All serious adverse event reports must include the patient number, age, sex, weight, 
severity of reaction (e.g. mild, moderate, severe), relationship to drug (e.g. probably 
related, unknown relationship, definitely not related), date and time of administration of 
test medications and all concomitant medications, and medical treatments provided.  
The sponsor-investigator is responsible for evaluating all adverse events to determine 
whether criteria for “serious” and as defined above are present.  The sponsor-
investigator is responsible for reporting adverse events to the UWCCC, industry 
collaborators Celgene and Genentech (sections 11.4.2 and 11.4.3), and the FDA 
(section 11.4.1) as described below. 
 
As the UWCCC Principal Investigator is acting as the Sponsor-Investigator (i.e., the PI 
holds the IND), the PI assumes responsibilities of the study sponsor in accordance with 
FDA 21 CFR 312.32.  Serious Adverse Events occurring on studies on which a UW PI is 


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acting as sponsor-investigator must be reported to the FDA within the appropriate time 
frame (see section 11.4.1).  Mandatory and voluntary reporting guidelines and 
instructions are outlined on the FDA website: 
http://www.fda.gov/Safety/MedWatch/HowToReport/default.htm   
 Sponsor-Investigator AE reporting to the FDA 
 The conduct of the study will comply with all FDA safety reporting requirements. These 
requirements will include: 
 
• 
Directly reporting to the FDA as soon as possible but no later than 15 calendar 
days any adverse events determined to be serious, unexpected, and reasonably 
related to the study drugs. 
• 
Directly reporting to the FDA as soon as possible but no later than 7 calendar 
days any unexpected fatal or life-threating suspected adverse reaction. 
• 
Preparation and submission of IND Annual Reports. 
 
Sponsor-Investigator (i.e, HO11414 Protocol PI) Reporting requirements to FDA: 
 
The Sponsor-Investigator (i.e., HO11414 Protocol PI) is required to notify the FDA of any 
adverse events associated with the use of study drug that meets 3 criteria: 
1.) The event was serious. An event is considered serious if resulted in: 
• 
Death 
• 
A life-threatening adverse drug event 
• 
Inpatient hospitalization of prolongation of existing hospitalization 
• 
Persistent or significant incapacity of substantial disruption of the ability to 
conduct normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life 
threatening, or require hospitalization may be considered serious when, 
based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition (FDA, 21 CFR 312.32; ICH E2A and ICH 
E6). 
2.) The event was unexpected (i.e., not included as an anticipated or known toxicity 
in the drug prescribing information or investigational drug brochure). This 
includes any incident, experience, or outcome that: 
• 
Is unexpected in terms of the nature, severity, or frequency in relation to 
the research risks that are described in the research protocol and 
informed consent document, Investigator’s Brochure, and prescribing 
information or other study documents AND 
• 
The characteristics of the subject population being studied AND  


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• 
Suggests that the research places subjects of others at a greater risk of 
harm (including physical, psychological, economic, or social harm) than 
was previously known or recognized 
3.) There is a reasonable possibility that the adverse event was associated with the 
use of the drug. 
Examples of “reasonable possibility”: 
• 
A single occurrence of an event that is uncommon and known to be 
strongly associated with drug exposure (i.e., Stevens-Johnson syndrome, 
angioedema) 
• 
One of more occurrences of an event that is not commonly associated 
with a drug exposure, but is otherwise uncommon in the population 
exposed to the drug 
• 
An aggregate analysis of specific events observed in the clinical trial that 
indicates those events occur more frequently in the drug treatment group 
than in a concurrent or historical control group. Aggregate analysis of 
adverse events will be analyzed with results reported quarterly in the 
regulatory binders, and also reported in research meeting minutes. The 
results of these aggregate analyses will also be reported in the IND 
annual report to the FDA. 
 
The duration of required safety reporting to the FDA will continue throughout all protocol 
therapy.  Serious adverse events that occur more than 30 days after the last 
administration of investigational agent will also require reporting if there is 
reasonable likelihood of attribution of the adverse event to the investigational 
agent.  


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Figure 1: Reporting responsibilities of Sponsor-Investigators to the FDA 
under 21 CFR 312.64(b) for serious and unexpected suspected 
adverse events. 
 
 
 
 
 
Print the FDA Medwatch form and applicable source documentation, and fax to: 
 
FDA Safety Reporting 
FAX: 301-796-9845 
 
Send Paper copies (1 original and 2 copies) of the FDA MedWatch Form 3500A 
and applicable source documentation to:  
 
Food and Drug Administration 
Center for Drug Evaluation and Research 
Division of Hematology Products 
5901-B Ammendale Road 
Beltsville, MD 20705-1266 
 Sponsor-Investigator AE Reporting to Celgene 
See Section 11.3 for summary instructions for SAE reporting for this study.  Serious 
adverse events (SAE) are defined above (Section 11.3.2).  The investigator must inform 
Celgene in writing using a Celgene SAE form or MEDWATCH 3500A form of any SAE 
within the reporting timeframes in Table 13. The written report must be completed and 
supplied to Celgene by facsimile or email within the reporting timeframes in Table 13. The 


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initial report must be as complete as possible, including an assessment of the causal 
relationship between the event and the investigational product(s).  Information not 
available at the time of the initial report (e.g., an end date for the adverse event or 
laboratory values received after the report) must be documented on a follow-up report.  A 
final report to document resolution of the SAE is required.  The Celgene tracking number 
(RV-CLL/-PI-0689) and the institutional protocol number should be included on SAE 
reports (or on the fax cover letter) sent to Celgene.  A copy of the fax transmission 
confirmation of the SAE report to Celgene should be attached to the SAE and retained 
with the patient records.  
 
 
Celgene Corporation 
Global Drug Safety and Risk Management 
Connell Corporation Park 
300 Connell Dr. Suite 6000 
Berkeley Heights, NJ  07922 
 
Fax:(908) 673-9115 
e-mail: drugsafety@celgene.com 
Please reference Protocol RV-CLL/-PI-0689.   
 Sponsor-Investigator AE Reporting to Genentech 
See Section 11.3 for summary instructions for SAE reporting for this study.   
Investigators must report all SAEs to Genentech within the timelines described below. 
The completed Medwatch/case report should be faxed immediately upon completion to 
Genentech Drug Safety at:  
 
(650) 225-4682 
OR 
(650) 225-5288 
 
• 
Relevant follow-up information should be submitted to Genentech Drug Safety as 
soon as it becomes available. 
• 
Serious AE reports, regardless of relatedness to RITUXAN will be transmitted to 
Genentech within the reporting timeframes in Table 13. 
• Additional Reporting Requirements to Genentech include the following: 
• 
Any reports of pregnancy following the start of administration with RITUXAN will be 
transmitted to Genentech within thirty (30) calendar days of the Awareness Date.  
• 
A final cumulative Case Transmission Verification of Adverse events reported 
previously from study start date to study end date will be provided to Genentech by 
the Sponsor-Investigator. 
• 
All Non-serious Adverse Events will be compiled into a report and provided to 
Genentech by the Sponsor-Investigator once all study subjects are off treatment. In 
addition to all SAE’s, pregnancy reports and AESI’s the following Special Situations 
Reports should be collected even in the absence of an Adverse Event and transmitted 
to Genentech within thirty (30) calendar days: 
• 
Data related to the Product usage during pregnancy or breastfeeding 


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• 
Data related to overdose, abuse, misuse, inadvertent/erroneous 
administration, medication error or occupational exposure, with or without 
association with an AE/SAE 
• 
Data related to a suspected transmission of an infectious agent via a 
medicinal product (STIAMP) 
• 
Lack of therapeutic efficacy 
• 
In addition, reasonable attempts should be made to obtain and submit the 
age or age group of the patient, in order to be able to identify potential 
safety signals specific to a particular population 
 
Occasionally Genentech may contact the reporter for additional information, clarification, 
or current status of the patient for whom and adverse event was reported. For questions 
regarding SAE reporting, you may contact the Genentech Drug Safety representative 
noted above or the MSL assigned to the study. Relevant follow-up information should be 
submitted to Genentech Drug Safety as soon as it becomes available and/or upon request. 
 
 Product complaints to Genentech 
 
Recently the FDA announced an update to the Post Marketing Safety Reporting 
regulation which requires the Marketing Authorization Holder (i.e., Genentech/Roche) 
to report product complaints to the FDA. A product complaint is any written or oral 
information received from a complainant that alleges deficiencies related to identity, 
quality, safety, strength, purity, reliability, durability, effectiveness or performance of a 
product after it has been released and distributed to the commercial market or clinical 
trial.  
 
Product complaints with an AE should be reported via e-mail to: 
usds_aereporting-d@gene.com OR 650-238-6067 
 
Product complaints without an AE should be reported via e-mail to  
Kaiseraust.global_impcomplaint_management@roche.com 
 
All complaints must be filed within 15 calendar days. Complaints can be reported using 
a Medwatch, CIOMS, or any Genentech-approved response reporting form. 
 
 Sponsor-Investigator AE Reporting to the Institutional Review Board 
(IRB) and Institutional Data Safety Monitoring Board (DSMB) 
The principal investigator is required to notify his/her IRB of a serious adverse event 
according to institutional policy.  
 Adverse event updates/IND safety reports 
Celgene and Genentech shall notify the investigator via an IND Safety Report of the 
following information: 
 


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• 
Any AE associated with the use of study drug in this study or in other studies that is 
both serious and unexpected. 
• 
Any finding from tests in laboratory animals that suggests a significant risk for human 
subjects including reports of mutagenicity, teratogenicity, or carcinogenicity. 
 
