Clinical trial NCT00899431
Conditions: Chronic Lymphocytic Leukemia
Keywords: Nonmyeloablative Stem Cell Transplantation Chronic Lymphocytic Leukemia CLL Immunomanipulation Fludarabine Lenalidomide Rituximab Thymoglobulin Stem Cell Transplantation
Sponsor: M.D. Anderson Cancer Center
Start date: 2009-05-06; Completion date: 2018-10-07
Enrollment: 39 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to learn if lenalidomide, when given with a stem cell transplant and chemotherapy (bendamustine, fludarabine, and rituximab), can help to control CLL. The safety of this treatment combination will also be studied.

Detailed description:
The Study Drugs Lenalidomide is designed to change the body's immune system. It may also interfere with the development of tiny blood vessels that help support tumor growth. Therefore, in theory, it may decrease or prevent the growth of cancer cells.

Bendamustine is designed to damage and destroy the DNA (genetic material) of cancer cells.

Fludarabine is designed to make cancer cells less able to repair damaged DNA (the genetic material of cells). This may increase the likelihood of the cells dying.

Rituximab is designed to attach to leukemia cells, which may cause them to die.

Before receiving the study drugs, 21 or more days must have passed since your last biological therapy, chemotherapy, radiotherapy, or other investigational therapy.

Before you begin therapy, you will have the following tests and procedures performed. The blood may need to be drawn daily. The doctor will tell you how often the other tests will need to be performed:

* You will have a physical exam.
* You will have blood transfusions of blood and platelets as needed.
* Blood (about 2 tablespoons) and urine will be collected for routine tests.
* Blood (about 6-10 tablespoons) will be drawn to check the effects of the transplant.
* You will have a chest x-ray and CT scans to check the status of the disease.
* You will have an ECG.
* You will have a bone marrow biopsy and aspirate, when the doctor thinks it is needed.

Study Treatment:

If you are found to be eligible to take part in this study, you will begin treatment within 30 days after the screening visit. All liquid study drugs will be given through a central venous catheter (CVC) that will be left in place throughout treatment. A CVC is a sterile flexible tube that will be placed into a large vein while you are under local anesthesia. Your doctor will explain this procedure to you in more detail, and you will be required to sign a separate consent form for this procedure.

On Days -13, -6, +1, and +8, you will receive rituximab over 5-7 hours by CVC.

On Days -5 to -3, you will receive fludarabine over 1 hour and bendamustine over 1 hour by CVC. You will be given standard drugs such as hydrocortisone and Tylenol to help decrease the risk of side effects. You may ask the study staff for information about how the drugs are given and their risks.

On Days -2 to -1, if the donor is not related or is not completely matched, you will receive thymoglobulin (ATG) over 4 hours by CVC. This will help to reduce the risk of your body rejecting the transplant.

On Days -2 to -1, if the donor is related, you will "rest" (not receive chemotherapy).

On Day -2, you will start to receive tacrolimus by CVC to help prevent graft-versus-host disease. This will be changed to a dose of tacrolimus by mouth, once you are discharged from the hospital. You will continue to take tacrolimus by mouth for 6-8 months following your transplant.

On Day 0, the blood stem cells that were collected from your donor will be transplanted (given back to your body) through the CVC over 30-45 minutes.

On Days 1, 3, and 6 after the stem cell transplant (and Day 11 if the donor is not related or not completely matched), you will receive methotrexate over 30-60 minutes by CVC to help prevent graft-versus-host disease.

On Day 7 after the transplant, G-CSF (filgrastim) will be injected under your skin once a day until your white blood cell counts recover. Filgrastim is designed to help increase the number of white blood cells.

Treatment with Lenalidomide:

If your blood cell counts are high enough and if you have not experienced side effects, between Days 90 and 100 after the transplant, you will be randomly assigned (as in the flip of a coin) into 1 of 2 groups. If you are in Group 1 you will take lenalidomide in addition to the treatment listed above. If you are in Group 2, you will not take lenalidomide.

If you are in Group 1, you will take lenalidomide 1 time every day for 3-12 months, depending on the disease response to the treatment.

You should swallow lenalidomide capsules whole, with water, at the same time each day. Do not break, chew, or open the capsules.

If you miss a dose of lenalidomide, take it as soon as you remember on the same day. If you miss taking your dose for the entire day, take your regular dose the next scheduled day (do NOT take double your regular dose to make up for the missed dose).

If you take more than the prescribed dose of lenalidomide you should seek emergency medical care (if needed) and contact the study staff right away.

You will be given standard drugs such as aspirin, Coumadin (warfarin), heparin, and/or allopurinol to help decrease the risk of side effects. You may ask the study staff for information about how the drugs are given and their risks.

If the doctor thinks it is needed, your dose and schedule of lenalidomide will be changed.

If you are in Group 2, you will take no additional drugs.

Pregnancy Tests While Taking Lenalidomide:

Women who are able to become pregnant must have 2 negative pregnancy tests: the first test within 10-14 days before lenalidomide is prescribed and the second test within 24 hours before lenalidomide is prescribed. This blood test will be taken as part of a routine blood draw. The prescription must be filled within 7 days.

Once a week for the first month you take lenalidomide, women who are able to become pregnant will have blood (about 1 teaspoon) drawn for a pregnancy test. Then, in females with regular menstrual cycles, blood (about 1 teaspoon) will be drawn for pregnancy testing every 4 weeks, at the end of study, and 28 days after the last dose of lenalidomide. If menstrual cycles are irregular, blood (about 1 teaspoon) will be drawn every 2 weeks, at the end of study, and 14 and 28 days after the last dose of lenalidomide.

Study Visits (both Groups):

You must stay in the Houston area for about 100 days after the stem cell transplant.

Between Days 25 and 35 and then about 3 months after the stem cell transplant:

* You will have a physical exam.
* You will have CT scans to check the status of the disease.
* You will have PET scan to check the status of the disease, if the doctor thinks it is needed.
* Blood (about 2 tablespoons) will be drawn for routine tests and to check the level of tacrolimus.
* You will have a bone marrow biopsy/aspirate to check the status of the disease.

Study Visits (Group 1):

If you are in Group 1, blood (about 2 tablespoons) will be drawn for routine tests weekly until the maximum dose of lenalidomide is reached, then once every 2 weeks while you are taking lenalidomide.

Follow-up:

Every 3 months during the first 18 months and then every 6 months up to 3 years:

* You will have a physical exam.
* You will have CT scans to check the status of the disease.
* You will have PET scans to check the status of the disease, if the doctor thinks it is needed.
* Blood (about 2 tablespoons) will be drawn for routine tests.
* You will have a bone marrow biopsy to check the status of the disease.

Length of Study:

You will be on study up to about 3 years. You will be taken off study if the disease gets worse or you experience any intolerable side effects.

End-of-Study Visit:

After you are off study, you will have an end-of-study visit:

* You will have a physical exam.
* You will have CT scans to check the status of the disease.
* You will have PET scans to check the status of the disease, if the doctor thinks it is needed.
* Blood (about 2 tablespoons) will be drawn for routine tests.
* You will have a bone marrow biopsy to check the status of the disease.

Data Confidentiality Plan:

Data will be collected in the SCT\&CT departmental database (BMTWeb). This database is password-protected, contains audit tracking, and follows all federal guidelines. Your personal identifying information will be removed for this analysis; no sensitive information will be shared.

This is an investigational study. All of the drugs used in this study are FDA approved and commercially available for the treatment of CLL. The use of the drugs together in this study is investigational.

Up to 80 patients will take part in this study. All will be enrolled at MD Anderson.

Arms: arm 1: Chemotherapy, Plus Lenalidomide - Lenalidomide starting dose 5 mg by mouth every other day; increase to 5 mg/d daily in 4-5 weeks for 6 - 12 months. Fludarabine 30 mg/m\^2 intravenously daily on days -5, -4, -3. Rituximab 375 mg/m2 intravenously on day -13, and 1000 mg/m\^2 on days -6, +1 and +8. Thymoglobulin 1.0 mg/kg intravenously over 4 hours (day -2 and -1). On Day 0, donor blood stem cells collected will be transplanted over 30-45 minutes. Bendamustine 130 mg/m2/day by vein daily on day -5, -4, -3 (following Fludarabine). Allopurinol 300 mg by mouth daily beginning at the start of lenalidomide therapy and continuing for 3 months. arm 2: Chemotherapy Treatment, No Lenalidomide - Fludarabine 30 mg/m\^2 intravenously daily on days -5, -4, -3. Rituximab 375 mg/m2 intravenously on day -13, and 1000 mg/m\^2 on days -6, +1 and +8. Thymoglobulin 1.0 mg/kg intravenously over 4 hours (day -2 and -1). On Day 0, donor blood stem cells collected will be transplanted over 30-45 minutes. Bendamustine 130 mg/m2/day by vein daily on day -5, -4, -3 (following Fludarabine).
Interventions: intervention 1: Lenalidomide intervention 2: Fludarabine intervention 3: Rituximab intervention 4: Thymoglobulin intervention 5: Stem Cell Transplantation intervention 6: Bendamustine intervention 7: Allopurinol
Intervention descriptions: intervention 1: Starting dose 5 mg by mouth every other day; increase to 5 mg/d daily in 4-5 weeks for 6 - 12 months intervention 2: 30 mg/m\^2 intravenously daily on days -5, -4, -3. intervention 3: 375 mg/m2 intravenously on day -13, and 1000 mg/m\^2 on days -6, +1 and +8. intervention 4: 1.0 mg/kg intravenously over 4 hours (day -2 and -1). intervention 5: On Day 0, donor blood stem cells collected will be transplanted over 30-45 minutes. intervention 6: 130 mg/m2/day by vein daily on day -5, -4, -3 (following Fludarabine). intervention 7: 300 mg by mouth daily beginning at the start of lenalidomide therapy and continuing for 3 months.

Protocol documents:
Prot_SAP_000.pdf: 
2007-0871 
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Page 1 
 
 
 
 
 
 
 
 
Protocol Title: Nonmyeloablative Stem Cell Transplantation 
with or without Lenalidomide for Chronic 
Lymphocytic Leukemia (RV-CLL-PI-0294) 
 
 
 
STUDY DRUG 
Revlimid® 
(lenalidomide) 
MD Anderson Protocol 
NUMBER: 
 
Celgene Tracking 
Number: 
2007-0871 
 
 
 
RV-PI-CLL-0294 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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STUDY PERSONNEL 
 
 
 
 
Supporter: 
Celgene Corporation 
86 Morris Ave, 
Summit, NJ  07901 
 
1-800-742-3107 
 
 
 
 
Study Location: University of Texas MD Anderson Cancer Center 
Principal Investigator: Issa F. Khouri, MD 
Study Coordinator: Glenda Woodworth, RN 


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Table of Contents 
Protocol Synopsis......................................................................................................... 4 
Background and Rationale ........................................................................................... 8 
Study Objectives and Endpoints  ............................................................................... 13 
Investigational Plan  .................................................................................................... 13 
Adverse Events  .......................................................................................................... 28 
Response Criteria  ....................................................................................................... 32 
Protocol Amendments/Deviations  ............................................................................. 32 
Data Management  ....................................................................................................... 33 
Biostatistical Analysis  ............................................................................................... 33 
Regulatory Considerations  ........................................................................................ 35 
References  ................................................................................................................. 37 
Appendices  ................................................................................................................ 39 
Appendix A: Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods  ....................................................................... 39 
Appendix B: Schedule of Study Assessments * .................................................. 41 
Appendix C: ECOG Performance Status Scale .................................................... 44 
Appendix D: NCI CTC Version 3.0 ......................................................................... 45 
Appendix E: CLL Staging – NCIWG Criteria ......................................................... 46 


2007-0871 
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Protocol Synopsis 
 
PROTOCOL TITLE: Non-Myeloablative Transplantation with or without Lenalidomide 
maintenance for CLL 
PROTOCOL NUMBER: 
2007-0871 
 
STUDY DRUG SUPPLIES: 
 
For study participants, Celgene Corporation will 
provide lenalidomide at no charge through the 
RevAssist® program. 
Revlimid®, lenalidomide 
INDICATION: 
CLL/Maintenance 
 
STUDY PHASE: 
Phase II 
 
Introduction: 
 
The clinical efficacy of lenalidomide in patients with relapsed or refractory CLL has now been 
confirmed in two independent clinical trials. Investigators conducted a phase II study at Roswell 
Park Cancer Institute (Buffalo, NY), in CLL patients progressing, or refractory to at least one prior 
therapy administering lenalidomide for 21 days of a 28-day cycle. Among the first 29 patients, the 
starting dose of lenalidomide was 25 mg/d, whereas the subsequent 16 patients started 
lenalidomide at 10 mg/d and the dose at 5 mg every 2 weeks as tolerated to a maximum of 25 
mg/d. Forty-five patients with a median of four (range, one to 10) prior therapies were enrolled, 
64% with Rai stage III/IV, 51% were fludarabine refractory, and 29% had Zap-70+ cells. In  
another phase II study, Ferrajoli et al used a starting dose of 10 mg every day followed by a dose 
escalation of 5 mg every 28 days to a maximum of 25 mg/d to treat 44 patients with a median of 5 
prior therapies, a median β2 microglobulin level of 4.3 mg/dL (range, 1.6 to 10.1 mg/dL),  
advanced Rai stage in 45%, fludarabine refractory in 27%, and prior alemtuzumab in 51%. 
 
The overall response in the Roswell Park study was 57.5% with a complete response rate of 
18%.The median time to best response was 5.9 months (range, 1.6 to 18.3 months) with a 
median progression-free survival of 19.4 months (range, 1.2 to 38 months). Complete responses 
observed in this study were associated with undetectable minimal residual disease by flow 
cytometry and polymerase chain reaction for immunoglobulin heavy chain gene. The overall 
response in the M.D. Anderson study was 32% with a 7% complete response rate. With a median 
follow-up of 11 months, the median duration of response was 12 months. 
 
Notably, clinical responses were observed even in patients with high-risk cytogenetics, Zap-70 
patients or those were fludarabine refractory. Additionally, patients in the Roswell Park study who 
developed disease progression while on lenalidomide responded when rituximab was added to 
lenalidomide (ORR71%), suggesting additive benefit. 
 