The investigator shall notify his/her IRB promptly of these new serious and unexpected 
AE(s) or significant risks to subjects, according to institutional policy. 
 
The investigator must keep copies of all AE information, including correspondence with 
Celgene, Genentech and the IRB on file (see Section 16.2 for records retention 
information). 
 
 


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12 Sponsor-Investigator Responsibilities and Oversight 
 Reporting Responsibilities to FDA 
 
A full description of FDA adverse event reporting requirements by the Sponsor 
Investigator are detailed in Section 11.4.1. The conduct of the study will comply with all 
FDA safety reporting requirements. These requirements will include: 
• 
Directly reporting to the FDA adverse events determined to be serious, 
unexpected, and reasonably related to the study drugs. 
• 
Regular review of aggregate adverse events at least every 3 months to 
determine if an increase in frequency of adverse events requires reporting to the 
FDA. 
• 
Preparation and submission of IND Annual Reports (due annually each January). 
 
IND Annual Reports 
If the FDA has granted an IND number, it is a requirement of 21 CFR 212.33, that an 
annual report is provided to the FDA within 60 days of the IND anniversary date.  21 
CRF 312.33 provides the data elements that are to be submitted in the report.  The 
Annual Report should be filed in the study’s Regulatory Binder, and a copy provided to 
Celgene Corporation as a supporter of this study as follows. 
 
 
Celgene Corporation 
 
Attn: Medical Affairs Operations 
 
Connell Corporate Park 
 
400 Connell Drive, Suite 700 
 
Berkeley Heights, NJ  07922 
 
In IND Annual Reports are generated a copy of this report should be forwarded to 
Genentech Drug Safety: 
 
Fax: (650) 225-4682 or (650) 225-4630 
 
 Protocol Deviations 
 
The Sponsor-investigator will review the protocol deviation log within 14 business days 
of the discovery of each deviation occurrence. 
 
 
 
 
 
13 Response Criteria 
 


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Baseline lesion assessments must occur within 6 weeks of study drug administration as 
indicated in Section 3, Schedule of study assessments. Efficacy assessments are 
scheduled to occur at the end of cycles 3 and 6 of induction therapy.  During the 
maintenance phases of treatment, efficacy assessments will be performed every 4 
months.  
 
Response and progression in cases of CLL will be evaluated using the revised Cheson 
Criteria.38 Response and progression in cases of SLL will be evaluated using the 
International Working Group guidelines for CLL.39 These criteria are outlined in detail in 
Appendix H. Radiological methodologies, techniques and/or physical examination, 
established at baseline for the assessment and measurement of each identified lesion will 
be used for all subsequent assessments.  


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14 Protocol Amendments/Deviations 
 Protocol Amendments 
Any amendment to this protocol must be agreed to by the principal investigator and 
reviewed by study supporters (i.e., Celgene and Genentech).  Amendments should only 
be submitted to the local IRB after consideration of study supporters’ reviews.  Written 
verification of IRB approval will be obtained before any amendment is implemented.   
 Protocol Deviations 
When an emergency occurs that requires a deviation from the protocol for a subject, a 
deviation will be made only for that subject.  A decision will be made as soon as possible 
to determine whether or not the subject (for whom the deviation from protocol was 
effected) is to continue in the study.  The subject’s medical records will completely 
describe the deviation from the protocol and state the reasons for such deviation.  In 
addition, the investigator will notify the IRB in writing of such deviation from protocol 
according to local policy. In addition, the investigator will inform the DSMC of the event 
around the protocol deviation, to determine if the subject should be removed from protocol 
therapy.  
Non-emergency minor deviations from the protocol will be permitted with approval of the 
principal investigator.  


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15 Statistical Considerations 
 Overview 
This single arm, open-label phase II study will be carried out an academic medical center 
as well as community practice sites. Participating centers will include the University of 
Wisconsin Carbone Comprehensive Cancer Center. The primary efficacy endpoint of this 
study is progression free survival (PFS). 
 Sample Size Calculation 
The primary efficacy endpoint of this study is progression-free survival (PFS) from the 
initiation of the maintenance therapy (PFS calculated beginning cycle 1, day 1 of 
maintenancy therapy). A standard induction regimen in newly diagnosed CLL and SLL 
with the highest reported overall response rates and PFS is the fludarabine, 
cyclophosphamide, and rituximab (FCR) chemotherapy regimen. Based on a recent 
randomized trial of the fludarabine and cyclophosphamide (FC) chemotherapy versus 
FCR chemotherapy, the observed 3-year PFS rate was 65% in patients receiving FCR 
chemotherapy versus 45% in the FC chemotherapy.106 The Kaplan-Meier estimates for 
the 2-year PFS probability were approximately 0.8 for the FCR chemotherapy and 0.6 for 
the FC chemotherapy arm. These values on PFS with FCR serve as a reasonable 
benchmark by which the proposed induction and maintenance regimen can be compared. 
For this study, we consider a 2-year PFS probability of 0.6 or less as clinically irrelevant. 
 
This study will test the null hypothesis that the 2-year PFS probability for subjects entering 
the maintenance therapy is at most 0.6 (equivalent to a median PFS of 32.6 months 
assuming an exponential distribution for PFS) versus the alternative that it is greater than 
0.6.  In the table below are given the required effective sample size for the maintenance 
phase of the study under various settings, assuming completion of accrual in 24-36 
months, a follow-up of 24 months (after the last patient has entered the maintenance 
phase), an exponential distribution for PFS, a one-sided significance level of α=0.10, using 
the Brookmeyer-Crowley method. 
 
 
 
 
2-year PFS probability for subjects entering maintenance  
Power 
0.75 
(Median PFS=57.8 
months) 
0.8 
(Median PFS=74.6 
months) 
0.85 
(Median PFS=102.4 
months) 
0.8 
41 
22 
13 
0.85 
51 
27 
16 
0.9 
65 
35 
21 
 
In order to detect the 2-year PFS probability with power 0.85, the required effective sample 
size is 27 subjects.  Assuming that up to 25% of the subjects in the induction therapy will 
not do well enough (CR, PR or SD) to enter the maintenance therapy or drop out after 
induction for reasons unrelated to objective response, a total of  36 subjects will be 
enrolled into the induction phase over 2.5-3.5 years. 


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 Statistical Analysis Plan 
 Primary endpoint  
The analysis will be undertaken when each subject has been potentially followed for a 
minimum of 24 months.  For each subject, time to progression will be defined as the 
number of days from the day of first lenalidomide and rituximab maintenance therapy 
(cycle 1, day 1 of maintenance therapy) to the day subject experiences an event of disease 
progression, initiation of alternate anti-neoplastic chemotherapy even in the absence of 
progression, or death, whichever comes first. If a subject has not experienced an event at 
the time of analysis, the subject’s data will be censored at the date of the last available 
evaluation. The 2-year PFS probability will be estimated using the Kaplan-Meier method. 
The null hypothesis that the 2-year PFS probability is at most 0.6 will be tested versus that 
alternative hypothesis that it is greater than 0.6.  A statistically significant result will support 
the development of a phase III trial.  PFS will be summarized using point estimate of the 
median PFS, and associated 90% confidence intervals.  The confidence interval will be 
computed using the Brookmeyer-Crowley method. The data will be presented graphically 
using Kaplan-Meier plots. 
 Secondary endpoints 
Objective response will be analyzed descriptively and summarized with the sample 
proportion and 90% confidence interval for the proportion of subjects with objective 
response. Toxicities will be summarized in a similar way. Data from all subjects who 
receive any study drug will be included in the safety analyses. The severity of the toxicities 
will be graded according to the NCI CTCAE, version 4.0 whenever possible. Frequency 
tables (type of toxicity and grade) for all toxicities with an attribution of possible or definite 
treatment related will be provided.  
 
For a given subject, overall survival (OS) will be defined as the number of days from the 
date of enrollment to the day the subject dies. Survival times of subjects who are still alive 
at the end of the follow-up period will be censored. OS will be summarized using point 
estimates of the median overall survival, along with the 95% confidence interval. Survival 
data will be presented graphically using Kaplan-Meier plots. 
 
 Accrual Rate 
 
Based on our experience with studies involving CLL/SLL subjects at UWCCC and affiliated 
sites, we anticipate an accrual rate of approximately 10-12 subjects per year. Therefore, 
it is expected that accrual will be completed within 3 years.  
 
16 Regulatory Considerations 
 


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 Investigator Responsibilities with Study Monitoring and Auditing 
Investigator responsibilities are set out in the International Conference on Harmonization 
(ICH) guideline for Good Clinical Practice (GCP) and in the US Code of Federal 
Regulations. 
 
Investigators must enter study data onto CRFs or other data collection system.  The 
investigator will permit study-related audits by Celgene, Genentech or its 
representatives, IRB/EC review, and regulatory inspection(s) (e.g., FDA, EMEA, TPD), 
providing direct access to the facilities where the study took place, to source documents, 
to CRFs, and to all other study documents. 
The investigator, or a designated member of the investigator’s staff, must be available at 
some time during audit visits to review data and resolve any queries and to allow direct 
access to the subject’s records (e.g., medical records, office charts, hospital charts, and 
study related charts) for source data verification.  The data collection must be completed 
prior to each visit and be made available to the Celgene and/or Genentech 
representative so that the accuracy and completeness may be checked. 
 Study Records Requirements 
All study records will be retained for at least 2 years after the investigation is completed.  
The investigator must ensure that the records and documents pertaining to the conduct 
of the study and the distribution of the study drug, be retained by the investigator for as 
long as needed to comply with national and international regulations (generally 2 years 
after discontinuing clinical development or after the last marketing approval). These 
records and documents include copies of CRFs and source documents (original 
documents, data, and records [e.g., hospital records; clinical and office charts; laboratory 
notes; memoranda; subject’s diaries or evaluation checklists; SAE reports, pharmacy 
dispensing records; recorded data from automated instruments; copies or transcriptions 
certified after verification as being accurate copies; microfiches; photographic negatives, 
microfilm, or magnetic media; x-rays; subject files; and records kept at the pharmacy, at 
the laboratories, and at medico-technical departments involved in the clinical study; 
documents regarding subject treatment and study drug accountability; original signed 
informed consents, etc.]). The investigator agrees to adhere to the document/records 
retention procedures by signing the protocol. 
 Institutional Review Board/Ethics Committee Approval 
The protocol for this study has been designed in accordance with the general ethical 
principles outlined in the Declaration of Helsinki.  The review of this protocol by the IRB/EC 
and the performance of all aspects of the study, including the methods used for obtaining 
informed consent, must also be in accordance with principles enunciated in the 
declaration, as well as ICH Guidelines, Title 21 of the Code of Federal Regulations (CFR), 
Part 50 Protection of Human Subjects and Part 56 Institutional Review Boards. 
The investigator will be responsible for preparing documents for submission to the relevant 
IRB/EC and obtaining written approval for this study.  The approval will be obtained prior 
to the initiation of the study. 


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The approval for both the protocol and informed consent must specify the date of approval, 
protocol number and version, or amendment number. 
Any amendments to the protocol after receipt of IRB/EC approval must be submitted by 
the investigator to the IRB/EC for approval.  The investigator is also responsible for 
notifying the IRB/EC of any serious deviations from the protocol, or anything else that may 
involve added risk to subjects. 
Any advertisements used to recruit subjects for the study must be reviewed and approved 
by the IRB/EC prior to use. 
 Informed Consent 
The investigator must obtain informed consent of a subject or his/her designee prior to 
any study related procedures as per GCPs as set forth in the CFR and ICH guidelines. 
Documentation that informed consent occurred prior to the subject’s entry into the study 
and the informed consent process should be recorded in the subject’s source documents.  
The original consent form signed and dated by the subject and by the person consenting 
the subject prior to the subject’s entry into the study, must be maintained in the 
investigator’s study files. 
 Subject Confidentiality 
Identifiable patient information will be maintained at the enrolling site.  All source 
documentation will be maintained within the subject’s research chart which will be 
accessible only to authorized personnel.  Study data will be collected in the UWCCC 
Oncore database.  Subject data will be coded, with the link to demographic information 
maintained within the Oncore database.  The study PI, statistician, and research team at 
UWCCC will have access to this information and will manage the study data.  Data will be 
maintained per federal guidelines.    
Celgene and Genentech affirm the subject’s right to protection against invasion of privacy.  
In compliance with United States federal regulations, the study supporters (i.e., Celgene 
and Genentech) require the investigator to permit representatives of Celgene Corporation 
and Genentech, when necessary, representatives of the FDA or other regulatory 
authorities to review and/or copy any medical records relevant to the study in accordance 
with local laws. 
Should direct access to medical records require a waiver or authorization separate from 
the subject’s statement of informed consent, it is the responsibility of the investigator to 
obtain such permission in writing from the appropriate individual. 
 Premature Discontinuation of Study 
The responsible local clinical investigator as well as Celgene and Genentech have the 
right to discontinue this study at any time for reasonable medical or administrative reasons 
in any single center or all participating centers.  Possible reasons for termination of the 
study could be but are not limited to: 
• 
Unsatisfactory enrollment with respect to quantity or quality. 


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• 
Inaccurate or incomplete data collection. 
• 
Falsification of records. 
• 
Failure to adhere to the study protocol. 
 


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17 References 
 
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previously untreated chronic lymphocytic leukemia. J Clin Oncol 2011;29:1175-81. 
77. 
Wiernik PH, Lossos IS, Tuscano JM, et al. Lenalidomide monotherapy in relapsed or 
refractory aggressive non-Hodgkin's lymphoma. J Clin Oncol 2008;26:4952-7. 
78. 
Chanan-Khan A, Egyed M, Robak T, et al. Randomized phase 3 study of lenalidomide 
versus chlorambucil as first-line therapy for older patients with chronic lymphocytic leukemia (the 
ORIGIN trial). Leukemia 2017;31:1240-3. 
79. 
Dohner H, Fischer K, Bentz M, et al. p53 gene deletion predicts for poor survival and non-
response to therapy with purine analogs in chronic B-cell leukemias. Blood 1995;85:1580-9. 
80. 
Dohner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic 
lymphocytic leukemia. N Engl J Med 2000;343:1910-6. 
81. 
Krober A, Seiler T, Benner A, et al. V(H) mutation status, CD38 expression level, genomic 
aberrations, and survival in chronic lymphocytic leukemia. Blood 2002;100:1410-6. 
82. 
Oscier DG, Gardiner AC, Mould SJ, et al. Multivariate analysis of prognostic factors in CLL: 
clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are independent 
prognostic factors. Blood 2002;100:1177-84. 
83. 
Krober A, Bloehdorn J, Hafner S, et al. Additional genetic high-risk features such as 11q 
deletion, 17p deletion, and V3-21 usage characterize discordance of ZAP-70 and VH mutation 
status in chronic lymphocytic leukemia. J Clin Oncol 2006;24:969-75. 
84. 
Rossi D, Cerri M, Deambrogi C, et al. The prognostic value of TP53 mutations in chronic 
lymphocytic leukemia is independent of Del17p13: implications for overall survival and 
chemorefractoriness. Clin Cancer Res 2009;15:995-1004. 
85. 
Gaidano G, Newcomb EW, Gong JZ, et al. Analysis of alterations of oncogenes and tumor 
suppressor genes in chronic lymphocytic leukemia. Am J Pathol 1994;144:1312-9. 
86. 
el Rouby S, Thomas A, Costin D, et al. p53 gene mutation in B-cell chronic lymphocytic 
leukemia is associated with drug resistance and is independent of MDR1/MDR3 gene expression. 
Blood 1993;82:3452-9. 
87. 
Wattel E, Preudhomme C, Hecquet B, et al. p53 mutations are associated with resistance 
to chemotherapy and short survival in hematologic malignancies. Blood 1994;84:3148-57. 
88. 
Lens D, Dyer MJ, Garcia-Marco JM, et al. p53 abnormalities in CLL are associated with 
excess of prolymphocytes and poor prognosis. British journal of haematology 1997;99:848-57. 
89. 
Barnabas N, Shurafa M, Van Dyke DL, Wolman SR, Clark D, Worsham MJ. Significance 
of p53 mutations in patients with chronic lymphocytic leukemia: a sequential study of 30 patients. 
Cancer 2001;91:285-93. 


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90. 
Lozanski G, Heerema NA, Flinn IW, et al. Alemtuzumab is an effective therapy for chronic 
lymphocytic leukemia with p53 mutations and deletions. Blood 2004;103:3278-81. 
91. 
Austen B, Powell JE, Alvi A, et al. Mutations in the ATM gene lead to impaired overall and 
treatment-free survival that is independent of IGVH mutation status in patients with B-CLL. Blood 
2005;106:3175-82. 
92. 
Stankovic T, Weber P, Stewart G, et al. Inactivation of ataxia telangiectasia mutated gene 
in B-cell chronic lymphocytic leukaemia. Lancet 1999;353:26-9. 
93. 
Stankovic T, Hubank M, Cronin D, et al. Microarray analysis reveals that TP53- and ATM-
mutant B-CLLs share a defect in activating proapoptotic responses after DNA damage but are 
distinguished by major differences in activating prosurvival responses. Blood 2004;103:291-300. 
94. 
Schaffner C, Stilgenbauer S, Rappold GA, Dohner H, Lichter P. Somatic ATM mutations 
indicate a pathogenic role of ATM in B-cell chronic lymphocytic leukemia. Blood 1999;94:748-53. 
95. 
Stilgenbauer S KA, Busch R, et al. 17p Deletion predicts for inferior overall survival after 
fludarabine-based first line therapy in chronic lymphocytic leukemia: first analysis of genetics in the 
CLL4 Trial of the GCLLSG. Blood 2005;106:abstract 715. 
96. 
Catovsky D, Richards S, Matutes E, et al. Assessment of fludarabine plus 
cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a 
randomised controlled trial. Lancet 2007;370:230-9. 
97. 
Grever MR, Lucas DM, Dewald GW, et al. Comprehensive assessment of genetic and 
molecular features predicting outcome in patients with chronic lymphocytic leukemia: results from 
the US Intergroup Phase III Trial E2997. J Clin Oncol 2007;25:799-804. 
98. 
Tam CS, O'Brien S, Wierda W, et al. Long-term results of the fludarabine, 
cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood 
2008;112:975-80. 
99. 
Byrd JC, Rai K, Peterson BL, et al. Addition of rituximab to fludarabine may prolong 
progression-free survival and overall survival in patients with previously untreated chronic 
lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 
9011. Blood 2005;105:49-53. 
100. 
Keating MJ, O'Brien S, Albitar M, et al. Early results of a chemoimmunotherapy regimen of 
fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. 
J Clin Oncol 2005;23:4079-88. 
101. 
Mosteller RD. Simplified calculation of body-surface area. N Engl J Med 1987;317:1098. 
102. 
DuBois D, DuBois EF. A formula to estimate the approximate surface area if height and 
weight be known. Arch Intern Medicine 1916;17:863-71. 
103. 
Elefante A, Czuczman MS. Bendamustine for the treatment of indolent non-Hodgkin's 
lymphoma and chronic lymphocytic leukemia. Am J Health Syst Pharm 2010;67:713-23. 
104. 
Moutouh-de Parseval LA, Weiss L, DeLap RJ, Knight RD, Zeldis JB. Tumor lysis 
syndrome/tumor flare reaction in lenalidomide-treated chronic lymphocytic leukemia. J Clin Oncol 
2007;25:5047. 
105. 
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at the Muscatatuck State School. Am J Ment Defic 1958;63:517-23. 
106. 
Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and 
cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, 
phase 3 trial. Lancet 2010;376:1164-74. 
107. 
Cheson BD, Bennett JM, Grever M, et al. National Cancer Institute-sponsored Working 
Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. 
Blood 1996;87:4990-7. 
108. 
Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. 
British journal of haematology 2004;127:3-11. 