Correlative investigations were conducted on pretreatment primary tumor cells to study the effect 
of lenalidomide on the tumor cell as well as its micro-environment. It was observed that exposure 
to lenalidomide failed to induce a direct proapoptotic effect on these CLL cells in vitro despite an 
obvious antileukemic effect in corresponding patients. Nevertheless, treatment with lenalidomide 
resulted in modulation of the CLL cell phenotype with upregulation of costimulatory mlecules 
(including CD80, CD86, and CD40). This change in surface expression of costimulatory 
molecules concurrently with increase in circulatory NK cells may explain the immediate immune 
recognition phenomenon clinically presenting as the flare reaction that is associated with 
antileukemic effects in vivo. 
 
The most common toxicity reported in the Roswell Park study was grade 1/2 fatigue (73%). The 


2007-0871 
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incidence of grade 3/4 neutropenia and thrombocytopenia was 70% and 45%, respectively, with 
only 15% of patients developing neutropenic infections. In the University of Texas M.D. Anderson 
Cancer Center experience, the incidence of grade 3/4 neutropenia and thrombocytopenia was 
39% and 15%, respectively, in 325 courses of treatment. The incidence of fatigue was 1%. 
Differences in toxicity between studies may reflect the lower starting dose of lenalidomide in the 
latter study. 
 
 
Allogeneic stem-cell transplantation after myeloablative conditioning is an effective therapy for 
relapsed chronic lymphocytic leukemia (CLL). The treatment-related mortality has been 
significant, however, with a 30-40% risk of death within 100 days of the transplant. Allogeneic 
transplantation can confer an immune mediated graft-versus-malignancy effect. This has 
stimulated the development of reduced dose, non-myeloablative conditioning regimens, which 
support allogeneic donor cell engraftment and allow graft-versus-leukemia effect to occur. 
 
Nonmyeloablative allogeneic transplantation is an effective therapy for patients with CLL who 
have failed conventional chemotherapy, and or who have high risk features or had Richter’s 
transformation. We have used successfully a conditioning fludarabine, cyclophosphamide, and 
rituximab (FCR) as conditioning regimen. However, about 50% of patients with refractory disease 
at study entry require early immunosuppression withdrawal after transplantation and donor 
lymphocyte infusion, due to either persistent or progressive disease. This is a significant cause of 
mortality and morbidity. Maintenance with lenalidomide after transplant may decrease both the 
need for immunomanipultation and the risk of graft-versus-host disease. 
 
Starting with patients enrolled in 2011, a conditioning fludarabine, bendamustine (130 
mg/m2/dayx3), and rituximab (FBR) as conditioning regimen has been developed in our 
Department (protocol 2008-0246), Bendamustine is proven to be effective in patients with CLL. 
With the FBR conditioning, 56% of patients did not nadir to an ANC<500 and 81% did not reach a 
platelet count of <20,000. An important detail that has thus far precluded randomization in 50% of 
patients after FCR. In addition, the FBR regimen has been well tolerated and is now given as 
outpatient. 
 
 
 
STUDY OBJECTIVES: 
 
Primary: 
 
To compare the need for immunomanipulation within 18 months after non-myeloablative 
allogeneic transplantation for CLL between the two combination therapies with or without 
lenalidomide maintenance. For this purpose, “immunomanipulation” is defined as any one of the 
following events: 
 
1) Cessation of administering tacrolimus treatment within the first 6 months after 
allotransplant due to persistent disease or progression. 
 
2) Boost of donor lymphocytic infusion (DLI) administered anytime between 3 and 18 months 
after allotransplant. 
 
 
Secondary: 
 
To evaluate: 
 
 
1) time to treatment failure 
2) time to molecular remission 
3) safety profile of the combination therapies 
4) acute and chronic graft-vs-host disease rates and 
5) percentage of blood donor cell after transplant in the recipient. 


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STUDY DESIGN: 
 
This randomized phase II trial compared FCR, and Thymoglobulin plus lenalidomide (FCR+ L) to 
FCR, and Thymoglobulin (FCR) in patients with CLL undergoing allotransplant on 25 patients 
enrolled from May 13, 2009 to December 2, 2010. 
 
Starting with patients enrolled in 2011, this randomized phase II trial will compare FBR, (and 
Thymoglobulin, if unrelated donor) plus lenalidomide (FBR+ L) to FBR, (and Thymoglobulin, if 
unrelated donor)(FBR) in patients with CLL undergoing allotransplant. 
 
The primary objective is to compare the need for immunomanipulation between the treatment 
groups. For this trial, immunomanipulation is defined as either the cessation of the administration 
of immunosuppression treatment within the first six months after allotransplant due to intolerability 
or the administration of DLI any time between 3 and 18 months after transplant. 
 
Our primary outcome is the need for immunomanipulation by month 18. Our target enrollment is 
to have a maximum of 60 patients to be randomized, and we expect to enroll 3 patients per 
month. We will follow all patients for 18 months. We also expect that 20 additional patients may 
be initially enrolled to receive the transplantation, but later may not meet the criteria for 
maintenance randomization. 
 
Based upon published data, we expect that 49% of the patients in the FCR arm will need 
immunomanipulation by 18 months. We do not expect this incidence to be different with FBR. We 
hope to see a reduction in this proportion in the FBR + L arm to 25%. 
 
Patients who are not in CR following transplant will be randomized in a 1:1 ratio between FBR  
and FBR + L. Patients will be stratified by the presence or absence of del 17 by FISH by PB at 
any point in time during their disease history, and the number of prior therapies received (less or 
equal to 2 vs greater than 2). Prior therapies are defined by 1) combination chemotherapies, 2) 
chemo-antibodies, 3) biological agents. The trial will be stopped early and a treatment selected as 
being “better” if the probability is 0.95 or more that the probability of needing immunomanipulation 
on one treatment arm is greater than for the other arm. However, if all 60 patients are enrolled, 
then a treatment will be selected as being “better” if the probability is 0.90 or more that the 
probability of needing immunomanipulation for one treatment is greater than the other. Additional 
details are provided below in the section labeled “Technical Details”. The operating 
characteristics of this study design based upon 2000 simulations of this trial are summarized in 
Table 1 below. 
 
 
We will report the posterior probability that the need for immunomanipulation in one arm is 
greater than the need for immunomanipulation in the other arm. 


2007-0871 
July 31, 2017 
Page 7 
 
 
 
Table 1. Operating Characteristics of Study Design 
Neither 
FCR 
FCR + L 
True Rate of Need for 
Immunomanipulation 
--- 
0.49 
0.25 
Pr(Selected) 
19.7% 
0 
80.3% 
True Rate of Need for 
Immunomanipulation 
--- 
0.49 
0.49 
Pr(Selected) 
81.8% 
8.9% 
9.3% 
True Rate of Need for 
Immunomanipulation 
--- 
0.25 
0.25 
Pr(Selected) 
75.5% 
3.8% 
20.7% 
True Rate of Need for 
Immunomanipulation 
--- 
0.49 
0.35 
Pr(Selected) 
53.5% 
0.6% 
45.9% 
True Rate of Need for 
Immunomanipulation 
--- 
0.60 
0.35 
Pr(Selected) 
26.5% 
0.2% 
73.3% 
 
 
 
Analyses of secondary endpoints include evaluation of: 
 
1) time to treatment failure 
2) time to molecular remission 
3) safety profile of the combination therapies 
4) acute and chronic graft-vs-host disease rates and 
5) percentage of blood donor cell after transplant in the recipient. 
 
 
Technical Details 
 
Starting with patients enrolled in 2011: The two treatment arms will be denoted by T (FBR) and 
TL (FBR + L). Denote the probability that a patient needs immunomanipulation in each arm as θT 
and θTL, respectively. Assume that θT and θTL are independent and that θT ~ Beta(aT,bT) and that 
θTL ~ Beta(aTL,bTL). Here, (aT,bT) can be interpreted as the number of prior successes and 
failures, respectively, in arm T, and (aTL,bTL) can be interpreted as the number of prior successes 
and failures in arm TL. The mean values of these distributions are aT/(aT + bT) and aTL/(aTL + bTL) 
 
In a previous trial of FCR, 19 of 39 patients required immunomanipulation by 18 months. We 
expect the same incidence with FBR. We discount the information available by 75% and assume 
that (aT,bT) = (4.9,5.1). We further assume that (aTL,bTL) = (0.98, 1.02), which has the same mean 
but a higher variance, reflecting that little information is available regarding the FBR + L arm. 
 
During the trial, the posterior probability that the need for immunomanipulation rate is greater in 
arm T is represented by pT(data) = Pr(θT > θTL). Similarly, pTL(data) = 1 – pT(data). If at any point 
during the trial pTL(data) > 0.95 (< 0.05) the trial will be terminated and treatment FBR + L will be 
selected as superior (inferior). If the maximum number of patients is enrolled in the trial and 
pTL(data) > 0.90 (< 0.10) treatment TL will be selected as superior (inferior). 


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Background and Rationale 
 
Introduction 
 
Lenalidomide is a proprietary IMiD™ compound of Celgene Corporation.  IMiD™ compounds 
have both immunomodulatory and anti-angiogenic properties which could confer antitumor and 
antimetastatic 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. (3) 
 
Although the exact antitumor mechanism of action of lenalidomide is unknown, a number of 
mechanisms are postulated to be responsible for lenalidomide’s activity against multiple 
myeloma. Lenalidomide has been shown to increase T cell proliferation, which leads to an 
increase in IL-2 and IFN-gamma secretion. The increased level of these circulating cytokines 
augment natural killer cell number and function, and enhance natural killer cell activity to yield an 
increase in multiple myeloma cell lysis (4).  In addition, lenalidomide has direct activity against 
multiple myeloma and induces apoptosis or G1growth arrest in multiple myeloma cell lines and in 
multiple myeloma cells of patients resistant to melphalan, doxorubicin and dexamethasone (5). 
 
Clinical experience in solid tumors with lenalidomide 
 
Twenty patients with varying types of solid tumors (13 with malignant melanoma, 2 each with 
carcinoma of the pancreas and non-small-cell lung cancer [NSCLC], 1 each with renal carcinoma, 
breast carcinoma, and carcinoid-unknown primary) were enrolled in a Phase 1 study of 
lenalidomide conducted at the St. George Hospital, London, UK. This was a non-randomized, 
open-label with-in patient dose-escalation design, where patients started on 5 mg/day for 7 days 
and then increased their dose every 7 days to 10 mg/day, 25 mg/day, and 50 mg/day for a total of 
4 weeks on therapy (6). 
 
Investigators at the NCI have enrolled 20 patients, including 18 patients with recurrent high-grade 
gliomas and 2 with other refractory CNS malignancies (1 recurrent atypical meningioma and 1 
multiple recurrent spinal hemangioblastomas) into a phase I trial of lenalidomide given on Days 1 
through 21 every 28 days. Treatment has been well tolerated with 1 grade 2 myelosuppression 
as the only toxicity > grade 1 (7). 
 
In an ongoing phase I trial in patients with refractory metastatic cancer conducted through the 
NCI, 12 patients with metastatic androgen independent prostate cancer have been enrolled. 
Lenalidomide was administered in daily doses of 5mg (3 patients), 10mg (3 patients) and 20mg (6 
patients). Dose limiting toxicity was seen at 20mg/day (1 grade 3 thrombosis and 1 grade 3 
hypotension). Stable PSA values for at least 8 weeks were observed in 6 patients (8). 
 
In a phase III, multi-center, randomized parallel group study comparing two dose regimens of 
lenalidomide, 293 patients with malignant melanoma were enrolled. Subjects were randomized 
to receive treatment with lenalidomide at a dose of 5 mg per day orally for 28 days or to 25 mg 
per day orally for 21 days with a 7 day rest (28 day cycle). Treatment continued until the patient 
developed disease progression or intolerable adverse events occurred. Interim analysis failed to 
show an advantage of one regimen over the other with respect to survival. Analyses of response 
rates are pending. The toxicity profile was similar in both dose groups and the most frequent 
adverse events were fatigue, seen in 32% of patients, followed by nausea and diarrhea, seen in 
24% and 20% of patients respectively.  Neutropenia and thrombocytopenia were seen in 2.4% 
and 2.0% of patients respectively. Grade 3 and 4 toxicities were seen infrequently (<15%). 
 
A second phase III randomized trial compared a lenalidomide dose of 25 mg daily orally for 21 
days with a 7 day rest (28 day cycle) to placebo in patients with metastatic melanoma. Three 
hundred and five patients enrolled on this study and a preplanned interim analysis failed to 
demonstrate a survival advantage. Response rates are being analyzed. The toxicity profile was 
favorable and similar to the previous phase III study. (14) 


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Clinical experience in multiple myeloma with lenalidomide 
 
In 2 phase I studies in multiple myeloma, a total of 41 patients have been treated with 
lenalidomide. In one study at the University of Arkansas, 15 patients who relapsed or were 
refractory to high dose melphalan therapy with stem cell transplant were treated for 4 weeks in an 
open-label safety study and were permitted to continue therapy in an extension phase of the trial. 
Patient cohorts were treated at the following daily doses: 5mg, 10mg, 25mg, and 50mg (9).  In a 
similar study at the Dana Farber Cancer Institute, 27 patients with rapidly advancing refractory 
multiple myeloma were enrolled (10). 
 
Anti-myeloma activity was observed in each of these 2 phase I studies. Decreases in neutrophil 
and platelet counts were the dose-limiting toxicities associated with lenalidomide. The maximum 
tolerated dose (MTD) was not reached within 28 days. Due to dose modifications associated with 
myelosuppression observed beyond Day 28 at the 25mg and 50mg daily dose levels, the dose 
schedule most widely used in future studies has been lenalidomide 25 mg on Days 1-21,  
repeated every 28 days. 
 
Pharmacokinetic analyses were performed on 15 multiple myeloma patients treated in the phase I 
studies. Absorption was found to be rapid on both Day 1 and Day 28 with time to maximum blood 
levels ranging from 0.7 to 2.0 hours at all dose levels (5mg, 10mg, 25mg, and 50mg). Plasma 
lenalidomide declined in a monophasic manner with elimination half-life ranging from 2.8 to 6.1 
hours on both Day 1 and 28 at all 4 doses. No plasma accumulation was observed with multiple 
daily dosing. Peak and overall plasma concentrations were dose proportional over the dosing 
range of 5mg to 50mg (11). 
 