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Appendix A – ECOG Performance Status Scale 
 
SCORE 
DESCRIPTION 
0 
Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Restricted 
in 
physically 
strenuous 
activity 
but 
ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to 
carry out any work activities.  Up and about more than 
50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
Dead. 
 


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Appendix B: Risks of Fetal Exposure, Pregnancy Testing 
Guidelines and Acceptable Birth Control Methods 
Risks Associated with Pregnancy 
The use of lenalidomide in pregnant females and nursing mothers has not been 
studied nor has the effect of the lenalidomide on human eggs and sperm.  
Lenalidomide is structurally related to thalidomide.  Thalidomide is a known 
human teratogenic active substance that causes severe life-threatening birth 
defects.  An embryofetal development study in animals indicates that 
lenalidomide produced malformations in the offspring of female monkeys who 
received the drug during pregnancy.  The teratogenic effect of lenalidomide in 
humans cannot be ruled out.  Therefore, a risk minimization plan to prevent 
pregnancy must be observed. 
All study participants must be registered into the mandatory Revlimid REMS® 
program, and be willing and able to comply with the requirements of the Revlimid 
REMS® program. 
Criteria for females of childbearing potential (FCBP) 
This protocol defines a female of childbearing potential as a sexually mature 
female who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 
2) has not been naturally postmenopausal for at least 24 consecutive months 
(i.e., has had menses at any time in the preceding 24 consecutive months). 
The investigator must ensure that: 
• Females of childbearing potential comply with the conditions for pregnancy 
risk minimization, including confirmation that she has an adequate level of 
understanding 
• Females NOT of childbearing potential acknowledge that she understands 
the hazards and necessary precautions associated with the use of 
lenalidomide 
• Male patients taking lenalidomide acknowledge that he understands that 
traces of lenalidomide have been found in semen, that he understands the 
potential teratogenic risk if engaged in sexual activity with a female of 
childbearing potential or pregnant female, and that he understands the need 
for the use of a condom even if he has had a vasectomy, if engaged in 
sexual activity with a female of childbearing potential or pregnant female.   
Contraception 
Females of childbearing potential (FCBP) enrolled in this protocol 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: 1) for at least 28 days before starting lenalidomide; 2) throughout the 


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entire duration of lenalidomide treatment; 3) during dose interruptions; and 4) for 
at least 28 days after lenalidomide discontinuation.  
The two methods of reliable contraception must include one highly effective 
method and one additional effective (barrier) method. FCBP must be referred to a 
qualified provider of contraceptive methods if needed. The following are examples 
of highly effective and additional effective methods of contraception:   
o Highly effective methods: 
▪ Intrauterine device (IUD) 
▪ Hormonal (birth control pills, injections, implants) 
▪ Tubal ligation 
▪ Partner’s vasectomy 
o Additional effective methods: 
▪ Male condom 
▪ Diaphragm 
▪ Cervical Cap 
Because of the increased risk of venous thromboembolism in patients with multiple 
myeloma taking lenalidomide and dexamethasone, combined oral contraceptive 
pills are not recommended. If a patient is currently using combined oral 
contraception the patient should switch to one of the effective method listed above. 
The risk of venous thromboembolism continues for 4−6 weeks after discontinuing 
combined oral contraception. The efficacy of contraceptive steroids may be 
reduced during co-treatment with dexamethasone. 
Implants and levonorgestrel-releasing intrauterine systems are associated with an 
increased risk of infection at the time of insertion and irregular vaginal bleeding. 
Prophylactic antibiotics should be considered particularly in patients with 
neutropenia.  
 
Pregnancy testing 
Must follow pregnancy testing requirements as outlined in the Revlimid REMS® 
program material. 


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Medically supervised pregnancy tests with a minimum sensitivity of 50 mIU/mL 
must be performed for females of childbearing potential, including females of 
childbearing potential who commit to complete abstinence, as outlined below. 
Before starting lenalidomide 
Female Patients: 
FCBP must have two negative pregnancy tests (sensitivity of at least 50 mIU/mL) 
prior to prescribing lenalidomide.  The first pregnancy test must be performed 
within 10-14 days prior to prescribing lenalidomide and the second pregnancy test 
must be performed within 24 hours prior to prescribing lenalidomide.  The patient 
may not receive lenalidomide until the Investigator has verified that the results of 
these pregnancy tests are negative. 
Male Patients: 
Must agree to practice complete abstinence or agree to use a condom during 
sexual contact with pregnant females or females of childbearing potential 
throughout the entire duration of lenalidomide treatment, during dose interruptions 
and for at least 28 days following lenalidomide discontinuation, even if he has 
undergone a successful vasectomy.   
During study participation and for 28 days following lenalidomide 
discontinuation  
Female Patients: 
• FCBP with regular or no menstrual cycles must agree to have pregnancy 
tests weekly for the first 28 days of lenalidomide treatment, including dose 
interruptions and then every 28 days throughout the remaining duration of 
lenalidomide treatment, including dose interruptions, at lenalidomide 
discontinuation, and at Day 28 following lenalidomide discontinuation.  If 
menstrual cycles are irregular, the pregnancy testing must occur weekly for 
the first 28 days of lenalidomide treatment, including dose interruptions, and 
then every 14 days throughout the remaining duration of lenalidomide 
treatment, including dose interruptions, at lenalidomide discontinuation, and 
at Day 14 and Day 28 following lenalidomide discontinuation.   
• At each visit, the Investigator must confirm with the FCBP that she is 
continuing to use two reliable methods of birth control at each visit during 
the time that birth control is required.   


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• If pregnancy or a positive pregnancy test does occur in a study patient, 
lenalidomide must be immediately discontinued. 
• Pregnancy testing and counseling must be performed if a patient misses 
her period or if her pregnancy test or her menstrual bleeding is abnormal.  
Lenalidomide treatment must be temporarily discontinued during this 
evaluation. 
• Females must agree to abstain from breastfeeding during study 
participation and for at least 28 days after lenalidomide discontinuation. 
Male Patients: 
• Must practice complete abstinence or use a condom during sexual contact 
with pregnant females or females of childbearing potential throughout the 
entire duration of lenalidomide treatment, during dose interruptions and for 
at least 28 days following lenalidomide discontinuation, even if he has 
undergone a successful vasectomy.   
• If pregnancy or a positive pregnancy test does occur in the partner of a male 
study patient during study participation, the investigator must be notified 
immediately. 
• Male patients should not donate semen or sperm during therapy or for at 
least 28 days following discontinuation of lenalidomide. 
Additional precautions 
• Patients should be instructed never to give lenalidomide to another person. 
• Patients should not donate blood during therapy and for at least 28 days 
following discontinuation of lenalidomide. 
• Only enough lenalidomide for one cycle of therapy may be prescribed with 
each cycle of therapy.  
• Any unused lenalidomide must be returned as instructed through Revlimid 
REMS® program. 


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Appendix C: Body Surface Area Calculations 
 
The preferred method for calculating body surface area is with the Mosteller formula:101 
 
BSA (m2)= [Height(cm) X Body weight (kg)/3600]1/2 
 
 
At some participating community sites, the Dubois formula102 is the primary BSA 
calculation used as part of an electronic medical record and drug ordering template. In 
such cases, calculations using the Dubois formula are permitted as long as there is no 
more than a 10% difference in dosing between the Mosteller and Dubois calculations. If a 
>10% difference in drug dosing is observed, then the Mosteller calculation must be used. 
Dubois formula:102 
BSA (m2)= 0.007184 X [Body weight (kg)]0.425 X [Height (cm)]0.725 
 
The same BSA will be used for each dose calculation of bendamustine and rituximab 
unless the subjects experiences a >10% change in body weight from the weight used for 
the most recent BSA calculation. 
 
 
 
 


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Appendix D: Rituximab Formulation, Preparation, and Adverse 
Effects 
1.A. 
Other names 
Rituxan™, IDEC-C2B8, chimeric anti-CD20 monoclonal antibody, NSC#687451 
1.B. 
Classification and mode of action: 
Rituximab is a chimeric murine/human gamma 1 kappa monoclonal antibody 
(Chinese hamster ovary [CHO] transfectoma). It recognizes the CD20 antigen 
expressed on normal B cells and most malignant B-cell lymphomas. It binds with 
high affinity to CD20-positive cells, performs human effector functions in vitro, and 
depletes B cells in vivo. The Fab domain of rituximab binds to the CD20 antigen 
on B-lymphocytes and the Fc domain recruits immune effector functions to mediate 
B-cell lysis in vitro. The biological effect is manifested by B-cell depletion in 
peripheral blood, lymph nodes, and bone marrow. 
1.C. 
Storage and stability 
 
Rituximab vials are stable at 2° to 8°C (36° to 46°F).  Do not use beyond 
expiration date stamped on carton. Rituximab vials should be protected from direct 
sunlight. 
 
Rituximab solutions for infusion are stable at 2 to 8C (36 to 46F) for 24 
hours and at room temperature for an additional 24 hours. However, since 
rituximab solutions do not contain a preservative, diluted solutions should be 
stored refrigerated (2 to 8C ).  No incompatibilities between rituximab and 
polyvinylchloride or polyethylene bags have been observed. 
1.D. 
Preparation 
Withdraw the necessary amount of rituximab and dilute to a final concentration of 
1 to 4 mg/mL into an infusion bag containing either 0.9% sodium chloride or 5% 
dextrose in water. Gently invert the bag to mix the solution. Discard any unused 
portion left in the vial.  Parenteral drug products should be inspected visually 
for particulate matter and discoloration prior to administration. Caution should 
be taken during the preparation of the drug, as shaking can cause aggregation and 
precipitation of the antibody. 
1.E. 
Administration 
Rituximab is administered intravenously. An in-line filter is not required. The initial 
rate is 50 mg/hr for the first 30-60 minutes. If no toxicity is seen, the rate may be 
escalated gradually in 50 mg/hour increments at 30-minute intervals to a maximum 
of 400 mg/hr. If the first dose is well-tolerated, the initial rate for subsequent doses 
is 100 mg/hr, increasing gradually by 50 mg/hr increments to maximum rate of 400 
mg/hr. If the patient experiences fever and rigors, the antibody infusion is 
discontinued. The severity of the side effects should be evaluated. If the symptoms 
improve, the infusion is continued initially at one-half the previous rate. Following 
the antibody infusion, the intravenous line should be maintained for medications 
as needed. If there are no complications after one hour of observation, the 
intravenous line may be discontinued.  Institutions may follow standard practice for 
infusion of Rituximab if different from the above guidelines.   


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Oral pre-medication (two 325 mg tablets of acetaminophen and 50 to 100 mg of 
oral diphenhydramine) may be administered 30 to 60 minutes prior to starting each 
infusion of rituximab. Since transient hypotension may occur during rituximab 
infusion, consideration should be given to withholding anti-hypertensive 
medications 12 hours prior to rituximab infusion.  The subject should be 
treated according to the best available local practices and procedures. 
1.F. 
Availability 
Rituximab will be provided for subjects in this study: Preservation-free injection 10 
mg/ml, in 10 and 50 mL single-unit vials 
 
1.G. 
Side effects – Please refer to package insert 
General: Rituximab is associated with hypersensitivity reactions which may 
respond to adjustments in the infusion rate. Hypotension, bronchospasm, and 
angioedema have occurred in association with rituximab infusion as part of an 
infusion-related symptoms complex. Rituximab infusion should be interrupted for 
severe reactions and can be resumed at a 50% reduction in rate when symptoms 
have completely resolved. Medications for the treatment of hypersensitivity 
reactions, e.g., epinephrine, antihistamines, and corticosteroids should be 
available for immediate use in the events of a reaction during administration. 
Cardiovascular: Infusions should be discontinued in the event of serious or life-
threatening cardiac arrhythmias. Subjects who develop clinically significant 
arrhythmias should undergo cardiac monitoring during and after subsequent 
infusions of rituximab. Subjects with pre-existing cardiac conditions including 
arrhythmias and angina have had recurrences of these events during rituximab 
therapy and should be monitored throughout the infusion and immediate post-
infusion period. 
Tumor lysis syndrome: Rituximab rapidly decreases both benign and malignant 
CD20 positive cells. Tumor lysis syndrome has been reported to occur within 12 
to 24 hours after the first rituximab infusion in subjects with high numbers of 
circulating malignant lymphocytes. Subjects with high tumor burden (bulky lesions) 
may also be at risk. Subjects at risk of developing tumor lysis syndrome should be 
followed closely and appropriate laboratory monitoring performed. Appropriate 
medical therapy should be provided for subjects who develop tumor lysis 
syndrome. Following treatment for and resolution of tumor lysis syndrome, 
subsequent rituximab therapy was administered in conjunction with prophylactic 
therapy for this syndrome in a limited number of cases.  
Hepatitis B virus: Hepatitis B virus (HBV) reactivation with fulminant hepatitis, 
hepatic failure, and death has been reported in some subjects with hematologic 
malignancies treated with rituximab. The majority of subjects received rituximab in 
combination with chemotherapy. The median time to the diagnosis of hepatitis was 
approximately 4 months after the initiation of rituximab and approximately one 
month after the last dose.  
1.H. 
Incidence of adverse effects 


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Incidence more frequent (>5%):  
Fever, chills, rigors, asthenia, headache, angioedema, hypotension, myalgia, 
dizziness, fatigue, throat irritation, abdominal pain, nausea, vomiting, leukopenia, 
thrombocytopenia, neutropenia, rhinitis, bronchospasm, pruritis, rash, urticaria 
Incidence less frequent (1-5%):  
Flushing, arthralgia, diarrhea, anemia, cough, hypertension, lacrimation disorder, 
pain, hyperglycemia, back pain, peripheral edema, paresthesia, dyspepsia, chest 
pain, anorexia, anxiety, malaise, tachycardia, agitation, insomnia, sinusitis, 
conjunctivitis, abdominal enlargement, postural hypotension, LDH increase, 
hypocalcemia, hyperesthesia, respiratory disorder, shortness of breath, tumor 
pain, pain at injection site, bradycardia, hypertonia, tachycardia, nervousness, 
bronchitis, and altered sense of taste. 
Incidence rare (<1%):  
Anaphylaxis, severe infusion-related adverse events which may result in death. 
Tumor lysis syndrome: subject with a high tumor burden or with a high number 
(50,000/mm3) of circulating malignant cells may be at higher risk of severe infusion-
related events. When treated with rituximab, some subjects with a history of 
hepatitis B may experience reactivation of their hepatitis that may be life-
threatening. 
1.I. 
Nursing/subject implications 
Monitor blood pressure, pulse, respiration, and temperature every 15 minutes X 4 
or until stable and then hourly until the infusion is completed. 
Have epinephrine for subcutaneous injections, diphenhydramine for intravenous 
injection, and resuscitation equipment for emergency management of 
anaphylactoid reactions available. 
Monitor and alter infusion rates in the presence of toxicities. 
Rituximab shows no significant effect on bone marrow reserve and no apparent 
increased rate of infections in heavily pretreated, relapsed lymphoma subjects. 
Prophylaxis for tumor lysis syndrome should be used in subjects with high tumor 
burden, particularly with markedly elevated numbers of circulating malignant cells.  


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Appendix E: Bendamustine Formulation, Preparation, and 
Adverse Effects 
I. 
Drug formulation and preparation 
I.A. 
Other names 
 
Treanda™, SDX-105, Bendeka™ 
Bendamustine is available in several formulations, including Treanda™ (available 
in liquid and powder formulations infused over 30-60 minutes), and Bendeka™ (a 
ready-to-dilute formulation available to infuse over 10 minutes). Bendeka™ was 
introduced in the market in December 2015 by Teva Pharmaceuticals, with the 
simultaneous decision by Teva to stop manufacturing Treanda™ during roll-out of 
Bendeka™. Generic marketing and availability of bendamustine is anticipated to 
be unpredictable in the months following introduction of the Bendeka™ product. 
Bendeka™ and Treanda™ are nearly identical in action and toxicities, and can be 
used interchangeably for administration of induction chemotherapy per the study 
protocol depending on availability of the bendamustine product and institutional 
preference. 
1.B. 
Classification and mode of action: 
Bendamustine is a DNA alkylating agent with amphoteric properties due to the 
nitrogen mustard group and butyric acid side chain. Bendamustine has multiple 
mechanisms of action related to the alkylating activity of the 1-methyl-
benzimidazole moiety and the nitrogen mustard group.  
Bendamustine acts as an alkylating agent causing intra-strand and inter-strand 
cross-links between DNA bases, thus directly inhibiting DNA replication, 
transcription, and repair. At equitoxic concentrations, bendamustine induces more 
DNA double-strand breaks than other alkylating agents (i.e., melphalan, 
cyclophosphamide, and carmustine). In addition, these breaks also appear to be 
more durable and less easily repaired than those induced by other agents. 
Bendamustine has also demonstrated pro-apoptotic activity in combination with 
other anti-cancer agents in several in vitro tumor models, including in primary 
tumor cells from CLL and non-Hodgkin lymphoma subjects. Treatment with 
bendamustine HCl has also demonstrated down-regulation of several cell cycle 
mitotic checkpoint regulators, including polo-like kinase 1 (PLK-1), aurora kinase 
A and cyclin B1. Bendamustine shows only partial cross-resistance with other 
alkylating agents when investigated in a variety of cell lines, which may be related 
to the relatively slow repair rate associated with this agent. No evidence of in vitro 
drug resistance to bendamustine was observed when the drug was tested in paried 
tumor cells expressing various drug resistance mechanisms including the 