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. All patients were treated on Days 1-21 of a 28-day cycle. Patients treated  
with 15mg BID experienced more myelosuppression and dose reductions compared with patients 
treated with 30mg 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 (12). 
 
A recent phase II trial utilizing lenalidomide plus dexamethasone for newly diagnosed multiple 
myeloma patients was recently reported by the Mayo Clinic. Lenalidomide was given orally 25 mg 
daily on days 1-21 of a 28-day cycle. Dexamethasone was given orally 40 mg daily on days 1-4, 
9-12, 17-20 of each cycle. Objective response was defined as a decrease in serum monoclonal 
protein by 50% or greater and a decrease in urine M protein by at least 90% or to a level less  
than 200 mg/24 hours, confirmed by two consecutive determinations at least 4 weeks apart. 
Thirty-one of 34 patients achieved an objective response, including 2 (6%) achieving complete 
response (CR), and 11 (32%) meeting criteria for both very good partial response and near 
complete response, resulting in an overall objective response rate of 91%. Of the 3 remaining 
patients not achieving an objective response, two had minor response (MR) and one stable 
disease. 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%). Lenalidomide®/dexamethasone is a highly active regimen with manageable side-effects in 
the treatment of newly diagnosed myeloma. 
 
A phase I/II trial of liposomal doxorubicin (Doxil®), vincristine, dexamethasone (DVd) and 
lenalidomide in heavily pretreated relapsed/refractory multiple myeloma patients is ongoing. The 
MTD of lenalidomide was 10mg on Days 1-21 in combination with Doxil® 40mg/m2 IVPB on Day 
1, vincristine 2mg IVP on Day 1 and dexamethasone 40mg PO on Days 1-4 cycled every 28 
days. All patients received amoxicillin, acyclovir and aspirin 81mg prophylactically. The dose 
limiting toxicity with lenalidomide 15mg on Days 1-21 in combination with DVd was sepsis/septic 
shock (13). Additional phase I trials of lenalidomide with chemotherapy in advanced malignancies 
are in progress. 
 
Celgene Corporation sponsored 2 multicenter, randomized, double-blinded, placebo-controlled 
phase III trials [1 U.S. (MM-009) and 1 international (MM-010)] in patients with relapsed or 
refractory multiple myeloma (14).  More than 350 patients were enrolled into each of these studies. 


 
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All patients had to be considered sensitive to dexamethasone and were treated with 
dexamethasone 40mg daily on Days 1-4, 9-12 and 17-20. In addition to receiving 
dexamethasone, patients were randomized to lenalidomide 25mg or placebo each given daily on 
Days 1-21. Cycles were repeated every 28 days.   After 4 cycles, there was a predetermined 
reduction of the dexamethasone dose to 40mg 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 subjects receiving the combination of lenalidomide (Len) plus 
dexamethasone (Dex) had significantly longer times to progression and higher response rates 
than those treated with single-agent dexamethasone. 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. 
 
 
Clinical experience in myelodysplastic syndromes (MDS) with lenalidomide 
 
An exploratory trial in 43 MDS patients with transfusion dependent or symptomatic anemia was 
conducted at the University of Arizona (15). Patients received lenalidomide at doses of 25mg or 
10mg per day, or of 10mg on Days 1-21, repeated every 28 days. All patients had had no 
response to erythropoietin or had a high endogenous erythropoietin level. Response rates were 
similar across the 3 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. Patients with a major response reached a median hemoglobin level of 13.2 
grams per deciliter, with a corresponding 5.3 grams per deciliter median increase from baseline. 
After a median follow-up of 81 weeks, the median duration of major response had not been 
reached and was more than 48 weeks. Of 20 patients with karyotypic abnormalities, 10 (50%) 
patients had a complete cytogenetic remission. The response rate was highest in patients with a 
clonal interstitial deletion involving chromosome 5q31.1 (10 out of 12, 83%). 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 10mg on 
Days 1-21, repeated every 28 days, to 44 patients, and at a dose of 10mg daily to the other 104 
patients. Transfusion independence was achieved in 93 patients (64%), with a median 
hemoglobin increase of 3.9g/dl. Cytogenetic response was achieved in 76% of transfusion 
independent patients with 55% achieving a cytogenetic complete response. Pathologic complete 
response was documented in 32 out of 110 (29%) evaluable patients. 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. 
 
Another Celgene sponsored trial (MDS-002) in patients with low to intermediate-1 risk MDS 
enrolled 215 patients, of whom, 166 were documented to have low to intermediate-1 risk MDS. 
Among the 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% or greater decrease in blood 
transfusion requirement. The median duration of transfusion-independence was 41 weeks. The 
median baseline hemoglobin level was 8.0g/dl, which increased by 3.2g/dl in responding patients. 
Among 20 patients evaluable for cytogenetic response, 9 patients (45%) experienced a 
cytogenetic remission (14). 
 
Clinical Experience in Chronic Lymphocytic Leukemia (CLL) 
 
The clinical efficacy of lenalidomide in patients with relapsed or refractory CLL has now been 
confirmed in two independent clinical trials. Investigators conducted a phase II study at Roswell 
Park Cancer Institute (Buffalo, NY), in CLL patients progressing, or refractory to at least one prior 
therapy administering lenalidomide for 21 days of a 28-day cycle16. Among the first 29 patients, 
the starting dose of lenalidomide was 25 mg/d, whereas the subsequent 16 patients started 
lenalidomide at 10 mg/d and the dose at 5 mg every 2 weeks as tolerated to a maximum of 25 
mg/d. Forty-five patients with a median of four (range, one to 10) prior therapies were enrolled, 


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64% with Rai stage III/IV, 51% were fludarabine refractory, and 29% had Zap-70+ cells. In  another 
phase II study, Ferrajoli et al17 used a starting dose of 10 mg every day followed by a  dose 
escalation of 5 mg every 28 days to a maximum of 25 mg/d to treat 44 patients with a 
median of 5 prior therapies, a median β2 microglobulin level of 4.3 mg/dL (range, 1.6 to 10.1 
mg/dL), advanced Rai stage in 45%, fludarabine refractory in 27%, and prior alemtuzumab in 
51%. 
 
The overall response in the Roswell Park study was 57.5% with a complete response rate of 
18%.The median time to best response was 5.9 months (range, 1.6 to 18.3 months) with a 
median progression-free survival of 19.4 months (range, 1.2 to 38 months). Complete responses 
observed in this study were associated with undetectable minimal residual disease by flow 
cytometry and polymerase chain reaction for immunoglobulin heavy chain gene. The overall 
response in the M.D. Anderson study was 32% with a 7% complete response rate. With a median 
follow-up of 11 months, the median duration of response was 12 months. 
 
Notably, clinical responses were observed even in patients with high-risk cytogenetics, Zap-70 
patients or those were fludarabine refractory. Additionally, patients in the Roswell Park study who 
developed disease progression while on lenalidomide responded when rituximab was added to 
lenalidomide(ORR71%), suggesting additive benefit. 
 
Correlative investigations were conducted on pretreatment primary tumor cells to study the effect 
of lenalidomide on the tumor cell as well as its micro-environment18. It was observed that 
exposure to lenalidomide failed to induce a direct proapoptotic effect on these CLL cells in vitro 
despite an obvious antileukemic effect in corresponding patients. Nevertheless, treatment with 
lenalidomide resulted in modulation of the CLL cell phenotype with upregulation of costimulatory 
mlecules (including CD80, CD86, and CD40). This change in surface expression of costimulatory 
molecules concurrently with increase in circulatory NK cells may explain the immediate immune 
recognition phenomenon clinically presenting as the flare reaction that is associated with 
antileukemic effects in vivo. 
 
The most common toxicity reported in the Roswell Park study was grade 1/2 fatigue (73%). The 
incidence of grade 3/4 neutropenia and thrombocytopenia was 70% and 45%, respectively, with 
only 15% of patients developing neutropenic infections. In the University of Texas M.D. Anderson 
Cancer Center experience, the incidence of grade 3/4 neutropenia and thrombocytopenia was 
39% and 15%, respectively, in 325 courses of treatment. The incidence of fatigue was 1%. 
Differences in toxicity between studies may reflect the lower starting dose of lenalidomide in the 
latter study. 
 
Tumor flare reaction is an important adverse effect of lenalidomide observed uniquely in patients 
with CLL. It is characterized by the sudden onset of tender swelling of disease-involved lymph 
nodes with overlying inflammation of the skin, enlargement of liver and/or spleen, low-grade 
fever, rash, and, rarely, with a rise in the peripheral-blood white cell count. The median duration 
of the flare reaction in the Roswell Park study was 14 days, with most patients experiencing the 
flare only during the first cycle. In neither of the two studies was the flare reaction the cause of 
termination of therapy. 
 
The incidence of flare reaction was significantly lower in the M.D. Anderson study. The  
differences between these studies may reflect disparities in patient populations (more heavily 
pretreated and prior treatment with alemtuzumab) or variation in starting dose (25 v 10 mg). In the 
Roswell Park experience, tumor flare correlated with clinical response; all but one patient who 
achieved a complete response had grade 3 or worse flare reaction. Ongoing studies will further 
clarify the importance of flare reaction. Although no deaths were attributed to tumor flare in either 
trial. 
 
 
Rationale for Allogeneic Stem Cell Transplantation for CLL and Use of 
Lenalidomide 
 
Allogeneic stem-cell transplantation after myeloablative conditioning is an effective therapy for 
relapsed chronic lymphocytic leukemia. The treatment-related mortality has been significant, 
however, with a 30-40% risk of death within 100 days of the transplant. Allogeneic 


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transplantation can confer an immune mediated graft-versus-malignancy effect. This has 
stimulated the development of reduced dose, non-myeloablative conditioning regimens, which 
support allogeneic donor cell engraftment and allow graft-versus-leukemia effect to occur19,20. 
 
Nonmyeloablative allogeneic transplantation is an effective therapy for patients with CLL who 
have failed conventional chemotherapy, and or who have high risk features or had Richter’s 
transformation. We have used successfully a conditioning fludarabine, cyclophosphamide and 
rituximab as conditioning regimen20. However, about 50% of patients with refractory disease at 
study entry require early immunosuppression withdrawal after transplantation and donor 
lymphocyte infusion, due to either persistent or progressive disease. This is a significant cause of 
mortality and morbidity. Maintenance with lenalidomide after transplant may decrease both the 
need for immunomanipultation and the risk of graft-versus-host disease. 
 
Starting with patients enrolled in 2011, a conditioning fludarabine, bendamustine (130 
mg/m2/dayx3), and rituximab (FBR) as conditioning regimen has been developed in our 
Department (protocol 2008-0246), Bendamustine is proven to be effective in patients with CLL. 
With the FBR conditioning, 56% of patients did not nadir to an ANC<500 and 81% did not reach a 
platelet count of <20,000. An important detail that has thus far precluded randomization in 50% of 
patients after FCR. In addition, the FBR regimen has been well tolerated and is now given as 
outpatient. 
 
 
Indications and Usage: 
Lenalidomide® (lenalidomide) is indicated 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. Lenalidomide®   
is also approved in combination with dexamethasone for the treatment of patients with multiple 
myeloma that have received at least one prior therapy. 
 
 
 
Adverse Events 
 
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. 
 
Lenalidomide may cause breakdown products of the cancer cells to enter the blood stream, which 
may lead to heart rate abnormalities, kidney failure, muscle twitching, and/or muscle cramps. 
Tumor flare reaction (TFR) has been reported frequently in CLL patients treated with 
lenalidomide. Tumor lysis syndrome (TLS) has been reported in CLL patients treated with 
lenalidomide. Precautions must be taken to prevent TLS including proper selection of patients 
with regard to renal function, correction of electrolyte abnormalities, and TLS prophylaxis and 
monitoring. 
 
Complete and updated adverse events are available in the Investigational Drug Brochure and the 
IND Safety Letters. 


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Study Objectives and Endpoints 
 
Objectives 
 
Primary objectives 
 
x 
To compare the need for immunomanipulation within 18 months after non-myeloablative 
allogeneic transplantation for CLL between the two combination therapies with or without 
lenalidomide maintenance. For this purpose, “immunomanipulation” is defined as any one 
of the following events: 1) Cessation of administering tacrolimus treatment with in the first 
6 months after allotransplant due to persistent disease or progression. 2) Boost of donor 
lymphocytic infusion (DLI) administered anytime between 3 and 18 months after 
allotransplant. 
 
Secondary study objectives 
 
x 
To evaluate 1) time to treatment failure; 2) time to molecular remission; 3) safety profile of 
the combination therapies; 4) acute and chronic graft-vs-host disease (GVHD) rates; and 
5) percentage of blood donor cell after transplant in the recipient. 
 
 
 
Endpoints 
 
Primary Endpoint 
 
x 
The primary endpoint is the need for immunomanipulation after non-myeloablative stem 
cell transplantation for CLL. The hypothesis is that lenalidomide will decrease the need 
for immunomanipulation, compared with the arm without it. 
 
Secondary Endpoints 
 
x 
To evaluate 1) time to treatment failure; 2) time to molecular remission; 3) safety profile of 
the combination therapies, and 4) aGVHD and cGVHD rates, 5) percentage of donor cell 
after transplant in the recipient. 
 
x 
For each treatment arm, the evidence of toxicity will be monitored closely. 
 
x 
The stopping boundaries for either arm are (# Grade 3 or 4 non-hematologic toxicity). 
 
x 
Adverse events will be tabulated by category and grade in each treatment arm. The rate 
of acute GVHD or chronic GVHD will be estimated. 
 
 
Investigational Plan 
 
Overall design 
 
Starting with patients enrolled in 2011: Patients with eligible CLL will receive an allogeneic stem 
cell transplantation after a non-myeloablative conditioning with fludarabine, bendamustine, and 
rituximab (FBR). Thymoglobulin will be added to enhance the donor engraftment rate of unrelated 
donors (a standard procedure undertaken in many SCT protocols, and most recently in 2008- 
0246). Between day 90 and 100 after transplantation, patients who engrafted donor cells (> 20% 
donor T cells from the blood), who had no severe acute GVHD (defined by no grade III-IV; or 
grade II but requiring < 16 mg -medrol/day), and with no unresolved toxicity of >grade 2, and 
adequate counts (ANC > 1,500; platelets > 70,000), and who are not in CR will be randomized to 
receive lenalidomide maintenance vs observation. 


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Conditioning Regimen 
 
 
The regimen is considered as standard of care, and consists of: 
 
Fludarabine (F) at 30mg/im² intravenously (i.v.) will be given daily on days -5, -4, -3. On the 
same days, Bendamustine (B) 130mg/m²/day will be given i.v . Rituximab (R) of 375 mg/m2 will 
be given i.v. on day -13; this will be followed by a dose of 1,000mg/ m² on days -6, +1 and +8. 
Patients receiving an unrelated transplant will be given rabbit anti-thymocyte globulin 
(Thymoglobulin) 1.0 mg/kg (day -2) and 1.0 mg/kg (day -1). Stem cell will be given on day 0. 
 
 
Allopurinol 300mg po daily beginning at the start of lenalidomide therapy and continuing for 3 
months as TLS prophylaxis is required for all subjects who are randomized to receive 
lenalidomide. 
 
 
Lenalidomide Maintenance 
 
Patients who are not in complete remission, including by molecular studies. 
Dose: 
1. Dose starting at 5 mg every other day; increase to 5 mg/d daily in 4-5 weeks (28-35 days 
from Dose #1 of Revlimid®), if well tolerated; then to 10mg/d in 4-5 weeks (28-35 days). 
 
2. If the daily dose of 10 mg is not tolerated, the dose will be decreased to 5 mg (and will 
not be increased again). 
 
3. If the dose of 5 mg is not tolerated, the dose would be decreased to starting level, at 5 
mg orally every other day. 
 
Duration of maintenance: 
 
1. Drug will be discontinued after 3 months if CR has been achieved with the lenalidomide 
maintenance (by CT, bone marrow biopsy and aspiration, PCR, flow cytometry, FISH) is 
achieved. 
 
2. If CR is not achieved by above criteria at 3 months, patients will then be re-assessed at 
6, 9, and 12 months by the same criteria. 
 
3. Maximum duration of maintenance, 12 months 
 
Patients will receive 1 baby aspirin/day while on lenalidomide to prevent deep vein thrombosis. 


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GVHD Prophylaxis 
 
Standard tacrolimus, methotrexate will be used for GVHD prophylaxis, as per our standard 
practice guidelines. Other supportive care guidelines will be followed as per our standard 
practice. 
 
Lenalidomide Description 
Revlimid® (lenalidomide), a thalidomide analogue, is an immunomodulatory agent with anti- 
angiogenic properties. The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -2H-isoindol-2-yl) 
piperidine-2,6-dione and it has the following chemical structure: 
 
Chemical Structure of Lenalidomide 
O 
O 
H 
N 
N 
O 
 
 
NH2 
 
3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione 
The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 259.3. 
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 
1.5 mg/ml. Lenalidomide has an asymmetric carbon atom and can exist as the optically active 
forms S(-) and R(+), and is produced as a racemic mixture with a net optical rotation of zero. 
LENALIDOMIDE® (lenalidomide) is available commercially in 5 mg, 10 mg, 15 mg and 25 mg 
capsules for oral administration. 
 
 
 
CLINICAL PHARMACOLOGY 
 
Mechanism of Action: 
 
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. 
 
Pharmacokinetics and Drug Metabolism: 
 
Absorption: 
 
Lenalidomide, in healthy volunteers, is rapidly absorbed following oral administration with 
maximum plasma concentrations occurring between 0.625 and 1.5 hours post-dose. 
Co-administration with food does not alter the extent of absorption (AUC) but does reduce the 
maximal plasma concentration (Cmax) by 36%. The pharmacokinetic disposition of lenalidomide 


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is linear. Cmax and AUC increase proportionately with increases in dose. Multiple dosing at the 
recommended dose-regimen does not result in drug accumulation. 
 
Pharmacokinetic sampling in myelodysplastic syndrome (MDS) patients was not performed. In 
multiple myeloma patients maximum plasma concentrations occurred between 0.5 and 4.0 hours 
post-dose both on Days 1 and 28. AUC and Cmax values increase proportionally with dose 
following single and multiple doses. Exposure (AUC) in multiple myeloma patients is 57% higher 
than in healthy male volunteers. 
 
Pharmacokinetic Parameters: 
Distribution: 
In vitro (14C)-lenalidomide binding to plasma proteins is approximately 30%. 
 
Metabolism and Excretion: 
 
The metabolic profile of lenalidomide in humans has not been studied. In healthy volunteers, 
approximately two-thirds of lenalidomide is eliminated unchanged through urinary excretion. The 
process exceeds the glomerular filtration rate and therefore is partially or entirely active. Half-life 
of elimination is approximately 3 hours. 
 
Supplier(s) 
 
Celgene Corporation will supply Revlimid® (lenalidomide) to study participants at no charge 
through the RevAssist® program. 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 Celgene’s RevAssist® program. 
 
Dosage Form 
 
Lenalidomide will be supplied as 5 mg capsules for oral administration. 
 
Packaging 
 
Lenalidomide will be shipped directly to patients via Biologics, a specialty pharmacy. Bottles will 
contain a sufficient number of capsules for one cycle of dosing. 
 
Only enough lenalidomide for 1 month of therapy may be provided to the patient at a time. 
 
Storage 
 
Lenalidomide should be stored at room temperature away from direct sunlight and protected from 
excessive heat and cold. 
 
Prescribing Information 
 
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 RevAssist® program. Per standard RevAssist® 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 Celgene’s RevAssist® program. Prescriptions must be filled within 7 days. Only 
enough lenalidomide for one cycle of therapy will be supplied to the patient each cycle. 
 
Other Non-Investigational Drugs 
 
Fludarabine may cause fever, loss of appetite, fatigue, confusion, numbness, nausea, vomiting, 
and/or diarrhea. It may cause you to have chills and/or feel tired and/or weak. It may cause 
vision and/or hearing problems. It may cause paralyzed arms and/or legs, muscle weakness, 
blindness, and/or coma. It may cause skin rash, mouth ulcers, sore throat, and/or hair loss. It 


 
 
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may cause tingling of the hands and/or feet. It may cause heart failure, lung scarring, bleeding 
from the bladder, and/or seizures. It may cause kidney, liver, and/or brain damage. It may also 
cause central nervous system damage, including cortical blindness, and/or permanent sterility 
(inability to produce children). It may cause your red blood cells to burst. 
 
Cyclophosphamide may cause diarrhea, nausea, vomiting, and/or loss of appetite. It may 
cause imbalance of salt and fluid status. It may cause irritation of the urinary bladder (where 
urine is stored). This can cause pain, blood in the urine, and/or scarring of the bladder. You 
should be able to avoid this by drinking 8-10 glasses of water a day and urinating every 2-3 
hours, especially before bedtime. You will be monitored closely and will be given fluids by mouth 
and vein to "flush out" the bladder, in an attempt to avoid this side effect. Cyclophosphamide  
may cause a metallic taste right after it is given. It may cause abdominal (stomach area) pain, 
ulcers in the mouth and/or stomach, and/or hair loss. It may cause headache, dizziness, stuffy 
nose, and/or shrinkage of the testicles. It may increase the risk of developing a second form of 
cancer. It may also cause loss of menstrual periods and/or allergic reaction. Cyclophosphamide 
may also cause damage to heart muscles, leading to severe weakening of the heart muscle 
(congestive heart failure). 
 
Bendamustine may cause fatigue, fever, headache, nausea, vomiting, diarrhea, constipation, 
loss of appetite, jaundice (yellowing and/or darkening of the skin), and cough. Bendamustine may 
likely cause low blood cell counts (white blood cells, red blood cells, and platelets). This means 
that while you take the drug, there is more of a chance of getting an infection, including 
pneumonia. You may become anemic and/or have problems with bleeding, bruising, fatigue, 
and/or shortness of breath. You may need a blood transfusion. Bendamustine may cause arm 
and/or leg swelling, fast heartbeat, low blood pressure, chest pain, worsening high blood 
pressure, chills, dizziness, difficulty sleeping, anxiety, depression, pain, skin rash, itching, dry  
skin, dehydration, low blood levels of potassium (possible weakness), increased blood levels of 
uric acid (possible gout), high blood sugar (possible diabetes), weight loss, sores in the mouth, 
abdominal pain, loss of appetite, upset stomach, heartburn, dry mouth, taste changes, fungal 
mouth infection, abdominal swelling, urinary tract infection, fever and low white blood cell counts, 
back pain, weakness, abnormal liver tests (possible liver damage), joint, bone, and/or limb pain, 
difficulty breathing, airway infection, inflammation of the sinuses, throat pain, pneumonia, head 
cold, wheezing, stuffy nose, infusion/catheter site pain, herpes infection, infection, allergic 
reaction, sweating, and night sweats. Bendamustine may cause heart failure, drowsiness, 
blistering skin rash, death of skin tissue, severe skin damage with loss of a large portion of skin, 
toxic skin reactions, low blood levels of calcium (possible weakness and/or cramping), low blood 
level of sodium (possible headache, confusion, seizures, and/or coma), inflammation of the 
mucus membrane, bone marrow disease where not enough blood cells are made, kidney failure, 
scarring of the lung, severe allergic reaction, severe blood infection, organ failure caused by  
blood infection, breakdown products of the cancer cells entering the blood stream (possible heart 
rate abnormalities, kidney failure, muscle twitching, and/or muscle cramps), and new occurrence 
of cancer. 
 
Rituximab may cause allergic reactions at the site of injection, including fever, chills, nausea, 
vomiting, headache, muscle aches, dizziness, and/or skin rash. It may cause swelling due to the 
build-up of fluid in the arms and/or legs. It may cause hives, breathing problems, low blood 
pressure, and/or sweating. It may cause tenderness and/or swelling at sites of lymphoma in the 
body. It may cause breathing problems and/or skin reactions. It may cause irregular or slow 
heartbeat, high blood pressure, and/or arthritis. 
 
 
Rituximab may cause disorders of blood vessels, lungs, and/or eyes. You will be carefully 
monitored for these reactions during the rituximab infusions. 
 
Rituximab may cause itching, runny nose, coughing, wheezing, flushing, and/or chest pain. It 
may cause loss of appetite, anxiety, malaise (sadness), agitation, nervousness, an inability to 
sleep, and/or abnormal blood tests. It may cause throat irritation, changes in taste, low oxygen 
levels in the blood, infections, asthma, increased sweating, and/or reactivation of hepatitis. 


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Rituximab may cause low or high blood sugar and/or rapid death of tumor cells (tumor cell lysis). 
After tumor cell lysis occurs, high amounts of uric acid will be released into your blood. When uric 
acid is present in large amounts in your blood, especially after receiving chemotherapy, the ability 
of your kidneys to filter uric acid can be overwhelmed and uric acid can form crystals within the 
kidneys. If crystals form in the kidneys, it can lead to kidney damage and possibly acute kidney 
failure. 
 
Materials taken from humans and animals were used in the making of rituximab. These materials 
are removed from the final product during the manufacturing process. However, infection from 
known or unknown substances may occur. In addition, an antibiotic called gentamycin was used 
in the making of rituximab, and very small amounts may still be present. It may also cause an 
allergic reaction. 
 
In people who have ever been infected with hepatitis B virus, there is a risk that the virus can flare 
up during treatment with drugs that affect your immune system, such as rituximab. This could  
lead to liver failure. The risk of hepatitis B virus flaring up may continue for several months after 
you stop taking rituximab. If you become jaundiced (yellowing of the skin and eyes) or develop 
viral hepatitis while taking rituximab or after stopping treatment, you should tell your study doctor 
immediately. Your study doctor will discuss this risk with you and explain what testing is 
recommended to check for hepatitis. 
 
 
Because rituximab is a mouse antibody that has been changed to make it similar to a human 
antibody, treatment with rituximab may cause the body to make human antibodies to the mouse- 
based antibody. These antibodies are called HAMA or HACA. The potential response of your 
body to rituximab may lead to decreasing the effectiveness of mouse-based antibody therapies 
for you in the future. 
 
Tacrolimus may cause kidney and/or liver damage, high blood pressure, high blood sugar, 
and/or diabetes. It may cause low levels of potassium, magnesium, and/or phosphate in the 
blood, which can lead to weakness or other neurological symptoms. Your hands may shake.  
You may have a burning feeling in the hands and/or feet. The drug may cause nausea, vomiting, 
constipation, seizures, coma, and/or confusion. An allergic reaction may occur. The drug may 
cause headache, difficulty sleeping, diarrhea, high blood pressure, blurred vision, chest pain, 
higher sensitivity to pain, ringing in the ears, sweating, enlarged heart, and/or weakening of the 
immune system, which may result in the development of infections. It may cause rapid growth of 
body hair, loss of appetite, weight loss, wheezing, facial flushing, yellowing and/or darkening of 
the skin due to bile in the blood, and/or abdominal pain. It may cause an increased risk of cancer 
of the lymph glands. It may also cause rashes, itching, changes in hearing, fluid in the lungs, 
and/or back pain. 
 
Methotrexate may cause low blood cell counts (white blood cells, red blood cells, and platelets). 
This means that while you take the drug, there is more of a chance of getting an infection, 
including pneumonia. You may become anemic and/or have problems with bleeding, bruising, 
fatigue, and/or shortness of breath. You may need a blood transfusion. 
 
Methotrexate may cause mouth sores, intestinal sores, liver damage, and/or kidney damage. It 
may cause vision problems, hearing problems, stomach ulcers, nausea, abdominal pain, 
weakness, chills, fever, and/or dizziness.  Damage to the central nervous system may also 
occur. 
 
Thymoglobulin® may cause low blood cell counts (white blood cells and platelets). This means 
that while you take the drug, there is more of a chance of getting an infection, including 
pneumonia. You may become anemic and/or have problems with bleeding, bruising, fatigue, 
and/or shortness of breath. You may need a blood transfusion. 
 
Thymoglobulin® may cause high blood pressure, buildup of fluid in the feet and legs, fast 
heartbeat, facial swelling, and/or lymph node swelling. It may cause low blood pressure affecting 


 
 
2007-0871 
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Page 19 
 
 
liver, kidney, heart, and/or lung functions. It may cause hives, shaking, chills, fever, headache, 
pain, weakness, dizziness, and/or fainting. 
 