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overexpression of P-glycoprotein, of multi-drug resistant-associated protein 
(MRP), or dihydrofolate reductase (DHFR).  
I.C Storage and stability 
Bendamustine vials should be stored at refrigerated temperatures of 2o to 8oC (36o 
to 46oF) and protected from light.  Bendamustine is stable for 5 hours when stored 
at normal room temperature conditions, 15oC to 30oC (59oF to 86oF). 
Bendamustine is a cytotoxic anticancer agent and should be handled according to 
the recommended procedures described in the current edition of the American 
Society of Health-System Pharmacists Technical Assistance Bulletin on Handling 
Cytotoxic and Hazardous Drugs. Procedures described in each institution’s 
pharmacy or hospital standard operating procedure manual should be followed 
when handling cytotoxic drugs. 
The Bendeka product is supplied in multi-dose vials. Although it does not contain 
any anti-microbial preservative, Bendeka is bacteriostatic. The partially used vials 
are stable for up to 28 days when stored in its original carton under refrigeration 2-
8oC or 36-46oF). Each vial is not recommended for more than a total of 6 dose 
withdrawals.  
1.D. 
Preparation 
The single-use vials should be opened and reconstituted as close to the time of 
subject administration as possible. Each vial of bendamustine should be 
reconstituted with 20 mg of sterile water for injection, shaken gently for about 2 
minutes, and then inspected for clarity of solution. If the solution is not clear after 
2 minutes, the vials should be shaken for an additional 3 minutes and inspected 
again. If the solution is not clear after 15 minutes, vials should be set aside and a 
replacement vial should be used. The final concentration within the vial is 5.0 
mg/mL. 
Immediately dilute the reconstituted solution in a 500 mL IV bag of normal saline, 
using appropriate venting procedures. The amount of reconstituted solution to be 
withdrawn from the vials should be calculated using the following formula: 
[Dose of study drug (mg) ÷ Vial concentration (mg/mL)] = Volume of drug solution 
(mL) 
The time from the start of product reconstitution to the completion of the transfer 
to the IV bag should not exceed 30 minutes. 


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1.E. 
Administration 
 
The bendamustine solution should be used promptly after reconstitution and 
dilution. The route of administration is by IV infusion over 30-60 minutes for 
Treanda™ and over 10 minutes for Bendeka™. The infusion line would be primed 
with drug solution. If medical conditions necessitate, e.g., fluid management issues 
of infusion reactions, the infusion may be given over a longer period of time, though 
the infusion should be ≤120 minutes. In-line filters are not required for 
administration. Refer to the Pharmacy Manual for more detailed instructions. 
1.F. 
Availability 
Commerical: Bendamustine is a white to off-white, crystalline powder. Mannitol is 
contained in the finished product as an excipient to enhance solubility during 
reconstitution of the powder. Bendamustine is lyophilized due to long-term 
instability in aqueous medium. Bendamustine is available in 100 mg single use 
vials. 
Bendeka is a clear colorless-yellow 25 mg/mL solution supplied in multi-dose vials 
(100 mg/4 mL vials).  
1.G. 
Drug interactions 
No formal pharmacokinetic drug-drug interactions have been determined for 
bendamustine. However, bendamustine’s active metabolites are formed via 
cytochrome P450 CYP1A2. Inhibitors of CYP1A2 (e.g., fluvoxamine, ciprofloxacin) 
have the potential to increase plasma concentrations of bendamustine and 
decrease plasma concentrations of active metabolites. Inducers of P450 CYP1A2 
(e.g., omeprazole, smoking) have the potential to decrease plasma concentrations 
of bendamustine and increase plasma concentrations of its active metabolites.  
1.H. 
Side effects – Please refer to package insert 
Hematologic: neutropenia (grade 3 or 4 neutropenia in up to 25% of treated 
subjects), thrombocytopenia infrequently requiring transfusions, and anemia.  
Infections: increased risk of infections (e.g., pneumonia) and sepsis have been 
reported following treatment with bendamustine. 
Infusion reactions and anaphylaxis: have been reported commonly in clinical trials 
with symptoms including fever, chills, pruritis, and rash. Rare reports of 
anaphylactic or anaphylactoid reactions have occurred.  
Tumor lysis syndrome: reported in several subjects treated with bendamustine, 
primarily during the first cycle of therapy.  


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Skin reactions: reported reactions include rash, toxic skin reactions, and bullous 
exanthema 
Elevated LFT’s: reported increase in total bilirubin and transaminases in up to 30% 
of subjects in some clinical trials. 
Gastrointestinal: frequent reporting of nausea, vomiting, and stomatitis.  
1.I. 
Fequency of adverse effects: 
Frequent adverse events: asthenia, fatigue, malaise, and weakness; dry mought; 
somnolence; cough; constipation; headache; mucosal inflammation and stomatitis; 
nausea, vomiting, and diarreha. Hematologic toxicity is very frequent including 
grade 3 and 4 neutropenia and thrombocytopenia. Mild elevation of liver function 
tests (total bilirubin and transaminases). 
Less common adverse events: hypersensitivity reactions, skin eruptions, fevers, 
chills, hypertension, pyrexia, and neutropenic infection.  
1.J. 
 Nursing/subject implications 
Subjects require close monitoring during the first infusion for evidence of 
hypersensitivity reaction, which is an uncommon but serious side effect with 
bendamustine. 
Hematologic toxicity is the primary dose-limiting toxicity, and hematologic nadirs 
should be expected in the third week of therapy.  
Infection, including pneumonia and sepsis, have been reported following treatment 
with bendamustine, usually in combination with myelosuppression. Subjects with 
myelosuppression need education regarding monitoring for signs of fever or 
infection. 
Prophylaxis for tumor lysis syndrome should be considered in subjects with high 
tumor burden, or elevated uric acid and/or LDH. 
Subjects should be educated on supportive measures for management of nausea, 
vomiting, diarrhea, constipation, and stomatitis. 
1.K. 
References 
Investigator’s Brochure,Bendamustine HCl for injection, version 04 (Dec. 2014). 
 


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Appendix F: Lenalidomide Formulation, Preparation, and 
Adverse Effects 
1.A. 
Other names:  
CC-5013, Revlimid® 
1.B 
Indications and usage  
Revlimid® (lenalidomide) is indicated for the treatment of subjects with transfusion-
dependent anemia due to Low- or Intermediate-1-risk myelodysplastic syndromes 
associated with a deletion 5q cytogenetic abnormality with or without additional 
cytogenetic abnormalities.  Revlimid® is also approved in combination with 
dexamethasone for the treatment of subjects with multiple myeloma that have 
received at least one prior therapy.  
1.C. 
Classification and mode of action 
REVLIMID® (lenalidomide), a thalidomide analogue, is an immunomodulatory 
agent with anti-angiogenic properties.  The mechanism of action of lenalidomide 
remains to be fully characterized. Lenalidomide possesses immunomodulatory 
and antiangiogenic properties.  Lenalidomide inhibited the secretion of pro-
inflammatory cytokines and increased the secretion of anti-inflammatory cytokines 
from peripheral blood mononuclear cells.  Lenalidomide inhibited cell proliferation 
with varying effectiveness (IC50s) in some but not all cell lines.  Of cell lines tested, 
lenalidomide was effective in inhibiting growth of Namalwa cells (a human B cell 
lymphoma cell line with a deletion of one chromosome 5) but was much less 
effective in inhibiting growth of KG-1 cells (human myeloblastic cell line, also with 
a deletion of one chromosome 5) and other cell lines without chromosome 5 
deletions.  Lenalidomide inhibited the expression of cyclooxygenase-2 (COX-2) 
but not COX-1 in vitro.   
1.D. 
Storage and stability  
Lenalidomide should be stored at room temperature away from direct sunlight and 
protected from excessive heat and cold.     
1.E. 
Preparation 
Lenalidomide is an off-white to pale-yellow solid powder. It is soluble in organic 
solvent/water mixtures, and buffered aqueous solvents. Lenalidomide is more 
soluble in organic solvents and low pH solutions. Solubility was significantly lower 
in less acidic buffers, ranging from about 0.4 to 0.5 mg/ml.  
Lenalidomide is available in capsule formulation at doses of 5 mg, 10 mg, 15 mg, 
and 25 mg capsules. 
1.F. 
Administration and availability 
Lenalidomide (Revlimid®) will be provided to research subjects for the duration of 
their participation in this trial at no charge to them or their insurance 
providers.  Lenalidomide will be provided in accordance with the Celgene 
Corporation’s Revlimid REMS® program.  Per standard Revlimid REMS® 
program requirements all physicians who prescribe lenalidomide for research 


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subjects enrolled into this trial, and all research subjects enrolled into this trial, 
must be registered in and must comply with all requirements of the Revlimid 
REMS® program.  Prescriptions must be filled within 7 days for females of 
childbearing potential and 14 days for all other risk categories.    
 