Thymoglobulin® may cause skin rash and/or itching. It may cause kidney damage, liver damage, 
and/or fluid leakage into tissues such as the lung, causing shortness of breath. It may cause high 
levels of potassium in the blood, which may mean kidney failure. 
 
Thymoglobulin® may cause abdominal pain, diarrhea, nausea, and/or vomiting. It may cause 
muscle aches, chest pain, back pain, joint aches, and/or nerve pain. It may cause allergic 
reactions. The allergic reactions may be severe, and may cause trouble breathing, bone pain, 
muscle pain, skin rash, and/or changes in blood pressure. 
 
Thymoglobulin® may cause an increased risk of developing new forms of cancer (lymphoma or 
leukemias). It may increase the risk of graft failure (problems with transplanting new tissue). It 
may cause the disease to reappear. 
 
 
 
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 2, Schedule of Study Assessments and unless otherwise specified, must 
take place within 28 days prior to initiation of therapy. 
 
Approximately (80) of subjects with CLL will be screened for enrollment and must meet the 
eligibility criteria below. It is estimated that 20 patients may not meet the necessary criteria after 
transplantation, to be randomized for maintenance. These 20 patients will be analyzed separately 
and followed for toxicity and response at the same frequency that the study patients are followed. 
 
Inclusion Criteria 
 
Subjects must meet the following inclusion/exclusion criteria to be eligible for the study. 
 
Inclusion criteria for the transplant procedure 
 
1. Age 18-75 years at the time of signing the informed consent form. 
 
2. Disease: 
 
2.1 
CLL in relapse, after failing conventional chemo-antibody combination therapy. 
 
2.2 
CLL patients who failed to achieve CR with frontline conventional chemo- 
antibody. 
 
2.3 
CLL patients with 17p deletion. 
 
2.4 
CLL in Richter’s. 
 
3. Able to adhere to the study visit schedule and other protocol requirements. 
 
4. Donor: HLA compatible related (HLA-A,-B,-DRBI matched or with one-antigen 
mismatched) or HLA compatible unrelated. 
 
5. ECOG performance status of d2 at study entry (see Appendix C). 
 
6. FEV1, FVC and DLCO > 40%. 
 
7. Left ventricular EF > 40% with no uncontrolled arrhythmias or symptomatic heart disease. 
 
8. Serum creatinine < 1.6 mg/dL. Serum bilirubin < 1.6 mg/dL. 
 
9. SGPT < 2x upper limit of normal. 
 
10. Voluntary signed, written IRB-approved informed consent before performance of any 
study-related procedure not part of normal medical care, with the understanding that 


2007-0871 
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consent may be withdrawn by the subject at any time without prejudice to future medical 
care. 
 
11. All previous cancer therapy, including radiation, hormonal therapy and surgery, must have 
been discontinued at least 3 weeks prior to treatment in this study. 
 
12. Disease free of prior malignancies for t5 years with exception of currently treated basal 
cell, squamous cell carcinoma of the skin, or carcinoma “insitu” of the cervix or breast. 
 
13. 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 study 
entry. 
 
14. Disease must be chemosensitive (ie, patients must have PR or better based on CT Scans, 
PET Scan, and bone marrow biopsy). 
 
15. Patients suspected to have Richter's transformation (such as elevated LDH) and/or who 
are PET positive, should have a lymph node biopsy to assess histological status of the 
disease. 
 
16. Patients must be off of alemtuzumab for 6 weeks prior to consenting. 
 
 
 
 
 
Exclusion criteria 
 
1. Any serious medical condition, laboratory abnormality, or psychiatric illness that would 
prevent the subject from signing the informed consent form. 
 
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. Use of any other experimental drug or therapy within 28 days of baseline. 
 
5. Known hypersensitivity to thalidomide, lenalidomide, bendamustine, fludarabine. For 
patients will unrelated donors: Known hypersensitivity to thymoglobulin. 
 
6. The development of erythema nodosum if characterized by a desquamating rash while 
taking thalidomide or similar drugs. 
 
7. Concurrent use of other anti-cancer agents or treatments. 
 
8. Known positive for HIV or infectious hepatitis, type A, B or C. 
 
9. Sinuses should be evaluated by either CT neck or CT sinuses to exclude infections 
 
10. Deep-vein thrombosis or pulmonary embolism with 3 months of study entry. 
 
11. History of serious infection requiring hospitalization within the last 3 months of 
consenting. 
 
 
 
 
 
 
 
 
† 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). 


2007-0871 
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Treatment Plan 
 
Conditioning Regimen 
 
Prior to starting the preparative regimen a related or unrelated donor will be identified. Whether  
the source of hematopoietic stem cells is the bone marrow or the peripheral blood, stem cell 
procurement will follow Department of Stem Cell Transplantation and Cellular Therapy standard 
procedures. A minimum of 2 x 106 CD 34 + cells/Kg (peripheral blood) or 1 x 106 CD34 + cells/Kg 
recipient body weight (bone marrow) should be available. 
The preparative regimen is as follows: 
1. Fludarabine 30 mg/m2 will be given intravenously daily on days -5, -4, -3. 
 
2. Bendamustine 130 mg/m2/day will be given intravenously daily on day -5, -4, -3 (following 
Fludarabine). 
3. Rituximab 375 mg/m2 will be given intravenously on day -13, and 1000 mg/m2 on days -6, 
+1 and +8. 
 
4. Patients receiving an unrelated donor will receive rabbit anti-thymocyte globulin (ATG) 1 
mg/kg (days -2) and 1mg/kg (day -1). 
 
5. Day zero is the day of stem cell transplant. 
 
ATG may be given as per other IRB approved protocol. Rituximab will be infused following 
standard procedures for the Department of Stem Cell Transplantation and Cellular Therapy. 
 
Supportive Care 
GVHD Prophylaxis 
Patients are to receive standard prophylaxis consisting of tacrolimus and mini-dose methotrexate. 
Methotrexate is given at 5 mg/m2 on transplant days 1, 3 and 6 for recipients of HLA-identical 
sibling transplants, and on day 1, 3, 6 and 11 for recipients of unrelated or mismatched related 
donor transplants. Tacrolimus starts on day -2 (targeting levels at 5-10 ng/mL) with monitoring of 
blood levels and dose adjustments as clinically indicated. 
 
Administration of blood products, intravenous fluids, allopurinol, G-CSF, antibiotic, antifungal and 
antiviral medications, will follow institutional and departmental guidelines and should be 
administered as clinically indicated. 
 
Lenalidomide Maintenance Treatment 
 
Treatment Assignments 
 
Patients who are not in CR will be randomized between days 90-100 after transplantation to 
receive or not, lenalidomide maintenance. 
 
Criteria to start lenalidomide after transplant in patients initially randomized to receive the drug: 
 
1. Absolute neutrophil count > 1,500 mm3. 
 
2. Platelet count > 70,000 mm3. 
 
3. No Active Bleeding. 
 
4. No clinical evidence of life-threatening infection. 
 
5. No uncontrolled acute GVHD [i.e., no acute grade III – IV; no acute grade II requiring. > 
16 mg steroids/day] 
 
6. Adverse events that may have occurred have resolved to < grade 2 toxicity. 


2007-0871 
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7. Engraftment of donor cells (i.e., > 20% donor T-cell from PB/PCR) 
 
8. 
Creatinine clearance >/= 30 
 
9. 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 A: Risks of Fetal Exposure, Pregnancy Testing 
Guidelines and Acceptable Birth Control Methods. 
 
10. All study participants must be registered into the mandatory RevAssist® program, and 
be willing and able to comply with the requirements of RevAssist®. 
 
Patients can start lenalidomide when randomized to the maintenance area, between days 90-100 
after transplantation. 
 
Duration of maintenance: 
 
1. Drug will be discontinued after 3 months if CR has been achieved with the lenalidomide 
maintenance (CT, bone marrow biopsy and aspiration, PCR, flow cytometry, FISH) is 
achieved. 
 
2. If CR is not achieved by above criteria at 3 months, patients will then be re-assessed at 
6, 9, and 12 months by the same criteria. 
 
3. Maximum duration of maintenance, 12 months 
 
Patients will receive 1 aspirin of 81 mg/day while on lenalidomide to prevent deep vein 
thrombosis. 
 
 
Tumor Lysis Syndrome (TLS) Prophylaxis (allopurinol and hydration) 
 
Tumor lysis syndrome (TLS), characterized by hyperkalemia, hyperuricemia, and 
hyperphosphatemia resulting from the rapid release of potassium, uric acid, and phosphate, has 
been reported in CLL patients treated with lenalidomide necessitating TLS prophylaxis including 
allopurinol and oral hydration. The risk of TLS is highest during the first few weeks of therapy and 
may be elevated when lenalidomide is re-started after treatment interruptions or when the 
lenalidomide dose is escalated. 
 
Allopurinol 300mg po daily beginning at the start of lenalidomide therapy and continuing for 3 
months as TLS prophylaxis is required for all subjects who are randomized to receive 
lenalidomide. 
 
Based on a patient’s reaction and laboratory parameters, TLS prophylaxis may be continued or 
restarted as needed at the Investigator’s discretion. 
 
Tumor Flare Reaction (TFR): 
 
 
 
 
 
† 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). 


2007-0871 
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Prophylaxis for (TFR) is not recommended for patients who receive lenalidomide. Grade 1 
TFR 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. Narcotic analgesics may be 
added as needed for pain control in subjects experiencing ≥ Grade 2 tumor flare. 
 
Patients who already have a history of deep-vein thrombosis or pulmonary embolism will receive 
either coumadin or low-molecular weight heparin while on lenalidomide. 
 
If patients develop thrombosis or embolism while they are receiving aspirin prophylaxis, 
lenalidomide will be held, patients will be anticoagulated, and once a stable anticoagulation is 
achieved, patients with be restarted on the same dose of lenalidomide. Patients will then continue 
to receive either coumadin or low-molecular weight heparin as long as they continue to receive 
lenalidomide. 
 
 
 
Visit schedule and assessments 
 
See Appendix B: Schedule of Study Assessments 
 
 
Pre-Transplant Evaluation 
 
The following tests/procedures will be performed within 30 days prior to signing a consent form 
for the protocol: 
 
A complete history and physical including the following information: diagnosis, PS, prior therapy 
and response, pulmonary function tests, MUGA or Echo and EKG. 
 
Staging of diseases: i.e., CT scans of the neck, chest, abdomen, pelvis, bone marrow biopsy and 
aspiration, CxR, PET scan, cytogenetics, PCR/ fluorescence in situ hybridization (FISH) studies 
for JH and immunophenotyping. 
 
Laboratory studies shall include: 
 
CBC with differential, platelet count, PT, PTT, creatinine, liver function tests, urinalysis, Beta 2 
microglobulin level, Hepatitis serology, HIV, HTLV-1, quantitative serum immunoglobulins, 
baseline peripheral CD4/CD8 counts and immunodeficiency panel. 
 
Enrollment into the RevAssist® program. 
 
Pregnancy Testing: Pregnancy tests before and during treatment, even if the patient agrees not 
to have reproductive heterosexual intercourse. Two pregnancy tests will be performed prior to 
receiving study drug, one within 10-14 days and the second within 24 hours of prescribing 
lenalidomide. 
 
Evaluation at 25-35 days and the first 100 days 
 
Staging of diseases: i.e., CT scans of the neck, chest, abdomen, pelvis, bone marrow biopsy and 
aspiration, CxR, PET scan (if previously positive), cytogenetics, PCR/ fluorescence in situ 
hybridization (FISH) studies, for JH and immunophenotyping. 
 
Chimeric studies, quantitative serum immunoglobulins, CD4/CD8 counts, serum immunoglobulin, 
immunodeficiency panel. 
 
Laboratory studies shall include: CBC with differential, platelet count, liver function tests, 
creatinine, electrolytes, tacrolimus levels and CMV, antigenemia, once a week, or more frequently 
if needed. 


2007-0871 
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Evaluation after the first 100 days: 
 
Staging with CT scans of the neck, chest, abdomen, pelvis, marrow biopsy and aspiration, PET 
scan (if previously positive), FISH, PCR for JH, flow cytometry at 6, 9, 12, 15 months, 18 months 
(+/- 2 weeks for each time point) and then every 6 months x 3 years (+/- 4 weeks for each time 
point). 
 
Chimeric studies 
 
Immunodeficiency panel with CD4/CD8 
 
CBC with differential, platelets, Cr, liver function tests, electrolytes 
Additional evaluation while on lenalidomide: 
CBC with differential, Serum chemistry basic metabolic profile, (sodium, potassium, chloride, 
CO2, BUN, creatinine, uric acid, ALT, AST, alkaline phosphatase, (bilirubin and glucose) 
platelets weekly until the maximum tolerated dose is reached, then once every two weeks 
thereafter. At every re-start of lenalidomide following an interruption, the afore mentioned tests 
should be performed weekly for the first 4 weeks, then once every 2 weeks. 
 
Pregnancy testing per the RevAssist® program. 
 
Pregnancy tests before and during treatment, even if the patient agrees not to have reproductive 
heterosexual intercourse. Two pregnancy tests will be performed prior to receiving study drug, 
one within 10-14 days and the second within 24 hours of prescribing lenalidomide. 
 
Frequency of pregnancy test to be done: 
 
1. Every week during the first 28 days of starting lenalidomide and a pregnancy test every 
28 days during the patient’s participation in this study if no menstrual cycle or menstrual 
cycles are regular or every 14 days if cycles are irregular. 
 
2. If the patient missed a period or has unusual menstrual bleeding. 
 
3. When the patient is discontinued from the study and at day 28 after discontinuation from 
the study if menstrual cycles are regular. If menstrual cycles are irregular, pregnancy 
tests will be done at discontinuation from the study and at days 14 and 28 after 
discontinuation from the study. 
 
Optional testing: 
 
Patients will be asked to have 2 x10cc heparin tubes and 1x15 red tube of blood at the time of 
consent. This will be repeated at 3, 6, 9, 12, and 15 months after transplantation. Cytokine levels 
and immune cell function (T-cell, B-cell, and NK-cell and dendritic cells) will be measured for 
correlation studies. Samples will be stored at Dr. James Reuben’s Lab; all leftover samples will 
be discarded. 
 