Drug will be shipped on a per patient basis by the contract pharmacy to the clinic 
site for IND studies. 
 
Only enough lenalidomide for one cycle of therapy will be supplied to the 
patient each cycle. 
Lenalidomide is supplied as capsules for oral administration.   
1.G. 
Special Handling Instruction 
Females of childbearing potential should not handle or administer lenalidomide 
unless they are wearing gloves. 
1.H. 
Drug interactions 
Results from in vitro metabolism studies and non-clinical studies have shown that 
lenalidomide is not metabolized by nor inhibits of induces the cytochrome P450 
pathway and unlikely to be subject to P450-based metabolic drug interactions. Co-
administration of lenalidomide with warfarin does not have an effect on the 
pharmacokinetics of warfarin.  
1.I. 
Adverse effects 
Complete and updated adverse events are available in the Investigational Drug 
Brochure and the IND Safety Letters. 
Most frequently reported adverse events reported during clinical studies with 
lenalidomide in oncologic and non-oncologic indications, regardless of presumed 
relationship to study medication include: anemia, neutropenia, thrombocytopenia 
and pancytopenia, abdominal pain, nausea, vomiting and diarrhea, dehydration, 
rash, itching, infections, sepsis, pneumonia, UTI, Upper respiratory infection, 
cellulites, atrial fibrillation, congestive heart failure, myocardial infarction, chest 
pain, weakness, hypotension, hypercalcemia, hyperglycemia, back pain, bone 
pain, generalized pain, dizziness, mental status changes, syncope, renal failure, 
dyspnea, pleural effusion, pulmonary embolism, deep vein thrombosis, CVA, 
convulsions, dizziness, spinal cord compression, syncope, disease progression, 
death not specified and fractures. 
General: Fatigue is common with lenalidomide, reported in up to 50% of subjects. 
Subjective fever and generalized edema has occurred in up to 20% of treated 
subjects. 
Hematologic: Neutropenia is a common complication of treatment with 
lenalidomide, although the incidence of neutropenic fever is relatively uncommon 
(<10%). Thrombocytopenia is common, but severe thrombocytopenia requiring 
platelet transfusions is uncommon. 
Skin: Rash and pruritis have been reported frequently (>30%) with lenalidomide. 


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Gastrointestinal: Some previous experience with lenalidomide have reported 
diarrhea in almost half of subjects, although most cases tend to be low-grade 
diarrhea. Constipation and nausea have been reported in up to 25% of subjects. 
Respiratory: Symptoms of nasopharyngitis, dyspnea, and cough have been 
reported in up to 20-25% of subjects. 
Musculoskeletal: Arthralgias and cramping have been reported relatively 
frequently during treatment with lenalidomide. 
Neurologic: Dizziness and headache have occurred with up to 20% of subjects 
treated with lenalidomide. Peripheral neuropathy is relatively uncommon (<10%). 
1.J.  
Investigator’s Brochure, Revlimid® (lenalidomide, CC-5013), March 2006.  
 
 
 
 
 
 
 
 
 
 
 


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Appendix G:  Guidelines on Reporting Suspected or Confirmed 
Pregnancies 
 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless 
of age or disease state) of a female subject occurring while the subject is on lenalidomide, 
or within 28 days of the subject’s last dose of lenalidomide, are considered immediately 
reportable events. Lenalidomide is to be discontinued immediately. The pregnancy, 
suspected pregnancy, or positive pregnancy test must be reported to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, using the Pregnancy Initial Report 
Form. The female subject should be referred to an obstetrician-gynecologist, preferably 
one experienced in reproductive toxicity for further evaluation and counseling. 
 
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either 
normal or abnormal outcome) using the Pregnancy Follow-up Report Form. If the outcome 
of the pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the 
Investigator should report the abnormal outcome as an AE. If the abnormal outcome 
meets any of the serious criteria, it must be reported as an SAE to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, within 24 hours of the Investigator’s 
knowledge of the event using the SAE Report Form. 
 
All neonatal deaths that occur within 28 days of birth should be reported, without regard 
to causality, as SAEs. In addition, any infant death after 28 days that the Investigator 
suspects is related to the in utero exposure to the IP should also be reported to Celgene 
Drug Safety immediately by facsimile, or other appropriate method, within 24 hours of the 
Investigator’s knowledge of the event using the SAE Report Form. 
 
Male Subjects 
If a female partner of a male subject taking investigational product becomes pregnant, the 
male subject taking IP should notify the Investigator, and the pregnant female partner 
should be advised to call their healthcare provider immediately. 
 
Celgene Drug Safety Contact Information: 
 
Celgene Corporation 
Global Drug Safety and Risk Management 
Connell Corporation Park 
300 Connell Dr. Suite 6000 
Berkeley Heights, NJ  07922 
 
Fax: 
 
(908) 673-9115 
E-mail:  
drugsafety@celgene.com 
 


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Appendix H:  Assessment of Response 
Criteria for response will utilize the Revised IWCLL 200839 for response which includes 
clinical, hematologic, and bone marrow features as derived from the initial NCI-WG 1996.107 
 
Assessment 
Complete 
response (All 
criteria below) 
Partial response 
 
Progressive 
disease 
≥1 criteria below 
Stable 
disease 
1 
Lymph nodes (by 
physical examination 
and CT scans†) 
Absence of 
lymphadenopathy 
> 1.5 cm on 
physical exam and 
CT scan  
 
≥50% reduction of 
as many as 6 
measurable lymph 
nodes 
 
≥ 50% increase 
in products of ≥2 
nodes on two 
consecutive 
determinations 2 
weeks apart (at 
least 1 node 
must be ≥ 2 cm); 
new palpable 
lymph nodes. 
Subject 
has not 
achieved 
either a CR 
or PR and 
does not 
meet 
criteria for 
PD 
2 
Liver and/or spleen 
size (by physical 
examination), if 
abnormal at baseline 
No hepatomegaly 
or splenomegaly 
≥50% reduction 
≥50% increase 
3 
Lymphocytes (per 
μL) 
<5000/μL,  no 
clonal B-cells by 
flow cytometry;  
≥50% decrease 
from baseline 
values 
≥50%  increase 
in lymphocytes 
(to ≥5000/ μL) 
4 
Polymorphonuclear 
cells (cells/μL) 
≥1500 
≥1500 or ≥50% 
increase from 
baseline 
 
5 
Platelets (per μL) 
>100,000 
>100,00 or ≥50% 
increase from 
baseline 
(untransfused) 
 
  6 
Hemoglobin (g/dL) 
>11 (untransfused) 
>11 or ≥50% 
increase from 
baseline 
(untransfused) 
 
7 
Bone marrow 
lymphocytes (%)‡ 
<30, no nodules 
Nodular 
lymphocytes in 
marrow 
 
8 
Duration of response 
≥ 2 months 
≥ 2 months 
 
9 
Other 
 
 
Transformation 
(Richter’s, PLL) 
†CT scans (chest, abdomen, pelvis) are required to confirm response at least 2 months after initial determination of complete 
or partial response.  
‡Bone marrow examination is required only to confirm complete response at least 2 months after initial determination of 
complete response. 
Response and Progression Criteria for CLL 


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Complete Response (CR) 
Complete remission (CR) requires all of the following for a period of at least two 
months from completion of therapy: 
• Absence of lymphadenopathy > 1.5 cm on physical exam and CT scan. 
• No hepatomegaly or splenomegaly on physical exam (a CT scan also may be 
used to assess). 
• No clonal B-cells in the blood by flow cytometry. 
• Normal CBC as exhibited by polymorphonuclear leukocytes ≥ 1,500/μL 
platelets > 100,000/μL, hemoglobin > 11.0 g/dL (untransfused); lymphocyte 
count < 5,000/μL. 
• Bone marrow aspirate and biopsy must be normocellular for age with < 30% of 
nucleated cells being lymphocytes. Lymphoid nodules may be present but 
must be T-cell in origin. If these are demonstrated to be clonal B-cells, 
subjects should be considered to be a partial response. Additionally, if bone 
marrow is positive by two color flow cytometry for CLL cells, it should be 
considered a partial response. If the marrow is hypocellular, a bone marrow 
should be performed in 2-3 months. If blood counts fail to recover 
(polymorphonuclear leukocytes < 1,500/μL, platelets < 100,000/μL) at the time 
of the response evaluation but there is otherwise no evidence of CLL 
otherwise, a repeat determination should be performed at the time of count 
recovery. 
Complete Response with incomplete recovery (CRi) 
Subjects who fulfill the criteria for CR after induction with the exception of a persistent 
cytopenia (CR with incomplete recovery, CRi) that is believed to be treatment-related will 
be considered a CRi. As stated above, subjects falling into this category should ideally 
undergo a repeat bone marrow when counts recover fully. If the bone marrow at this time 
reveals no CLL, these subjects will be considered to be in complete remission at that time 
Partial Response (PR) 
Partial response (PR)  requires a ≥ 50% decrease in peripheral lymphocyte count 
from pre-treatment value, ≥ 50% reduction in lymphadenopathy of as many as 6 