Dosing Regimen 
 
The drug will be in the morning at approximately the same time each day. Only enough 
lenalidomide for one month of therapy will be supplied to the patient. 
 
Lenalidomide capsules should be swallowed whole, and should not be broken, chewed or 
opened. 
 
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. 


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Patients 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 5.5). 
 
Special Handling Instructions 
 
Females of childbearing potential should not handle or administer lenalidomide unless they are 
wearing gloves. 
 
Record of administration 
 
Accurate records will be kept of all study drug administration (including prescription dispensing 
and dosing) will be made in the source documents. 
 
 
 
Dose Continuation, Modification and Interruption 
 
Subjects will be evaluated for AEs at each visit with the NCI CTCAE v3.0 (Appendix D: NCI 
CTCAE v3.0) used as a guide for the grading of severity. Refer to Sections 6.5.1, 6.5.2 and 6.5.3 
for full instruction on initiation of a new cycle of therapy and dose modifications during a cycle of 
therapy. 
 
 
 
Dose Reduction Steps 
 
 
Table 1: LENALIDOMIDE Dose Escalation Steps 
Dose Level 2 
10 mg daily 
Dose Level 1 
5 mg daily 
Starting Dose 
5 mg every other day 
 
Instructions for Dose Modifications or Interruption During a Cycle 
 
Dose Modification Guidelines for Lenalidomide 
NCI CTC Toxicity Grade 
Action 
Grade 3 neutropenia associated with fever 
(temperature >38.5° C) or Grade 4 neutropenia 
(ANC <500/mm3, <75% of baseline)*. 
1) Hold (interrupt dose). 
2) Follow CBC weekly until resolution or 
stabilization 
3) If neutropenia has resolved to < grade 2, 
implement one dose reduction and continue 
therapy. 
4) If neutropenia is the only toxicity for which a 
dose reduction is required, GCSF may be used 
and the lenalidomide dose maintenance. 
Thrombocytopenia Grade 4 (platelet count 
<25,000/mm3)*. 
1) Hold (interrupt dose). 
2) Follow CBC weekly until resolution or 
stabilization 
3) If thrombocytopenia resolves to < grade 2, 
implement one dose reduction and continue 
therapy. 
Non-blistering rash 
Grade 3 
1) If grade 3, hold (interrupt) dose. Follow 
weekly until resolution or stabilization. 
2) If the toxicity resolves to <grade 1, 
implement one dose reduction and continue 


2007-0871 
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Grade 4 
therapy. 
1) Discontinue lenalidomide study drug. 
Desquamating (blistering) rash-any Grade 
Discontinue lenalidomide study drug. 
Erythema multiforme 
Grade 3 
Discontinue lenalidomide study drug. 
Neuropathy 
Grade 3 
 
 
 
 
 
Grade 4 
1) If grade 3, hold (interrupt) dose. Follow 
weekly until resolution or stabilization. 
2) If the toxicity resolves to <grade 2, 
implement one of dose reduction and continue 
therapy. 
Discontinue lenalidomide study drug. 
Sinus bradycardia/other cardiac arrhythmia 
Grade 2 
 
 
 
 
 
 
> Grade 3 
1) Hold (interrupt dose). Follow at least weekly 
until resolution or stabilization. 
2) If the toxicity resolves to <grade 1, 
implement one dose reduction and continue 
therapy. 
Discontinue lenalidomide study drug. 
Allergic reaction or hypersensitivity 
Grade 3 
 
 
 
 
 
 
Grade 4 
1) Hold (interrupt dose). Follow at least weekly 
until resolution or stabilization 
2) If the toxicity resolves to <grade 1, 
implement one dose reduction and continue 
therapy. 
Discontinue lenalidomide study drug. 
Venous thrombosis/embolism 
>Grade 3 
Hold (interrupt) dose and start anticoagulation; 
restart at investigator’s discretion (maintain 
dose level). 
Hepatic or other non-hematologic toxicity 
assessed as lenalidomide-related 
> Grade 3 
1) Hold (interrupt) dose. Follow at least weekly 
until resolution or stabilization. 
2) If the toxicity resolves to <grade 2, 
implement one dose reduction and continue 
therapy. 
Tumor flare refractory to oral pain meds and/or 
antihistamines 
Hold dose and differentiate tumor flare from 
progression. Restart therapy at the 
investigator’s discretion. 
 
 
 
Treatment and Dose Modification for Tumor Lysis Syndrome for Patients receiving 
Lenalidomide 
 
All subjects meeting criteria of laboratory TLS or ≥ Grade 1 TLS according to the Cairo-Bishop 
Definition of Tumor Lysis Syndrome (see Appendix R) should receive vigorous intravenous 
hydration and should be considered for rasburicase therapy as needed to reduce hyperuricemia, 
until correction of electrolyte abnormalities. 
 
x 
In cases of laboratory TLS and Grade 1 TLS (see Appendix R: Cairo-Bishop Definition of 
Tumor Lysis Syndrome), lenalidomide will be continued at the same dose without 
interruption or dose reduction. TLS prophylaxis measures outlined in Lenalidomide 
Maintenance should be continued or re-instituted. 


2007-0871 
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x 
Subjects with ≥ Grade 2 TLS (see Appendix R: Cairo-Bishop Definition of Tumor Lysis 
Syndrome) will be managed as follows in addition to intravenous hydration and 
consideration for rasburicase therapy (above). 
 
o 
Hold (interrupt) treatment. 
 
o 
First episode: restart lenalidomide at the current dose with appropriate TLS 
prophylaxis after resolution of electrolyte abnormalities to Grade 0. 
 
o 
Subsequent episodes: restart lenalidomide with appropriate TLS prophylaxis 
after resolution of electrolyte abnormalities to Grade 0. At physician discretion, 
the lenalidomide dose may be restarted at the current dose or lenalidomide may 
be reduced by 1 dose level. 
 
o First or subsequent episodes: subjects should be closely monitored for signs of 
TLS after resuming treatment. To monitor for TLS, serum chemistry and uric 
acid tests should be performed at least every week following initiation of 
lenalidomide for 4 consecutive weeks and on Day 3 or 4 following initiation of 
lenalidomide. 
 
 
 
Treatment compliance 
At all times, when dispensing study drug, research center personnel will review the instructions, 
printed on the packaging, 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 patient diary. 
 
Any unused Revlimid® (lenalidomide) should be returned to the patient for disposition in 
accordance with the RevAssist® program. 
 
 
 
Concomitant Therapy 
 
Recommended Concomitant Therapy 
Subjects should receive full supportive care, including transfusions of blood and blood products, 
antibiotics, antiemetics, antihistamines, and allopurinol when appropriate. 
 
 
 
Anticoagulation Consideration 
 
Lenalidomide increases the risk of thrombotic events in patients who are at high risk or with a 
history a 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), anthracyclines (Doxil, Adriamycin) and erythropoietin the risk of thrombosis is 
increased. 
 
For this study, patients will receive one aspirin (81 mg) a day while on lenalidomide. Low 
molecular weight heparin may be utilized in patients that are intolerant to aspirin. Coumadin 
should be used with caution and close monitoring of INR. 
 
Patients who already have a history of deep-vein thrombosis or pulmonary embolism will receive 
either coumadin or low-molecular weight heparin while on lenalidomide. 
 
If patients develop thrombosis or embolism while they are receiving aspirin prophylaxis, 
lenalidomide will be held, patients will be anticoagulated, and once a stable anticoagulation is 
achieved, patients with be restarted on the same dose of lenalidomide. Patients will then continue 
to receive either coumadin or low-molecular weight heparin as long as they continue to receive 
lenalidomide. 


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Prohibited Concomitant Therapy 
 
Concomitant use of sargramostim (GM-CSF), other anti-cancer therapies, including radiation, 
thalidomide, or other investigational agents is not permitted while subjects are receiving study 
drug during the treatment phase of the study. 
 
 
 
Discontinuation of Lenalidomide 
 
Treatment will continue for one year or the occurrence of any of the following events: 
 
1. 
Disease progression. 
 
2. 
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. 
 
3. 
Discontinuation of lenalidomide for any reason. 
 
4. 
Major violation of the study protocol. 
 
5. 
Withdrawal of consent. 
 
6. 
Lost to follow up. 
 
7. 
Death. 
 
8. 
Pregnancy or suspected pregnancy. 
 
9. 
Immobility or unwillingness to have follow-up visit and/or laboratory test required by this 
protocol. 
 
 
 
Follow-Up 
 
At treatment discontinuation, subjects will undergo a safety assessment approximately 30 days 
post the last dose of study drug. Additional off study evaluations, per the Schedule of 
Assessments. 
 
 
Adverse Events 
 
Adverse Events 
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. 
Complete and updated adverse events are available in the Investigational Drug Brochure and the 
IND Safety Letters. 
 
MD Anderson (Sponsor) Reporting Requirements for Serious Adverse Events and Dose 
Limiting Toxicities: 
 
Serious Adverse Event (SAE) Definition 
 
A serious adverse event is one that at any dose (including overdose): 
 
1. 
Results in death 


2007-0871 
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2. 
Is life-threatening1 
 
3. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
4. 
Results in persistent or significant disability or incapacity2 
 
5. 
Is a congenital anomaly or birth defect 
 
6. 
Is an important medical event3 
 
7. 
Pregnancy 
 
1“Life-threatening” means 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. 
2“Persistent or significant disability or incapacity” means that there is a substantial disruption of a 
person’s ability to carry out normal life functions. 
3Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in situations where none of the outcomes listed above occurred. Important medical 
events that may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the patient 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. 
 
Adverse Drug Reaction Reporting 
 
Toxicity will be scored using CTCAE Version 3.0 for toxicity and adverse event reporting. A copy 
of the CTCAE Version 3.0 can be downloaded from the CTEP homepage (Appendix D). All 
appropriate treatment areas should have access to a copy of the CTCAE Version 3.0. All 
adverse clinical experiences, whether observed by the investigator or reported by the patient, 
must be recorded, with details about the duration and intensity of each episode, the action taken 
with respect to the test drug, and the patient’s outcome. The investigator must evaluate each 
adverse experience for its relationship to the test drug and for its seriousness. 
 
The investigator must appraise all abnormal laboratory results for their clinical significance. If any 
abnormal laboratory result is considered clinically significant, the investigator must provide details 
about the action taken with respect to the test drug and about the patient’s outcome. 
 
Serious Adverse Events Reporting: The principle investigator has the obligation to report all 
serious adverse events to the University of Texas M. D. Anderson Cancer Center (MDACC) IRB 
via the Office of Protocol Research and to Celgene within 24 hours. 
 
In IND studies, all serious adverse events must be reported to the FDA by the investigator  
through the Office of Research Education & Regulatory Management (ORERM) as required by 21 
CFR 312.32. These reports are to be filed utilizing the University of Texas M. D. Anderson 
Cancer Center Adverse Event Reporting Form. This includes serious, related, labeled (expected) 
and serious, related, unlabeled (unexpected) adverse experiences. All other serious adverse 
events not requiring expedited reporting should be reported to MDACC IRB and ORERM within 5 
business days. 
 
All deaths during treatment or within 30 days following completion of active protocol therapy must 
be reported within 24 hours of knowledge regardless of the attribution. SAEs beyond 4 weeks 
after the end of study drug administration will be reported if thought to be drug related. 
 
NOTE: Instructions concerning procedures and reporting for pregnancies below. 


2007-0871 
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Pregnancies 
 
Pregnancy of a female subject or the female partner of a male subject occurring while the subject 
is on lenalidomide or within 4 weeks after the subject’s last dose of lenalidomide are considered 
expedited reportable events. If the subject is on lenalidomide, it is to be discontinued immediately 
and the subject is to be instructed to return any unused portion of lenalidomide to the Investigator. 
The pregnancy must be reported by the investigator to MDACC IRB and ORERM AND to  
Celgene Corporation Drug Safety within 24 hours of the Investigator’s knowledge of the  
pregnancy by phone and facsimile using the SAE Form. 
 
The Investigator will follow the pregnant female until completion of the pregnancy, and must notify 
Celgene Corporation Drug Safety of the outcome as specified below. The Investigator will  
provide this information as a follow-up to the initial SAE. 
 
If the outcome of the pregnancy meets the criteria for immediate classification as a SAE (i.e., 
spontaneous abortion [any congenital anomaly detected in an aborted fetus is to be documented], 
stillbirth, neonatal death, or congenital anomaly), the Investigator should follow the procedures for 
reporting SAEs (i.e., report the event to Celgene Corporation Drug Safety by facsimile within 24 
hours of the Investigator’s knowledge of the event) and report the event to MDACC IRB and 
ORERM. 
 
Any suspected fetal exposure to lenalidomide must be reported to Celgene, MDACC IRB AND 
ORERM within 24 hours of being made aware of the event. The pregnant female should be 
referred to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation 
and counseling. 
 
All neonatal deaths that occur within 30 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 30 days that the Investigator suspects is 
related to the in utero exposure to lenalidomide should also be reported. 
 
In the case of a live “normal” birth, Celgene Corporation Drug Safety MDACC IRB AND ORERM 
should be advised as soon as the information is available. 
 
 
Celgene Drug Safety Contact Information: 
 
 
Celgene Corporation 
Drug Safety 
86 Morris Avenue 
Summit, N.J. 07901 
 
Toll Free: 
(800)-640-7854 
Phone: 
(908) 673-9667 
Fax: 
(908) 673-9115 
e-m ail: 
drugsafety@celgne.com 
 
 
Investigator Reporting Responsibilities 
 
The conduct of the study will comply with all FDA safety reporting requirements.  Serious 
Adverse Events Reporting: The principle investigator has the obligation to report all serious 
adverse events to the University of Texas M. D. Anderson Cancer Center (MDACC) IRB via the 
Office of Protocol Research and also to Celgene within 24 hours. 
 
IND Annual Reports 
If the FDA has granted an IND number, it is a requirement of 21 CFR 312.33, 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 


2007-0871 
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filed with MD Anderson’s ORERM, who will then forward to FDA. An additional copy should be 
placed in the study's Regulatory Binder and a copy must be sent to Celgene Corporation as a 
supporter of this study as follows: 
 
Celgene Corporation 
Attn: Medical Development 
86 Morris Avenue 
Summit, NJ 07901 
Tel: (908) 673-9000 
 
All adverse experience reports must include the patient number, age, sex, severity of reaction 
(mild, moderate, severe), relationship to study drug (probably related, unknown relationship, 
definitely not related), date and time of administration of test medications and all concomitant 
medications, and medical treatment provided.  The investigator is responsible for evaluating all 
adverse events to determine whether criteria for “serious” and as defined above are present. The 
investigator is responsible for reporting adverse events to Celgene as described below. 
 
 
Expedited reporting by Principal Investigator to Celgene 
 
Serious adverse events (SAE) are defined above. The investigator should inform Celgene of any 
SAE within 24 hours of being aware of the event. This must be documented on an MD Anderson 
SAE form. This form must be completed and supplied to MDACC IRB, ORERM and Celgene 
within 24 hours/1 business day. The initial report must be as complete as possible including an 
assessment of the causal relationship between the event and the investigational product(s) if 
available. 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 
MD Anderson SAE form. A final report to document resolution of the SAE is required. The MD 
Anderson Protocol Number (2007-0871) and the Celgene protocol number (RV-CLL-PI-0294) 
should be included on SAE reports 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. 
 
Report of Adverse Events to the Institutional Review Board 
 
The principal Investigator is required to notify his/her Institutional Review Board (IRB) of a serious 
adverse event according to institutional policy. 
 
Sponsor Reporting to the FDA 
 
Adverse drug reactions that are Serious, Unlisted/unexpected, and at least possibly 
associated to the drug, and that have not previously been reported in the Investigators 
brochure, or reference safety information document should be reported promptly to the Food and 
Drug Administration (FDA) in writing by each investigator/physician engaged in clinical research. 
A clear description of the suspected reaction should be provided along with an assessment as to 
whether the event is drug or disease related. 
 
The sponsor shall notify the FDA by telephone or by fax of any unexpected fatal or life  
threatening experience associated with the use of the drug. As soon as possible, but no later than 
7 calendar days after the sponsors initial receipt of the information. Each phone call or fax shall 
be transmitted to the FDA new drug review division in the Center for Drug Evaluation and 
Research or the product review division in the Center for Biologics Evaluation and Research that 
has responsibility for review of the IND if applicable. 
 
Adverse event updates/IND safety reports 
 
Celgene shall notify the Investigator via an IND Safety Report of the following information: 
 
1. Any AE associated with the use of study drug in this study or in other studies that is both 
serious and unexpected. 


2007-0871 
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2. 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/EC promptly of these new serious and unexpected AE(s) 
or significant risks to subjects. 
 
The Investigator must keep copies of all AE information, including correspondence with Celgene 
and the IRB/EC, on file. 
 
 
 
Response Criteria 
 
Response criteria will be defined by the NCIWG. In addition, patients will undergo CT Scans. 
PET and marrow aspiration and biopsy, flow cytometry, PCR and FISH to evaluate response. 
 
Instructions for interpreting response criteria for lesion evaluation and best overall response may 
be found in Appendix F. 
 
Neutrophil engraftment is defined as a sustained ANC > 0.5 x 109/L for at least 3 consecutive 
days. Platelet engraftment is defined as a sustained transfusion-independent platelet count.> 20 
x109/L for seven consecutive days without transfusion support. 
 
 
Definition of success/efficacy 
 
Patient alive, engrafted, in remission 18 months, without requiring immunomanipulation. 
 
 
 
Definition of toxicity 
 
Not able to tolerate the lowest dose of 5 mg every other day, because of toxicity. 
 
Primary graft failure is defined as failure to achieve an ANC > 0.5 x 109/L for 3 consecutive days 
by day 28, with <10% cellularity on bone marrow biopsy and no evidence of donor chimerism and 
no evidence of persistent disease. 
Secondary graft failure is defined as a sustained decline of ANC below 0.5 X 109/L of for 3 
consecutive days after initial documented engraftment with no evidence of disease progression. 
 
 
 
 
Protocol Amendments/Deviations 
 
Protocol amendments 
 
Any amendment to this protocol must be agreed to by the Principal Investigator and reviewed by 
Celgene. Amendments should only be submitted to IRB/EC after consideration of Celgene 
review. Written verification of IRB/EC 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 


2007-0871 
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and state the reasons for such deviation. In addition, the Investigator will notify the IRB/EC in 
writing of such deviation from protocol. 
 
 
Data Management 
 
Analyses and Reporting 
 
Data will be analyzed and reported as per the statistical design in the Biostatistical Analysis 
section. 
 
Study monitoring and auditing 
 
Investigator responsibilities 
 
Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice (GCP) and 
in the US Code of Federal Regulations. 
 
The Investigator will permit study-related monitoring visits and audits by MDACC’s ORERM, 
Celgene, or its representatives, IRB/EC review, and regulatory inspection(s) (e.g., FDA, EMEA, 
TPP), 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 monitoring 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 MDACC ORERM and the Celgene representative so that the accuracy and 
completeness may be checked. 
 
 
Biostatistical Analysis 
 
This randomized phase II trial compared FCR, and Thymoglobulin plus lenalidomide (FCR+ L) to 
FCR, and Thymoglobulin (FCR) in patients with CLL undergoing allotransplant on 25 patients 
enrolled from May 13, 2009 to December 2, 2010. 
 
Starting with patients enrolled in 2011, this randomized phase II trial will compare FBR, (and 
Thymoglobulin if unrelated) plus lenalidomide (FBR+ L) to FBR, (and Thymoglobulin if unrelated 
donor) (FBR) in patients with CLL undergoing allotransplant. 
 
The primary objective is to compare the need for immunomanipulation between the treatment 
groups. For this trial, immunomanipulation is defined as either the cessation of the administration 
of immunosuppression treatment within the first six months after allotransplant due to intolerability 
or the administration of DLI any time between 3 and 18 months after transplant. 
 
Our primary outcome is the need for immunomanipulation by month 18. Our target enrollment is 
to have a maximum of 60 patients to be randomized, and we expect to enroll 3 patients per 
month. We will follow all patients for 18 months. We also expect that 20 additional patients may 
be initially enrolled to receive the transplantation, but later may not meet the criteria for 
maintenance randomization. 
 
Based upon pilot data, we expect that 49% of the patients in the FCR arm will need 
immunomanipulation by 18 months, and we hope to see a reduction in this proportion in the FCR 
+ L arm to 25%. We expect the same incidence to occur with FBR. 
 
Patients will be randomized in a 1:1 ratio between FCR (now FBR) and FCR (now FBR)+ L. 
Patients will be stratified by the presence or absence of del 17 by FISH by PB at any point in time 
during their disease history, and the number of prior therapies received (less or equal to 2 vs 


 
 
2007-0871 
July 31, 2017 
 
 
 
Page 34 of 46 
 
greater than 2). Prior therapies are defined by 1) combination chemotherapies, 2) chemo- 
antibodies, 3) biological agents. The trial will be stopped early and a treatment selected as being 
“better” if the probability is 0.95 or more that the probability of needing immunomanipulation on 
one treatment arm is greater than for the other arm. However, if all 60 patients are enrolled, then 
a treatment will be selected as being “better” if the probability is 0.90 or more that the probability  
of needing immunomanipulation for one treatment is greater than the other. Additional details are 
provided below in the section labeled “Technical Details”. The operating characteristics of this 
study design based upon 2000 simulations of this trial are summarized in Table 1 below. 
 
We will report the posterior probability that the need for immunomanipulation in one arm 
is greater than the need for immunomanipulation in the other arm. 
 
 
Table 1. Operating Characteristics of Study Design 
Neither 
FCR 
FCR + L 
True Rate of Need for 
Immunomanipulation 
 
--- 
0.49 
0.25 
Pr(Selected) 
19.7% 
0 
80.3% 
True Rate of Need for 
Immunomanipulation 
 
--- 
0.49 
0.49 
Pr(Selected) 
81.8% 
8.9% 
9.3% 
True Rate of Need for 
Immunomanipulation 
 
--- 
0.25 
0.25 
Pr(Selected) 
75.5% 
3.8% 
20.7% 
True Rate of Need for 
Immunomanipulation 
 
--- 
0.49 
0.35 
Pr(Selected) 
53.5% 
0.6% 
45.9% 
True Rate of Need for 
Immunomanipulation 
 
--- 
0.60 
0.35 
Pr(Selected) 
26.5% 
0.2% 
73.3% 
 
 
Analyses of secondary endpoints include evaluation of: 
 
1) time to treatment failure 
2) time to molecular remission 
3) safety profile of the combination therapies 
4) acute and chronic graft-vs-host disease rates and 
5) percentage of blood donor cell after transplant in the recipient. 
 
 
Technical Details 
 
Starting with patients enrolled in 2011: The two treatment arms will be denoted by T (FBR) and  
TL (FBR + L). Denote the probability that a patient needs immunomanipulation in each arm as θT 
and θTL, respectively. Assume that θT and θTL are independent and that θT ~ Beta(aT,bT) and that 
θTL ~ Beta(aTL,bTL). Here, (aT,bT) can be interpreted as the number of prior successes and 
failures, respectively, in arm T, and (aTL,bTL) can be interpreted as the number of prior successes 
and failures in arm TL. The mean values of these distributions are aT/(aT + bT) and aTL/(aTL + bTL) 
 
In a previous trial of FCR, 19 of 39 patients required immunomanipulation by 18 months. Since 
we expect the same incidence with FBR, we will use the same statistical guidelines thus far 
adopted with FCR. Patients who have been treated with FCR will be included within the final 
analysis and the total number patients randomized will not change. We discount the information 


2007-0871 
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available by 75% and assume that (aT,bT) = (4.9,5.1). We further assume that (aTL,bTL) = (0.98, 
1.02), which has the same mean but a higher variance, reflecting that little information is available 
regarding the FBR + L arm. 
 
During the trial, the posterior probability that the need for immunomanipulation rate is greater in 
arm T is represented by pT(data) = Pr(θT > θTL). Similarly, pTL(data) = 1 – pT(data). If at any point 
during the trial pTL(data) > 0.95 (< 0.05) the trial will be terminated and treatment FBR + L will be 
selected as superior (inferior). If the maximum number of patients is enrolled in the trial and 
pTL(data) > 0.90 (< 0.10) treatment TL will be selected as superior (inferior). 
 
 
Data Confidentiality Plan 
 
Data will be collected in the SCT&CT departmental database (BMTWeb). This database is 
password-protected, contains audit tracking, and follows all federal guidelines. Your personal 
identifying information will be removed for this analysis; no sensitive information will be shared. 
 
Data from this clinical trial will be shared with PA17-0588 which is a retrospective data analysis 
study.  No new testing will be undertaken on any specimen.  (See Waiver of Informed Consent.) 
 
Safety evaluation 
 
Data from all subjects who receive any study drug will be included in the safety analyses. 
Subjects who entered the study and did not take any of the study drug(s) and had this confirmed, 
will not be evaluated for safety. 
 
The severity of the toxicities will be graded according to the NCI CTCAE v3.0 whenever possible. 
 
 
Regulatory Considerations 
 
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. 
 
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. 


2007-0871 
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Study records requirements 
 
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the study drug, that is 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; 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.]) 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). The Investigator agrees 
to adhere to the document/records retention procedures by signing the protocol. 
 
 
 
Premature discontinuation of study 
 
Single center 
 
The responsible local clinical Investigator as well as Celgene have the right to discontinue this 
study at any time for reasonable medical or administrative reasons in any single center. Possible 
reasons for termination of the study could be but are not limited to: 
 
1. Unsatisfactory enrollment with respect to quantity or quality. 
 
2. Inaccurate or incomplete data collection. 
 
3. Falsification of records. 
 
4. Failure to adhere to the study protocol. 
 
Study as a whole 
 
Celgene reserves the right to terminate this clinical study at any time for reasonable medical or 
administrative reasons. 
 
Any possible premature discontinuation would be documented adequately with reasons being 
stated, and information would have to be issued according to local requirements (e.g., IRB/EC, 
regulatory authorities, etc.). 


2007-0871 
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References 
 
 
(1) Dredge K, Horsfall R, Robinson S, Zhang L-H, Lu L, et al. Orally administered 
lenalidomide (lenalidomide) is anti-angiogenic in vivo and inhibits endothelial cell 
migration and Akt phosphorylation in vitro. Microvascular Research 69. 2005;56-63. 
(2) Corral LF, Haslett PAJ, Muller FW, Chen R, Wong LM, et al. Differential cytokine 
modulation and T cell activation by two distinct classes of thalidomide analogues that 
are potent inhibitors of TNF-alpha. J Immunol. 1993;163:380-386. 
(3) Schafer PH, Gandhi AK, Loveland MA, Chen RS, Man H-W, et al. Enhancement of 
cytokine production and AP-1 transcriptional activity in T cells by thalidomide-related 
immunomodulatory drugs. J of Pharmacology and Exp Therapeutics. 2003;305:1222- 
1232. 
(4) Davies FE, Raje N, Hideshima T, Lentzsch S, Young G, et al. Thalidomide and 
immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple 
myeloma. Blood. 2001;98:210-216. 
(5) Hideshima T, Chauhan D, Shima Y, Raje N, Davies F, et al. Thalidomide and its 
analogs overcome drug resistance of human multiple myeloma cells to conventional 
therapy.  Blood. 2000;96:2943-2950. 
(6) Bartlett JB, Michael A, Clarke IA, Dredge K, Nicholson S, et al. Phase I study to 
determine the safety, tolerability and immunostimulatory activity of thalidomide analog 
lenalidomide in patients with metastatic malignant melanoma and other advanced 
cancers. British J of Cancer. 2004;90:955-961. 
(7) Fine HA, Kim L, Royce C, Duic JP, Cohen LJ, et al. A phase I trial of lenalidomide, a 
potent thalidomide analog, in patients with recurrent high-grade gliomas and other 
refractory CNS malignancies. Proc ASCO. 2003;Abstract #418. 
(8) Liu Y, Tohnya TM, Figg WD, Gulley JL, Arlen PM, et al. Phase I study of lenalidomide 
(Revimid), a thalidomide derivative, in patients with refractory metastatic cancer. Proc 
ASCO. 2003;Abstract #927. 
(9) Zangari M, Tricot G, Zeldis J, Eddlemon P, Saghafifar F, et al. Results of phase I study 
of lenalidomide for the treatment of multiple myeloma (MM) patients who relapse after 
high dose chemotherapy (HDCT). Blood. 2001;98:775a Abstract #3226. 
(10) Richardson PG, Schlossman RL, Weller E, Hideshima T, Mitsiades C, et al. 
Immunomodulatory drug (lenalidomide) overcomes drug resistance and is well tolerated 
in patients with relapsed multiple myeloma. Blood. 2002;100:3063-3067. 
(11) Wu A, Scheffler MR. Multiple-dose pharmacokinetics and safety of lenalidomide in 15 
multiple myeloma patients. Proc ASCO. 2004;Abstract #2056. 
(12) Richardson PG, Jagannath S, Schlossman R, Zeldenrust S, Rajkumar SV, et al. A 
multi-center, randomized, phase 2 study to evaluate the efficacy and safety of two CDC- 
5013 dose regimens when used alone or in combination with dexamethasone (Dex) for 
the treatment of relapsed or refractory multiple myeloma (MM). Blood. 2003;Abstract 
#825. 
(13) Hussein MA, Karam MA, Brand C, Pearce G, Reed J, et al. Doxil (D), vincristine (V), 
reduced frequency dexamethasone (d) and Lenalidomide (R) (DVd-R) a phase I/II trial in 
advanced relapsed/refractory multiple myeloma (Rmm) patients. Blood. 2004;Abstract 
#208. 
(14) Data on file. Celgene Corporation. 
(15) List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, et al. Efficacy of lenalidomide in 
myelodysplastic syndromes. N Engl J Med. 2005;352:549-57. 
 