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measurable lymph nodes, and/or ≥ 50% reduction in splenomegaly and/or hepatomegaly 
for a period of at least two months from completion of therapy. Additionally, these 
subjects must have one of the following: 
• Polymorphonuclear leukocytes ≥ 1,500/μL or 50% improvement from 
pretreatment value 
• Platelets > 100,000/μL or 50% improvement from pre-treatment value 
• Hemoglobin > 11.0 g/dL (untransfused) or 50% improvement from pretreatment 
value 
Stable disease (SD) 
Stable disease is defined as less than a PR (see above) but is not PD (see below). 
Progressive disease (PD) 
Progressive disease (PD, non-responders) requires the following: 
• 
≥ 50% increase in the products of at least two lymph nodes on two consecutive 
determinations two weeks apart (at least one lymph node must be ≥ 2 cm); 
appearance of new palpable lymph nodes. 
• 
≥ 50% increase in the size of the liver and/or spleen as determined by 
measurement below the respective costal margin; appearance of palpable 
hepatomegaly or splenomegaly, which was not previously present. 
• 
≥ 50% increase in the absolute number of circulating lymphocytes to at least 
5,000/μL. 
• 
Transformation to a more aggressive histology (i.e., Richter’s syndrome or 
prolymphocytic leukemia with ≥ 56% prolymphocytes). 
• 
The progression of any cytopenia (unrelated to autoimmune cytopenia), as 
documented by a decrease of Hb levels >2 g/dL or to < 10 g/dL, or by a decrease 
of platelet counts > 50% or to < 100,000/μL, which occurs at least 3 months after 
treatment, defines disease progression, if the marrow biopsy demonstrates an 
infiltrate of clonal CLL cells. During therapy, cytopenias cannot be used to define 
disease progression. 
 
 
 
International Working Group Criteria for response in NHL (Cheson, JCO 2007)  


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Response 
Definition 
Nodal masses 
Spleen, Liver 
Bone marrow 
CR 
Disappearance 
of all evidence 
of disease 
FDG-avid or PET positive 
prior to therapy; mass of 
any size permitted if PET 
negative 
Not palpable, 
nodules 
disappeared 
Infiltrate cleared on 
repeat biopsy; if 
indeterminate by 
morphology, 
immunohistochemitstry 
should be negative.2 
Variably FDG-avid or PET 
negative; regression to 
normal size on CT1 
PR 
Regression of 
measurable 
disease and no 
new sites 
50% decrease in SPD of 
up to 6 largest dominant 
nodes or masses;3 no 
increase in size of the 
other nodes 
>50% decrease 
in SPD of 
nodules (for 
single nodule in 
greatest 
transverse 
diameter); no 
increase in size 
of liver or spleen 
Irrelevant if positive 
prior to biopsy; cell 
type should be 
specified 
FDG-avid or PET positive 
prior to therapy; one of 
more PET positive at 
previously involved site 
Subjects who achieve 
CR by the above 
criteria, but have 
persistent morphologic 
bone marrow 
involvement will be 
considered PR4 
Variable FDG-avid or PET 
negative; regression on CT 
SD 
Failure to 
attain CR/PR 
or PD 
FDG-avid or PET positive 
prior to therapy; PET 
positive at prior sites of 
disease and no new sites 
on CT or PET 
 
 
Variably FDG-avid or PET 
negative; no change in size 
of previous lesions on CT 
Relapsed 
disease or 
PD5 
Any new lesion 
or increase by 
>50% of 
previously 
involved sites 
from nadir 
Appearance of a new 
lesion(s) >1.5 cm in any 
axis;6 >50% increase in 
SPD of more than one 
node;7 or >50% increase in 
longest diameter of a 
previously identified node 
>1 cm in short axis 
>50% increase 
from nadir in the 
SPD of any 
previous lesions 
New or recurrent 
involvement 
Lesions PET positive if 
FDG-avid lymphoma or 
PET positive prior to 
therapy 
Abbreviations: CR=complete remission; FDG[18F]=fluorodeoxyglucose; PET=positron emission tomography; CT=computed 
tomography; PR=partial remission; SPD=sum of the product of the diameters; SD=stable disease; PD=progressive disease. 


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1Lymph nodes/nodal masses ≤1.5 cm in their greatest transverse diameter for nodes >1.5 cm before therapy. Previously 
involved nodes that were 1.1 to 1.5 cm in their long axis and more than 1.0 cm in their short axis before treatment must 
have decreased to ≤1.0 cm in their short axis after treatment. 
2A sample that is negative by immunohistochemistry but that demonstrates a small population of clonal lymphocytes by flow 
cytometry will be considered a CR until data becomes available demonstrating a clear difference in subject outcome. 
3These nodes or masses should be selected according to all of the following; they should be clearly measurable in at least 
2 perpendicular dimentions; if possible they should be from disparate regionsof the body; and they should include 
mediastinal and retroperitoneal areas of disease whenever these sites are involved.  
4When the bone marrow was involved before therapy and a clinical CR was achieved, but with no bone marrow assessment 
after treatment, subjects should be considered partial responders. 
5Lymph nodes should be considered abnormal if the long axis is >1.5 cm regardless of the short axis. If a lymph node has 
a long axis of 1.1-1.5 cm, it should only be considered abnormal if its short axis is more than 1.0 cm. Lymph nodes ≤1.0 X 
≤1.0 cm will not be considered as abnormal for relapse or PD. 
6Increased FDG uptake in a previously unaffected site should only be considered relapsed or PD after confirmation with 
other modalities. In subjects with no prior history of pulmonary lymphoma, new lung nodules identified by CT are mostly 
benign. Thus, a therapeutic decision should not be made solely on the basis of the PET without histologic confirmation. 
7To be considered progressive disease, a lymph node with a diameter of the short axis of <1.0 cm must increase by ≥50% 
and to a size of 1.5 X 1.5 cm or more than 1.5 cm in the long axis. 
 
Time to Progression 
Time to progression will be measured as the time from when the subject started treatment 
to the time the subject is first recorded as having disease progression, or the date of death 
if the subject dies due to causes other than disease progression. 
Time to Treatment Failure 
Time to treatment failure will be measured as the time from when the subject started 
treatment to the time the subject is withdrawn due to: adverse events, progressive 
disease/insufficient therapeutic response, death, failure to return, and refused 
treatment/did not cooperate/withdrew consent.  The date of last dose of treatment will be 
used as the date of event in the case that PD was not recorded earlier. 
Survival 
Survival will be measured as the time from start of treatment to the date of death or the 
last date the subject was known to be alive. 
Time to Response 
For subjects who achieve a major objective response (CR or PR of measurable disease), 
the time to response will be assessed as the time from start of treatment to the date of 
response. 


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Appendix I:  Cairo-Bishop Definition of Tumor Lysis Syndrome108 
 
Table 14:  Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome 
(LTLS) 
Uric Acid 
≥ 476 μmol/l (≥ 8.0 mg/dl) or 25% increase from baseline 
Potassium 
≥ 6.0 mmol/l (≥ 6.0 mEq/l) or 25% increase from baseline 
Phosphorous 
≥1.45 mmol/l  (≥ 4.5 mg/dl) or 25 % increase from baseline 
Calcium 
≤ 1.75 mmol/l (≤ 7.0 mg/dl) or 25% decrease from baseline 
Laboratory tumor lysis syndrome (LTLS) is defined as either a 25% change or level above or below 
normal, as defined above, for any two or more serum values of uric acid, potassium, phosphate, and 
calcium within 3 days before or 7 days after the initiation of chemotherapy.  This assessment assumes 
that a subject has or will receive adequate hydration (± alkalinization) and a hypouricaemic agent(s). 
 
Table 15:  Cairo-Bishop Definition of Clinical TLS 
The presence of laboratory TLS and one or more of the following criteria: 
1. Creatinine:  ≥ 1.5 ULN (age > 12 years or age adjusted) 
2. Cardiac arrhythmia / sudden death 
3. Seizure* 
ULN, Upper limit of normal 
*Not directly attributable to a therapeutic agent 


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Table 16:  Cairo-Bishop Grading System for TLS 
Grade 
LTLS 
Creatinine 
Cardiac Arrhythmia 
Seizure 
0 
- 
≤ 1.5 x ULN 
None 
None 
1 
+ 
1.5 x ULN 
Intervention not 
indicated 
None 
2 
+ 
> 1.5 – 3.0 x ULN 
Non-urgent medical 
intervention indicated 
One brief generalized seizure; seizure(s) 
well controlled or infrequent; focal motor 
seizures not interfering with ADL 
3 
+ 
> 3.0 – 6.0 x ULN 
Symptomatic and 
incompletely 
controlled medically 
or controlled with 
device 
Seizure in which consciousness is 
altered; poorly controlled seizure 
disorder; breakthrough generalized 
seizures despite medical intervention 
4 
+ 
> 6.0 x ULN 
Life-Threatening 
Seizures of any kind that are prolonged, 
repetitive, or difficult to control 
5 
+ 
Death* 
Death* 
Death* 
LTLS, laboratory tumor lysis syndrome; ULN, upper limit of normal; ADL, activities of daily living 
*Probably or definitely attributable to clinical TLS 
 


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Appendix J:  Cockcroft-Gault estimation of CrCl: 
 
Cockcroft-Gault estimation of creatinine clearance (CrCl):  
(Cockcroft, 1976; Luke 1990) 
 
CrCl (mL/min) =  
    (140 –age) x (weight, kg)__           
   (Males) 
 
72 x (serum creatinine, mg/dL) 
 
CrCl (mL/min) =  
    (140 –age) x (weight, kg)_    x 0.85         
   (Females)  
72 x (serum creatinine, mg/dL)