(16) Chanan-Khan A, Miller KC, Musial L, Lawrence D, Padmanabhan S, et al. Clinical 
efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic 
leukemia: Results of a phase II study. J. Clin Oncol. 2006;5343-5349. 
 
(17) Alessandra Ferrajoli, Bang-Ning Lee, Ellen J. Schlette, Susan M. O'Brien, Hui Gao, et al. 
Lenalidomide induces complete and partial remissions in patients with relapsed and 
refractory chronic lymphocytic leukemia. Blood. 2008;111:5291-5297. 


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(18) Chanan-Khan A, Porter CW. Immunomodulating drugs for chronic lymphocytic 
leukaemia. Lancet Oncol. 2006;7:480-488. 
 
(19) Khouri IF. Reduced –intensity regimens in allogeneic stem-cell transplantation for non- 
hodgkin lymphoma and chronic lymphocytic leukemia. Hematology Am Soc hematol 
Educ Program. 2006;390-397. 
 
(20) Khouri IF, Saliba RM, Admirand J, O’Brien S, Lee MS, et al. Graft-versus-leukaemia 
effect after non-myeloablative haematopoietic transplantation can overcome the 
unfavorable expression of ZAP-70 in refractory chronic lymphocytic leukaemia. Br J 
Haematol. 2007;137:355-363. 


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Appendices 
 
 
 
 
Appendix A: 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. The risks to a fetus are not known. 
However, because lenalidomide is related to thalidomide, and thalidomide is known to cause 
severe birth defects, the following requirements must be observed. 
 
All study participants must be registered into the mandatory RevAssist® program, and be willing 
and able to comply with the requirements of RevAssist®. 
Females of childbearing potential (FCBP)† must agree to use two reliable forms of contraception 
simultaneously or to practice complete abstinence from heterosexual intercourse during the 
following time periods related to this study: 1) for at least 28 days before starting study drug; 2) 
while participating in the study; and 3) for at least 28 days after discontinuation from the study. 
The two methods of reliable contraception must include one highly effective method (i.e. 
intrauterine device (IUD), hormonal [birth control pills, injections, or implants], tubal ligation, 
partner’s vasectomy) and one additional effective (barrier) method (i.e. latex condom, diaphragm, 
cervical cap). FCBP must be referred to a qualified provider of contraceptive methods if needed. 
 
Before starting study drug: 
 
Female Subjects: 
 
x 
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 (prescriptions must be filled within 7 
days). The subject may not receive study drug until the Investigator has verified that the 
results of these pregnancy tests are negative. 
 
Male Subjects: 
 
x 
Must agree to use a latex condom during sexual contact with females of childbearing 
potential while participating in the study and for at least 28 days following discontinuation 
from the study even if he has undergone a successful vasectomy. 
 
 
 
During study participation and for 28 days following discontinuation from the study: 
 
All Subjects: 
 
x 
If pregnancy or a positive pregnancy test does occur in a study subject or the partner of a 
male study subject during study participation, lenalidomide must be immediately 
discontinued. 
 
Female Subjects: 
 
x 
FCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly for 
the first 28 days of study participation and then every 28 days while on study, at study 
 
† 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). 


2007-0871 
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Page 40 
 
discontinuation, and at day 28 following discontinuation from the study. If menstrual 
cycles are irregular, the pregnancy testing must occur weekly for the first 28 days and 
then every 14 days while on study, at study discontinuation, and at days 14 and 28 
following discontinuation from the study. 
 
x 
In addition to the required pregnancy testing, the Investigator must confirm with FCBP 
that she is continuing to use two reliable methods of birth control at each visit. 
 
x 
Pregnancy testing and counseling must be performed if a subject misses her period or if 
her pregnancy test or her menstrual bleeding is abnormal. Study drug treatment must be 
discontinued during this evaluation. 
 
 
 
Male Subjects: 
 
x 
Must agree to use a latex condom during sexual contact with females of childbearing 
potential while participating in the study and for at least 28 days following discontinuation 
from the study even if he has undergone a successful vasectomy. 


2007-0871 
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Page 41 
 
 
Appendix B: Schedule of Study Assessments * 
 
Nonmyeloablative Stem Cell Transplantation with or without Lenalidomide for Chronic Lymphocytic Leukemia (RV-CLL-PI-0294) 
Protocol 2007-0871 
Issa F. Khouri, MD 
Evaluation 
SCT&CT 
Pretreatment 
During Study (post transplant) 
 
Within 
30 days 
25-35 
days 
 
3 months 
6 months 
(+/- 2 weeks) 
9 months 
(+/- 2 weeks) 
12 months 
(+/- 2 weeks) 
15 months 
(+/- 2 weeks) 
Assessment 
R 
Date 
R 
Date 
R 
Date 
R 
Date 
R 
Date 
R 
Date 
R 
Date 
History & Physical 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
PS 
X 
Stage 
X 
MUGA/Echo, EKG, Pulmonary Function Tests 
X 
Prior Therapies 
X 
GVHD & Toxicity 
X 
X 
X 
X 
X 
X 
Staging of Disease 
X 
X 
X 
X 
X 
X 
CT Neck 
X 
X 
X 
X 
X 
X 
X 
CT Chest 
X 
X 
X 
X 
X 
X 
X 
CT Abdomen & Pelvis 
X 
X 
X 
X 
X 
X 
X 
BM Biopsy & Aspiration 
X 
X  
X  
X  
X 
X 
X 
CxR 
X 
X 
X 
 
PET Scan 
X 
X 
if previously 
positive 
 
X 
if previously 
positive 
 
X 
if previously 
positive 
X 
if previously 
positive 
X 
if previously 
positive 
X 
if previously 
positive 
Cytogenetics 
X 
X 
X 
X 
X 
X 
X 
PCR/FISH 
X 
X  
X  
X 
X 
X 
X 
Laboratory Studies 
CBC 
X 
X  
X  
X  
X 
X 
X 
Platelet Counts 
X 
X 
X 
X 
X 
X 
X 
PT 
X 
PTT 
X 
Creatinine 
X 
X  
X  
X  
X 
X 
X 
2 Microglobulin Level 
X 
Hepatitis Serology 
X 
HIV 
X 
 
 
 
 
 
HTLV-1 
X 
Tacrolimus levels 
X 
X 
CD4/CD8 (PB) 
X 
X 
X 
X 
X 
X 
X 
Liver Function Test 
X 
X 
X 
X 
X 
X 
X 
Immunodeficiency Panel (PB) 
X 
X 
X 
X 
X 
X 
X 
Chimeric Studies (PB, T Cells, Myeloid) 
X 
X 
X 
X 
X 
X 
Quantitative Immunoglobulins 
X 
X 
X 
X 
X 
X 
X 
Optional Blood Work 
X 
X 
X 
X 
X 
Pregnancy Test 
X†‡ 
Urinalysis 
X 


2007-0871 
July 31, 2017 
Page 42 
 
 
Nonmyeloablative Stem Cell Transplantation with or without Lenalidomide for Chronic Lymphocytic Leukemia 
(RV-CLL-PI-0294) 
Protocol 2007-0871 
Issa F. Khouri, MD 
Evaluation 
SCT&CT 
During Study (post transplant) 
18 months 
(+/- 2 weeks) 
24 months 
(+/- 4 weeks) 
30 months 
(+/- 4 weeks) 
36 months 
(+/- 4 weeks) 
Assessment 
R 
Date 
R 
Date 
R 
Date 
R 
Date 
History & Physical 
Physical Examination 
X 
X 
X 
X 
PS 
Stage 
MUGA/Echo, EKG, Pulmonary Function Tests 
Prior Therapies 
GVHD & Toxicity 
X 
X 
X 
X 
Staging of Disease 
X 
X 
X 
X 
CT Neck 
X 
X 
X 
X 
CT Chest 
X 
X 
X 
X 
CT Abdomen & Pelvis 
X 
X 
X 
X 
B M Biopsies & Aspiration 
X  
X  
X 
X 
CxR 
PET Scan 
 
X 
if previously 
positive 
 
X 
if previously 
positive 
 
X 
if previously 
positive 
X 
if previously 
positive 
Cytogenetics 
X 
X 
X 
X 
PCR/FISH 
X 
X 
X 
X 
Laboratory Studies 
 
 
 
 
 
CBC 
X 
X 
X 
X 
Platelet Counts 
X 
X 
X 
X 
PT 
 
 
 
PTT 
Creatinine 
X  
X 
X 
X 
2 Microglobulin Level 
Hepatitis Serology 
HIV 
HTLV-1 
 
 
 
 
 
Tacrolimus levels 
CD4/CD8 (PB) 
X  
X  
X 
X 
Liver Function Test 
X 
X 
X 
X 
Immunodeficiency Panel (PB) 
X 
X 
X 
X 
Chimeric Studies (PB, T Cells, Myeloid) 
X 
X 
X 
X 
Quantitative Immunoglobulins 
X 
X 
X 
X 
Optional Blood Work 
Pregnancy Test 
Urinalysis 


2007-0871 
July 31, 2017 
Page 43 
 
 
 
Nonmyeloablative Stem Cell Transplantation with or without Lenalidomide for Chronic Lymphocytic Leukemia (RV-CLL-PI-0294) 
Protocol 2007-0871 
Issa F. Khouri, MD 
SCT&CT 
 
Additional Tests for Patients Receiving Lenalidomide 
Week 1 
Week 
2 
Week 3 
 
Week 4 
Every 
2 Weeks 
Every 
28 Days 
Study 
Discontinued 
28 days after Study 
Discontinued 
CBC with differential, 
sodium, potassium, 
chloride, CO2, BUN, 
creatinine, uric acid , 
ALT, AST, alkaline 
phosphatase, 
bilirubin, glucose, 
platelets 
X^ 
X^ 
X^ 
 
 
 
 
 
 
 
 
 
X^ 
 
 
 
 
 
 
 
 
 
X^ 
 
Register patient in 
RevAssist® Program 
d28 days 
from 
Screening 
 
 
 
Pregnancy Test 
X †‡ 
X†‡ 
X†‡ 
 
 
X†‡ 
 
 
 
X†‡ 
X†‡ 
X†‡ 
Prescribe Revlimid® 
X☼ 
 
 
X☼ 
Assess Revlimid® 
toxicity (if applicable) 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
x 
*Variations of ± 3 days of the scheduled visit are permitted. 
x 
^ At every re-start of lenalidomide following an interruption: Weekly until the maximum dose is reached, then once every 2 weeks. 
x 
†Pregnancy 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 consecutive months (i.e., has had menses at any 
time in the preceding 24 consecutive months). 
x 
‡Pregnancy tests must occur within 10 – 14 days and again within 24 hours prior to prescribing lenalidomide (prescriptions must be filled within 7 days). 
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 A: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth 
Control Methods). 
x 
☼Lenalidomide must be prescribed through and in compliance with Celgene’s RevAssist® program.  Prescriptions must be filled within 7 days.  Any 
unused Revlimid® (lenalidomide) should be returned to Celgene for disposition in accordance with the RevAssist® program. 


2007-0871 
July 31, 2017 
Page 44 
 
 
 
Appendix C: 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. 


2007-0871 
July 31, 2017 
Page 45 
 
 
 
Appendix D: NCI CTC Version 3.0 
 
 
TOXICITY WILL BE SCORED USING NCI CTC VERSION 3.0 FOR TOXICITY AND ADVERSE 
EVENT REPORTING. A COPY OF THE NCI CTC VERSION 3.0 CAN BE DOWNLOADED 
FROM THE CTEP HOMEPAGE: (HTTP://CTEP.INFO.NIH.GOV). ALL APPROPRIATE 
TREATMENT AREAS HAVE ACCESS TO A COPY OF THE CTC VERSION 


2007-0871 
July 31, 2017 
Page 46 
 
 
 
 
Appendix E: CLL Staging – NCIWG Criteria 
 
 
Table 1. NCI-Working Group Response Guidelines for CLL 
 
 
Response Criteria 
CR 
Physical exam 
Normal 
Symptoms 
None 
Lymphocytes (x 109/L) 
<4 
Neutrophilis (x 109/L) 
>1.5 
Platelets (x 109/L) 
>100 
Hb (g/dL) 
>11 (untransfused) 
Bone Marrow lymphs (%) 
<30; no nodules 
PR 
Physical exam (nodes, and/or liver, spleen) 
>50% decrease 
Plus > 1 of: 
Neutrophilis (x 109/L) 
>1.5 
Platelets (x 109/L) 
>100 
Hemoglobin (g/dL) 
>11 or 50% improvement 
Duration of CR or PR 
>2 mo 
Progressive disease 
Physical exam (nodes, liver, spleen) 
>50% increase or new 
Circulating lymphocytes 
>50% increase 
Other 
Richter’s syndrome 
Stable disease 
All others